Excerpts 2021/2020/2019/2018


(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. 


(from the November/December 2020 Issue on Autism)

Autism: Enhancing Social Relatedness

The Oxytocin-Vasopressin Axis

Targeting the oxytocin-vasopressin ‘axis’ has been arguably the therapeutic strategy that comes closest to directly addressing a core behavioral component of ASD. A case can certainly be made that the disruption in interpersonal ‘drive’, skills, and tolerance is the most phenotypically distinct element of ASD; it may be the most painful for the families of these patients. 

While the oxytocin system has been most closely linked to, and targeted, in autism, vasopressin and oxytocin circuits are interwoven and complementary. Oxytocin agonism and vasopressin inhibition were anticipated to have similar downstream effects (with a possible exception, noted below). Unlike most of the treatment schemata that are operative in other domains of autistic symptomatology, there have been targets available for intervention which appear intrinsically related to this core component. Unfortunately, to this point, they have not proven fruitful, oxytocin has not been the general booster of social cognition and drive it had been hoped to be, though the very limited brain access for intranasal oxytocin, and its ephemeral half-life, means that the oxytocin hypothesis has not had a definitive test. Vasopressin-1a antagonism has been a clinical disappointment as well, and may have been more thoroughly disproven as a therapeutic option, though there it can be argued that the balovaptan patient population should have been more specifically defined, and there have been questions as to whether the Vineland (a nonspecific scale tapping a range of behaviors) may have been a suboptimal choice. 


Oxytocin, as an upregulator of affiliative drive and/or a downregulator of amygdala-based anxiety/fear responses, received a lot of popular press coverage for several years (the ‘Cuddle Hormone’), certainly there is intuitive appeal to the concept of a pharmacological intervention that might increase affiliative behaviors, spurring what might be hoped to be a self-perpetuating virtuous cycle, affording the opportunity to experience social contact as rewarding, thereby increasing the likelihood of continued social engagement. There were pilot studies indicating that oxytocin might be of benefit in autism, improving eye gaze, social awareness/emotional recognition, and interpersonal responsivity.  One imaging study indicated an increase in activity in the fusiform gyrus, wherein the recognition of human faces appears to be generated, perhaps increasing the valence of human vs. nonhuman object responsivity. Whether this means that there is a deficiency in endogenous oxytocin levels (as is indicated by a Stanford group’s work), or the provision of oxytocin serves to work around some other structural or neurochemical anomaly, has yet to be defined, or operationalized. 

The plasma half-life of oxytocin is only three minutes, but it has been believed that the duration of CNS activation considerably exceeds that, perhaps tenfold. It is possible that one only needs an initial, facilitative effect that would allow someone to enter into interaction, after which both behavioral therapy and the (hopefully and increasingly)intrinsic reward of human interaction would hopefully sustain that behavioral change. However, oxytocin, used as Pitocin in obstetric settings, has safety issues with chronic use, its effect on the vasopressin-1b receptor can lead to hyponatremia. There are also animal findings suggesting that longterm exogenous oxytocin may downregulate the production of endogenous oxytocin.

An Australian study assessed the impact of intranasal oxytocin in 31 young  (ages 3-8) children over a five week period. This double-blinded study showed a significant impact upon caregiver-rated social responsiveness. Stanford hosted a 32pt pediatric autism trial, administering intranasal oxytocin once daily for four weeks. The impact of drug vs. placebo approached but fell shy of statistical significance, but when endogenous oxytocin levels were included as a co-factor, the oxytocin-treated children showed significant improvement in social functioning (but not repetitive behaviors), especially those with the lowest endogenous levels.  

MGHhas been  running a 100pt study of intranasal oxytocin and cognitive-behavioral/social skills therapy, it was supposed to be completed at the end of 2017, but was still recruiting subjects last summer.

A Duke group completed a 290pt pediatric autism trial of intranasal oxytocin, no results have been announced. A Hamamatsu University group is running a 144pt trial of intranasal oxytocin.

A Toronto group ran a 70pt trial in adults, that trial appears to have wrapped up late last year, no results have been disclosed.

Small molecule oxytocin-receptor agonists at one time received some attention, Wyeth developed WAY267464, a first-generation prototype, but that program demised.

Carbetocin is an oxytocin analog with a longer half-life, but Kyalin Biosciences has not been able to find funding to develop it for autism.

Besides targeting oxytocin receptors, alternative tactics could involve increasing the release of endogenous oxytocin. The melanocortin-4 system, which has been heavily studied in the area of feeding/obesity, has been shown (by work at Emory University) to be a route by which oxytocin release can be increased downstream. Given its linkage to key metabolic processes, melanocortin-4 would have its own safety/tolerability issues as a target.

As was noted earlier, an indirect route to increasing oxytocinergic circuit activation in animal models where Nlrg3 has been knocked out is to inhibit MNK kinases, and there is a tool compound (ETC-168) that does that, enhancing neuronal and behavioral activity.


Two vasopressin receptor subtypes (1a and 1b) are found in circuits connecting to the limbic system, V-1a is the predominant subtype in the CNS. Vasopressin-1a receptor activation is believed to impact the valence of negative affective stimuli; vasopressin levels are elevated in animal models of depression and anxiety, and in relevant areas of the cortex and limbic region. Vasopressin-1a antagonists had originally been considered avenues to anxiolysis, but as was noted above, inhibiting the vasopressin system may have effects similar to those achieved via oxytocin activation.  

In a 223pt adult PhII that provided treatment for 12 weeks (at three dose levels), Roche‘s vasopressin-1a antagonist balovaptan/ RG7314,  no improvement was seen on a social responsivity scale, but improvements in the two higher dose groups were reported on socialization and communication. Roche then went  into a 350pt Phase III, but that trial was stopped last April following a dismal futility analysis, two pediatric studies were terminated as well.

Azevan Pharmaceuticals developed two orally-bioavailable vasopressin-1a antagonists, SRX246 and its backup, SRX251. SRX246  was cited as meeting its primary and secondary endpoints in a Phase II for Intermittent Explosive Disorder. Phase II trials in Huntington’s irritability and PTSD have been completed, with no disclosure of results, which almost certainly means failure. 

Blackthorn Therapeutics had licensed a selective vasopressin-1a  antagonist (BTRX-323511), to be aimed at autism. Blackthorn had expected to go into PhI earlier this year, but after Roche‘s balovaptan implosion, it seems improbable that they are going to proceed until they devise a more productive route to assessing efficacy.

Conversely, there have been reports of improvement from increasing vasopressin levels. In a 28 pt pediatric study of intranasal vasopressin, which was placebo-controlled, the vasopressin group increased their score on a social responsiveness scale by an average of 13 points, significantly better than the placebo group. The level of improvement was greater in children with lower baseline levels of vasopressin, or higher availability of vasopressin receptors. These constitute possible biomarkers predicting treatment response, and the researchers suggested that this might be a vasopressin-deficient subgroup of the ASD population, similar to the greater response of oxytocin-deficient children to treatment with that hormone. A Stanford group reported positive results for intranasal vasopressin in a 50pt trial, a 100pt trial will be completed in 2022. Vasopressin augmentation may now get a closer look for a segment of the ASD population.

A prominent ASD researcher suggested to NIR that glutamatergic procognitive drugs could be another route to boosting the activity of brain circuits relevant to social responsivity, which means that procognitive drug trials will have to monitor social engagement as well.

Other Targets

With ketamine having been tried in such a broad plethora of disorders, it was not surprising that it was tried in autism, with social withdrawal the primary focus. Roivant Sciences, the progenitor of Axovant, provided support for the trial, done at U. Cincinnati. 21 individuals ages 14-29 were treated with two doses of intranasal ketamine or placebo.  No benefit was observed. There is a trial ongoing that combines ketamine with dexmedetomidine, the latter under development for Alzheimer’s agitation; this is unlikely to go any better.

N-acetyl cysteine, a dietary supplement with antioxidant properties, is one of those substances whose frequent deployment in academic trials seems more a function of its availability than its actual utility. But there was a recent paper that reported N-acetyl cysteine attenuated hyperactivity and social withdrawal in mice with an autism-related gene deletion (16p 11.2 DEL), presented as evidencing its role as an ‘excitation/inhibition modulator.’ The same paper reported that the anti-migraine drug eletriptan had a similar impact on those phenotypic features, which was equally unconvincing.

The Miscellaneous and Dubious

Cell Therapy

Stem cell ‘therapy’ has been a profitable refuge for any number of programs which constitute quackery under the guise of medical practice. We are not going to go into these enterprises in any detail, they tend to rely on vaguely articulated premises  of anti-inflammatory effects. One such program utilizes autologous mesenchymal cells, those cells injected into the subarachnoid space, ostensibly migrating to the “injured area,” as if autism constitutes some type of traumatic injury. Given the evidence that autism is instead a disorder of  dysfunctional neural networks, this seemed to be, at best, ill-considered. There is less vagueness around the motivation, one such Panama-based clinic includes autism as one of the therapeutic areas for which their mesenchymal stem cells are suited: Their fees start at “$15,825 for children and $23,150 for adults.” But to their credit, they do throw in a “Hilton hotel room with breakfast, WIFI....”   

BrainStorm Therapeutics reported that in a mouse model trial, a single administration of their NurOwn (autologous mesenchymal) cells led to behavioral and cognitive improvement in those mice. But cell replacement therapy is not generally seen as an avenue to treating ASD at present, and the presence of pseudo-clinical hucksters at the fringes does not lend credence to the concept.

(from the May/June 2020 Issue)

Depression: Rebooting the System-Psychedelics

Back in 2018, we said this: “Academic groups at Johns Hopkins and the University of Helsinki are running Phase II trials exploring the use of psilocybin in major depression. The Johns Hopkins study is enrolling 24 patients, and should produce top-line data this year. Is this a high-probability candidate for use in highly refractory depression? Given the times, it is hard to say anything but no to that, but then again, there were times that the neurotherapeutic use of ketamine, and the broad utilization of medical marijuana, would have seemed equally implausible.” No domain within neurotherapeutics has been more radically transformed over the past two years than this one. Research into the therapeutic benefits offered by nontraditional psychoactive drugs, thwarted for decades, is moving forward, at a dramatic clip. There have been small studies indicating longterm antidepressant effects, lasting months, provided by one or two psilocybin sessions. Some observations have provided more questions than answers: A Louisiana State group did a trial comparing the effects of LSD, psilocybin, and ketamine in a rodent model of depression, and reported (2020) that the two psychedelic drugs provided a more durable antidepressant effect than did ketamine. But our attention was seized by their statement “our results…suggest that a subjective existential experience may not be necessary for therapeutic effects“, begging the question of what might constitute a ‘subjective existential experience’ for a rat, and how one would measure it.

Michael Pollan’s How to Change Your Mind, detailing his extensive exploration of psychedelic research, both above ground and underground, has afforded the area a bonanza of public exposure, not an unmitigated boon, since there is always the risk that this resurgence could be undermined by countervailing forces alarmed by the prospect–as happened fifty years ago. But buttressed by FDA support (and designation of psilocybin as a potential ‘breakthrough’ therapy for TRD), companies like Compass Pathways and ATAI Life Sciences have brought rigor and expertise to exploring the therapeutic potential of the unorthodox. Compass Pathways presented data from their 89pt PhI trial of COMP360/psilocybin, which demonstrated the feasibility and tolerability of systematized psilocybin sessions. A 216pt, double-blinded, dose-ranging (three dose levels) PhII trial, utilizing highly regarded academic centers in the US and EU, has been enrolling patients for the past  year, assessing MADRS impact for up to three months after a single administration.  It had been expected to be finished in early 2021, that timeframe has been disrupted by the Covid-19 pandemic. One additional challenge: while the lowest dose used in the Compass trial is considered to be a relative ‘placebo’, with very attenuated effects, there is no viable way to provide a truly blinded placebo experience.

Psilocybin, as do most psychedelic therapies (the exceptions including MDMA), works primarily through 5HT-2a receptor agonism, though psilocybin has been reported to also have 5HT-1a agonist binding, and LSD has some dopamine receptor binding. This class of drugs appear to produce a profound, albeit time-limited, reconfiguration of cognitive biases/beliefs regarding an individual’s sense of self and relationships with others. Accordingly, controlled trials of psilocybin involve some preparatory sessions, a drug session that involves accompaniment by a specialty-trained psychologist or therapist, and is followed by at least one ‘debriefing’ session which is aimed not only at outcome assessment, but aiding and abetting the ‘digestion’ of the experience. This class of drugs is also being studied in a range of other disorders (e.g. PTSD, substance abuse, headaches), but the complexity of the administration regimen, particularly the 6-8 hours required for the core drug-administration (and the as-yet undefined possible benefit from eventual readministration) likely would put this out of reach for  the majority of the TRD population–this would be the premium-class intervention for the well-heeled. 

To address this market accessibility issue, there is a search for drugs that might provide some of the same cognitive ‘reset’ that appears to be afforded by psilocybin, but in a more time-efficient framework. Atai Life Sciences, which has a major stake in Compass Pathways, (and acquired majority ownership of Perception Neuroscience, for R-ketamine) is sponsoring a search for other, lesser known psychedelic molecules, some of which have been produced by underground chemists far out of the mainstream of drug research. Atai has spun out a subsidiary, Entheogenix, specifically tasked with that compound hunt, with one major focus being on compounds that might have a shorter duration of effect. They do exist: Peruvian shamans (and their California underground counterparts) have developed a cottage industry of guided ayahuasca experiences, ayahuasca being the botanic source of the psychedelic compound dimethyltriptamine/DMT. While shorter, because of the use of a concurrent MAO-inhibiting botanical to extend the duration, ayahuasca experiences can last up to six hours, which (shamanic supervision aside) would still preclude any broad applicability.

(from the March/April 2020 Issue)

Epilepsy: Dravet Syndrome

This is an epileptic encephalopathy–also known as Severe Myoclonic Epilepsy of Infancy–with a US population size of up to 15,000 cases.  It leads to pronounced developmental delays affecting cognition, motor function, and autonomic function, and is treatment-refractory. There appears to be a substantial genetic component, with 80% of Dravet patients having a loss of function in their Nav 1.1 sodium channel due to SCN1A mutations. 

Some GABAergic drugs worsen Dravet seizures, as do sodium channel blockers. Clobazam has had significant utilization in the US, while in Europe, Biocodex’s stiripentol has long been used, this drug believed to be acting via either the GABA-A alpha-3 or beta-3 subunit. US approval was finally received in 2018 for the use of Diacomit/stiripentol as an adjunct to clobazam in the treatment of Dravet.


Back in 2013, a case of Dravet Syndrome was highlighted by a CNN report on the medical use of a strain of marijuana that had high levels of cannabidiol, which galvanized attention regarding the use of cannabinoids in childhood epilepsies. Even though cannabidiol shows only weak anti-seizure activity in animal models, given a dramatic reduction in seizure activity for that child, such anecdotal human data jump-started cannabinoid utilization in Dravet and other pediatric epilepsies, with some parents moving to states where they could legally obtain CBD-preferential strains of cannabis. Seven years later, medical marijuana is legal in thirty-three states in the US, recreational marijuana is legal in eleven states, and in the pharmaceutical world, it has been GW Pharmaceuticals that has made the most of the opportunity. GW Pharma was ideally positioned to exploit its expertise with purified cannabis extracts in order to develop Epidiolex, a plant-derived liquid cannabidiol extract. GW Pharmaceuticals ran a 120pt PhIII trial of Epidiolex (20mg/kg) in Dravet Syndrome (the average age was ten, with a history of having failed four other AEDs), assessing the reduction of seizure activity from baseline over fourteen weeks. The results showed that Epidiolex to be useful, albeit far from a panacea: The Epidiolex group showed a mean seizure frequency reduction of 39%, compared with 13% for placebo. Epidiolex (which uses a sesame oil suspension) is also not side effect-free, with somnolence, diarrhea, fatigue, and vomiting all seen in 10% or more of those patients; 13% of the Epidiolex group withdrew from treatment due to side effects. Following a second successful trial, GW Pharma obtained FDA approval, and 2019 sales of Epidiolex totalled $296 million, approaching a $400 million annualized rate during 4Q. They have also received approval for the treatment of Lennox-Gastaut Syndrome and have filed for use in Tuberous Sclerosis.

The diarrhea often associated with Epidiolex’s sesame oil suspension is problematic, though GW Pharma hopes to remedy this via the development of a capsule formulation. Serina Therapeutics has developed a polymer-linked formulation of cannabidiol that they state would avoid the chronic GI side effects associated with Epidiolex’s current oil formulation; SER-228 is in early preclinical development. 

Insys Therapeutics was developing a synthetic form of cannabidiol, to be aimed first at Dravet and LGS.  However, their former CEO and other managers were convicted on federal racketeering charges related to kickbacks paid physicians to prescribe Insys’ fentanyl product, and Insys filed for bankruptcy last year.


Anecdotal reports of Dravet symptoms being impacted by fenfluramine (which acts via the release and inhibited reuptake of serotonin), the drug that first came to attention as part of the ‘fen-phen’ anti-obesity combination of the 1990s, turned into an open-label prospective study done in Belgium wherein 7 of 9 patients receiving low-dose fenfluramine showed a greater than 50% reduction in seizure rate, the other two patients showed a reduction as well. Side effects included sleepiness and appetite reduction, no valvulopathy was observed, though this was a minuscule sample. The therapeutic principle was supported by zebrafish work showing that fenfluramine had antiepileptic effects in SCN1A-mutation zebrafish.

Zogenix took on (via the acquisition of Brabant Pharma)  the development of ZX008/fenfluramine in pediatric epilepsies, first pursuing Dravet Syndrome. Since higher-dose fenfluramine use had been associated with pulmonary hypertension when used for obesity (‘fen-phen’), the FDA was stringent in their demands for echocardiogram monitoring, which led to a delay in the inception of pivotal trials. But once underway, in a prospectively-defined merged analysis of two Phase III studies of 119 child/adolescent patients, the higher dose of ZX008 produced a 63.9% placebo-adjusted mean reduction in baseline seizure frequency, and a median reduction of 72.4% in seizure frequency, compared with 17.4% median reduction for placebo. These results were numerically superior to the decrease provided by Epidiolex in Dravet, albeit not tested head-to-head. Prominent side effects were somnolence, lethargy, and fatigue, but while appetite suppression was frequently seen (unsurprising given its legacy as an anti-obesity drug), the GI side effects so frequently reported with Epidiolex were not present with ZX008. Zogenix initially received a CRL from the FDA for Fintepla/ZX008, but the NDA has been resubmitted. While the PDUFA date has just been extended to June 25, we do expect Fintepla to be approved, and it will provide robust competition to Epidiolex in Dravet Syndrome, based on both its efficacy and tolerability advantages.

Other Targets

Ovid Therapeutics made news when they partnered with Takeda on the latter’s TAK-935, a drug that addresses a novel target, inhibiting cholesterol 24-hydroxylase. The premise is that 24-hydroxylase functions as an inhibitor of 24-hydroxycholesterol, which itself functions as an endogenous positive allosteric modulator of NMDA receptors–hence it is an overly circuitous route to glutamatergic activity suppression. It had been taken through four Phase I trials, but it was not high on Takeda’s priority list, so they collaborated with Ovid, who is emphasizing rare epilepsies with the program.  An 18pt Phase I/II trial in adults with rare epilepsies (Dravet, LGS, CDKL5) showed a dose-dependent reduction in 24HC levels, very tentatively (due to the tiny cohort size) correlated with a reduction in seizure frequency: the seven patients who reached target reductions  in plasma 24HC had a mean decrease in seizure frequency (at 85 days, in the open-label extension phase) of 69%, compared with a decrease of just 3% in those who did not reach that biomarker criterion. Three patients who were also receiving perampanel showed an increase in seizure activity, indicating an iatrogenic synergy between these two drugs that both target glutamatergic systems.  

OV935 is now in a 126pt pediatric rare epilepsy study (Dravet and LGS) that uses a revised titration and duration protocol, following patients for a total of five months, and excludes patients receiving perampanel. That trial is projected to complete in mid-2021. The wisdom of combining DS and LGS patients in the same study is questionable, given that LGS is far less diagnostically defined than is Dravet; they feature different seizure types (drop and convulsive seizures, respectively); and the Zogenix results with Fintepla in the two disorders suggests that treatment responsivity can vary between the two disorders. Ovid is also combining patients with two different rare disorders, 15q duplication and CDKL5 deficiency, in another 30pt open-label pilot study, finishing later this year, introducing heterogeneity into patient samples is a debatable tactic.

Verapamil is a L-type calcium channel blocker utilized in the United States for hypertension, cardiac arrhythmias, and headaches for over thirty years. The premise for its adjunctive use in Dravet Syndrome is that it improves defects in autonomic control by downregulating sympathetic nervous system activity, though it has also been hypothesized that verapamil may slow the transport of anti-epileptic drugs out of cells, thereby improving their pk profile. There are reports of children with Dravet Syndrome who responded to the use of verapamil as an adjunct, the effect persisting for several months. Mayo Clinic ran a Phase II trial whose results were apparently ambiguous, and it is not clear who would bankroll further testing given the drug’s generic availability and the increasingly competitive environment in Dravet treatment.

Supernus is developing Biscayne‘s Huperzine A, in XR form, for Dravet; that program (SPN-817) is currently in PhI.

Gene Editing

Stoke Therapeutics  has developed an oligonucleotide (STK-001) that targets the mRNA for mutant Nav1.1/SCN1A protein, decreasing its production, while bringing Nav1.1/SCN1A production to near normal levels. In mouse studies, 76% of DS-model mice were seizure free  (from postnatal days 22-46) after receiving STK-001, compared with 48% of mice receiving placebo infusions. The frequency of seizures in treated mice was reduced by 80%, and the survival rate (to day 90) was 97% of treated mice, 23% for the placebo group. Nonhuman primate studies showed that STK-001 increased Nav1.1 expression throughout the cortex. Stoke was able to raise $163 million in their 2019 IPO (and $130 million previously) on the basis of this promising work, and hopes to initiate a PhI/II trial in 1H:20. This program represents a nightmare scenario for Dravet drug developers, since if it works as hoped, it could do for the 90% of Dravet patients with the mutation what the gene-editing therapies have done for SMA, which could make symptomatic treatments irrelevant. But this has yet to be established in human testing.

Right behind Stoke is Encoded Therapeutics, which has raised $158 million thus far, from high quality VCs, to develop its AAV gene therapy programs. The lead program (ETX101) is in Dravet, where they are using AAV to deliver transcription factors that are intended to upregulate the expression of SCN1A/Nav1.1 channels in inhibitory neurons. They apparently have preclinical data that tells them they can provide both payload and location specificity, they hope to be in human testing next year.

CURNA, a company spun out of Emory University, developed CUR-1740, another antisense oligonucleotide targeting mutated SCN1A, which reportedly increased functional SCN1A mRNA eightfold in a human fibroblast model. Opko Health acquired CURNA, naming the asset OPK8801. Back in 2017, Opko claimed the IND would be filed before the end of the year, and two years later, that has not yet occurred–which likely means that the ASO did not pan out, and has been shelved.

LifeSplice Pharma developed a splicing oligonucleotide that reduces the expression of SCN8A receptors, found primarily on excitatory neurons. In a mouse model of Dravet, LSP-SCN8 reduces mortality ‘dramatically.’ They received a $700K NIH grant back in 2014 for this program, followed five years later by a $670K grant aimed at furthering preclinical development. Thus this program is moving at a snail’s pace.

(from the January/February 2020 Issue)

Negative Space: Missing Pieces in the Aducanumab Story

It was the most eagerly awaited event of the Alzheimer’s holiday season: Biogen had promised to provide additional data buttressing its decision to remove aducanumab from the futility dustbin, and after a fresh coat of paint, submit it to the FDA for approval in the treatment of Alzheimer’s. CTAD’s annual meeting provided a suitable setting, and it was a packed house on December 5. Biogen’s Samantha Haeberlein provided an extensive review of aducanumab data and the rationale for claiming that disease-slowing had been demonstrated in the truncated Phase III trials. But it was not so much what was shown and said, but rather more what was missing, that was most striking. Among the omissions:

Dissent. The panel of discussants at the Biogen presentation were primarily investigators for the PhIII trial in question, plus Paul Aisen from USC, an amyloid-theory stalwart. They spoke movingly of their wish to have something to offer patients otherwise bereft of hope, and  the importance of extending a patient’s capacity for autonomous functioning. Our background is clinical, we get it, but in this scientific setting, it came across as cheerleading based on a pre-specified wishlist, not clear-eyed science. There was no shortage of skeptics in the room, surely someone qualified could have been invited to participate as a spokesperson for the loyal opposition. Instead, the panel seemed to be parroting the party line.

Microphones. At CTAD, as at most large conferences, microphones are placed at various locations around the room so that questions can be asked of the presenter after the presentation has finished. For Biogen’s aducanumab talk, and for no other session, those microphones had been removed. In their place, attendees were invited to text questions to a moderator who selected a few softball queries, dutifully responded to by panel members. Oddly, when asked about regional differences, Biogen’s curt response was “we are not commenting on that” (why not?). This was a curated and controlled media moment, not the opportunity for scientific interchange for which CTAD would in theory have been an ideal locale.

The extended version of ARIA’s song. Biogen acknowledged the high rate of ARIA-E and H  in the 10mg/kg, APOE4+ group, 50-54%, but was dismissive around the details, stating that only 20-29% of these cases were symptomatic, and “the majority” were able to eventually resume aducanumab. What happened to the plurality who were not able to resume treatment? In the PhII PRIME study, 22% of ARIA cases were severe (Biogen disclosed only that ‘78% were mild to moderate’, one had to do the math to figure out the rest). What percentage were severe in Phase III? And what happened to those patients? One of the panel members stated that he is comfortable ‘managing ARIA’, which may well be the case, backed up as he is by Brown University Medical School’s resources and imaging capabilities. That may not be so easily duplicated by general practice neurologists in the field. This is a safety issue not to be so cavalierly dismissed–the FDA will not ignore it.

Having seen one media report of an “electric atmosphere” following the Biogen presentation,we can report that NIR spoke to at least a dozen attendees about that presentation, and without exception, the reaction was one of disbelief and annoyance at having been subjected to an infomercial for aducanumab and the amyloid hypothesis. Or to put it another way, the atmosphere was more shocked than electric.

The Bottom Line:
Statistical purists may suggest that the announcement of the futility analysis results, and subsequent trial termination, irrevocably altered the framework for everything that followed, including the inclusion of later subjects and the post hoc revisiting  of the ENGAGE trial. If so, it would then follow that neither study can be properly described as successfully documenting efficacy, and at most, the EMERGE trial puts forth a hypothesis to be tested. But if the FDA were hewing to this strict standard, and saw neither trial as constituting a valid pivotal study, we suspect that this would have been conveyed to Biogen during subsequent discussions. So for those keeping score at home, we will chalk up EMERGE as appearing to support aducanumab’s case. But on the other hand, all the post hoc genie-lamp rubbing cannot turn ENGAGE into anything other than a failed trial, indeed some numerical trends showed a worsening of the aducanumab group compared to placebo. So one trial was positive, one negative. Which was the outlier? Post hoc data mining cannot definitively answer that question.

What will happen now? There are a few possible scenarios:

A Tiebreaker is Required: If the FDA follows its own procedures and precedents, a third Phase III will be mandated. ENGAGE was not confirmatory, and those hoping that the Phase II results from the PRIME trial might substitute forget that the whole dose-response pattern in that trial was turned on its head. A tiebreaker should and will be the outcome, unless the following occurs:

Aducanumab Turns Into A Political Football: Given Alzheimer’s massive toll, well-meaning people may well decide that ‘something is better than
.’ We can also imagine a political environment, with a Presidential election looming, and an impeachment trial that will not end with a conviction, where this would be seen as a potential crowd-pleasing ‘win’. Regulators will be under great pressure to be ‘flexible’, and there are examples of doing so in the past, single trial approvals in Duchenne Muscular Dystrophy and Parkinsonian psychosis come to mind. But this is different, in both the stakes and scale. The sheer size of the Alzheimer’s market dwarfs either of those, and there are safety issues with aducanumab not seen in those other contexts. To open the floodgates of demand for an Alzheimer’s treatment would mean millions of people could be exposed to a drug of unclear utility, wherein the impact of even a low-incidence adverse event will be greatly magnified by the size of the population using it. And in terms of reverberating effects: At best, aducanumab would be a mediocre treatment making the enrollment of trials for other, potentially superior therapies, nearly impossible, save for treatment failures unlikely to respond to any disease-modifier, or those with ‘unmanageable’ ARIA.

These concerns will not matter one iota to those who see this as potentially adding to the case for a Presidential re-election. In their view, a win is a win is a win, and the ability to claim that this administration ‘cured’ Alzheimer’s would be intoxicating. The most cynical scenario we can conjure up combines ‘‘It’s a nice little Agency you have here, it would be a shame if something happened to it’ and ‘I need a favor, though.’

The window of timing opportunity would be narrow, given that Biogen will file the NDA in early 2020, just months before the election. We can imagine immense pressure to act ASAP. However, there is also a new FDA Commissioner now in place, for whom the calculations could be both medico-ethical and political. We would like to think the former would rule the day, but if the latter is a factor, and if Stephen Hahn wants to be Commissioner longer than one year, he would have to consider the likelihood that if he is perceived as having ‘caved’ to Administration pressure, and the Democratic candidate then wins in November, his tenure will be short. This calculation would be inverted in the scenario of a Trump re-election.

Any eventual approval for aducanumab would have significant conditions attached. Given the ARIA issue, we expect a REMS requirement for quarterly MRI scans for the first eighteen months of a prescription, good news for the owners of imaging centers.

It seems almost bizarre to suggest that a decision that could affect millions of lives, cost billions of dollars in health care expenditures, and could constitute a major obstacle to the validation of other therapies in development, could be impacted by election-year maneuvering. But bizarre has become the new normal.

One Other Alzheimer’s Note

We do not question the sincerity of aducanumab’s supporters within the Alzheimer’s community. We do question the  objectivity of their judgment. Aducanumab, as has been the case with previous high-profile projects, has become the poster child for cognitive dissonance theory, people seeing what they want to see in order to maintain consistency with long and deeply held beliefs. Paul Aisen proclaimed at CTAD that aducanumab is a “truly major advance”. We recall a previous CTAD where Aisen concluded that the solanezumab Phase III data set ‘proved’ the amyloid hypothesis. Neither statement was accurate, though we are sure that Aisen believes both to be true. The degree to which well-intentioned experts can twist their thinking in the service of cognitive congruency was exemplified by a later CTAD panel on BACE inhibitors, a class where the story has turned to the assessment and reversal of drug-induced cognitive worsening. Most presenters seemed to acknowledge that the therapeutic window for BACE inhibition, other than perhaps for rare autosomal dominant AD, is essentially nil. A couple of them suggested that, while BACE inhibitors impair memory, they seem to improve language fluency, a pyrrhic victory at best.  Banner Health’s Eric Reiman took a contrarian view, proposing (as did Aisen the next day) that BACE inhibition should continue to be explored as a therapeutic option, particularly in APOE4+ patients without amyloid deposits, arguing that brain volume loss comes early and is neither ‘progressive’ nor clearly correlated with cognitive deterioration, which he stated might be both ‘tolerable’ and reversible. The notion that patients whose disease involves cognitive decline might be able to ‘tolerate’ treatment-induced impairment seems incongruous at best. While Reiman may have been intentionally provocative in his suggestions, they did illustrate the pretzeled logic that so often permeates the Alzheimer’s field.


Moments after their CTAD presentation, Biogen held a conference call for major investors/analysts. Where they fielded a number of questions in real-time; they were more open to investors than to their scientific peers. In that call, they provided more detail about their rationale for seeing ENGAGE as a net positive for aducanunab, but they still responded to a number of queries with ‘we’re not going to talk about that.‘ There continues to be a dearth of ARIA outcome information, other than bland assurances that it is ‘manageable.’ They insist they have no intention of running another pre-NDA trial. What do they know that we do not? Plenty, that’s a low bar. But Biogen’s parsing and filtering of information still strikes a sour, defensive note to our ears.


(from the November/December 2019 Issue)

Excerpt from the review of Parkinson’s


LRRK2, mutations of which are found in 1-3% of PD patients, has long been considered one of the more promising novel PD targets, given evidence that gain-of-function mutations in this kinase interfere with lysosomal function and are associated with neurodegeneration in Parkinson’s. This is true in the LRRK2 mutation population, but possibly in sporadic PD as well. However, LRRK2 has turned out to be a challenging target. In 2015 Genentech reported that two of its LRRK inhibitors were associated with lung tissue pathology in a preclinical model. A praiseworthy consortium of pharma companies with LRRK2 programs collaborated, under MJFF, in running preclinical testing of all the available LRRK2 candidates. The compounds from Genentech, Pfizer, and Merck were all associated with pneumocyte pathology at higher doses, indicating that this was an ‘on-target’ class effect. However, low doses of the Pfizer and Merck molecules did not cause lung vacuoles, even though they produced significant reduction in brain levels of LRRK2, and the lung changes incurred by the Genentech compound were completely reversed two weeks post-dosing.

The conclusion was that it might be possible to walk a dosing tightrope around the pulmonary safety concerns, though Genentech decided that they would not pursue the target, and outlicensed their compounds to Denali Therapeutics, as is discussed below. Merck is in early stage development with a replacement for MLi-02, Pfizer ended up spinning out PFE-360 to Cerevel, where it is not at the front of their developmental queue.

Denali has been the company that has pressed on most aggressively with LRRK2. DNL201 was the first candidate to finish PhI, and to then enter a PhIb safety/tolerability study, which was to finish in September. Similarly, they initiated (this past September) a PhIb study of DNL151, enrolling patients with and without LRRK2 mutations. Two doses are being tested for safety, in 24 patients, results are expected in early 2020. They will then select which molecule to enter into PhIII studies during 2020.

Denali has come to believe that LRRK2 inhibition may be applicable to idiopathic PD. A U.Pittsburgh group found that LRRK2 kinase-induced damage can be found in post-mortem brain tissue from sporadic PD patients. They proposed that this heightened kinase activity creates oxidative stress and contributes to a failure to clear alpha-synuclein, leading to toxic aggregation. However, in a classic intra-Pennsylvania dispute, a U.Penn group reported that LRRK2 inhibition, via Merck‘s MLi-2 compound,  was not neuroprotective against alpha-synuclein pathology in a mouse model: The motor phenotype was unchanged, as was alpha-synuclein accumulation. They suggested that the role of LRRK2 inhibition as a tactic in idiopathic PD has not yet been validated.

Biogen has initiated PhI testing of an ASO (BIIB094) against LRRK2 developed by Ionis. 62 patients will be enrolled, including both LRRK2 mutation positive and negative subtypes. Results are expected in 2022.

A Harvard group (Isacson et al) is working preclinically with an antisense approach to LRRK2-mutation cases, seeking to achieve stable reductions in LRRK2 production by editing out two common mutations (R1441C and G2019S).

E-Scape is focused on the LRRK2 mutation population with a selective inhibitor (it does not inhibit wild-type LRRK2) that they expect will avoid the pulmonary pathology associated with these predecessors, and thus has a much broader therapeutic window. This is in discovery stage.

GSK is not a company that has earned much mention in these pages in recent years other than for the sake of snarky nostalgia, but GSK did sign a four-year agreement with 23 and Me last year that includes GSK’s preclinical LRRK inhibitors for PD. The deal gives GSK access to the 23 and Me database in the service of clinical trial patient selection and compound validation. The inference is that GSK intends, at some point, to go into the clinic with a LRRK inhibitor, if one passes muster. This would be the most tangible indicator of their long-rumored return to neuroscience.

Lundbeck/Zenobia Therapeutics worked together on identifying LRRK2 inhibitors, but the program failed, Zenobia folded. Ipsen Group partnered in 2012 with Oncodesign regarding LRRK2 inhibitors, this program was subsequently partnered with Servier.

It is worth noting that a 2019 paper linked LRRK2 to stress-induced impairment of GI motility, attributing this to impaired signalling in the hypothalamus. Separate from the putative involvement of LRRK2 in stress-related pathways, it must be wondered whether this could also be associated with the Parkinsonian hypomotility that has been deemed an early pathological sign of PD-induced changes in the gut-brain microbiome.

(from the September/October 2019 Issue)

Excerpt from the review of Alzheimer’s

The TauRx Blues

Only one alleged tau-targeting agent has produced clinical efficacy results–TauRx has received over $250 million from a Singaporean investor group, and returned nothing of value. The premise began with Rember, a purified form of the venerable staining agent methylene blue, which the CSO claimed was a tau-aggregation inhibitor. There are independent reports that Rember/methylene blue’s mechanisms involve antioxidant and MAO inhibitory properties, and does not promote tau clearance, thus this may not have been a actual test of the tau hypothesis.

TauRx originally came to attention when they claimed disease-modification in a 321pt Phase II trial, wherein the rate of decline over 50 weeks was reportedly reduced by 81%, a dose-response relationship cited with the two lower doses, 30mg and 60mg. The highest dose, 100mg, did not produce any benefit whatsoever, TauRx stated that the 100mg dose had chemically interacted with its gelatin capsule and was converted into a non-active form. Then, while the formal placebo-controlled period was 24 weeks, they proceeded to claim that the 100mg dose, administered for the next 60 weeks, functioned as a placebo. This was a convenient rationalization, since patients receiving Rember had blue urine, the actual placebo group did not, so the trial had been essentially unblinded from the start.

A second-generation compound (TRx0237/LMTX) went directly into two Phase III trials in Alzheimer’s and a Phase II in Frontotemporal Dementia, using a low dose (4mg) of TRx0237 as the ‘control’ group. TRx0237 failed in the first Phase III, an 891pt study in mild-moderate AD. TauRx assembled a specious post hoc supposition that the 15% of patients not on other Alzheimer’s drugs (essentially cholinesterase inhibitors, most patients had been treated with a ChEi as a monotherapy, some added memantine) separated robustly from placebo. TauRx speculated that ChEis might block (somehow) the binding of TRx0237 to some constellation of receptor sites. But at the same time, the investigators also suggested that the 4mg BID dose might actually have some clinical activity, that it was not biologically inert. This lysed whatever was left of their credibility, the same group cannot serve as a placebo and low-dose intervention at the same time.

A second Phase III was claimed to show that the 100mg dose, the active intervention, and the 4mg dose, intended as the control, both significantly improved ADAS-cog and ADCS-ADL deterioration rates when not accompanied by a ChEi or memantine. Thus any variance in outcome appeared to be largely a function of whether patients were receiving a symptomatic treatment, most probably reflecting differences in their rate of disease progression. TauRx tried to attribute the difference to TRx0237, rather than fundamental differences in the treatment populations, and even said they wanted to further develop the ostensible placebo-dose of 4mg as an active therapeutic.

This was reminiscent of the Affiris debacle in 2014. When a company seems confused as to which is a placebo and which is an active drug in a clinical trial, that is a red flag. Last year, we wrote that the “TauRx program appears to have finally lost the support of that Singaporean investor group, and is unlikely to be viable going forward“. This was incorrect, TauRx did somehow convince investors to fund a nine-month duration study for LMTX, utilizing a cognitive and functional endpoint cobbled together from the ADAS-cog and ADCS-ADL, using the 4mg BID dose they had deployed in the previous study as the placebo control group. The trial is aimed at enrolling 300 pts, plus an additional 75 patients being given 8mg dosing BID. The Company stated that positive results from this trial, in combination with previous efficacy data (which, it should be remembered used a dose 25 times higher, again, with the 4mg dose serving as the active arm in this trial having served as the placebo in that trial), would confirm the clinical utility of LMTX in AD. As we have noted in the past, since the placebo does not turn urine blue, this trial is not truly blinded, which is more than can be said for their investors.

(from the March/April 2019 Issue)

Excerpt from the review of Stroke


There is a ‘cytokine cascade’ of inflammatory factors that is precipitated in stroke. Interleukin-1(IL-1), interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-alpha) fuel the inflammatory process by recruiting leukocytes to the area, fueling apoptosis. The several companies which have targeted IL-1 and IL-6 in multiple sclerosis did not turn their attention to stroke. Xigen did make stroke one of the lead indications for its jnk inhibitor XG-102, and completed a 10pt Phase 1b study with XG-102, but then exited.   

CCR5 (CC chemokine receptor 5) has been proposed by a UCLA group as a target for addressing neuroinflammation in stroke (and TBI), and to improve stroke rehabilitation outcomes. Stroke patients with a CCR5 gene mutation causing a loss-of-function had more improvement in sensorimotor and cognitive functioning at six months and a year post-stroke. In mice, blocking CCR5 expression led to a better functional outcome in stroke models,and showed  improved dendritic spine density. The UCLA group has initiated a Phase II/III trial using the CCR5 blocker Selzentry/maraviroc, which is marketed for the treatment of HIV infection. The trial will enroll 60 patients who are within 4 weeks of their stroke (ischemic or subcortical hemorrhagic); their performance on two motor tests are the co-primary endpoints, other motoric measures of stroke recovery are among the secondaries. This trial is expected to complete around the end of this year.

MediciNova/Kyorin‘s ibudilast, a MIF and PDE4 inhibitor, has long been approved for the treatment of stroke in Japan and Korea, albeit for post-stroke dizziness in specific. US academic groups have been looking at its possible utility in MS or addictive disorders, no further development in stroke is likely.

Armagen developed AGT-110, a TNF decoy receptor fused with the transport antibody, that is intended to use the decoy receptor to reduce available levels of TNF-alpha, reducing its inflammatory effects. They claim that in a mouse model, AGT-110 reduces stroke volume by 62%, but their focus has been on rare diseases, this program has made no progress.

ArunA Biomedical, which had been developing stem cell therapeutics, has changed course somewhat, and is now developing exosomes (vesicles) obtained from neural stem cells as a means of treating stroke. Its lead exosome product, AB126, is currently being tested in pig models of stroke, following mouse model testing which showed decreases in infarct size and improved functional outcomes. Exosomes are a non-immunogenic vehicle for providing mRNA and cytokines that facilitate growth/repair–ArunA’s current working hypothesis regarding the as-yet-unproven mechanism, is that it operates via an anti-inflammation route, steering macrophages to an anti-inflammatory role and reducing pro-inflammatory T-cell generation.


A Columbia group initially cited complement component-1q (C1q) as a novel target in stroke, as C1q knockout mice show much less damage in a stroke model. The mechanism was not clear at that point, though the suppression of mitochondrial oxidation was suggested as a possibility.  Based on work done since that time, ig appears that C1q operates as a key initiating factor for the classical complement pathway, which triggers microglial activation, the release of  inflammatory cytokines, and the tagging of synapses for pruning. C1q is the major target for Annexon, which has raised $153 million in the past four years, arguably aided by the fact that they do not list stroke as an indication of interest (they do cite AD, HD, SMA, FTD). ANX005 is their lead C1Q mAb.

A University of Colorado/Medical University of South Carolina collaboration on complement system pathology has been spun out into AdMIRx, with stroke as the lead CNS indication (other indications include kidney disease and rheumatoid arthritis). They have developed a technology for inhibiting complement activation locally, in areas contiguous to a stroke infarct: Cerebral ischemia causes the production of a neuronal marker, an epitope, that triggers activation of complement C3d, which then tags those neurons for phagocytosis. AdMIRx’s B4Crry combines an antibody that recognizes that  ischemic marker with to a complement inhibitor. This  reduces local neuroinflammation associated with microglial activation and phagocytosis of neurons in the stroke penumbra. Because the marker is  primarily found in the penumbra, this limits the scope of B4Crry’s impact to that vulnerable area. In animal models, a single infusion of B4Crry reduced C3d in the brain, reduced neuropathological symptoms and necrosis, providing for improved functioning 15 days later. B4Crry is preclinical.

There are other companies targeting complement system components as an anti-inflammation tactic, but InflaRx (C5a) is not pursuing stroke, nor is Apellis (C3), or the most clinically advanced complement-focused company, Alexion.

With the overall surge of research attention in neuroscience to the prominent role of neuroinflammation, there are a raft of yet-to-be-validated inflammation targets that have been suggested for study:

DSTN/destrin (actin depolymerizing factor) upregulation has been reported by a U. Pittsburgh group to decrease pro-inflammatory markers and reduce BBB leakage in a mouse model. They also claim improvement in spatial memory in those same mice. Another U. Pittsburgh researcher reported that increasing IL-33 decreases neuronal death in vitro, and reduces infarct volume in vivo. Work done at University of Texas has pinpointed IL-27 as biasing neutrophils towards an anti-inflammatory role in rodents, though the group has turned its focus towards downstream iron metabolism mediated by IL-27, stating that IL-27 itself might not have a sufficient safety margin as a target. Knocking down levels of TRAF6 (TNF receptor factor6) was reported by a Wuhan University group as reducing infarct size and reduced neurologic impairment in a mouse model.

Some of the molecular culprits pursued in other neurodegenerative disorders have also been proposed as playing a destructive role in stroke. A University of Wisconsin researcher reported alpha-synuclein knockout reduces infarct volume and improves survival/functioning  in the MCA stroke model. Neither of the two major groups in human trials with alpha-synuclein mAbs (Biogen/Neurimmune and Roche/Prothena) have evidenced any interest in expanding into stroke. A U. South Wales team cites tau as a target for stroke therapy–knocking out tau reduces neurological deficits and time to recovery in mouse models.

An attempt to repurpose an MS drug turned out to be a road to nowhere for Biogen, developing natalizumab for stroke. They ran this integrin alpha(4) inhibitor through Phase IIb, hoping for an anti-inflammatory impact, but the trial failed to hit any of its endpoints, and the program was terminated.


(from the January-February 2019 Issue)

Winter Is Coming: Rallying the Undead (Mechanisms)

There have been multiple sightings of resurrected mechanisms, long thought dead and gone, now alive, or more provisionally, undead. Whether they will be shown to be truly viable, or just products of overexercised fantasy, remains to be seen:

This glutamatergic receptor subtype was long heralded as a route to cognitive enhancement by Cortex  Pharmaceuticals, Lilly, Servier, and Organon (amongst many), revisited by Takeda, and quietly, by Pfizer. While Takeda ran into tox concerns with TAK-653, Pfizer showed enough with PF-04958242 to catch Biogen‘s eye, not an easy catch, given that schizophrenia is the putative focus. Biogen acquired the compound, overcoming what had become an industry antipathy for AMPA in particular, and their own reticence about Psychiatry in general. Will the PhIIb bring AMPA fully back to life, for CIAS? This MOA now has its best shot ever.

2) Pheromones:
Pheromones have not elicited a lot of attention in the industry, though one tiny firm did focus upon them–Pherin Pharmaceuticals. Pherin has been walking a narrow tightrope between corporate life and death for the past two plus decades, as they sought to develop intranasal drugs based on pheromones. Janssen, Organon, and Taisho had all taken turns partnering this work 15-25 years ago, all eventually departed. Columbia U. psychiatrist and Pherin consultant Michael Liebowitz has single-handedly kept PH94B (an intranasal spray intended for use by females in socially stressful situations) alive, overseeing three underfunded pilot studies from which significant impact on anxious distress in a Social Anxiety population was reported–the study cited as preparation for Phase III enrolled just 23 women. VistaGen has now partnered  PH94B, they plan to go into PhIII.

3) PARP inhibitors were once seen as a viable intervention for neurodegeneration, but Guilford Pharmaceuticals failed with their program, others moved into oncology, where PARP has been a useful target, and toxicity less of a concern. A Johns Hopkins group has now shown that low-doses of approved (for cancer) PARP inhibitors (Rubraca, Lynparza), as well as veliparib, show in vivo and in vitro signs of efficacy in an alpha-synuclein model, reducing neuron loss and alpha-synuclein pathology, which points to a role for PARP in PD pathophysiology. Now we will see if AbbVie, AstraZeneca, or Clovis Oncology will choose to explore this–it is only a good fit for AbbVie.

4) NeuroHealing‘s subQ apomorphine for coma-awakening is finally going back into a clinical trial–in Belgium.

5) Feinstein Institute researchers just published that ‘rewiring’ can be imaged in patients who had received AAV2-GAD gene therapy in a 2008-10 Neurologix trial for Parkinson’s. Neurologix declared bankruptcy in 2012.


(from the Sept/Oct Alzheimer’s Review)

Passive Vaccines: the AB mAbs

The passive vaccine approach uses monoclonal antibodies to bind/deactivate beta-amyloid, and this has become the most popular route taken by late-stage programs, with ambiguous, mixed results at best. The hypotheses for why so many have failed include the stage of disease being too advanced, the brain penetrance for the antibodies too limited, or the beta-amyloid species targeted the wrong one.

Bapineuzumab: In Phase II, Elan/Wyeth‘s (eventually, Pfizer/JNJ‘s) bapineuzumab missed its endpoints for cognition, but they had already initiated a massive Phase III program, based on a posthoc analysis that showed a bifurcation based on the ApoE4 genotype: The 65% who were carriers showed no significant benefit from bapineuzumab, although their completers had a slightly (2.6 ADAS-cog points) better outcome than the placebo group. The non-carriers showed a difference of 5 ADAS-cog points, which did reach significance. This became an example par excellence of the problems presented by differing background rates of decline: The placebo group’s rate of decline was essentially the same as the drug group until they reached the final six months of the trial, when a nosedive took them towards the extreme end of the range in terms of the slope of cognitive decline. Vasogenic edema was a complicating factor, and the drug failed in Phase III.

Solanezumab: Lilly’s solanezumab/LY2062430 preferentially targeted soluble amyloid monomers rather than plaques and fibrils. In theory, this reduces vasogenic edema risk, since it spares plaque attached to the endothelial walls of the brain vasculature. But it also requires that the antibody neutralize an enormous ‘pool’ of amyloid. After a 52pt Phase II, covering only a twelve-week period, Lilly deemed solanezumab ready for two Phase III trials, that enrolled 1000 patients each, with solanezumab administered twenty times over eighty weeks. Those trials both failed on their primary endpoints. However, Lilly seized upon a posthoc analysis of data pooled from both trials that they believed pointed to cognitive benefit in patients with mild AD. The finding that benefit was restricted to mild patients could be interpreted as meaning that, by the time Alzheimer’s has reached moderate stage, it is too late to intervene in the amyloid pathway, and Lilly chose to interpret it that way. They also noted that 26% of the patients enrolled on the basis of cognitive impairment had negative results on florbetapir scans, concluding that the lack of plaque meant that these individuals did not have Alzheimer’s, or at the very least, did not have sufficient amyloid involvement to make solanezumab responsivity likely. This overlooks the confound that florbetapir only identifies plaque, while solanezumab targets soluble beta-amyloid, not plaque.             

Lilly’s final Phase III trial (EXPEDITION3), enrolled 2100 patients who met the criteria for mild AD, infusions given monthly for eighty weeks, and amyloid pathology had to be shown via imaging or CSF assay. In theory, this enhanced the homogeneity of the population, but constitutes a pathophysiological tightrope: Scanned patients had to be advanced enough to have significant plaque deposits that show on PET, but not so advanced that they had anything more than mild cognitive impairment. All of this was for naught: The Sola group showed a consistent pattern of slowed decline on the six measures, ranging from 7% on the FAQ (p=.14) to 15% on the ADCS-ADL (p=.009) and on the CDR-SB (p=.004).  On the primary endpoint, the ADAS-cog14, the drug group declined 11% less than the placebo group (p=.095). Lilly acknowledged that the magnitude of observed therapeutic benefit, generally in the 11-15% range, was not clinically meaningful, and thus did not warrant continued development–a refreshing example of ethical clarity–some might have considered filing based on the overall preponderance of evidence, from all solanezumab trials, that the drug has a statistically ‘visible’ effect on disease-progression, even if the clinical impact was so small as to be invisible. This conundrum will be encountered again in the AD area, not everyone will make the ethical choice.

Solanezumab was also selected for two major prospective studies of intervention in nonsymptomatic individuals:

1) The A4 Alzheimer’s study of nonsymptomatic elderly individuals with evidence of amyloid pathology based on florbetapir scans. 1150 individuals are to be enrolled in this five-year treatment duration study, largely funded by the NIH, results coming in 2022.

2) Solanezumab is one of three treatments (along with gantenerumab and a BACEi) used in the DIAN trial, enrolling genetically vulnerable individuals, compared with placebo, plus family members without the genetic mutation. That study, assessing whether any of the three drugs impacts the progression of genetically vulnerable individuals to AD, should have its solanezumab/gantenerumab outcome data in 2019, the arm with JNJ’s BACEi will complete its biomarker (amyloid-PET) phase in 2023, but the drug’s impact on cognitive decline will be tracked longterm.

Aducanumab: Licensed by Biogen from Neurimmune in 2007, this mAB targets an undisclosed beta-amyloid epitope, identified as relevant in elderly individuals who had not shown any cognitive deterioration, the premise being that this reflects AD-‘resistance.’ It is not intuitively apparent why a ‘resistance’-linked target would still be pertinent in an active AD population that was non-‘resistant’. Aducanumab binds to plaque and fibrils, not monomers, which differentiates it from solanezumab.

Biogen ran a 166pt study (30-32 patients per dose-group) PhIIb. There were four dose levels, 1mg/kg, 3mg/kg, 6mg/kg, and 10mg/kg, all infused on a monthly basis. The 6mg/kg dose  was added after the study was underway, due to vasogenic edema concerns and a high discontinuation rate with the 10mg dose. The 6mg dose did not separate from placebo at 26 weeks on the CDR-SB or MMSE, unlike the other doses, thus the dose-response relationship was not what was hoped for. The other major cognitive assessment tools used, the NTB and FCSRT, showed no effect from the drug at any dose.

The most positive interpretation of the data is that the drug, at best, produced an approximately six-month’s worth of impact on the pace of degeneration. However, the rate of vasogenic edema in the 6mg group was almost the same as seen with the highest dose (10mg) group. Biogen stated that the cases of vasogenic edema emerged early and eventually resolved, but that was within the context of a clinical trial setting wherein neuroimaging was routine. While 78% of ARIA cases were described as ‘mild to moderate’, 22% were more severe, some requiring hospitalization. Top-line results from the ongoing long-term extension study were just released, going out 36-48 months. The numbers of patients in each treatment group is dwindling, but the trendlines of amyloid reduction and (limited) impact on decline rates apparently remain the same, and the incidence of ARIA (vasogenic edema) is 25%, as detected by neuroimaging. Given what appears to be a limited magnitude of therapeutic impact, the cost-benefit analysis of whether the gain achieved is commensurate with the safety monitoring needed remains very much in doubt.

Because of the association of vasogenic edema risk with the ApoE4 genotype and dosing, the Phase III trials, each enrolling 1350 mild AD patients, are slowly titrating dosing. Originally limited to 6mg doses in the ApoE4+ groups, the EMA eventually gave Biogen permission to go as high as 10mg, the same as for ApoE4- patients. The treatment duration is eighteen months, and unlike the previous trial, these trials will allow concurrent ChEi use. One would hope that an interim futility analysis is planned, but otherwise these trials will not finish until 2020. Even if the hint of a signal proves out in the larger trials, they face the distinct risk that achieving even a borderline level of clinical impact will court the risk of vasogenic edema. It should be noted that there is a minority school of thought that holds that some vasogenic edema may be necessary in order to disrupt the blood-brain-barrier and thereby facilitate brain access for the mAb, but the aducanumab record thus far suggests that the degree of vasogenic edema ‘achieved’ too often goes beyond anything that could be construed as beneficial.

Gantenerumab: The results for aducanumab led Roche to reconsider its plan to shelve R1450/gantenerumab, a mAb (licensed from Morphosys) that attacks both plaque and fibrillar forms of AB. There have been reports of vasogenic edema, not surprising given its plaque-targeting and stimulation of microglial activity, even though less than 1% of the mAb reaches the brain. Originally, the drug entered Phase II, focused on prodromal AD, this was then expanded into a pivotal Phase II/III trial, more than doubling the planned enrollment, to 770, given monthly for two years, Roche conducted an interim analysis that they interpreted as providing a ‘go’ signal, the trial continuing into its Phase III stage, but it was eventually terminated in the wake of an interim futility analysis. The gantenerumab group did show significantly reduced CSF p-tau and total tau over a one year period, and PET-scan data indicating better brain amyloid clearance compared to placebo. Additionally, the interim analysis of the first 312 completers did not include 190 patients who had dropped out, and Roche subsequently concluded that the removal of patients who were rapidly progressing while on placebo prevented the identification of a signal, and that a nascent, dose-related post hoc signal of effect on progression rate could be discerned, and that higher dosing was needed. Interestingly, in the small group of completers who had florbetapir imaging, reductions in amyloid plaque load appeared associated with a reduction in phosphorylated tau in CSF, suggesting that impacting either of the major AD targets can impact the other.

The drug continues in another Phase III trial that began in 2014, aimed at enrolling 1000 mild AD patients, but it was cut back to 389 patients, data expected next year. In an attempt to focus higher dosing on a slightly earlier-stage population, Roche has recently initiated two 760pt, two-year duration Phase III studies in MCI/prodromal AD patients, which will report in 2022. Along with solanezumab and a BACEi, gantenerumab is offered in the DIAN trial (previously described) as a preventative/slowing option; enrollment is complete, data for the two mAbs is expected in 2019.   

Crenezumab: This AB antibody program came from AC Immune, who outlicensed it to Genentech in 2006. It is based on an Ig backbone thought to be less pro-inflammatory than its peers in terms of stimulating microglial activity,  it does show activity against both soluble and insoluble forms of beta-amyloid. It is likely to have a lower risk of vasogenic edema, and was chosen as the disease-modifier of choice for the API trial, as is described below.

Crenezumab failed in a 431pt Phase II trial that enrolled both mild and moderate AD patients, using both subQ and IV delivery. The IV was deemed equivalent to a ‘high’ dose, and in the mild subgroup of patients, a statistically significant impact (3.44 point mean difference) was seen on the ADAS-cog, reflecting a 52% reduction in the rate of decline on that endpoint, along with a 41.5% reduction in the rate of decline on the CDR-SB. Post hoc analyses of the high-dose (n=247) population by MMSE score at entry showed a relatively consistent trend towards  cognitive preservation, on the ADAS-cog and some domains of the CDR-SB, in more mildly impaired patients, with an inverse correlation between baseline severity and improvement. Such posthoc population parsing is fraught with risk, but it was sufficient to convince Genentech to run another trial. A 750pt Phase III, using a two year treatment period and restricting enrollment to patients with mild AD (MMSE>22) is projected to finish in 2021.

Crenezumab also continues in the API study, a prospective trial wherein the mAb is used as prophylaxis in members of an extended Colombian family (approximately 5000 members) with a presenilin gene variant associated with very early onset AD. A variety of biomarkers are being tracked, and the trial will run until 2020, though interim results are expected before then. Such prospective studies should begin to answer the question of whether amyloid antibodies work when employed early enough, if one assumes that the API trial, this particular presenilin mutation, and the accelerated dementia that it produces, are sufficiently similar to sporadic AD to be predictive for the nonfamilial type. Which will cast a significant shadow of doubt across any trends that may emerge.

Roche has thus doubled down on the amyloid mAb concept; they control two Phase III mAB candidates that have each offered just enough posthoc promise–from their own data and from a competitor’s–to offer a rationale for continuation. Both crenezumab and gantenerumab are also in prophylaxis studies that are partly funded by other entities, and will not report data for years. NIR had previously commented that it was hard to imagine Roche funding two amyloid mAb programs in parallel, not when there are other targets worthy of exploration and investment–but they are indeed doing so, at a cost that is reported to be over $4 billion. We continue to doubt that they will end up getting ‘their money’s worth.’

BAN2401: BioArctic (subsequently partnered with Eisai) developed an antibody that attacks AB protofibrils. BAN2401 was subsequently repartnered by Eisai with Biogen, and was the subject of the most recent round of hyperbolic Alzheimer’s headlines. BAN2401’s Phase II data from a substantially scaled dose-finding trial (854 patients treated, four dose levels ranging from 2.5mg/kg bimonthly to 10mg/kg bimonthly) were billed as showing both a significant impact upon amyloid levels and a dose-related impact upon progression rates. The highest dose was reported to show a 30% slowing of decline on the ADCOM (a composite endpoint developed by Eisai) at eighteen months; a 46% slowing of decline on the ADAS-cog, and a 26% slowing of decline on the CDR-SB, all compared with the placebo group. Which would most likely have exceeded even Biogen/Eisai’s expectations, had only it been genuine. Once again, a major pharma company(s) had tripped itself up with an unrealistically parsed presentation of data from a high-profile Alzheimer’s amyloid-antibody trial. They neglected to mention a confounding factor that invalidated all of the comparisons between the highest-dose cohort and the placebo group: ApoE4 genotype. While the study was underway, regulators became concerned (due to aducanumab) that the risk of vasogenic edema (VE) was excessive when combining the highest dose with ApoE4+ genotypes, and stopped the enrollment of ApoE4+ patients in the high-dose group, while withdrawing ApoE4+ patients from the study who had not been in for at least six months. What this produced was a highly apparent discrepancy between the 71% of patients in the placebo group with an ApoE4+ genotype, versus the 30% in the high-dose group.

This matters, because the best evidence available indicates that ApoE4+ alleles are associated with more rapid clinical decline in Alzheimer’s. Following a spate of studies with conflicting findings, Holtzman et al reported in Nature last year data from the state-of-the-art ADNI study: Over a ten year period, patients homozygous for ApoE4 declined at a 23% more rapid rate than ApoE4 negatives, heterozygous patients declined 14% faster than ApoE4 negative patients. Which strongly suggests that the slower decline in the BAN2401 highest-dose group was partially due to their having a less-pathological ApoE4 genotype. Biogen/Eisai could have, but did not, report on what percentage of BAN2401-study patients were homozygous as opposed to heterozygous, but a simple eyeball assessment suggests, indeed compels, the conclusion that the reported rates of slowed decline on the aforementioned outcome measures were tainted by this confound, and should have been reported with an bold-type asterisk, if reported at all. Our unsophisticated assessment of the outcome curves suggests that when the ApoE4 imbalance is taken into account, that BAN2401’s impact on progression is in a range where clinical significance is dubious.

The second issue is safety, vis-a-vis ARIA/vasogenic edema. One out of every seven (14.6%) of ApoE4+ patients who did receive the highest dose-regimen of BAN2401 developed ARIA, though only three out of the 48 cases were considered ‘severe.’ While this appears to indicate a less problematic prevalence of ARIA than seen with aducanumab, if BAN2401 were deployed in the Alzheimer’s population as a clinical option, that might still be considered an unacceptable risk given the sheer numbers of patients involved.

As was the case for aducanumab, one can argue that there are hints of success to be found here; this antibody was at its essence designed to reduce amyloid levels, and the PET scan data shows that it does so, in a dose-related manner. But whether such beta-amyloid reductions lead to clinically meaningful impact on disease progression is still not proven. Both of the 10mg hint-of-a-signal groups also display a not insubstantial rate of ARIA/VE for both E4+ and E4- groups. In other words, efficacy and risk continue to be inextricably intertwined for the beta-amyloid mAbs, and whether there is enough of the former to justify the latter continues to be unclear.

A German group (Technical University Munich) reported that some amyloid mAbs appear to increase cortical neuron hyperexcitability in the presence of AB, which could have a negative effect on cognitive function. This has yet to be shown in humans. One hypothesis is that this might occur as a result of breaking down plaque into oligomers that directly trigger hyperexcitation. Thus, beyond the questions of brain access and target suitability traditionally raised, there is a possibility that amyloid mAbs could trigger deleterious consequences that offset  some or all of the benefit that might have been expected from AB dissolution/clearance.