Excerpts 2023/2022/2021


From NP Fall Issue 2023


Huntington’s provides a blood-chilling signature which affords a level of definitiveness seldom seen in brain-based disorders. The huntingtin protein, which is essential for early development and longterm neural maintenance, is turned by mutation into a bomb with a very long, inexorable fuse, though the pace of progression, and the time of eventual detonation, is not so easily predicted. But the certainty of diagnosis has not yet translated into unambiguously effective treatment; clinical results have demonstrated that, even when the target has been identified and attacked, the outcome is nowhere near certain. This partly reflects the decades-long timeline for disease progression: Save for a small proportion of cases on the cusp, the CAG sequence repeat characteristic of HD leaves little doubt about what will happen, only ample ambiguity regarding when. The number of repeats predicts the speed with which the disease will manifest itself–albeit with variability attributed to the impact of other modifier genes on the emergence of the HD phenotype. Individuals with a critical number of repetitions in the gene encoding the huntingtin protein eventually begin a slow slide into depression, dementia, and a movement disorder which includes impaired voluntary motor control and involuntary, choreiform writhing. 

To oversimplify it, the longer the genetic stutter, the earlier the disease will reach critical mass and then symptomatically explode. Even when individuals have as many as 35 CAG repeats, the huntingtin protein functions normally. It is in the range of 36-40 repeats wherein there is a borderline zone: HD symptoms may never appear; it may be that in those cases, the accumulation of mutant Htt protein does not reach a pathological threshold during a normal lifetime. Smaller numbers of CAG repeats also increases the likelihood that the choreiform movement disorder that is a key diagnostic sign may not manifest early, and their diagnosis may in turn be considerably delayed. The presence of 40 repeats or more means that Huntington’s symptoms will eventually develop, with higher repeat counts associated with earlier onset and a higher salience of motor symptoms. At a thankfully rare 60 repeats and above, the onset is so accelerated that these individuals (5-10%) can develop juvenile-onset HD. 

But there is a caveat: An MGH group found that the number of CAG repeats in Huntington’s is modified over a patient’s lifetime by the activity of genes associated with DNA maintenance and repair. Increases in CAG repeats drive phenotypic disease onset, different haplotypes can have onset-accelerating or onset-delaying effects. The number of CAG repeats is thus changeable, the absolute repeat number at a given timepoint does not reliably predict whether and when the phenotype will manifest itself. Individuals with 27-35 CAG repeats have some risk of that number expanding into the active disease range. Additionally, CAGs may be modified ‘en route’, impacting disease-emergence and the pace of progression. 

The Epidemiology

There are approximately 42,000 patients with Huntington’s in the US. Estimates of the number who have the mutation but have not yet become symptomatic with manifest illness range up to 200,000. The intensity and duration of custodial care eventually needed, and the fact that the modal patient experiencing symptom-onset is an adult in the prime of life (between 30-55) magnifies the socioeconomic burden; HD is an orphan disorder  with an outsized impact. For most Huntington’s patients (early onset cases tend to progress more rapidly) the expected lifespan after diagnosis is in the ten to twenty year range, an eternity for the families who have to watch their loved ones writhe and wither. Estimates of the overall costs attributable to HD in the US have been in the $2.5 billion range annually; CHDI and IQVIA have been collaborating on a project to refine the estimates of the cost-burden for HD in the US, part of a global observational study funded by CHDI (a vital nonprofit that spends $80-120 million per year on HD research). 

HD has crystallized the mixed blessing proffered by genetic testing untethered to treatment choices. While it can be identified, given that there is nothing that can be done at present to alter the course of the disease, such knowledge is accompanied by a sense of helplessness. Depending on their own temperament and familial circumstances, some patients at risk for HD prefer to know, in order to prepare themselves and their families. On the other hand, some who are aware that they may carry this mutation prefer to tolerate the desperate anxiety of not knowing their diagnosis, in the hope that fate will be kind to them.

Brain scans can detect striatal anomalies in HD patients up to fifteen years before overt behavioral symptoms display themselves, but the slow pace of deterioration means that the assessment of changes in response to intervention is difficult. There has also been a lack of standardized models for tracking HD deterioration, though the ‘Huntington’s Disease Harmonization Consortium‘ has assembled a database of 8000 MRIs from 2000 HD patients, in the service of establishing structural biomarkers for disease-status and progression. Prodromal cognitive deficits have been identified via neuropsychological testing seven years before the disease declares itself, changes in mutant huntingtin assays have been explored as potential biomarkers, but have yet to be validated.  

One interesting ancillary element is work that has been done on the relationship between the age of onset (of manifest symptoms) and hypertension. There had been a hypothesis that hypertension delays HD onset, but over time the hypothesis has changed, with some European data suggesting that the use of calcium channel blockers to treat hypertension might instead accelerate onset.

Knowing the molecular culprit has translated into the major theme for disease-modification. Finding a way to delete or neutralize mutant huntingtin, while sparing enough wild-type huntingtin for necessary neural functioning, has been at the heart of the divergent approaches to gene therapy in HD that have begun to yield clinical results, mixed though they are.

The Clinical Picture

Misdiagnosed psychiatric disturbances are often the first ambiguous sign of emerging HD, with fits of anger or depressive episodes the first warning flag, ushering in dramatic changes in personality. But for other patients, the motor signs precede the psychiatric symptoms. It had been thought that early motoric manifestations are associated with higher CAG counts, but a European observational study of over 6300 patients showed that this is not the case, and that those symptoms are more likely to come first in patients with later onset. In that study, 42.4% had a psychiatric or cognitive symptom before any motor signs emerged; the majority had motor symptoms first, or concurrent with nonmotor signs. As was noted earlier, choreiform-silent HD tends to be associated with shorter CAG repeats.

Mood symptoms are of course highly nonspecific, but when choreiform movements are observed, they herald something much more dire than a depressive disorder, and tend to be the impetus (along with a family legacy of HD) for the genetic testing that finally confirms the grim prognosis. Writhing and impaired voluntary motor control eventually leave patients wheelchair-bound, often helmeted in order to prevent inadvertent self-injury. Personality changes and depression are preceded or followed by motor dyscontrol and cognitive deterioration, which eventually devolve into dementia. Between depression and the devastating prognosis, suicide is a frequent concern, with over 25% of HD patients attempting suicide at some point; some 5-7% of HD patient deaths are attributable to suicide. The dramatic movements thought to be emblematic of the disease are not correlated with the rate of cognitive decline. Those are instead associated with a growing impairment in voluntary movement control. The tragic endstage is epitomized by Parkinsonian rigidity and eventual immobility, the patient finally demising due to secondary medical complications. 

The Neurobiology

The motif of critical proteins misfolded and then aggregated into toxic conglomerates, is generally, albeit not universally, thought to provide the pathological understructure for most neurodegenerative disorders. The role of such a toxic aggregate appears more clearcut in HD than the still debated contributions of amyloid and/or tau in Alzheimer’s, alpha-synuclein  in Parkinson’s, or TDP-43 in ALS. There are those (e.g. Humbert et al, 2020)who consider the lifelong impact of mutant huntingtin to constitute a neurodevelopmental disorder, not just a degenerative one.

The signature CAG stutter leads to the expression of abnormally lengthened huntingtin; such mutant huntingtin (mHtt) misfolds and aggregates together and cannot be sufficiently disposed of via the usual maintenance/clearance operations. Instead, the mHtt coheres into toxic oligomers. Post-mortem examination of HD patient brain tissue shows huntingtin oligomers within cells in the striatum, where they produce their effects upon motor function via the destruction of GABAergic tracts, and in the neocortex, which accounts for the changes in cognitive capabilities and affective control that become so salient as the disease progresses. Mutant huntingtin aggregates also travel between cells, thereby propagating degeneration. 

But it is more complex than that. There are multiple isoforms of mutant Htt, associated with variants of SNPs. Wave Life Sciences at one time had projected that their first two SNP targets in HD would cover 80% of the HD population, then they suggested that ‘over two-thirds’ would be accounted for. When their programs for both those SNPs failed, they refocused on a third SNP, found in about 40% of the HD population. But beyond the three or more mHtt isoforms that, if targeted selectively, could be required in order to cover the bulk of the HD population, there are other processes relevant to this target array: 

1) CAG repeats can change over time, and with them, the profile of an individual’s phenotypic status and progression. The past few years has featured considerable work, particularly by the GeM-HD Consortium, on explaining the variance in age-of-onset not determined by the number of CAG repeats, the latter accounting for about 60% of the variance. Variations in genes associated with gene repair has drawn particular emphasis: As was noted earlier, in 2018 Gusella et al (MGH) reported that the number of CAG repeats in Huntington’s can be modified over a patient’s lifetime by the activity of two haplotypes. The first alters the FAN1 gene, resulting in the acceleration or delay of onset, depending on modifiers either reducing FAN1 gene function or increasing its expression respectively. The other haplotype involves the acceleration of onset via either the RRM2B or UBR5 genes. But in their work, these two sources of modification appear to account for just 1.6% of the variation in onset, thus there are numerous other factors yet to be delineated.

2) A group at U.Florida (Ranum et al) reported that, beyond mutant huntingtin, there are four more proteins produced by ‘repeat-associated non-ATG-translation’ (RAN). All of these rogue proteins (the various isoforms of mHtt and the four RAN cousins) aggregate and are neurotoxic. Longer CAG repeats appear to be associated with higher RAN levels; healthy control brains do not show any of these proteins. In theory, though the toxic contribution of each subtype has yet to be delineated, these RAN-proteins could mean that other toxic targets could be, or must be, addressed. However, the originators have focused on the salience of RAN proteins in c9orf72 mutations in ALS and FTD, Huntington’s has not been their priority. 

3) A 2016 paper from a UCLA group noted that Huntington’s is associated with increased methylation in brain tissue, and proposed that this reflects an epigenetically induced acceleration in neural ‘age’ in some brain areas. The authors found that patients with HD showed an overall 3.2 year increase in neurobiological age. There was a negative correlation between the number of CAG repeats and epigenetic aging, the authors suggested that the effects of epigenetic aging may be primarily observable in early-stage disease, and that high CAG repeat patients tended to show more advanced cellular dysfunction. It remains to be seen whether epigenetic aging predicts earlier disease onset, accelerated progression, or both–and whether targeting the process can alter either one.

4) The MutSB complex is comprised of two subunits, MSH2 and MSH3, enzymes involved in DNA mismatch repair (MMR), mediating the pathological expansion of Htt into mHtt. There is discovery stage work being done by CHDI and LoQus23 Therapeutics on modulating that activity in order to delay onset.

Current Therapeutics

One key clinical question is–by what point in the disease must intervention start in order to have an appreciable impact on its subsequent course? There is no proven disease-modifying therapy for Huntington’s, but there have been tantalizing signs that targeting huntingtin is the right track for doing so. Up to now, treatment has been limited to compensatory  measures of circumscribed impact and value. Antipsychotic drugs with dopamine-blocking components have often been used for the treatment of motor symptoms. The first HD-specific, approved symptomatic treatment was Xenazine/tetrabenazine, a VMAT2 inhibitor originally developed by Roche, which addresses only choreiform movement symptoms. Tetrabenazine provides modest symptomatic improvement in more than 80% of patients receiving it. Drowsiness and Parkinsonian symptoms are the main adverse effects, along with the risk of depression and suicidal ideation (the drug is similar to reserpine), concurrent treatment with antidepressants is often recommended. Xenazine exceeded expectations in terms of market-penetration and payer-acceptance, but the drug’s patent exclusivity ended.  

Auspex developed a deuterated form of tetrabenazine that was acquired, along with the company, by Teva. Phase III results showed a significant impact on chorea, with a 4.4 point reduction compared to 1.7 points with placebo, 51% were rated as very improved, compared to 20% of the placebo arm. Tolerability appeared considerably better than that seen with tetrabenazine, very few patients needed to have dose reductions due to AEs, and depression/anxiety were not elevated. Austedo was finally approved for HD in 2017, as well as for Tardive Dyskinesia. In HD, it produced a 7.4pt reduction on the UHDRS, compared with 3.4 points for placebo, with 11% of patients experiencing somnolence. It has had a rapidly accelerating ramp-up in sales aided by the introduction of an XR formulation: By mid-2023 it had reached a $1.2 billion annualized pace, sold for both HD and TD, with sales predicted to more than double from there by 2027. 

Neurocrine Biosciences’ Ingrezza/NBI-98854 is a once-daily VMAT2 inhibitor that was approved for Tardive Dyskinesia in 2017. Eventually, Neurocrine successfully ran a 120pt PhIII for Ingrezza in Huntington’s, yielding a UHDRS reduction of 4.6 points compared with 1.2 points on placebo. 42.9% of Ingrezza patients were judged ‘much improved’ or better, compared with 13.2% of the placebo group. The FDA approved that sNDA in August. Even before that approval, Ingrezza had maintained its lead over Austedo, reaching an annualized sales rate of over $1.6 billion in 2Q:23. 

Future Therapeutics: Symptomatic 

The Odyssey: Pridopidine

Pridopidine aka Huntexil aka ACR16 aka TV7820 has been on as bizarrely elongated a developmental odyssey as we can recall, helmed by a succession of owner/sponsors: Carlsson Research, NeuroSearch, Teva Pharma, and finally, Prilenia Therapeutics. 

Carlsson Research conducted a 58pt PhII with ACR16,  at the time believed to be a dopamine stabilizer, which they claimed showed improvement in both cognition and motor function. NeuroSearch bought Carlsson in 2006 to acquire Huntexil/pridopidine, seeing this as a route to supplanting tetrabenazine. The 2010 results of a 437pt Phase III trial, using 45mg and 90mg doses, initially were described as showing statistically significant improvement on both involuntary and voluntary movement measures, and the separation of drug from placebo increased over time, suggesting the disease process itself had been modified. However, this dataset utilized a post hoc adjustment that was not part of the pre-specified primary endpoint analysis, and a second 227pt Phase II/III (using 20mg, 45mg, and 90mg doses) ended up with the primary endpoint missing statistical significance (p=.078) at three months. NeuroSearch was eventually told that another Phase III would be required, and their hope of going higher in dosing in order to maximize therapeutic effect was thwarted by dose-related QTc effects. With its fiscal resources strained, NeuroSearch finally sold the program to Teva Pharmaceutical in 2012. 

With HD-specialist Michael Hayden as CSO,Teva ran a 408pt PhII trial (PRIDE-HD) using doses ranging from 45 mg to 112.5mg, twice daily. That trial finished in 2016. It failed to show significance at 26 weeks or 52 weeks on the UHDRS motor score, or on a physical performance test. However, Teva claimed a positive impact for the 45mg dose (an effect not seen with other doses) at 52 weeks on a total functional capacity measure. Teva said that this was evidence that they were impacting disease progression–several HD KOLs went public with their disagreement with this claim, which was based on a cherry-picked secondary endpoint. Additionally, 18% of the pridopidine group had discontinued treatment due to side effects. Because of a high placebo response rate, the results were not seen as definitively ruling out a motoric benefit, but there was no credible support for the claim of disease-modification.

In the course of Teva’s work with pridopidine, the mechanism had been further defined as a sigma-1 agonist (along with binding at D3, adrenergic-A2C, and 5HT-1a receptors). A 2019 paper in Cell reported that sigma-1 activation induces autophagy, which could in theory reduce toxic levels of mutant huntingtin aggregates.

In the meantime, Teva acquired Auspex for $3.5 billion, and thus owned deutetrabenazine, renamed Austedo/SD-809. As was previously discussed, Austedo received FDA approval in 2017, which made pridopidine a lame duck program, and Teva terminated its development.

When Teva eliminated its neuroscience R&D, including Michael Hayden’s role as CSO, he took pridopidine with him, and founded Prilenia Therapeutics. Prilenia’s only asset is pridopidine, which they claim has therapeutic potential in a broad spectrum of disorders. They initiated a PhII trial in PD-LID that was eventually terminated due to Covid-19. However, they were able to bring in the first tranche of a $62.5 million funding round, and MGH’s Healey Center also chose pridopidine as one of the compounds to be tested in ALS patients (for which they reported a signal in rapidly-progressing patients).

A 480pt PhIII for pridodipine as a disease-slowing intervention in Huntington’s reported top-line results in early 2023; pridodipine failed to hit its primary endpoint, but Prilenia emphasized ‘nominally significant’ trends on disease progression and secondary endpoints (including cognition, based on just one cognitive test, the Stroop) for patients not receiving neuroleptic and chorea-specific drugs. Prilenia did not provide detail regarding the size of the treatment-responsive group or the size of the reported treatment effect, stating they would disclose those over time.

We have long wondered if the literary metaphor apropos to pridopidine may have shifted from The Odyssey to Moby Dick: Hayden’s work is not to be dismissed out-of-hand, but after all this time, pridopidine still has not proven its value in any of the neurodegenerative disorders for which benefit has been envisioned, neither modifying disease-progression or affording symptomatic benefit. 

SAGE Therapeutics’ NMDA receptor PAM, SAGE-718, is believed to bind to a unique binding site on the NMDA receptor complex. The biomarker they are using (24S-HC), related to cholesterol processing and synaptic plasticity, has also been linked to cognition, and SAGE-718 has been expected to have procognitive effects. In a healthy volunteer PhI, Sage reported improved working memory and problem-solving, albeit on just two specific neuropsych tests. Improved executive function was reported in HD patients, in an open-label, six patient cohort. 

Sage decided to run pilot studies in other procognitive contexts before proceeding in HD, but are now running three PhII trials in HD. A 178pt trial is administering SAGE-718 once-daily for 84 days, with changes in cognition the primary, functional status on the UHDRS the main secondary. The trial is expected to run through 2024. Results may be in a few months earlier from an 80pt study that is administering SAGE-718 over a 28 day dosing period, cognitive measures emphasized. A 300 pt open-label extended safety study is also ongoing. 

PDE10 inhibition was once considered to be a route to improving cognition and motor function via downstream dopamine-system effects, but PDE10 has been a difficult target. Pfizer’s PF-02545920 went the farthest, but failed to produce improvement on any symptom domain in a 271pt Phase II in HD that reported results at the end of 2016. Lundbeck had a failure in a schizophrenia PhII with Lu AF11167, a PDE10A inhibitor. Omeros, Biocrea and Zenobia Therapeutics all had PDE10 inhibitors that demised early on. 

The vasopressin system is interlinked with the better-known oxytocin system, and has been seen as a potential access point for mediating episodic anxiety/irritability and sociability. Azevan Pharma’s SRX246, a vasopressin-1a antagonist, went through a 106pt Phase II aimed at reducing irritability in Huntington’s patients. The trial was finished at the end of 2018, but when the results  were finally published in late 2020, they were presented as if the trial was designed to only establish safety and tolerability, and was claimed to have shown both. There was no mention of impact on irritability or aggression, even though one or both had to be present for a patient to be enrolled, and standard assessments for both were done over the three month treatment duration (long enough for this mechanism to show an effect on neuropsychiatric symptoms, if it had any). The absence of any mention of activity in these domains was curious, begging the question of why Azevan claimed “exploratory efficacy endpoints demonstrated clinical benefit as well” when they were not even mentioned in the publication. NINDS apparently provided Azevan with funding for additional toxicology work and manufacturing in 2020, but that seems like a waste of resources. Neumora has a vasopressin-1a antagonist program, but they have not cited HD as a potential treatment area, focusing on AD-agitation.

Future Therapeutics: Disease Modification 

Mutant huntingtin has been the target of choice, with relevant disease-modification options including: Reducing the production of mutant huntingtin; inhibiting its aggregation; increasing clearance; and altering mHtt in order to reduce its toxicity. But there is also a spectrum of tactics, both upstream and downstream of mutant huntingtin, for potentially impacting disease development and progression. This includes targeting other genes that  mediate the number of CAG repeats and/or intervening in downstream processes (e.g. apoptosis, neurotrophin underproduction) triggered by mHtt. 

Huntingtin’s Role

The huntingtin premise is made more complicated by ambiguity regarding the pathways linking mHtt and the HD phenotype. Work on identifying the modifier genes that impact the rate of symptom development in patients who begin with the same number of CAG repeats is ongoing. If genes that delay onset can be identified and mimicked pharmacologically, this could offer another array of potential targets. 

In models, mutant Htt is toxic to neurons and glial cells via multiple routes of impact: It is known to alter gene transcription, dysregulate NMDA receptor functioning, impair potassium channel function and glutamate uptake; interfere with mitochondrial processes; trigger neuroinflammation; and to impair neurotrophin transport/availability.

The mechanistic hypotheses include: 

1) that mHtt aggregates are harmful, a direct participant in the neurodegenerative process. Mutant Htt is cleaved into fragments that clump together, forming inclusion bodies. Additionally, mRNA is produced that leads to the production of toxic fragments  within neurons. 

Because the presence of mHtt aggregate fragments can occur without neuron loss, and conversely, neuron loss can occur without aggregates being present, some have postulated that it is mHtt in soluble, oligomeric form that is actually the toxic actor, reminiscent of the debate about the different forms of beta-amyloid in Alzheimer’s.

2) Other abnormal proteins are produced as a result of the presence of mHtt, including polycysteine and polyalanine, that themselves form toxic aggregates. 

3) HD could involve a loss-of-function mechanism, wherein normal Htt’s prosurvival effects are lost, accelerating the slide down the ‘slippery slope’ of cell death. However, while mutant Htt outweighs Htt in HD patients, Htt still exists in considerable proportion. We had previously noted that the initial Roche/Ionis ASO data suggested that huntingtin could be significantly reduced without losing necessary functions provided by the wild-type protein. But the final data pointed towards the opposite, because the high-dose group in fact did worse than placebo, which could mean that there was a salient loss-of-function.

Beyond mutant huntingtin itself, the question is begged as to whether any of pathways downstream of its direct effects may offer a useful target for intervention. Among the several downstream processes that have been suggested as potential intervention points: 

1) Work has linked mutant huntingtin to activation of the jnk inflammatory/apoptotic cascade. 

2) Several mitochondrial protection points have been cited: A Cornell group published research in Nature Medicine that connected mutant huntingtin to cell death due to mitochondrial damage via DRP1, and a University of Barcelona team published work in 2020 also linking DRP1-driven mitochondrial fragmentation in mouse models of HD.

3)UCLA researchers suggested that mutant huntingtin reduces  the flow of neurotrophic factors to oligodendrocytes, and that resultant demyelination is part of the process that leads to HD symptoms. Blocking that inhibition, or providing compensatory trophic support, could be a therapeutic option. This is a loss of function premise, where the absence of intact wildtype huntingtin diminishes the production of BDNF, which would otherwise play a neuroprotective role. 

4) Huntingtin also plays a role in neurogenesis vis-a-vis the generation and differentiation of new neurons, thus mHtt may lead to a loss of neurogenic functions.

5) The caspases that cleave huntingtin take a role parallel to the secretases in Alzheimer’s, contributing to the aggregation of malformed proteins. Caspases 3 and 6 have been cited as putative culprits in this process, and their inhibition (usually facilitated by normal Htt) is cited as a potential treatment strategy. Zenobia Therapeutics had long ago identified caspase-6 as an excitotoxic bridge from mHtt to the HD phenotype, and reported that preventing caspase-6 induced cleavage reduced mHtt fragment accumulation and slowed the emergence of behavioral signs in animal models. However, this work did not come to a successful end, and Zenobia did not survive. 

Chronic Administration: Gene-Editing

The road most frequently taken has been to knock-down the production of mutant Htt, reducing its pathological aggregation, while hopefully allowing for the continued expression of wild-type Htt (the proportions of Htt to mHtt vary between patients and between brain regions) for cell maintenance. The two main tactical paths are to either provide chronic administration of products (e.g. antisense oligonucleotides/ASOs) that temporarily reduce mHtt production, or to provide a gene that permanently alters the ratio of mutant to wild-type Htt production, in a more classic rendition of gene therapy.  

Originally, it seemed impossible to parse out mHtt as a class, it exists in several isoforms, and knocking down all of them requires reducing huntingtin levels overall, including the wild-type form. In the past, NIR had espoused the concern that ‘chronic downregulation of all huntingtin protein, including wild-type, would probably be disastrous, due to the deletion of huntingtin’s role in development and neurotrophin production; huntingtin functions as a prosurvival factor.‘ Part of the thinking around the negative impact of reducing Htt overall was due to the role wild-type Htt plays in early neural development, but studies of adult neural function in animals has indicated that Htt is less critical at later stages of maturation. For the most part, companies have operated on the belief that a nonselective but partial ‘knockdown’ might attenuate the pathological effects of mutant Htt while permitting sufficient wild-type Htt activity to foster needed neural functions.

A pioneering program in this category is Roche/Ionis’ intrathecal antisense therapeutic, tominersen, which is not isoform-selective. For a while, it looked like a therapeutic miracle was in the making: In 2018, tominersen/RG6042 made headlines when the results from a 46pt Phase I/II trial were announced. The five dose levels produced reductions in overall huntingtin levels ranging from 20-42%, compared to a mean increase of 10% in placebo patients. The reduction in mHtt in the two highest dose cohorts averaged 40%, with the highest reductions around 60%. While no overall differences on functional and cognitive measures were seen between the tominersen and placebo groups, positive posthoc correlations were found between the amount of mHtt reduction and improvement on the composite UHDRS, motor functioning, and a measure of visuomotor processing. One anomalous finding was for neurofilament light chain (NfL), which had been expected to decrease over time with tominersen. Instead, there was a transient increase in neurofilament levels, which eventually returned to baseline. The high-dose groups also showed MRI signs of brain volume loss. But Roche set these biomarker anomalies aside, believing that the cognitive results and the seeming lack of safety issues rendered this ready for PhIII.

Roche and Ionis quickly moved into what was to be a 909pt (up from an original goal of 660) Phase III trial. There were two dose-levels; intrathecal injections either every eight weeks, or every sixteen, with outcome measured at 101 weeks. After 791 patients had been enrolled, and 17 months of treatment, an enormous scale for a HD trial, Roche pulled the plug after a DSMB finding of futility. Not only was there no benefit for disease-arrest, but the higher-dose, every-eight-week group performed worse than placebo (the lower dose also trended negatively), and the high-dose was linked to more adverse effects, with increased, albeit reversible, ventricular enlargement, and increases in neurofilament light chain that were worst in the high-dose group. The reason for this disease-worsening is unclear, though excessive knock-down of wild-type Htt is one hypothesis. That had seemed to be the end for tominersen, but subsequent post hoc data mining yielded a signal of benefit in younger, prodromal HD patients with a lower disease burden. In January, Roche began enrolling a 360pt PhII, two lower dose-levels administered every four months, top-line data expected in mid-2025. But with the deleterious impact seen in the previous study, we expect interim analyses to be deployed, with fatal effect.

Then there is Wave Life Sciences, partnered with Takeda, whose raison d’être is specificity. Wave has focused on the development of stereopure ASOs, aimed at specific SNP variants. By targeting those specific mutations, Wave Life Sciences believed that wild-type Htt is spared, avoiding a loss-of-function scenario. 

The SNP-1 (WVE-120101) and SNP-2 (WVE-120102) candidates entered the clinic in 2017, and originally were expected to produce topline results in early 2019. However, by the end of 2021, they had produced initial results from just the first 39 patients enrolled in the 120102 trial. That data was disappointing: The mean change in mHtt across the four dose groups was just 12.4%, and surprisingly, there was no change in total (Htt and mHtt) protein levels. There was also no impact on neurofilament/NfL. Wave stated that there was evidence that the response was dose-related, and added a top (32mg) group to both active studies, double the previous high dose. That was for naught, one week after the news about tominersen’s PhIII, Wave announced that both of their higher-dose subtype-selective trials had also failed to show any benefit. Wave attributed that failure to a dosing/potency issue, and devised a new chemical family that yielded an ASO against SNP-3, found in about 40% of HD patients. That ASO has gone into PhI/II, a single dose cohort showed mHtt reduction and preserved wild-type Htt levels. Additional multi-dose findings are expected soon. It does not appear that Wave is still pursuing SNP-1 or SNP-2 HD.

Ionis had developed allele-specific Htt ASOs as well, these do not appear to be prioritized, none have reached the clinic. However, U.Mass researchers reported last year that they have developed siRNA therapeutics that selectively silence specified SNP’s in mouse models, while maintaining wild-type Htt expression. 

The simplicity of oral delivery accounts for much of the appeal of gene splicing modifiers. PTC Therapeutics released interim data for PTC518 (an oral splicing modifier) in June, reporting on 22 early-stage  patients at twelve weeks of treatment, the end of the first phase of the trial, aimed at safety and pk measures (the second, nine month phase will focus on functional effects). With a long half-life yielding effects for 72 hours, there was a mean, dose-related reduction of 30% in mHtt levels, a trend towards NfL reduction. While no toxicity has been reported, PTC518 was placed on a partial clinical hold in October 2022, pausing US enrollment, as the FDA reviewed changes in the trial protocol (extending the placebo-controlled portion to a total of 12 months). EU and Australia enrollment continues, completion projected in 2024. 

Novartis had its own oral splicing modulator, branaplam, but dropped development in HD due to the side effect profile. Branaplam had previously shown itself to not be problem-free, a PhI/II trial in Spinal Muscular Atrophy had been stopped due to peripheral nerve and spinal cord damage.  

Vico Therapeutics has developed an ASO that blocks CAG repeat expansions in both HD and Spinocerebellar Ataxia (SCA1 and 3). In preclinical models,VO659 selectively knocked down levels of mHtt, Delivered intrathecally, VO659 entered PhI/II this past April, with an enrollment goal of 65 patients. The trial is dose-ranging, with the lowest two doses only administered to SCA1/3 patients, early HD patients will be added when the third dose cohort is reached. The drug is administered four times over thirteen weeks, patients then tracked for 23 weeks. Completion is expected in 3Q:25.

Alnylam has spent more than a decade developing a siRNA program (ALN-HTT) that preclinically, ameliorated pathology when infused into the striatum.  This program was specifically brought into the joint development portfolio when Regeneron partnered with Alnylam is 2019, but it remains in preclinical stage. The work has evolved into the development of a C16-siRNA conjugate that has yielded (via a single intrathecal infusion)Htt lowering for three months, up to 90% reduction in the cortex, at a level that was tolerated in a mouse model. Six month animal results were similar, there were no adverse event findings in terms of NfL elevations or histopathological changes. The group has not yet assessed the impact on phenotypic features and whether there is sufficient activity in the putamen to produce benefit.

Biogen and Atalanta include HD in their partnership, a discovery-stage project aimed at utilizing divalent siRNA (two connected siRNAs) in order to decrease Htt production. In mice, Htt production was reduced for six months after a single intrathecal administration. Htt reduction was also reported in non-human primates, with broad CNS distribution.  In a 2019 paper, the group claimed ‘minimal off-target effects’, though the broad and nonselective impact on Htt begs the question of whether longterm Htt suppression could prove problematic.  

Sangamo’s zinc-finger DNA-binding protein strategy has been pursued in Huntington’s. CHDI provided $1.3 million to fund discovery work on ZFP transcription factors targeting mutant huntingtin expression, and Shire added this target to a 2012 deal covering monogenic disorders. In April 2019, Takeda/Sangamo reported that they had screened 1600 ZFP candidates and identified a lead. Their HD-patient iPS cell data showed that they could knock down mHtt levels by up to 99% while not excessively impacting (86% preserved) wild-type Htt. In mouse testing, this mHtt ZFP was delivered via an AAV vector, and produced similar reductions in mHtt, lasting for 33 weeks post-injection, and functional benefit was observed. An IND had originally been anticipated in 2015, but while the work was published in 2019 (Nature Medicine) the program is in limbo, still preclinical stage some eight years later. 

In September, Roche partnered an undisclosed, early-stage Ionis RNA-targeting program relevant to HD.

Takeda and Anima Biotech have a discovery-stage program developing small molecule mediators of mRNA production of mHtt, reported to be highly-selective for the mutant protein and tissue-specific. 

Alchemab, taking a page from Neurimmune’s work on disease-resistance in Alzheimer’s (which, judging by aducanumab, has not panned out that well) has identified endogenous antibodies in HD patients who are progressing more slowly than one would expect based on their genetic loading, on the premise that these antibodies (not found in controls or patients with normal progression rates) may provide resiliency. ATLX-1095, which binds to mHtt aggregates and facilitates microglial clearance,  is in preclinical development.

Exicure had a discovery-stage program involving a spherical structure for Htt oligonucleotides they believe would enhance uptake in deep brain regions. Ipsen had signed a collaboration agreement in 2021, but as Exicure entered a period of fiscal peril and corporate reorganization, it ceased its internal work on the project just over a year later. The collaboration was dropped, though Ipsen retained the option to re-enter that agreement. Considering the dire straits where Exicure now finds itself, we suspect that is a moot point.

The emergence of RNA-targeting programs, and gene editing techniques such as CRISPR, offers the tantalizing prospect of editing-out gene defects–though it also raises the spectre of potential off-target effects. A Swiss group reported that they had been able to almost completely stop the production of aggregating mHtt in transgenic mice using CRISPR, reducing it by 90%. However, that work also suppressed wild-type Htt, which did create a loss-of-function issue. That U.Lausanne group hopes to edit the Htt gene at targeted SNPs, similar to what Wave Life Sciences sought to do, leaving the production of wild-type Htt intact. Based on the paucity of follow-up publications, that is still a work in progress.

In 2022, a UCSD group (Morelli et al) published preclinical work regarding a (CRISPR-cas13) system they used to reduce the production of mHtt. Administered to HD-model mice via AAV into the striatum, they showed reduced mHtt RNA and mHtt, with functional benefit  and decreased brain atrophy observed as well over eight months. No off-target adverse effects were reported.  

Another group (Yan et al, 2023) ran a CRISPR-Cas9 study in pigs to assess whether they could safely knock down mHtt levels. They claimed that delivering the AAV via stereotaxic injection, or via IV administration, reduced mHtt levels and produced functional benefit. The report that IV administration provided sufficient therapeutic levels without toxicity requires replication.

‘One-Shot’ Gene Therapy

UniQure: With semi-disaster having befallen both the Roche/Ionis and Wave Life Sciences Huntington’s programs, UniQure has achieved a higher profile in HD. One substantive vulnerability in the ASO story has been the reliance upon CSF delivery, a systemic approach whose lack of selectivity opens the door for both efficacy and safety issues. While the stereotactic gene therapy delivery used by UniQure has not been a panacea in Parkinson’s, UniQure’s protocol offers a degree of mechanistic precision lacking with its predecessors. AMT-130 utilizes a convection-enhanced AAV5 vector to deliver micro-RNA into the striatum with MRI guidance, three bilateral injections into the putamen and caudate nucleus, two dose-levels tested in PhI/II. Patients must have 40 or more CAG repeats to qualify. The goal is to block huntingtin expression where knockdown of mutant huntingtin might be most useful, while hopefully avoiding a potentially problematic knockdown of wild-type Htt throughout the parenchyma. If successful, this would constitute a one-shot gene therapy. On the other hand, it is not reversible, unlike the transient impact of ASOs on gene expression.  The degree of technical skill required by the CED-facilitated neurosurgical implantation procedure is intimidating. A third cohort will explore shortening the time required for the implantation procedure.

Since this is a nonselective tactic, reducing both wildtype and mutant Htt, the possibility exists that this broad-spectrum suppression could have negative effects, as occurred with tominersen. UniQure believes that its stereotactic, convection-enhanced dosing skews knockdown to improve tolerability, reducing striatal Htt levels by 50% to 75%, but only by 25-50% in the cortex, hopefully avoiding a loss-of-function issue. 

The first twenty patients have been treated, beginning with ten in the low-dose cohort, another ten in the high-dose. Ten of the twenty have received sham injections–there are another six to be enrolled in the high dose group. At twelve months post-infusion, both the high and low dose groups showed slowing of progression compared with the sham control group and historical controls. The good news in June 2023 was that the low dose of AMT-130 at two years slowed progression on the Total Motor Score scale, and the eighteen-month data for the high-dose patients indicated a dose-related improvement in slowing. Total Function and cUHDRS scores were also preserved for both dose-levels.

However, the two main CSF biomarkers, neurofilament light chain (NfL) and mHtt readouts were contradictory: After a transient post-surgical spike, NfL levels decreased from baseline, 24 month data for the low-dose group showed reductions compared to both the sham control and historical trends. However, mHtt levels increased by almost tenfold (40% vs. 4.7%) more in the high dose group compared with the control group at twelve months. There was considerable variability in the high dose group, which UniQure tried to explain as reflecting limitations of the mHtt assay process. However, the high mHTT readout in some high-dose patients caused some consternation among analysts, with UniQure’s valuation promptly cut in half.

There is a second, open-label PhIb/II trial that will enroll 15 additional patients, six in the low-dose cohort, nine receiving the high-dose.

Voyager Therapeutics’ VY-HTT01 used AAV9 to deliver an RNAi payload knocking down Htt production. In nonhuman primate studies, VY-HTT01 was reported to reduce Htt mRNA by 67-68% in striatal regions, 32% in cortical samples. It was one of the programs optioned by Sanofi, only to have those rights returned. Voyager terminated the program in light of a new inhouse generation of capsids that, in one animal model, provided a thousand-fold improvement in brain transgene expression compared with AAV9 vectors. The revised HD program is aimed at using an allele-specific, novel AAV capsid that spares wild-type Htt, can be delivered via IV, and has diminished liver targeting, enhancing its tolerability. The siRNA payload-in-development also targets MSH3, an enzyme involved in the pathological expansion of CAG repeats, and hence affecting the onset of manifest disease. The new HD capsid program is still in discovery stage.   

AskBio (aka Asklepios Biopharmaceutical), acquired by Bayer, has an AAV-delivered gene therapy program in Huntington’s. AB-1001 is administered via bilateral injections in the striatum. A five patient PhI/II is fully enrolled, and includes some preliminary efficacy measures at 52 weeks, with longterm followup going out another four years. When two optimal dose levels have been identified, 3-6 patients will be enrolled in each cohort.  When an optimal (in terms of dose-limiting toxicities) dose is finally selected, six additional patients will be enrolled at that dose.

Roche has an RNA editing partnership with Shape Therapeutics, which features Shape’s AI-driven AAV capsid platform, that they believe allows them enhanced tissue specificity. Shape emphasized Alzheimer’s and Parkinson’s, but probably also includes Shape’s program targeting Htt. This work is still in discovery stage. 

Spark Therapeutics, spun out of the Children’s Hospital of Philadelphia, and acquired by Roche in 2019 for $4.3 billion, had a preclinical stage AAV-delivered gene silencing program, SPK-miHTT, for Huntington’s. In non-human primate testing, they knocked down mutant Htt levels up to 90%. We had previously wondered how Roche would handle this program in light of tominersen, but despite tominersen’s last ditch resuscitation, Roche is surely accentuating its next-gen alternatives.

Affiris had two mHtt vaccine candidates in early preclinical stage testing, one of which is an active vaccine (‘bi-epitopic’), one is a mAb. Preliminary animal findings for mAB C6-17 showed reduced mHtt and improved functionality, but that program appears to have been shelved, Affiris has shifted its inhouse programming to hypercholesteremia.


A MGH group (Gusella et al) found CAGs are altered by other genes, with increased expansion impacting the age of symptom onset; such genes are associated with DNA maintenance and repair (MMR, DNA mismatch repair). This makes them potentially risky as targets for intervention, since off-target effects could have unforeseen, potentially disastrous results. There are companies that are seeking to mediating the expansion of CAG repeats via intervening at MMR, though their track record is mixed at best.

Promising work on MMR malfunction has been done by LoQus23 Therapeutics, funded by Dementia Discovery Fund and Novartis Venture Fund. LoQus23 has collaborated with HitGen in screening the latter’s library for small molecules that may impact the MMR process (via MSH3) and thereby ameliorate its impact on CAG expansions and symptomatic onset. Somewhat surprising, given Pfizer’s withdrawal from neuroscience, is the fact that a Pfizer group has also been screening MSH3 inhibitors. They report having identified MSH3 selective small molecules, and are now trying to optimize them. 

A UC Irvine group has reported that the enzyme PIAS1 mediates the accumulation of toxic mHtt aggregates; knocking down PIAS1 reduces aggregation and improves the behavioral phenotype in animal models. The group also linked PIAS1 to DNA damage repair pathways via the enzyme PKNP, suggesting a dual function for PIAS1 knockdown. The question is how to accomplish PIAS1 reduction safely.

Triplet Therapeutics was focused on the upstream role of genes within the MMR pathway in spurring increases in CAG repeats in HD, and the use of ASOs and siRNA to achieve a partial knockdown of these genes. TTX-3360 was an ASO that modified genes governing repeat expansions (Rapid Expansion Destruction, or RED), with Huntington’s the first indication. Triplet raised $59 million, and ran preclinical testing in iPS cells and mouse models, as well as in nonhuman primates, achieving significant knockdown in the striatum and other target regions. Triplet had projected initiating clinical testing in 2021, but had trouble raising additional funding after initial studies indicated the ASO had some neurotoxicity. In late 2022, the investors pulled the plug and shut down the company.

Locana Therapeutics, using technology spun out of UCSD, was using CRISPR to target mRNA for genes mediating REDs in Huntington’s. This program never made it past early preclinical development before Locana went out of business.

Targeting mHtt

As a monogenic disorder, Huntington’s epitomizes a context where genetic manipulation might eventually provide an upstream route to disease-modification, even a cure. The latter is raised by the tantalizing prospect of intervening at the very root of the pathophysiological process. For all neurodegenerative diseases that involve a toxic protein motif, the eventual emergence of overt symptoms belies the decades of aberrant aggregation that preceded it. This is near certain in Huntington’s, where there is no doubt as to the identity of the lethal ‘weapon’. Even if mutant huntingtin production can be safely reduced, the question remains as to how one contends with the ‘toxic  waste’ already embedded in critical brain regions. If gene therapies aimed at mHtt production were to hit their mark, the production of mHtt is very unlikely to be completely shut down, and the neutralization of existing mHtt could still be of clinical significance.

Having said that, this could be a time-limited, generational issue. Unlike other neurodegenerative disorders where identifying patients at risk, before they come anywhere near prodromal stage, is not yet feasible, Huntington’s risk can be delineated via genetic testing, albeit with a narrow band of uncertainty around certain parameters of CAG repeats and the potential for repeat expansion. Once a disease-modifier is validated, the dilemma that individuals have faced regarding the utility of testing when no treatment is available would largely vanish: Anyone with a familial history of HD would have genetic testing early on, positive results triggering the initiation of disease-arresting therapy that would prevent the accumulation of mutant huntingtin aggregates from ever approaching neurotoxic levels. But this exists only in theory at present, and targeting mutant huntingtin production has proven to be more challenging than might originally have been thought. Thus defusing and removing toxic elements continues to be pertinent.


Vybion developed an antibody (INT41) that they claimed binds to huntingtin and prevents its aggregation, while inhibiting its binding to chromatin and cell membranes. In a mouse model, animals treated with AAV-delivered INT41 show no cognitive deterioration. Vybion had hoped to be in the clinic in 2015, using Convection Enhanced Delivery of viral vectors delivering the gene for INT41, but as of 2018, they were still in preclinical stage, and with no news for five years, their viability appears nil.

Work done at Stanford using the chaperone TRiC showed that TRiC prevents mHtt aggregation. Similarly, a UCSD group reported (in PNAS) in vitro data utilizing a novel model mimicking cortical-striatal interaction, wherein a subunit of TRIC inhibited mHtt aggregation and the resultant impairment of BDNF transport to the striatum. However, the TRIC premise appears to have lost its momentum, perhaps because recent work has suggested TRiC may play a role in uncontrolled proliferation, raising concerns regarding oncogenic effects. 

Misfolded Protein Removal

Toxic huntingtin, in soluble and/or insoluble form, can be removed to prevent destructive cellular effects. As is the case with Alzheimer’s and Parkinson’s, toxicity results when such aggregates cannot be eliminated via cellular waste disposal systems, both ubiquitin-proteasome activity and autophagy. Improving either or both of those processes would be an avenue to reducing the  toxic ‘load’ placed upon neurons by mHtt.  


Fostering the functioning of the ubiquitin-proteasome system could be a route to disassembling and removing mHtt aggregates. It has been noted that the proteasome activator PA28 improves cell viability, improving proteasome functioning may promote the removal of mutant huntingtin. 

The ubiquitin ligase UBR5 (the gene for which also plays a role in mediating CAG repeats) appears to be a key role to promoting aggregate-clearance. In a c.elegans model, silencing UBR5 production leads to a rapid increase in toxic aggregates. A U. Cologne group has used iPS cells derived from HD patients to confirm that UBR5 depletion is associated with a dramatic increase in toxic huntingtin aggregates. However, those researchers have been working with a silencing model to show the negative effects of deleting UBR5–they have yet to identify a means of upregulating UBR5 levels to foster neuroprotection.

Working from a concept that was initially pursued by CHDI in developing CHDI-709, Arvinas has a orally-bioavailable PROTAC protein degradation program that links soluble mHtt to an E3 ligase in order to tag it for ubiquitination and clearance, before it can begin to aggregate. The clearance spares wild-type Htt. They have shown BBB-penetrance for their prototypes. They have in vitro data suggesting that clearing soluble mHtt also has an indirect impact on the level of insoluble aggregates. This is much earlier in development than their AD/tau program, but the HD PROTAC has shown adequate pk characteristics in mouse models.

 PAQ Therapeutics’ ‘ATTEC’ technology promotes autophagy by linking the autophagy regulating factor MAP1LC3B to a neurodegenerative protein. Earlier work pointed to the likelihood that targeting mHtt in Huntington’s could be a first emphasis, but after announcing a $30 million round and a collaboration with Insilico in 2021, there has been no news in two years. 

Casma Therapeutics also had an autophagy program against huntingtin, but has become increasingly vague over time, disclosing only an ‘exploratory’ program in ‘Inflammation’. 

Rapamycin has been reported to increase autophagy and decreases mHtt accumulation in a HD model, which could be an alternate route to reducing mutant huntingtin, though it appears to only be useful if introduced early in the disease process, and its immunosuppressant effects complicate chronic utilization. 

Unfolded Protein Response/UPR

A Spanish group (Lopez-Hurtado et al) reported in 2016 that NovoNordisk’s diabetes drug repaglinide delayed symptom onset and reduced atrophy in a mouse model of HD. Their hypothesis was that repaglinide inhibits a toxic interaction between DREAM (Downstream Regulatory Element Antagonistic Modulator) and a transcription factor (ATF6) associated with UPR. They reported that DREAM-knockout increased survival, though somewhat confusingly, they also reported DREAM levels were lower in HD striatal tissue and in transgenic mice–which they attributed to an endogenous neuroprotective response. In 2019, they reported having developed a better inhibitory DREAM ligand, IQM-PC330, with superior potency and duration of effect. Both IQM-PC330 and PC332 have also been shown to be kv.4 potassium channel blockers. The group has not obtained an industry partnership for this work, and the originators appear to be focused on potential analgesic applications. 

Other Disease-Modifying Tactics

Complement Inhibition

The complement system has been implicated in Alzheimer’s and Huntington’s, disrupting the tagging of potentially toxic aggregates, impairing their removal by phagocytosis. Annexon Bioscience has focused on Clq as a key element in facilitating the clearance of damaged cells/components; C1q tags healthy synapses for removal when hyperactivated by stressors, resulting in excessive synaptic pruning and neurodegeneration. Annexon is developing Clq inhibitors that are intended to not impact other components of the complement pathway, allowing those immunological elements to remain functional. ANX005 completed a 28pt, open-label PhII pilot study back in 2022. In this trial, patients with manifest or potential HD received ANX005 IV for twenty-two weeks. Patients appeared to stabilize over the nine months of the study, in contrast to a historical reference group wherein deterioration occurred. The improvement was most salient in those patients with high levels of the complement marker, C4a, which supported Annexon’s targeting premise. However, five patients out of the 28 had dropped out of the study, which raised concerns regarding tolerability. But in the three for whom treatment seemed linked to their adverse events, it turned out that all had a previously undiagnosed autoimmune condition. Future testing will include screening for that biomarker. Annexon states they plan to begin PhIII in 2024, their resources are currently focused on their Geographic Atrophy program. Allyx Therapeutics has not pursued HD with their repurposed complement modulator.

Neuroinflammation/Immune System Dysfunction

Laquinimod, Teva/Active Biotech’s immunomodulator, had been reported to reduce cytokine production and to restore motor function and striatal volume in HD mouse models. Teva ran a 400pt Phase II that came up empty on the primary endpoint after one year of treatment. Active Biotech reported that the trial did reveal changes in markers of neuroinflammation and atrophy, but acknowledged there was no linkage to functional measures. 

The kynurenine pathway is disrupted in HD, and it has been hypothesized that inhibiting KMO, an enzyme that produces metabolites, including quinolinic acid, could be useful in HD. Psychogenics developed a mouse model that displays 120 CAG repeats, both cortical and striatal atrophy, and proinflammatory changes in kynurenine metabolism. CHDI (in conjunction with Psychogenics and Evotec) sponsored mouse studies of a KMO-inhibitor, CHDI-340246, and while the inhibitor normalized some electrophysiological measures, no impact on behavior or the rate of progression was seen. Lundbeck developed KMO blockers that target the kynurenine signalling pathway, relevant to inflammation in HD, based on animal models. In 2018, Lundbeck outlicensed the KMO-blocker program to MindImmune Therapeutics, but MindImmune’s focus has been on a different Alzheimer’s program. Kynexis is now developing an old Mitsubishi KAT2 inhibitor, but not for HD.


Calcium influx and excitotoxicity intersect in Huntington’s, and calcium dysregulation can affect the mitochondria permeability transition, leading to cell destabilization. There are also reports that NMDA receptor activity is increased, which could lead to glutamatergic excitotoxicity. It has been suggested that extrasynaptic NMDA receptors are more prevalent in HD, and that glutamatergic activation of these receptors triggers apoptosis. 

Axonis has animal model data suggesting that its KCC2  (chloride transporter) targeting program may provide an alternate route to reducing excitotoxicity in HD, but that is very early-stage; their first focus is SCI–PhI readiness is expected a year from now.

A Cornell group had worked on the role of the enzyme transglutaminase-2 in a HD model, noting that overactivity of that enzyme renders cells more vulnerable to oxidative stress. Reducing transglutaminase-2, either via pharmacological or RNAi means, produced neuroprotection in vitro. One program that sought to utilize this pathway in HD came from Raptor Pharmaceuticals, with Procysbi/cysteamine. A French academic group ran a 96pt, 18-month duration Phase II trial in HD. In early 2014, an analysis of the first 89 patients showed a slowing of deterioration of motor function was reported. The effect was more pronounced in patients not also taking tetrabenazine–one hypothesis for this was that tetrabenazine had attenuated visible motor symptoms, providing less ‘bandwidth’ within which Procysbi’s impact could be detected.

Raptor tried to convert its open-label extension into something more definitive by initiating treatment in additional patients, setting up a delayed-start comparison, claiming the results showed a statistical trend towards a slowing of disease-progression. They cited a more robust trend for completers, though this would be skewed by the fact nonresponders would be much less likely to be completers. Raptor also claimed trends on the UHDRS Functional Scale, nothing was said about cognition. At the time, Raptor said that they would proceed into a pivotal trial, but when Horizon Pharma acquired Raptor in late 2016, development in HD ended. 

As was noted on p.80, a Cornell group reported that mutant huntingtin triggered mitochondrial fragmentation, both in vitro and in vivo, and that the pathway by which this damage occurs is via an interaction between mutant huntingtin and an enzyme involved in mitochondrial fission, DRP1, work subsequently supported by a University of Barcelona team.

Mitoconix was a Stanford spinout that was working with a dynamin-1 inhibitor they believed inhibited mitochondrial fission. The lead compound, MTC-1203, showed efficacy in mouse models of HD and PD. They were able to raise $20 million in 2017, but the program turned out to not be viable, and Mitoconix shut down.


Alterity (formerly Prana Biotechnology’s metal-binding tactic had been proposed to have anti-excitotoxic effects and to keep metal ions from exacerbating huntingtin aggregation. They ran a 109pt Phase II for PBT2 in HD, which yielded only a fluke finding on a single neuropsych measure, and they shifted their corporate focus to MSA.


Acetylation is suppressed by mutant huntingtin, which in turn leads to the decreased transcription of proteins necessary for cellular survival/stability, including CREB and BDNF.  A drosophila model showed that inhibiting deacetylase slows degeneration and cell death, perhaps via enhancing autophagic removal of protein aggregates. Thus HDAC inhibitors could be applicable to Huntington’s, though most existing HDAC inhibitors have BBB access and/or side effect issues. Alkermes has not cited HD as an interest for their preclinical work, nor has Eikonizo Therapeutics, with their preclinical, brain-penetrant HDAC6 inhibitors. Otsuka’s partnership with Eikonizo only mentions ALS in specific, but does cite  ‘rare diseases’ as a more inclusive area of interest..

Another approach to epigenetic modifications is Oryzon Genomics’ LSD1 inhibitor vafidemstat. in clinical studies across several therapeutic domains. They have said they have HD animal-model data suggesting that vafidemstat could have utility in HD, but HD is not currently on their expansive menu for development.


Vaccinex has long been developing pepinemab/VX15, an antibody against the guidance factor semaphorin-4D, which they believe contributes to HD damage via proinflammatory/apoptotic effects. Vaccinex initiated a 116pt Phase II back in 2015, with the antibody administered monthly. However, after the first 36 patients were run, the protocol was amended and another 265 patients eventually enrolled, including both prodromal and early HD disease, receiving monthly IV infusions of pepinemab for eighteen months. Vaccinex reported in 2020 that, while the primary endpoints were missed, the pepinemab group (179 patients) with more advanced, manifest disease showed a trend towards improvement in cognition on two components from the HD-CAB composite battery, However, the scores covered a range from plus or minus just over  0.1 point on the HD-CAB, a minuscule range of no clinical significance. A trend towards benefit in manifest, choreiform disease was also reported on the CGI-C, a  measure of general functioning, and on MRI assessment of ventricular expansion and caudate atrophy. However, this was generally seen as a failure. Vaccinex has taken pepinemab into a PhI/II in Alzheimer’s, and cites it as Phase III ‘ready’ in manifest HD. The investigators subsequently published their results in Nature Medicine, unconvincingly claiming that the results justified going into PhIII for HD, but they have backed off, stating that they are evaluating their strategy, in discussions with the FDA about a PhIII. However, they had just $1.9 million in cash mid-2023; without a partner they have no path forward, and none is likely to emerge.

A group at University of Cambridge reported a QC inhibitor decreased mHtt aggregation and cell death in drosophila. Vivoryon/Probiodrug has been developing a QC inhibitor (PQ912) for AD, but has not cited any interest in HD.


A University of Padua group reported in mid-2023 that boosting the level of MTF1, a transcription factor, counteracts the toxic effects of mHtt, including oxidative stress. In transgenic mice, MTF1 improves motor function and reduces mHtt aggregation. 

A UCLA group had reported back in 2014 that ATM (ataxia-telegiectsia-mutated) kinase activity is elevated in HD mouse model cells and appeared to contribute to mHtt-triggered cytotoxicity. Developing selective AMT-kinase inhibitors has been challenging, due to the need to avoid a kinase essential to autophagy. But in 2021, a CHDI/Charles River consortium reported success, producing more selective ATM inhibitors that are orally bioavailable and have superior pk characteristics.

Durably Under-the-Radar

CHDI has had a very longterm collaboration with Evotec assessing targets and screening small molecules for HD. This partnership began in 2006, and was most recently extended from 2018 to 2023. There has been no announcement yet as to another extension, and little externally discernible progress. The collaboration has yet to bring anything into the clinic, and Evotec continues to state that “With access to these resources, CHDI has all the tools in place to rapidly discover novel drugs against Huntington’s disease targets and further optimise them to the point of clinical development.” To this point, the alliance is a prime example of patience, with the first tangible payoff the development of a PET-ligand for mHtt (Compound (11C)-2) that is selective for mHtt over amyloid or tau aggregates, and has performed well in nonhuman primates. The next step is clinical validation.

CHDI is nothing if not patient: They have also had a collaboration with Charles River Laboratories since 2005,  which has yielded some novel targets, as well as animal models and molecular screens. The collaboration  recently reported on the development of ATM (ataxia telangiectasia-mutated) kinase inhibitors as therapeutic candidates in HD. The first generation of molecules risked downregulating autophagy, they have now devised  optimized candidates that may be selective enough to avoid those off-target effects. CHDI has also long collaborated with Psychogenics on the development of HD mouse models and the screening of candidate compounds. 

Neurotrophins for Neuroprotection

BDNF is an important contributor to neural development and neuroprotection, and normal huntingtin upregulates BDNF. The loss of wild-type huntingtin means less BDNF is available, and the brain is left more vulnerable to degeneration. It should be noted that this is not universally accepted: A Northwestern U. group suggested that it is not BDNF deficiency that underlies decreased neuroplasticity in HD, but that it is instead the dysregulation of p75 neurotrophin receptors that impairs plasticity. But for those focused on the BDNF angle, BDNF could in theory be introduced via viral vectors or engineered cells, albeit with the difficulties attendant to those technologies. One study used AAV to introduce BDNF expression in the subventricular zone, and in a mouse model, increased striatal neuron survival. INSERM used AAV to deliver genes expressing the neurotrophic factor CNTF, and in a rat model, provided neuroprotection to the striatum. The late Ceregene sponsored a rodent trial where AAV delivery of neurturin to the striatum produced neuronal protection and functional improvement, but funding issues shelved that work. Another Ceregene study, delivering GDNF via AAV, improved behavioral function in mice.  

A UC Davis group has used mesenchymal stem cells to produce BDNF in mouse models of HD, while a Korean group (CHA University) reported that BDNF-overexpressing neural stem cells, implanted in a HD rat model, interwired and produced functional improvement.

A U. Penn group reported in 2014 that mTORC1 activity is impaired in HD, and upregulating it by introducing Rheb in mouse models reduced atrophy. A Kyungpook University group (Nam et al) has reported that AAV delivery of the gene for Rheb upregulates neurotrophic factors and is neuroprotective, including in Huntington’s.

Cell Therapy

Cell replacement therapies have not received anywhere near the attention in Huntington’s that they have in Parkinson’s. Most cell-implant concepts for HD have focused on the striatum, which would be primarily relevant to motor symptoms, not the cognitive or psychiatric deterioration also seen in HD. In a review of the HD cell therapy literature published in 2021, Bachoud-Levi reported that of the 70 HD patients treated with fetal cell therapy in open-label studies since 1990, four showed durable improvement lasting over six years, and this includes a major study (MIG-HD) that enrolled 45 patients. There were several methodological issues that complicated the interpretation of these results, and the perennial questions regarding stem cell therapy in all CNS contexts apply here: What are the right cells, at what level of differentiation, implanted how and where in patients at which level of disease-progression, that provide a better likelihood of positive outcome?   A 2023 publication of mouse model findings from a University of Rochester group reported that implanting ‘young’ glial cells provided replacement of pathogenic cells delayed disease progression.  But that is a long way from testability in humans.

California’s CIRM has provided over $27 million in grants for HD cell therapy work, including $12 million to a UC Irvine group that reported their human neural stem cells reduce mHtt accumulation in mice, and improve functioning. As was noted above, a CHA University group reported functional benefit from the implantation of BDNF-overexpressing neural stem cells in a rodent model of HD, though that would seem a neurotrophin-delivery method, not a means of achieving structural interwiring.

The question is also begged as to whether these cells can survive. A study of fetal cell implants reported that grafts in the putamen and caudate survived but did not interwire with host tissue, and did not provide any clinical benefit. Another trial reported post-mortem data on three patients, implanted with fetal grafts a decade or more before. Some interwiring was noted, but the grafted tissue then degenerated more rapidly than did the host cells around it, suggesting that microglial activation produced a hostile environment within which the cells could not survive and function. A review by Gogel and Gubernator concluded that HD cell implantation offers temporary symptomatic improvement, but no lasting benefit, due to a lack of longterm interwiring and survival, the latter attributed to microglial activation and excitotoxicity. 

An Emory group combined gene therapy (RNAi-induced lowering of mHtt) and cell therapy (neural progenitor cells engineered to differentiate into GABAergic neurons), and reported that HD-model mice showed ‘significant improvement in motor functions’ and in lifespan when they received both–more than when they received the cell implants alone. The implanted cells in fact differentiated into multiple neuronal types, thus they were sufficiently integrated into the ‘locale’ that their development was reflective of local signals. 

Programs to Watch


Sage’s SAGE-718 has promise as a cognitive enhancer in HD; two PhII trials should have results coming next year.

Prilenia Therapeutics has postulated disease-modifying effects for pridopidine, but based on the compound’s lengthy history, one can argue that they would be fortunate to find any symptomatic benefits. Their large PhIII with top-line results failed earlier this year, Prilenia has not fully disclosed the post-hoc signals they claim supports pridopidine in patients not receiving neuroleptic or anti-chorea drugs. It must be wondered how long the funding leash will be for Prilenia.

Disease Modifiers

Our optimism regarding nearterm disease-modification in Huntington’s vaporized in the wake of tominersen’s meltdown, and Roche’s decision to go into another PhIII with early-stage patients strikes us as an attempt to traverse an unbridgeable gap between efficacy and safety–we will not be surprised if the trial ends up terminated early. 

Selectivity has not been a panacea, given the outcomes for the first two Wave Life Sciences oligonucleotides, we do not expect anything better from the third.

UniQure’s AMT-130 program has generated some impact on the rate of progression, and it may be that the mHtt elevation seen in the higher-dose cohort is a fluke. But even at best, AMT-130 would be a difficult product to administer, and would not be scalable even to the limited size of the HD population. Voyager’s revised HD program combines mHtt and MSH3 targets, which in theory could augment its impact, but it is very early in development. 

Slowing disease progression by modifying DNA mismatch repair (MMR) is an alternate strategy, one that has the advantage of being small-molecule based. LoQus23 and (surprisingly) Pfizer are both active therein, but neither has yet reached the clinic.

Annexon saw enough in PhII that they plan to start PhIII next year with the c1q inhibitor ANX005, and Arvinas has an oral PROTAC selective for mHtt, but is very early in its development. Allyx Therapeutics has thus far been focused solely on Alzheimer’s.

CHDI has been supporting up to 75 FTEs at Evotec for the past seventeen years, eventually we will see what that investment has produced and if it has value.


Huntington’s offers more mechanistic clarity than most of its neurodegenerative peers; we have certainty as to the antecedent genetic flaw that leads to the pathology, and there is a level of diagnostic definitiveness that greatly simplifies the task of trial enrollment. But recent failures illustrate the daunting fact that even this level of granular clarity does not guarantee success. 

The size of the prodromal and manifest Huntington’s population is in the 150-200,000 range in the US, making this far more than a minor market for any company that can develop a disease-slowing treatment. Such a drug would be administered early, and outside of the one-shot gene therapies, chronically. 

In the wake of the success achieved in Spinal Muscular Atrophy, we had said for a few years that Huntington’s would be the next neurodegeneration success story. That is no longer the case. With all due respect to the biomarker work-around in ALS-SOD1, and the perenially disappointing amyloid mAbs, slowing FTD-GRN is more likely to be the next clearcut achievement in CNS disease-modification, before the HD puzzle is solved.

From NP Winter Issue 2023

Lecanemab’s Risk-Benefit Conundrum:

Anti-amyloid mAbs have been the repository of more wishful thinking than any other category of neurotherapeutics. Which accounts for this quote from the CMO for Alzheimer’s UK, who said in reference to lecanemab: “It’s just a first step, but this new Alzheimer’s drug could be a huge breakthrough.” Which to our eyes seems semi-detached from reality, given that there is ample debate as to whether lecanemab’s treatment effect, barely visible to the empirical naked eye, will be perceptible to patients and families beyond hopeful expectancy. Less aspirational and more to the practical point were two critical quotes to be found in a November 27 piece in Science titled ‘Second Death Linked to Potential Antibody Treatment for Alzheimer’s  Disease‘, quotes that bring into stark profile the dilemma that prescribers and families are going to face when it comes to lecanemab and, most likely, donanemab as well:

Even if that (antibody treatment) only means 6 or 12 more months of knowing who their kids are…it’s meaningful to dementia patients and their families.”  (University ofKentucky neuroscientist Donna Wilcox)

s“As soon as they put it (tPA) in her, it was like her body was on fire, She was screaming, and it took like eight people to hold herdown.”  (the husband of a patient who died)

The conundrum? There may be no more heart-wrenching an anecdotal image of the toll taken by AD than a parent who not longer recognizes their own children; evoking that nightmare scenario is a potent gambit for those advocating the use of an anti-amyloid mAb. But the calculation of acceptable risk is transformed when contemplating the even-more-awful image of an elderly parent ‘screaming…like her body was on fire.’ Many families (and physicians) who might otherwise consider worthwhile any chance of extending autonomy and awareness will recalculate the risk-benefit analysis if the risk includes even a small possibility of such horrific suffering. 

The context of the death was this: A woman who had received lecanemab (believed to have been initiated in the open-label extension) developed stroke symptoms and was administered tPA. The thrombolytic triggered extensive cerebral bleeding which led to her death a few days later. The autopsy found signs of cerebral amyloid angiopathy (CAA), which perhaps had weakened the blood vessels, a weakening exacerbated by the impact of the mAb on vascular amyloid, so that tPA then precipitated a massive rupture nd hemorrhage. CAA is another manifestation of amyloid pathology, and is believed to be present in up to half of AD patients, though it is difficult to diagnose other than post-mortem. There was another report of a lecanemab-linked death where a patient had also received an anticoagulant, for atrial fibrillation, and a third death, details unavailable.  A subsequent (1/4/23) case report in NEJM suggested that the stroke reflected a causal role of lecanemab in the onset of stroke. 

This reminds us that, when discussing the emergence of ARIA-E (edema) or ARIA-H (microhemorrhages), sponsors tend to emphasize that 98-99% of ARIA patients ‘fully resolve’ after the mAb is stopped and treatment is provided. We have always wondered about the other 1-2%, those that do not ‘fully resolve.’ 1-2% sounds rare, but when talking about a disease affecting 6.5 million patients in the US alone, that represents a potentially substantial subgroup. In the case of the lecanemab CLARITY trial, 2.8% of lecanemab patients developed symptomatic ARIA-E, 81% of whom were described as fully resolved at four months, which begs the question of what happened with the other 19%, who comprised 0.53% of the active treatment group; 21 patients whose longterm AE sequelae were not disclosed. This blind spot is from a rigorously executed and monitored study, where the level of clinical oversight surely exceeded what can generally be expected in clinical practice.

It has been suggested that the risk of potentially dangerous CAA would be reduced if amyloid mAB therapy was restricted to patients with mild AD, but according to the Science report, this woman had only retired from a professional position a year before, so this was relatively early, and her CAA was not flagged by Eisai’s screening. APOE4+ patients appear to carry more risk of ARIA-E, but with that genetic loading found in up to 70% of the AD population, that is not a viable exclusionary criterion. Thus it may not be possible to parse out the at-risk population, leaving families and prescribers to contend with the fear that a well-intentioned intervention might have deadly results. 

With all due respect to the claims that lecanemab is a potentially “huge breakthrough“, a .45 point impact on the CDR-SB falls well short of the one point difference commonly cited as the Minimum Clinically Important Difference for that measure. Even ICER seemed befuddled: “In aggregate, the net health benefits of lecanemab in patients with early AD may be small or even substantial, but there remains a possibility of net harm from ARIA.” Which covers the full gamut of possible outcomes.

Unlike Biogen with Aduhelm, Eisai did leave the microphones in the CTAD auditorium, though the questions lobbed from the floor were softballs that sounded like pre-specified plants. Eisai pushed back on the safety issue raised by the patient deaths, though they acknowledged that these risk factors would have to be weighed in a treatment decision.  

We have expected that a significant subset of Alzheimer’s patients would be willing to try a therapy that could be even modestly useful in extending functional independence, but this presumes that the downside is not overly daunting. The phrase ‘like her body was on fire‘ will reverberate in the Alzheimer’s community, reducing the portion that believes the limited upside gains are worth such uncommon but devastating risks, and deterring physicians leery of taking them on. Even Eisai cited a target market penetrance of just 100,000 patients by year three of the launch, which, given the size of the AD population, is strikingly tiny. Perhaps that explains their pricing Leqembi at $26,500 per year, portraying this as an $11,100 discount to the ‘real”value of the drug, well beyond the $8500-20,600 range estimated by ICER. Eisai seems to expect very limited adoption; if they truly believe in its value, they might have considered pricing it lower and expanding its range.

‘Psychedelics Update’

2022 was a year where the psychedelic therapies movement featured an odd mélange of the credible and the absurd, reflecting the still-early developmental stage of this area. A few examples of each:

Credible: The New England Journal of Medicine, which epitomizes traditional medical practice as much as does any publication, published Compass Pathways‘ detailed findings from their ground-breaking PhII trial of psilocybin in TRD. The detailed findings support our initial comment that ‘COMP360’ is a “tool, not a panacea.” 29% of the high-dose group were in remission after three weeks, not an unimpressive accomplishment in a refractory population, but a panacea would not leave 71% of the treatment population behind. Compass is about to launch a PhIII study that will enroll ‘almost 1000’ TRD patients, adding a second dosing three weeks after the first. Given the complexity of the undertaking, it was reassuring that Compass hired an Otsuka drug executive, Kabir Nath, to become their CEO, an essential addition of industry expertise to a Company that had lacked the organizational coherency required for this developmental stage. The question remains open as to whether Compass’ IP strategy is viable, or whether they are blazing a path that eases the way for numerous competitors as well.

Incredible: The National Park Service issued a Public Service Announcement reminding readers that they should eschew licking the Sonoran desert toad which is a source of the psychedelic molecule 5-MeO-DMT, along with other, potentially less appetizing alkaloids. We suspect that the numbers of toad-lickers is relatively small, but it is a reminder that, unlike any other area of drug development, even as the biopharm industry attempts to systematize and medicalize the testing and eventual deployment of these substances, there is an extensive parallel movement that is geared towards the sacramental, spiritual, and relatively unregulated use of psychedelics. This is a movement that reflects thousands of years of ethnobotanical tradition that intermittently percolates into broader public awareness. NIR is sympathetic to that tradition and its aspirations, but that is not the focus of our coverage, aimed at exploring the possible expansion of the quasi-spiritual into a broader utilization in the treatment of psychiatric distress and illness. We occasionally trigger an ‘OK Boomer’ reflex response from those who believe that the lessons of the sixties and seventies are not relevant to this psychedelic renaissance, and/or that attempts to medicalize psychedelics are greed-driven and antithetical to their consciousness-raising potential. While we disagree, there may be no nearterm route to bridging that divide. But surely we can at least agree on this: Sonoran toads should only be licked if they have provided informed consent and chosen a ‘safe word.’

The Role of Psychotherapeutic Support/Integration:

The degree to which psychedelic therapies rely upon psychotherapeutic support for maximum treatment impact is a critical component of the clinical development process, with adherents on both sides of the argument. Much of the anecdotal literature regarding psychedelics/empathogens from the 1950s and 1960s came from psychotherapists who utilized psychedelics as adjuncts to ongoing therapy, not as stand-alone interventions. This tradition was recapitulated by the first two pioneers to make it into highly controlled clinical testing: MAPS‘ work with MDMA in PTSD, Compass‘ psilocybin trial in TRD. Both of these trials emphasize preparatory and integration work as integral to the therapeutic experience, but this comes at considerable cost: The MAPS MDMA protocol utilized more than forty(!) therapist hours, the Compass PhII trial required at least fifteen hours, which will increase with their PhIII, since that utilizes two dosing sessions. Such therapeutic packages require extensive training to ensure that the therapists follow the protocol, with varying allowances for skilled improvisation. Such protocols, if commercialized, would carry a hefty pricetag, well into five figures. Companies like Small Pharma and Beckley Psytech have also adopted psychotherapeutic support as core elements of their clinical trial structure.

In contrast, MindMed is running its pilot study of LSD in Generalized Anxiety Disorder without any psychotherapeutic prep or integration: A ‘monitor’ sits with the patient during the twelve hour dosing for the sake of safety, but that is it. Somewhat to our surprise, MindMed’s CMO is an eloquent advocate of psychodynamic psychotherapy, but he explains the MindMed approach as zeroing in on the purely pharmacological impact of the LSD session, without conflation with psychotherapy. It is reassuring that this decision was not based on a devaluation of psychotherapy per se, but it is ironic that, despite the embrace of the concept that medication and psychotherapy are best delivered in concert, the program would eschew it in testing this legacy psychedelic. One can make the logical case that this protocol could set the stage for a relatively more affordable psychedelic treatment program, though we question the practicality of such a long-duration agent. Somewhat tongue-in- cheek, we would note that the use of LSD without psychotherapy as anxiolysis does not enjoy extensive anecdotal support, there were no reports of a ‘Great Tranquillity’ during the years 1966-69. Our bias is that, given the generally acknowledged salience of ‘set and setting’, that this sacrifices the potential value promoted by incorporating psychological preparation into that ‘set’ from the outset. Synergy is a terrible thing to waste.

Even as some companies in the US experiment with reducing the psychotherapeutic component, Health Canada has now mandated two therapists be ‘in-the-room’, while setting standards for preparation and integration work. This was partially due to the MAPS PhII scandal where two therapists were grossly inappropriate with a patient, though that episode showed the risks even with a therapist pair. Based on these guidelines, MindMed’s LSD trial would be not be permitted in Canada.

The Most Critical Question in Psychedelics:

Are hallucinations a bug or a feature? Do the erstwhile benefits of compounds aggregated under the umbrella of ‘psychedelics’ reflect an impact upon neuroplasticity, and if so, does such psychoplastogenicity require a psychedelic, hallucinatory experience? While the initial consensus leaned towards the widely held belief that an efficacious therapeutic journey requires a ‘trip’, companies like Delix, Cognesy, Onsero, Psilera, and BetterLife are among those holding that a hallucinatory experience is a nonessential side effect. From a traditional pharma viewpoint, relevant to partnering potential, eliminating the ‘trip’ and turning these molecules into at-home, self-administered pills would be far more familiar, and appealing framework, than figuring out how to commercialize a therapeutic package that must be administered in a clinic setting.

For NIR’s part, we find intuitive resonance in the idea that some cognitive-behavioral patterns are so structurally embedded that they must be disassembled in order to promulgate fresh neural iterations. Our suspicion is that some behaviorally entrenched disorders, particularly addictions that have ‘hijacked’ the neural reward system, may require full-blown ‘demo and renovation’ for lasting change. Indeed, the very promising Johns Hopkins work on smoking cessation and NYU‘s alcohol abuse trials use exceptionally high doses of psilocybin, ranging up to more than 60% above Compass‘ high dose. On the other hand, the dramatic but transient disarray of hallucinatory experience may not be as crucial in anxiety disorders, for example. But this is purely speculation, the proof will be in the data yet to come.

But while we await solidly grounded, empirical evidence, it is hard to shake the feeling that this class of psychoactive drugs is somehow different. Even Onsero‘s founder, the eminent and highly rational neuropharmacologist Bryan Roth, said this at ACNP: “There may be something magical about psychedelics per se.”


From NP Summer Issue 2022

Excerpt from Psychedelics Review: Bad Ideas

Deprofessionalization in the Name of Democratization: The safe therapeutic utilization of psychedelics requires screening patients for those who might benefit while providing adequate preparation, support, and integration, but also requires screening out those who should not be treated with psychedelics. Anxiety about the spectre of psychedelics being restricted to the well-to-do is understandable, but dumbing down the screening and treatment processes for the sake of broadening access is risky. Screening out those patients who might be vulnerable to psychotic decompensation requires a degree of professional training well beyond Oregon’s proposed 120 hours, it is even beyond physicians who have been trained in anesthesiology rather than psychiatry. The Compass results show that, even for those not at risk of psychosis, the majority of patients may end up disappointed by the results: Professional preparation, support, and integration did not prevent suicidal acts in this monitored, supervised treatment group, one can only imagine what the risks would be without these safeguards.

LSD for anything: This may seem overly dogmatic, but twelve hour drug sessions exceed the bounds of what can be reasonably expected in most treatment contexts, with intrinsic unnecessary and hard-to-manage excess. If pressed to consider possible exceptions, Addiction and Cancer Pain are perhaps contexts where such duration is either desirable or tolerable. But proposals to add a chemical adjunct (e.g. a 5HT-2a antagonist) that terminates the LSD effect at some pre-selected timepoint is a clumsy adaptation that will go nowhere, given the availability of alternatives that are inherently shorter-acting. With all due respect to the recent Liechtl clinic paper (see p.11), there is ample anecdotal weight to the argument that LSD carries some added risk of anxiogenesis. When it comes to psychedelic treatments that are not strictly boutique-level in their accessibility, these factors make LSD a non-starter. This is particularly true for a couple of proposed treatment contexts:

ADHD and LSD: There is literature supporting the concept that ADHD reflects a network failure to suppress default mode activity when there is a task at hand requiring attentional focus. Psychostimulants appear to inhibit default circuit activation, thereby permitting focus without mental ‘wandering.’ But there is a difference between an ADHD scenario where one is seeking to suppress default mode functioning in the service of making planning and problem-solving more figural, in contrast to the most popular psychedelic premise (best articulated by Carhart-Harris) that suppressing default mode functioning via psychedelics allows a broad emergence of new networks and novel ideational activity. In other words, there is a difference between psychedelic-induced neural equipotentiality and psychostimulant-enhanced engagement with a singular cognitive focus, the former more associated with novel, creative thinking, and latter with pragmatic task-orientation. Yet there are those who believe that psychedelic micro-dosing is a viable alternative to psychostimulants in the treatment of ADHD. This has arisen partly via anecdotal reports from the LSD micro-dosing subculture that emerged in Silicon Valley. NIR believes that this is a reverse-engineered fallacy, the enhancement of creative thinking in individuals who formerly utilized Adderall and other stimulants as performance enhancers does not mean that they were treating actual ADHD, and does not mean low-dose LSD is a valid option for treating Adult ADHD. But MindMed has gone ahead with an EU trial of LSD in ADHD. From a safety and regulatory viewpoint, and the fact that the non-psychedelic impact of micro-dosing can be easily thwarted by combining doses, this is a non-starter.

Neurodegeneration and LSD: There are credible researchers who view psychedelics as increasing neuroplasticity and the building of new neural connectivity, ‘psychoplastogens’ potentially remediating neurodegeneration. Classic psychedelics are known to possess anti-inflammatory effects, a 2020 publication identified a specific chemical component of 5HT-2A agonists, 2C-H (2,5-dimethoxyphenethylamine), as the anti-inflammatory factor, active in animal models of asthma, but we do not have much optimism for procognitive or anti-inflammatory effects from psychedelics that might significantly impact Alzheimer’s. A Johns Hopkins study is assessing the impact of psilocybin on anxiety, depression, and cognition in early Alzheimer’s, but while an impact on anxiety and depression seems achievable, we doubt that a procognitive benefit can be anticipated. Eleusis reported that low-dose LSD was well-tolerated by healthy older adults in a PhI, and the CEO said (in Forbes) that “this (classic psychedelics) could be a therapy to modify the course of Alzheimer’s“. While the theme of neuroinflammation as a contributor to many disorders has resonated loudly over the past decade, thinking of this as widening the potential market for classic psychedelics or their progeny seems both misguided and highly inefficient: There will be better routes to address neuroinflammation and/or fostering neurotrophic effects. Psychedelics could help with the emotional accompaniments of dementia, depression and anxiety (e.g. Biomind is in PhII with oral 5-MeO-DMT for Alzheimer’s depression and anxiety), but they are not next-gen candidates for arresting the neurodegenerative disease process.

Micro-dosing: Commonly attributed to Silicon Valley experimentation in performance enhancement, there  has also been the trendy emergence of ‘micro-dosing’, using a ‘subperceptual’ dose level that does not precipitate hallucinations. Adherents claim that this promotes creativity and productivity. Micro-dosing was discussed in the preceding section on ADHD, but in the long run, it likely to be the province of recreational rather than therapeutic use, particularly when it comes to long-acting agents like LSD and mescaline.

There’s No Place Like Home (for Ketamine?): There are a few companies that have seized upon the pandemic-induced boom in telemedicine as an excuse for at-home ketamine ‘therapy’, neglecting the attention to set and setting that is intrinsic to psychedelic therapies. Mindbloom has generated considerable media coverage–some quite critical–of their at-home sublingual ketamine program. Sessions are conducted without an in-person guide: “we’ll be there in spirit, and in video.” While sublingual ketamine is less bioavailable than IV, this promise is not reassuring. Home-delivering a highly psychoactive drug without any, even amateurish, in-person accompaniment/supervision–what could go wrong? Innerwell just raised $3 million to fund its at-home ketamine protocol, which claims to emphasize a psychotherapy component.

Nue Life Health raised $23 million in a Series A with which to fund their at-home ketamine therapy program, which include a trendy digital therapy-by-app component. It also relies on sublingual ketamine that is delivered to the patient’s home, the patient expected to provide their own ‘sitter’ (no training or experience required). They have now partnered with Field Trip Health, using FT’s ketamine protocol, which might fortunately include upgrading the monitoring/support element.

Pasithea Therapeutics proposes ketamine treatments in patients’ homes, administered by anesthesiologists. At least this model includes a professional component, albeit generally lacking psychiatric training, but such anesthesiology ‘house calls’ would be a costly gimmick.

Each of these companies feature psychiatrists as founders, though their actual level of involvement is ambiguous. In each case, they should know better. 

From NP Spring Issue 2022

Excerpt from Stroke Review: Quelling Excitotoxicity

During the 1990’s, stemming the excitotoxic tide was considered the wave of the future for stroke treatment, based on the hope that the impact of glutamate overrelease could be ameliorated. This search ventured into a molecular minefield: Merck’s MK-801 was a competitive NMDA blocker which remains the imperfect gold standard against which candidates are preclinically tested. Unfortunately, in addition to its ability to reduce infarct size, MK801 caused vacuoles in the brain. The parade of failures continued, killing programs from Bristol-Myers Squibb, Elan,Paion, Merck, Cambridge NeuroScience, Janssen, Astra, Pfizer, Hoechst, Novartis, and NPS.  AMPA, glycine and polyamine site blockers were considered as  other options for reducing glutamatergic activation, but compounds from NeuroSearch, CoCensys and GSK all eventually failed. 

Magnesium infusion (which has effects at the NMDA receptor) had been associated with decreased mortality in a pilot stroke study, and NINDS finally ran a 1700 pt PhIII trial, with paramedics administering magnesium sulfate in the field to maximize the time advantage, followed by an inpatient magnesium infusion. Ironically titled FAST-MAG, it was exceptionally slow to enroll, and when it finished eight years later, it came up completely empty.  

NoNO: One of the very few neuroprotective, clinical-stage drug NCE candidates left standing for ischemic stroke after the long marathon of attrition is NoNO’s nerinetide. Nerinetide is an IV-administered peptide that blocks PSD-95, co-localized with NMDA receptors, from activating downstream neurotoxic pathways (e.g. nitric oxide) otherwise triggered by NMDA receptor hyperactivation. A Phase II was done in patients undergoing repair of subarachnoid brain aneurysms, with an IV infusion given at the end of the procedure. The trial was completed in mid-2011, having enrolled 185 patients: No effect was seen on the volume of lesions, or on either the Rankin or NIHSS, but an impact on the number of lesions was reported. NoNO was able to find additional funding, and after one false start, initiated a Phase III trial aimed at enrolling 1120 AIS patients, with nerinetide administered via infusion. That trial showed nerinetide missed its primary endpoint, but patients who did not first receive tPA showed a 40% reduction in mortality. Further work indicated that tPA and nerinetide have a negative chemical interaction, tPA deactivating nerinetide. NoNO then initiated a 1020pt Phase III where nerinetide would be given first, by EMTs, well before tPA  can be cleared for use by CT scan. Results are cited as being expected during 3Q:22. While this process still requires the neuroprotectant to achieve access to infarcted tissue, and decades of disappointment have left stroke researchers rather hope-deficient, there is some quiet excitement about this nerinetide trial, and the possibility that neuroprotection may finally be within reach.

NoNO has announced that they have developed protease-resistant next-generation PSD-95 antagonists that can ‘coexist’ with tPA/alteplase, opening up the full gamut of stroke patients to treatment and improving access to the penumbra.

Avilex Pharma is a University of Copenhagen spinout also targeting PSD-95, in the service of reducing excitotoxicity and oxidative stress. AVLX-144 is a peptide that is reportedly 1000X more potent than nerinetide, more effective at reducing infarct sizes in mouse models, and with better BBB penetrance. Last December, Simcere partnered AVLX-144 for China, making an undisclosed upfront payment which,  along with undisclosed milestones, could total up to US$175 million. This funding should allow Avilex to finally start PhII testing for AVLX-144.

Selective NR2B subtype inhibitors developed at Emory were licensed to the startup NeurOp, animal data showing that infusing the prototype compound prior to arterial occlusion reduced infarct volume. NeurOp developed NR2B antagonists designed to be active only in the acidified environment found post-stroke. NP10679 will first be directed towards subarachnoid hemorrhage, and following the completion of PhI testing, NeurOp expects to enter PhII in 2023.

From NP Winter Issue 2022.

This image brought to mind NP’s first assessment of the full PhIIb dataset for aducanumab,  published in NP Sept/Oct 2015. Or to put it another way, seven years and almost $12 billion ago. It offers a reminder of the selective blindness that led Biogen to pursue the biggest strategic blunder ever made in pharma drug development. All of this was avoidable.

September 2015  

<<Aducanumab: As was disclosed at AAIC, 26 patients in total completed all cognitive test sequences in the long-awaited 6mg/12 month group. That is not a cohort size about which much is generally said when it comes to Alzheimer’s. Anomalies in the readout could reflect some outlier patient(s) whose impact would be greatly magnified by the small n. But when Biogen presented the results, they claimed that they fell in line with the preliminary data from last March, which is not completely true. The rate of decline on the CDR-SB did indeed place the 6mg group between the 3mg and 10mg groups, but it was much closer to the 3mg group. The neat dose-response relationship that had initially surfaced in March vaporized: The MMSE score decline for the 6mg group was almost identical to the very limited effect seen from 1mg, while the 3mg and 10mg groups clustered together in an oasis of statistical significance. The impact on amyloid plaque was linear, but since that did not consistently line up with functional effect, this raises more questions than it answers. Finally, the incidence of vasogenic edema in the 6mg group (37%) was nearly the same as in the 10mg group (41%), far above that seen with 3mg (6%). So the hope that the 6mg dose might ‘walk the tightrope’ and somehow provide 10mg dosing efficacy along with 3mg dose adverse effects was not fulfilled, or at least, not in this trial. While Biogen tried to reassure observers that the vasogenic edema findings were not particularly problematic (“typically resolved within 4-12 weeks”), the fact is that while 78% were “mild to moderate”, this means 22% were more severe. In a trial that enrolls 166 patients and makes brain scans easily available, that is manageable. In a general Alzheimer’s population, perhaps not. For example, if 100,000 patients were to receive aducanumab at the 6mg dose, and if the incidence rate in this trial is predictive, 37,000 could develop vasogenic edema, with 7500 of those cases being severe.

That becomes a clinical monitoring and management challenge that could outweigh what looks like a modest-at-best treatment effect: Even the most seemingly efficacious dose (10mg) achieved just a 2.25 point difference on the MMSE decline rate at 12 months, on a test where three points is the minimum considered to be clinically meaningful. On the CDR-SB, where mild Alzheimer’s patients decline 1.4 points annually, the 10mg dose approached that level with a 1.24 point effect, the 6mg dose had just a .76 point impact, close to the ‘six-month’s worth’ noted for the MMSE. Again, these are tiny dose cohorts, and may not mean anything, but the additional data only beclouded the issue for aducanumab.

Even though the consensus of AD experts NIR consulted with was that aducanumab has made a more convincing case for a signal than has solanezumab; because of the added concern about vasogenic edema, the aducanumab headline reads like this: Aducanumab May Do Something, But Not Much–It Might be Better Than Nothing, But Possibly Not.>>

And that’s where the story continues to stand almost seven years later. Such a waste.

(from the Winter Issue CNS Sector Review)


1) Schizophrenia: The pharmacotherapy of schizophrenia has been essentially static for at least two decades, with all due respect to the minor changes around the tolerability edges provided by more recently introduced drugs. Core deficits involving cognitive sharpness and motivation, the oft-cited cognitive and negative symptoms, have never been consistently and safely (in reference to clozapine) impacted. That appears to be changing: Sunovion will have PhIII results in 2022 from ulotaront/SEP-363856, a 5HT-1a/TAAR1 activator; Karuna anticipates PhIII results for its muscarinic agonist KarXT in 2022. There are other drugs in earlier stages of development in schizophrenia (Cerevel, Boehringer Ingelheim, Merck, Neurocrine Biosciences, Biogen) that are worth tracking, but the two frontrunners will offer important new options for the treatment of a wider spectrum of schizophreniform symptoms, translating into tangible gains in real-world functioning for these patients.    

2) A Direction for Compass: As we noted in our 11/9 Neurogram+, and in this issue’s Psychedelics Update section (p.31), Compass’ landmark, 233pt PhIIb trial of psilocybin in Treatment Resistant Depression (TRD) was  a success, albeit grossly underappreciated. The therapeutic dose was established (25mg), which produced rapid (2 day) and durable (12 week) improvement on the MADRS. Expectations had been fueled for a panacea, an expectation fueled by euphoric anecdotes in the popular press, so there was disappointment that depressive symptoms remitted in just one out of every four patients in the high-dose group. In this chronically depressed population, where depression has become embedded in a patient’s engrained concept of personal identity, this is impressive enough. It shows that psychedelics have a role to play in the treatment of some psychiatric disorders, but will not offer radical transformation to all comers. Had the trial failed, it might have turned off the waterfall of cash infusions that have populated a wide swathe of relatively newco’s; this is a dose of combined hope and reality that may temper and focus that investment more pragmatically.  The longterm viability of psilocybin therapy was further enhanced by Compass’ later report that combining psilocybin with ongoing SSRI therapy did not appear to diminish its therapeutic impact or tolerability. With Compass’ share price down over 50% during 2021, one can only imagine what would have happened if they’d had bad news.

3) Fiscal Flow: 2021 was never going to match the record set in 2020 for institutional investment and partnerships with small and midsize CNS companies, but it ended up a respectable historical third, behind 2020 and 2018. Disease-modifiers for neurodegeneration came in first, Psychiatry was a strong second, consistent with its renaissance as an investment focus.

2021 saw a decreased flow of IPOs, with Acumen‘s $160 million, Eliem‘s $92 million, and Cognition Therapeutics’ $52.5 million the stand-outs, followed by a bevy of micro-IPOs, as was noted above. But the funding flow was steady, particularly for the new wave of portfolio companies looking to emulate the Bridge Bio model (before Bridge itself melted down after a clinical failure). Neumora and Atai were first and fourth, and had Neurvati disclosed its Blackstone funding total, it would have been near the top as well.
There is more information about institutional investment and funding activity on p.7-8 and 13.

3) Biogen exercised its option on TMS-007, a novel thrombolytic that in PhII, demonstrated a window of 12 hours post-stroke for utilization, compared with 3-4 hours for tPA. The latter is generally insufficient to permit imaging to rule out hemorrhagic stroke, only 3-5% of stroke patients receive tPA. Add in the forthcoming results from NoNo‘s second PhIII trial of their stroke neuroprotectant, nerinetide, and one can well imagine a long-awaited transformation of the neuropharm standard of care for ischemic stroke–of which there almost 800,000 per year in the US alone.

4) MDMA in PTSD: The countercultural non-profit group MAPS pulled off a PhIII with results that would be the envy of any Big Pharma running a trial in Psychiatry: A treatment effect of .91 is a magnitude generally only encountered in some psychostimulant trials in ADHD. The second PhIII was originally projected to finish this year, now the timeframe has shifted to the end of 2022.   

5) Emalex Biosciences: The time between trial completion and readout had us concerned, but the results were quite positive: A 153pt PhIIb trial of ecopipam (D1 antagonist) in pediatric Tourette’s–a low-profile but very undertreated therapeutic area–was very successful.

6) Patience pays off: In January 2015, Neuropore partnered its preclinical alpha-synuclein anti-aggregation compound NPT200-11 with UCB Pharma. A few months later, they went into PhI, which finished in early 2016. UCB then took NPT200-11/UCB5099 inhouse for extensive vetting, not starting PhII in Parkinson’s until almost five years later, in late 2020. A year later, Novartis has now partnered with UCB on UCB0599 (and an earlier-stage alpha-synuclein mAb), paying $150 million upfront to UCB. More than once, NIR wondered if the lengthy delay in clinical progression augured ill for UCB0599, it turns out that it did not.


(from the November/December Review of Parkinson’s)

Gene Therapy

Gene therapy per se has not been particularly relevant to PD as a whole, given the lack of a highly contributory single gene target. It is, in theory, applicable to select subtypes, for example the GBA gene mutation subgroups discussed earlier, and perhaps could be turned to boosting the overall level of GCase in idiopathic PD, as is the case for Prevail Therapeutics, though such programs begin with genetic-subtypes like PD-GBA, as is discussed in that section (see p.25).   

Gene therapy has been tested in a relatively general category of sporadic PD, often in the service of either delivering neurotrophic factors, or boosting dopamine levels:

Upregulating neurotrophic factor expression was the goal of Ceregene’s program. CERE-120 involved the delivery of neurturin-expressing genes via AAV. A 58pt Phase IIb’s results were negative on the primary endpoint (off-time), but were positive on several other endpoints. Histological assessments indicated that, damaged striatal projections did not adequately transport neurturin from the putamen injection areas to the substantia nigra. Ceregene then did another Phase IIb, adding 1-2 injection sites in each substantia nigra, in order to address striatal tracts from both cell bodies and terminals. The data did not show any significant separation from placebo, both the CERE-120 and sham surgery groups showed improvement on the UPDRS  ‘off’  time scale. Ceregene was acquired for almost nothing by Sangamo Biosciences, which had no interest in their clinical programs.

Bayer‘s subsidiary AskBio is in PhIb using an AAV to deliver the gene for GDNF to the putamen. Ten patients had been enrolled as of this past June.

Brain Neurotherapy Bio is sponsoring a 12 pt study of AAV2 delivered GDNF gene therapy, a study that began in mid-2020, and will have topline results in 2023.

The other subtheme for gene therapy in sporadic Parkinson’s was the facilitation of dopamine-expression: Voyager Therapeutics developed VY-AADC, an AAV2-delivered product for the gene encoding AADC, which facilitates the conversion of levodopa into dopamine. Voyager believed they could achieve 5+ years of payload delivery with this technology, and that stabilizing dopamine availability could be disease-modifying, a theory yet to be proven. After three years of PhIb testing, Voyager and their partner-at-the-time Neurocrine Biosciences (Sanofi had previously exited), announced that 14 of the 15 patients treated had shown an overall improvement, average OFF time reduced by 1.91 hours, average ON time increased by 2.23 hours daily. However, the trial, already disrupted by Covid-19, was then halted in its tracks by the FDA: They placed a clinical hold on the program due to MRI abnormalities in some patients. Soon after, Neurocrine exited from the Parkinson’s portion of the partnership, and Voyager announced a couple months later that they would not advance the program on their own, in the face of FDA requirements that were going to be difficult and expensive to meet. Voyager stated that they expected “to turn the future development and commercialization of VY-AADC over to a partner once the potential path forward for the program is determined.” The prospect of finding a partner eager to take on a gene therapy program that is fundamentally symptom-reducing at its core, with a safety signal that could be difficult to resolve, is somewhere between zero and dismal. Voyager has removed VY-AADC from its published pipeline and has moved on to developing a new generation of capsids, partnered with Pfizer. VY-AADC was an expensive experiment that did not pan out.

In the same dopamine-augmentation vein, Oxford Biomedica developed ‘ProSavin’, a lentiviral vector delivering three genes encoding enzymes for dopamine synthesis. In a monkey model, the monkeys showed durable reversal of their motor deficits, going out 27 months without loss of efficacy. In Phase I/II, using four dose levels, the 24 month data showed low-dose patients with a mean UPDRS improvement of 20%, the highest being 30%. In the highest dose group, Oxford reported a mean improvement of 30% on the UPDRS, with one patient showing a 41% improvement. Oxford decided to instead focus on OXB-102, which in preclinical testing, appeared to be five times more potent than ProSavin. Axovant Gene Therapies (later renamed Sio Gene Therapies) partnered OXB-102 for $30 million upfront, and began a multi-dose cohort sequence of PhI/II testing. In 2019, Axovant announced that first cohort showed a UPDRS average’ improvement of 17 points, a mean improvement of 29%. At the end of 2020, the second dose cohort yielded ‘two evaluable patients’ for whom the ‘mean improvement was 21 points, or 40%, though high variability in individual patient responses has already been a hallmark of this program. Dosing apparently stopped due to a manufacturing delay at Oxford Biomedica, they predict resumption of the trial in 2022.

More than a decade ago, Neurologix developed an AAV2 delivered PD therapy that provided the GAD gene expressing the precursor to GABA. Delivered to the subthalamic nucleus, it was intended to modulate hyperactivation in that region. Clinical results were ambiguous, and the company went bankrupt. A Feinstein Institute group went back and assessed neural activation patterns in the 15 GAD patients compared with the 21 who received sham surgery. They reported that AAV2-GAD patients showed evidence of an alternate network being activated, one that linked the subthalamic nucleus to motor regions, which was in turn associated with improvement on the UPDRS. Those changes, and the motor function improvement, were not seen in the sham surgery group. This work has been picked up by MeiraGTx Holdings, which cites their program as being in PhII, clearly referring to the old Neurologix study. For their part, MeiraGTx projected filing a new IND for AAV-GA in 3Q:21, which did not happen; they are focusing most of their corporate energy on a retinitis pigmentosa program.

Biogen and Sangamo are partnered on ST-502, a preclinical ZFP designed to suppress the SNCA gene.

Matthew Disney’s group at Scripps Florida developed a small molecule that targets the mRNA for SNCA, reducing alpha-synuclein production. In an in vitro model, the molecule also was protective against SNCA fibrils, thus its impact was not just on production.

Atalanta has partnered its U.Mass-sourced siRNA technology, which links multiple modified siRNA molecules, with Roche/Genentech for Parkinson’s (and Alzheimer’s). They believe that these ‘branched siRNAs’ promote long-lasting gene downregulation in deeper portions of the brain parenchyma.

Alnylam has used its RNAi technology in PD models, and reported that they were able to lower alpha-synuclein levels in a mouse model of PD, using the RNAi product Mayo852m. But PD is not cited on their pipeline.

A University of Pittsburgh group used an AAV-delivered RNAi against alpha-synuclein mRNA in a rodent model. At 12 months post-innoculation, alpha-synuclein mRNA was reduced in the substantia nigra by 90%. The knockdown did not produce any evidence of neurodegeneration or functional deficits, suggesting that alpha-synuclein knockdown does not interfere with necessary biological functions.

Micro-RNAs have been postulated to be an access point for disease-modification, but other than ApicBio‘s SOD1 program, in PhI/II, this is early-stage.


(from the March/April Review of Psychedelic Therapeutics)

Other Considerations (p.30-32)

1) REMS and Cost: There is good reason to expect that clinical efficacy will be demonstrated by some of these psychedelic therapy programs, since MAPS obtained an impressive treatment effect with MDMA in its first PTSD PhIII. That does not guarantee success for Compass Pathways’ PhIIb for psilocybin in depression, but there are reasons for optimism. If there is success for that trial as well, and both of these pioneer programs makes it successfully through PhIII and on to NDA filing, there are issues that will loom large at that intersection of the regulatory and the commercial.

MDMA and psilocybin both have histories as drugs of abuse. The safety record for psilocybin is near-pristine, more so than for MDMA, and the latter’s association with euphoria and ‘raves’ are sure to be of concern to the FDA and DEA in the US, and the corollary regulatory bodies in the EU and Japan. But given that the FDA has deemed both a ‘breakthrough therapy’, for disorders that are undertreated (PTSD) or are treatment-refractory (TRD), the momentum would seem to be on the side of approval. As a precedent, marijuana has had greatly broadened acceptance as both a therapeutic and recreational agent in the US. Oregon is the first state to give governmental cover to the therapeutic use of psilocybin, as has Canada. 

It is not as if Pharma has uniformly shied away from developing pharmaceutical products that are at risk of abuse–opioid analgesics and psychostimulants have been highly controlled but commercially successful. However, the opioid epidemic is a cautionary note for what can go wrong with abuse-vulnerable products. The reality is that psychedelics are far different from those classes, they are not prone to physical or psychological dependence. But their overblown reputation precedes them, and will provoke some anxiety in the pharma industry and for regulators. 

When approval comes, there will be concerns regarding drug diversion and misuse, so we expect extraordinarily stringent REMS requirements to be in place. This not just requiring a centralized pharmaceutical dispensary, but in terms of the treatment packaging that has been such a salient part of the clinical development process for both. We would expect that the REMS requirements will include hewing to the protocols with which the drugs were validated, and that is a potential problem: How does one turn MDMA or psilocybin into a viable product when the protocols are so costly?  For example, the MAPS PhIII protocol involves three drug administration sessions, each (thus far) requiring an overnight stay, plus preparatory and integrative therapy sessions that produce a total of 42 hours of therapist time for each patient, not including psychiatrist/medical or assistant hours, or the cost of the space and the drug itself. Even though MAPS is working on eliminating the overnight stay requirements, one can easily imagine a treatment course cost of well over $20,000 for each PTSD patient. Military-PTSD cases might be covered by Department of Defense or VA funding, but otherwise, outside of addiction treatment, we expect strenuous pushback by commercial insurors on psychedelic therapy packages. Some micro-companies naively predict that insurors will eagerly embrace psychedelic therapies because of their superior, cost-effective impact, they have obviously never dealt with insuror gatekeepers.

Compass Pathways has designed a comparatively less onerous treatment protocol, there is just one dosing session, and even with preparatory and integrative therapy hours, the total therapist time is around 15 hours, plus assistant and psychiatric/medical/space costs. But even if the cost is under half of the MAPS PTSD protocol, that is going to be resisted by payors concerned about the size of the potential treatment population. Unlike MAPS, Compass has an investor base that will expect healthy revenue growth.

2) Democratization: The question is whether psychedelic therapies are destined to be solely a platinum priced premium treatment tier for the well-off. The development of ‘psychedelic spas’ by companies like Field Trip, with upscale furnishings and aesthetics, will have appeal for a narrow slice of the PTSD and depression patient populations, but this leaves out the majority. There is already some discussion about how to democratize psychedelic therapy access so that it does not become yet another context for growing inequality. For example, ATAI Life Sciences has its Introspect digital therapy subsidiary developing apps that would provide adjunctive therapy support, and is considering the use of Virtual Reality to maximize the subjective aesthetics of the treatment environment, creating Virtual psychedelic spas, as it were. This would not eliminate treatment inequality, there will still be a difference between a highly trained therapist and an app, but it could provide a pragmatic complement. 

3) Parsing Patients: There has been a strong self-selection bias in the patient populations that have enrolled in these trials. Many of them had a positive attribution assigned to ‘psychedelic therapy’, some have already had experience with psychedelics via underground sources. It will be interesting to see whether observed efficacy diminishes as the net is cast in a larger pool of prospective patients who may not have such an engrained expectancy. But beyond predispositions to belief, and besides the economic factors that will inevitably be relevant to treatment choice, it may be that potential treatment-responders could be identified as such prior to making a choice that may be expensive and time-consuming. For example, there is more than one isoform of the 5HT-2A receptor, it may be wondered whether those isoforms may have differential responsivity to different drugs. Entheon acquired HaluGen for its self-administered swab test, which claim to identify the “20% of people” with a specific 5HT-2A variant they believe to be overly reactive to serotonergic psychedelics, and the presence of a CYP2B6 genetic variant that slows  ketamine metabolism, hence increasing its bioavailability. Entheon says that the test, whose degree of human validation is unclear, is being prepared for commercial launch. 

4) Clinical Complexities: The treatment protocols utilized by MAPS, Compass, and Usona are the most complicated psychiatric trial protocols NIR has seen. But there are other clinical trial challenges not as immediately apparent. First of all, it is near-impossible to devise a classic placebo control, this is one of the rare instances where patients know within an hour or two whether or not they received the active drug. There are occasional exceptions, there are patients who have had a subperceptual experience on a full dose of a drug, believed they had received a placebo, and yet eventually reported having had a positive experience–this is experientially complicated and not predictable. Sponsors have generally turned to a low-dose version of the compound being tested as the control measure, the alternative is to use an alternative, nonpsychedelic but ‘palpable’ control, such as niacin or, as was done in some ketamine trials, midazolam, a benzodiazepine. Secondly, since patients generally know if they received placebo, there is the challenge of ensuring that they comply with followup visits weeks or months later, when they may indeed feel shortchanged by the trial process. That is one of the situations where the skill of the therapist in establishing an alliance makes the difference between a full and incomplete data record.

5) Safety: With the exception of ibogaine, the broad category of psychedelics is, physiologically, a relatively safe one. As was noted earlier, the classic psychedelics can induce hypertensive episodes, and how they interact with other serotonergic drugs is an issue very pertinent to drug ‘washout’ before trials and in eventual clinical use. MDMA is known to have cardiac safety issues. But dependency and concerns regarding potentially fatal overdoses are relatively low-profile. Certainly there can be acute panic and confusional states, and the classic psychedelics are generally thought risky for anyone with prodromal schizophrenia, based on concerns that a psychotic decompensation can be hastened. There are a few researchers who think that MDMA could be useful in schizophrenia, but most do not consider this worth the risk.

The field will have to hew to high training standards and careful patient screening, psychedelic therapy and training conferences are popping up at a dizzying pace, which means that quality control is going to become more challenging. It only takes one highly publicized tragedy to skew the societal conversation: Fifty years ago, American TV personality Art Linkletter claimed that his daughter’s suicide was caused by her ingestion of LSD, and while this tragic event did not create the backlash that led to the outlawing of all psychedelic research in the US, it helped catalyze it. NIR has detected a certain degree of idealistic naiveté re-emerging during this cycle of psychedelics research, which belies the potency of reactionary political dynamics manifested in ways that we have all witnessed.

(from the January/February CNS Sector Overview)


1) Biogen: Aducanumab must be parsed into a category of its own (see p. 10-11), and the fact that Biogen accounted for 76% of all partnership upfronts in CNS during 2020 is a bit unnerving. But paying $1.53 billion upfront to partner Sage‘s zuranolone program in depression is mind-boggling for several reasons. First, it concretizes Biogen’s willingness to invest in Psychiatry, which we had wondered about given the low profile of their only existing Psych program, the Ampakine trial in CIAS. It also demonstrates (again) that Biogen’s dedication to neurotherapeutics and its enormous resources allow it to make very substantial investments in licensing (as it also showed in the Denali deal). Third, they undoubtedly did painstaking due diligence about the Sage program, regarding which NIR had doubts, and signing on to this scale affirms that there is value to be unlocked with the zuranolone/interval dosing paradigm. Finally, it is a reminder that even if aducanumab does not end up approved and commercialized, Biogen has numerous other programs of potential high value. One way or the other, there will be life after aducanumab.  

2) Fiscal Flow: 2020 was the best year on record for institutional investment in small and midsize CNS companies. Which reflects a remarkable degree of focus given the chaos so rampant elsewhere. There was also refreshing diversity in the treatment areas gathering attention: While neurodegeneration came in first, Psychiatry was a strong second. Companies with their own products entering the market were the biggest beneficiaries; SK Biopharma, Intra-Cellular, Biohaven, and Zogenix accounted for six of the ten largest rounds. Partnering upfronts also reached a new record level, $3.95 billion, eclipsing 2018’s $2.7 billion by a remarkable margin, thanks to Biogen‘s willingness to spend on the grand scale (almost $3 billion in upfronts).There is more information about both institutional investment and funding activity on p.17.

The first half of 2020 saw a dearth of IPOs, with Passage Bio the exception (we do not attribute much importance to the $12 million Annovis ‘IPO.’) But 2H, particularly July and August, saw a constant stream of IPO activity, with Annexon, Praxis Precision Medicine, Athira Pharma, Taysha Gene Therapies, and Compass Pathways going public via IPO. Cerevel took the SPAC route to the same destination, Yumanity utilized a reverse merger.

3) Acadia Pharmaceuticals and Neurocrine Biosciences have both broadened their portfolios in a tangible embrace of a wider role in neuroscience, fueled by, but not limited to, the success of their self-marketed lead assets, Nuplazid and Ingrezza. We have often questioned the wisdom of small companies aspiring to be fully vertical, developing commercial capabilities rather than partnering with companies already established in that domain. But Acadia and Neurocrine are case studies of small companies that have done so successfully, with the fruits of such labor reinvested in pipeline expansion. It is where Intra-Cellular hopes to be in a couple of years, once Caplyta establishes itself.  

4) Psychedelics: After five decades of underground semi-dormancy, the re-emergence of psychedelic substances as potential therapeutics in Psychiatry and Pain blasted off this past year, with investors looking for a way into an area that had been completely off-radar for fifty years. Compass Pathways was the first such company to go public in the US, raising a total of $246.6 million in 2020. Atai Life Sciences, which owns 29% of Compass, raised $125 million in its own Series C. Canada’s Mind Medicine went public in Toronto, raising a total of US$44 million this year.  MAPS (the Multidisciplinary Association for Psychedelic Studies) raised over $100 million thus far to run a Phase III for MDMA in PTSD, though the lack of detail in the trial report left most questions still to be answered. There is also a flock of micro-companies looking to participate in the hottest new subsection of the neuro-world; some are competent, others are dubiously conceptualized and constituted. The rapid infiltration of this formerly discredited work into mainstream thinking is epitomized by the fact that the Johns Hopkins study results reported on p.2 were published in the stalwart of mainstream medicine, the Journal of the American Medical Association. An upcoming issue of NeuroPerspective will cover the area of Psychedelic Therapies in detail.

5) Sage Therapeutics took a gamble on an innovative interval dosing paradigm in depression which became all-the-higher-profile after Covid-19 demolished their nascent Zulresso franchise in Post-Partum Depression. And despite all the naysaying, including ours; their extension data, and Biogen‘s partnership, confirm that the gamble was well-placed, their ROI is already off-the-charts.

6) Denali published details of their proprietary approach to using the transferrin receptor to gain CNS entry for large molecule payloads. They had been very close-mouthed up to this point, and had publicly emphasized their small-molecule programs. But there is now a timeline for the clinical validation of their technology for delivering antibodies, enzymes, and ASOs.

7) Lilly acquired Prevail Therapeutics and Disarm Therapeutics, while partnering with Evox, in a 2020 reconfiguration that, in aggregate, advances Lilly’s CNS portfolio a decade, from a somewhat antiquated set of 2015-era priorities to programs that have a shot at being cutting-edge in 2023. 

8) Cortexyme: It was just an interim analysis, designed to establish whether there was either a nearly 100% chance of success, or of abject failure, based on the first 300 patients. But the fact Cortexyme’s atuzaginstat will continue to its planned end, without a recommendation to increase the sample size beyond 643 patients, is a positive for this dark horse Alzheimer’s candidate, pursing a distinctly minority-view mechanistic hypothesis. It was not at all realistic to hope for ‘overwhelming efficacy’ after just 300 enrollees, and the absence of clear futility (underperforming placebo) does not guarantee anything. But the December unblinding of the full dataset is near the top of ‘must-see’ data events for 2021.

Mixed Bag

1)Biogen Becomes Too Big to Fail: This is the flip side of the dominant role Biogen has assumed in the neuro sector: Providing 76% of the partnership upfront payments for a year is unhealthy, no single company should be in such a key position in a critical pharmaceutical industry domain. This is not a criticism of Biogen by any means, they have ‘walked the walk’ by making such large-scale investments, but it does render the sector uncomfortably vulnerable to disruptions in Biogen-world, perturbations that have already begun (threats to Tecfidera, Spinraza) and will resonate, if not detonate, should aducanumab fall as short in its regulatory review as it did in its clinical testing.  

2) Neurocrine/Takeda Alliance: As was mentioned on p.4, this deal marks a bold move by Neurocrine to widen and deepen its developmental reach in Psychiatry, which is indubitably a good thing. But it is also ‘mixed’, because it reflects Takeda’s withdrawal from the small-molecule CNS space, which is a loss. Takeda had been looking to off-load these programs for at least a year, and while still maintaining some degree of involvement, (like with the Ovid alliance), they have shifted their emphasis elsewhere. 

3) Six CGRP antagonists: In under three years, the CGRP antagonist platform has gone from zero to sixapproved therapies that constitute the first major post-triptan wave in migraine. There are now four approved (Teva, Lilly, Novartis/Amgen, Lundbeck/Alder) CGRP-antagonist injectibles for prevention, and two oral CGRP antagonists (AbbVie and Biohaven) approved for acute migraine  treatment. AbbVie’s atogepant and Biohaven’s rimegepant (label-expansion) are both on their way to approval as orally-bioavailable prophylaxis, bringing the total to seven different drugs. Given the patient preference for oral options in almost every circumstance, AbbVie and Biohaven’s prophylactic options will pose imposing threats to the injectibles that narrowly preceded them. As we have noted over time, none of these are panaceas, but all have demonstrated efficacy. The great news is that these are valuable additions to the clinical armamentarium, the bad news is that they all arrived in such a compressed timeframe, competing for the substantial migraine market not satisfied with the triptan standards. We cannot recall a neurotherapeutic area that ever saw so many quality programs come to fruition in such a short period of time. The longterm value of some, if not most, of these franchises will be a disappointment to the companies who got them there. 

4) NoNO: Their PSD95 inhibitor nerinetide failed in PhIII,  the drug missed its primary endpoint. However, in the 446 patients (40% of 1105 patients in total) in the study who did not first receive tPA, the difference in the percentage of patients achieving full independence was 59.4%, compared with 49.8%, and mean infarct size was 22% smaller. More impressively, mortality was reduced by 40%, which reached statistical significance. It appears  tPA and nerinetide interact deleteriously, and NoNo is preparing a Phase III where nerinetide is given first, by EMTs, since tPA cannot be used until hemorrhagic stroke has been ruled out by CT scan. That trial is expected to read out this year, a promising candidate in a therapeutic area long bereft of pharmacological hope.   


1) Worst aducanumab faux pas. It’s hard to choose from such a lengthy roster of candidates; Aducanumab’s marathon journey is discussed elsewhere (see p.10-11). But here are two quotes from the ADCOM materials of 11/6/20 that should never have been said, and should never be said again: 

a) Combined FDA and Biogen Briefing Information for the November 6, 2020 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee”

b) “Does Study 302, viewed independently and without regard for Study 301, provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?”  

Since when do sponsors co-write presentation summaries with the Agency reviewing the subject of those summaries? Why the FDA bedded down so publicly with Biogen is a mystery all its own, but whatever the answer, it isn’t good enough to justify such a blatant conflict of interest. And only such conflicted  judgment could have yielded Point  B, the first question presented to the ADCOM, which instructed them to review data out of context, without regard to contradictory input, despite the necessity of considering ‘the totality’ of the data.  

2) Covid-19 and Zulresso: When it comes to undeserved corporate collateral damage, it is hard to top the toll taken by the coronavirus on Sage Therapeutics‘ erstwhile launch of Zulresso in Post-Partum Depression. They had already found the preparation of inpatient sites to meet the REMS requirements attached to this 60 hour infusion regimen to be very slow-going, but once the pandemic hit, few if any new mothers were going to be brought into a viral war zone in order to treat their PPD, no matter how severe. As a result, Sage’s launch process was cut off at the knees, leading to the layoff of 340 employees in order to maximize the runway for their cash resources. Zulresso was likely to be an interim option for severe PPD, a bridge to the eventual advent of oral zuranolone for PPD, but the dismantling of the Zulresso marketing group reflects the finality with which Covid-19 shut that window of commercial opportunity. Zuranolone is likely to be of  value in Post-Partum Depression once approved, even without the lead-in from Zulresso. There was no error on Sage’s part, they were tripped up by circumstances that could not have been predicted, or better managed. 

2) Reading the Tau Leaves: So far, not so good.  Progressive Supranuclear Palsy had been hoped to be the fast route to POC, but AbbVie and Biogen both saw their initial forays in PSP fail. Axon-Neuroscience had announced success for their active vaccine in a PhII trial, without detail. They finally reported that there was no overall difference on cognitive testing, but in a pre-specified analysis of just 43 enrollees under age 67, the Company reported that decline rates were reduced by 26-42%, and plasma neurofilament (NfL) levels and atrophy increased at a slower rate in the vaccine group. Axon-Neuroscience claims this represents a disease-modifying effect, and plans to run a Phase III trial covering 24-30 months of treatment. It is unclear what this post hoc data parsing means in light of the other failures. 

Finally, the Genentech/AC Immune PhII trial for semorinemab in Alzheimer’s was a failure, which casts considerable doubt on the hope that, lacking access to intracellular tau, mAbs could modify disease-course by intercepting tau en route as it propagates from neuron to neuron. There are other tau mAb programs which differ in epitope binding, but the  task of finding relevance in anti-tau therapeutics may eventually rest on access to intracellular tau, aspired to by Biogen/Ionis ‘ anti-tau ASO, and the Lilly/AC Immune tau ‘morphomer’ program.  

3) NIR often makes the point that statistical significance without clinical significance is useless. Arguably, the converse is true as well. BrainStorm had hoped that their mesenchymal stem cells, injected intrathecally, would generate sufficient neurotrophic impact to slow the progression of ALS–NIR has consistently questioned the utility of this nonspecific payload and targeting. The primary and secondary endpoints were definitively failed, the Company claimed a ‘clinically meaningful’ impact on a pre-specified subgroup of early-stage patients: But p-values of .288 and .198 on the two main endpoints come nowhere near any contemporary criterion for statistical validation.  

4) Proof-Reading 101: After their Alzheimer’s PhII/III, Axsome reported that the reduction on the CMAI was -15.4 points, compared with -11.5 points for placebo, a mean reduction from baseline of 25.6%, a mean reduction for placebo of 19.1%. But Axsome also claimed that AXS-05 reduced CMAI scores by a mean of 48%, compared with 38% for placebo, roughly double the change that their own figures for the CMAI indicated. They had also stated that a change of 30% or more on the CMAI was the threshold for clinical significance (notably, the 25.6% change in their CMAI scores would fall short of this), and that 73.2% of AXS-05 patients met that criterion, compared with 57.1% of the placebo group. This made no sense; if the actual mean change was 25.6%, it is highly unlikely that almost three quarters of the AXS-05 group had improvements of over 30%. At best, this qualifies as sloppy. We inquired about the discrepancies, but received no reply.