from the January-February 2017 Issue
The Year of Living Dangerously–the Sequel, Coming to Everyone’s Neighborhood….
2016 passes into the history books with hardly a ripple, the progress of humankind towards a brighter tomorrow smoothly advancing without so much as a hiccup. 2017 promises to be modestly more dramatic, with pundits predicting outcomes ranging from Apocalypse to Armageddon. The stock market has been booming. Somewhere, we can hear Nero fiddling as the Empire binges on ayahuasca.
When it comes to the biopharma world in general, there was a sense of déja vu. Another year, another amyloid antibody yielded its bounty of disappointment. Some pharma observers believe that the sudden 180 degree turn in Presidential mindsets means that the heat on the industry will be off, the pressure on pricing diminished by an industry-friendly administration. It does not look that way to everybody. NIR quoted Allergan‘s Brent Saunders in November, now we cite this excerpt from a piece he wrote for the December 1 issue of Forbes:
“…our industry has a social contract. Patients understand that making new medicines requires significant investment. Companies doing the hard, long and risky work of bringing new medicines to market have generally understood that they have to price medicines in a way that makes them accessible to patients while providing sufficient profit to encourage future investment. Everybody wins when it works the way it should. But some have violated this social contract, and the whole industry is under attack. The election results don’t change that debate. The election may give the industry time to demonstrate that it can self-govern. Time to demonstrate that the social contract is alive and well. If not, our elected leaders may act without us–at the peril of innovations that could help millions of patients.”
Citing Tufts estimates for the cost of developing drugs, and whining about the costs of Innovation, have been burned out as arguments with the public audience. They simply do not believe us, and an administration with a limited tolerance for scientific truth, a minimal attention span, a low bar for ‘facts’, and a penchant for populism cannot be relied upon as a shield when we offer such a convenient target: It’s not as if we make something useful, like air conditioners. The bill is coming due for Pharma’s public relations, which have been a chronically abysmal failure. We have allowed callow sociopaths like Martin Shkreli to seize the limelight and frame all of us as bathed in a miasma of unmitigated greed. This is not accurate, and is not fair, but we have failed to make our case or live up to our part of the social contract. If we do not show some collective spine in developing self-discipline, it will be done for and to us.
from the January-February 2017 Issue
Everything You Always Wanted To Know About the Amyloid Hypothesis (But Were Afraid To Ask Because the Shareholders Might Not Like What They Hear)
“Maybe we’re all just stumbling from the right questions to the wrong answers, or maybe from the right answers to the wrong questions.” –Malek, R. Mr. Robot 2016
“This (the sola study) is confirmation of the amyloid hypothesis, our strongest confirmation to date.” –Aisen, P. 12/8/16 CTAD
Which just shows how low the amyloid bar is, confirmation-wise. But in this instance, the conversation ricocheted from the wrong question to the wrong answer.
The wrong question: ‘What do these results say about the amyloid hypothesis?’
This infers that there is a single, archetypal amyloid hypothesis (AH), but in fact there are several, because there are multiple iterations of the Amyloid Hypothesis which have evolved over time as the earlier versions began to show their flaws.
AH 1.0: The original hypothesis says that Alzheimer’s is caused by the accumulation of amyloid plaque within the brain. If AH 1.0 were correct, aducanumab’s ability to reduce plaque deposition by 25-30% should translate into tangible cognitive/functional benefit. But while the 10mg dose showed a tentative signal on the CDR-SB, the 6mg dose, in spite of its similar PET-scan credentials, was a flop at 110 weeks. That could be due to the variance born of small cohorts, only a larger trial will tell. It is worth noting that solanezumab, in spite of not binding to plaque at all, produced a consistent albeit clinically meaningless effect on cognition.
Any question about AH 1.0 is the wrong question. It’s like asking about the ‘link’ between vaccinations and autism.
AH 2.0 postulates that amyloid in some non-plaque form (e.g. fibril, oligomer, monomer) is the causal key to Alzheimer’s. One counter-argument to AH 2.0 is offered by solanezumab, which produced a dramatic effect upon plasma amyloid, increasing it 500-800 fold, but the weakness of the therapeutic effect in the face of that biomarker does not portend a robust relationship. Sola’s first two Phase III trials showed an increase in total CSF AB40 as well, again without any connection to a clearcut treatment effect. The sola results neither prove nor disprove AH 2.0: We do not know if the weak response promoted by solanezumab means that the antibody binds to a suboptimal form of AB; not enough antibody reached the brain to bind enough AB; the patients were too advanced to benefit from a post hoc reduction of AB; or the answer includes a combination of some or all of these. It is worth noting that a recent in vitro study published in PNAS (Sun et al) did not support the traditional contention that longer, more aggregation-prone variants of beta-amyloid (e.g. AB42) would be associated with more severe, earlier-onset forms of Alzheimer’s–no correlation was found. While this does not disprove the amyloid hypothesis, it adds to the evidence stacked against AH1.0 or AH2.0.
AH 3.0 proposes that amyloid is a secondary rather than primary pathophysiological feature; it is not the foremost pathological actor, but plays some facilitative or ancillary role. This is consistent with the recent hypothesis that amyloid sets the stage for tau to disperse and cause the bulk of the direct damage. AH 3.0 seems to be best current model for understanding the data up to this point, one that leaves open the possibility that targeting amyloid could have a clinically meaningful role in AD treatment–-but by no means guarantees it, and makes it unlikely to be the optimal target for a monotherapy.
But wait, there’s more. These are lower profile, partly because of the potential for terminal embarrassment for the leading lights of neuropharm if it turns out that either one is true.
AH 4.0 says that amyloid is benign. It could be a warning flag for ‘system errors’, cellular misprocessing of APP which exerts a toxic effect separate from amyloid-as-byproduct. It could reflect problems in APOE processing, which have been linked to effects on neuroinflammation and mitochondrial function that do not trace their roots back to amyloid.
AH 5.0 claims that amyloid has been framed, not only wrongly convicted, but in reality playing an erstwhile (albeit eventually futile) part in defending the brain. Rudy Tanzi has proposed that beta-amyloid plays a role as a defense against infection, encapsulating microbes in amyloid protofibrils. A University of Madrid group hypothesized that beta-amyloid is a defense against fungal infection, while Cortexyme is based on UCSF work indicting a bacterial protease as critical to Alzheimer’s in an infection motif, though in that scenario, beta-amyloid is an ancillary but damaging byproduct, more in line with AH 3.0.
None of these have been proven. AH 1.0 has been largely disproven, but the rest are all conceptual models, hypotheses to be tested.
Returning to CTAD, and the question posed to the sola panel: It was ‘wrong’ because it referred to ‘the amyloid hypothesis’, as opposed to ‘an amyloid hypothesis,’ without specifying which one. And with all due respect to Paul Aisen, who knows far more about Alzheimer’s than NIR ever will, he provided the ‘wrong answer’, regardless of which AH species he may have been referring to: Nothing was ‘confirmed’ by the sola results.
So much has been invested by so many in the amyloid hypotheses that any results that do not contradict it/them is seized upon like a drowning man grabbing hold of a flotation ring. There are outstanding scientists who have devoted their professional lives to the explication of one or more Amyloid Hypotheses, and it is human nature to seek corroboration, particularly when there is no viable reverse gear by which they can switch belief systems.
Having commented upon the confluence of ‘wrong questions’ and ‘wrong answers’ as pertains to the Amyloid Hypotheses, we have our own list of questions and answers about the state of the mAb art and what this means, some of which are guaranteed to be just as ‘wrong’ as those discussed above. Being wrong is an inevitable side effect of scientific inquiry, where it becomes problematic is when a belief system takes on a life of its own, despite evidence to the contrary.
At the CTAD presentation of the detailed results from the most recent sola trial, Lilly‘s Eric Siemers several times responded to questions with the honest and accurate “I really don’t know.” For most of the questions oft-asked, no one knows the answer, yet. But based on the hodgepodge of information gleaned from the several AB mAb trials that have reported results, this is how it looks.
1) Solanezumab reached statistical significance in its impact on four out of six outcome variables. What future does it have, if any?
The drug 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). Based on the selection of the ADAS-cog14 as primary, the trial failed, this would at best be considered a trend. Recalling that Lilly had originally cited co-primary endpoints, including a functional endpoint combining the ADCS-iADL and FAQ, eyeballing the p values for those two tests suggests that combining them would not have reached statistical significance, and would not have changed the verdict on the trial. It should also be kept in mind that the p values reported were not corrected for their multiplicity, they would have been higher had they been corrected.
But that really does not matter–Lilly acknowledged that the magnitude of observed therapeutic benefit, generally in the 11-15% range, is not clinically meaningful, and thus does not warrant continued development for sola. The fact that the primary endpoint missed hitting p=.05 saved Lilly from having to decide whether to file for a drug that they knew achieved statistical but not clinical significance in its effect, a debate that would have been roiled by commercial needs as much as clinical and ethical considerations. The same question might have been begged by the p=.004 value reported for the CDR-SB, a functional endpoint being utilized as the primary by Biogen in its aducanumab Phase III program. At the time that the EXPEDITION3 trial was being designed, the CDR-SB was not viewed as a primary endpoint candidate, but even if it had been, a 15% slowing of decline is not clinically meaningful. Lilly should be commended for its current clarity on this point. There are companies that would have considered filing based on the overall preponderance of evidence, from all solanezumab trials, that the drug does have a statistically ‘visible’ effect on disease-progression. But Lilly had expected, with the requirement of amyloid-positive biomarkers for inclusion, that this ‘purer’ patient population would reveal a treatment effect of around 30%, close to what they reported from the amyloid-positive dataset pooled from the first two trials. Falling so far short of that begs questions of what might have happened had a higher dose been used (the drug is very well tolerated), or if they had somehow identified an earlier-stage population (hard to do when requiring amyloid biomarkers for inclusion) for intervention, but also suggests that tweaking dose and population is unlikely to achieve clinically meaningful results. Lilly did hedge on whether they would consider going ahead with sola based on such tweaks. Lilly’s announcement the day after CTAD that they were partnering with AstraZeneca on another AB1-42 antibody program may be tangible proof that they have moved on from sola–although that particular choice seems like switching from Coke to Pepsi for health reasons, unlikely to make any difference at all.
2) What does the sola outcome say about Biogen and aducanumab?
Not much, though it may reassure Biogen that CDR-SB is a more sensitive endpoint and perhaps better for their Phase III program. The Phase IIb data for aducanumab did suggest a possible signal, but the small size of the study makes this tentative, as does the very shaky dose-response relationship. The 6mg dose group performed more poorly than the 3 or 10mg groups on the CDR-SB, and matched placebo on the MMSE. It is not reassuring that switching the placebo group to active treatment with the 3mg or 6mg dose at 12 months did not seem to impact the slope of deterioration at all, while the slope of the 10mg group was inconsistent. The aducanumab data also does not support AH 1.0: The two highest dose levels reduced plaque deposition rates by 25-30%, but while the 10mg dose showed the strongest association with cognitive benefit, the 6mg dose performed poorly, in spite of its PET scan results. Reducing plaque is meaningless save as a marker of specific target-engagement. Aducanumab shows a trend suggesting the highest dose has an effect on cognitive decline, but the dose-response relationship is nonlinear, and the inconsistency means that the small size of the dataset precludes taking anything as having been demonstrated efficacy-wise.
Aducanumab Sings an ARIA-again: These less-than-exemplary efficacy results came at the price of a substantial incidence of vasogenic edema/ARIA, a safety issue not encountered by solanezumab. At CTAD, Biogen reported results from a 23pt titration trial of aducanumab, wherein APOE4 patients, who are most at risk of ARIA, showed a reduction of ARIA frequency when the dose of aducanumab was slowly titrated up to 10mg: Titration reduced the incidence of ARIA by 36%, from the 55% seen in the fixed dose 10mg group, down to 35%. But all of those ARIA cases developed on the 3 or 6mg dose-levels; thus avoiding the 10mg dose in Phase III, where 6mg is the highest dose being given APOE4 patients, is unlikely to avoid ARIA. Biogen accentuated the fact that in the extended treatment phase of the regular PhIIb trial, no patients developed ARIA during their second year of drug treatment. But 25% of the group who switched from placebo to 3 or 6mg did develop ARIA. Thus while it is mildly reassuring that those who do not develop ARIA relatively early, during their first year of treatment, are unlikely to develop it later, this does not offset the significant incidence of ARIA, even with titration, even at lower doses.
In the original Phase IIb, 22% of ARIA cases were severe, some requiring hospitalization, which would justify a back-of the-envelope projection that about 6% of the APOE4 population (which is roughly two-thirds of the AD population overall) would develop severe ARIA. This is not an inconsequential safety problem. APOE4 genotyping can be easily done, but administering MRI scans on a routine and repeated basis to hundreds of thousands, even millions, of AD patients would constitute a major logistical and financial headache, but this scale of incidence cannot be ignored. Biogen does have experience with a safety issue with Tysabri, where PML is of much lower frequency, albeit much higher lethality, and identifying a predictor of PML vulnerability became a high priority. Biogen knows better than anyone that they have two tasks: Not only showing that there is a consistent benefit afforded by aducanumab that is clinically meaningful, but also to find some biomarker identifying at-risk patients who would need early and repeated imaging.
3) What do the sola/adu results say about the amyloid hypotheses?
Nothing definitive. AB mAbs are not a homogenous group, they target different epitopes on beta-amyloid and hence bind very different beta-amyloid species. Solanezumab only binds AB monomers; aducanumab does not bind monomers, but instead binds to aggregates (plaque, fibrils, oligomers). There are those who think that the monomer binding approach is too inefficient, sopping up large pools of AB monomers using an antibody that has very limited (0.1%) brain penetrance is unwieldy at best.
The consistent but therapeutically impotent response produced by solanezumab raises as many questions as answers. If the antibody binds to a suboptimal form of AB, what is optimal? Setting aside plaque as a failed candidate, one could consider targeting oligomers only (as Acumen does with their antibody) to see if that is a more focused and efficient target. If not enough antibody reached the brain to bind enough AB, that does not infer that Lilly should run a high-dose sola trial, the magnitude of benefit strikes us as simply to small to be correctable via dosing. But with just .1% of the antibody achieving brain penetrance, one could seek technologies that enhance brain availability, a theme Roche and Genentech have been enthusiastically pursuing. If the patients were too advanced to benefit from a post hoc reduction of AB, one would have to find a valid and reliable marker of pre-Alzheimer’s (and pre-plaque) MCI to zero in on during the testing. Since using PET and CSF levels did not produce the kind of differentiation hoped for, this throws into question the criteria via which many sponsors now seek to achieve a more homogenous patient population.
4) Next steps?
With all the resources allocated to bapineuzumab, solanezumab, gantenerumab, crenezumab, and aducanumab, we still do not know if the amyloid theory that spawned them offers any hint of a blueprint for clinical therapeutics–or not. Lilly’s effort to now be rational about sola’s prospects stands out for its rarity. Hopefully, the rationality with which Lilly stopped sola’s development will not become diluted and diverted into some exploratory study using higher doses in MCI patients.
Whether other antibody programs might thread the therapeutic efficacy needle more effectively than the first three remains to be seen. There are several still on deck in various stages of development: Roche/Genentech have gantenerumab and crenezumab; Lilly has the new collaboration with Astra Zeneca; Acumen has its oligomer-specific antibody; Biogen/BioArctic, Sanofi have others. It is worth noting that Roche/Genentech are running their trial of crenezumab dosing at 60mg/kg–at the very least, this represents an imposing manufacturing challenge, since a dose might average 4.2 grams of antibody. We propose that the Millennials now spawning craft breweries by the bushel be recruited to manufacture artisanal antibodies in small scale.
The eyes of the amyloid world will now turn to Merck‘s BACEi Phase III program; verubecestat will report its first results next year. BACEi in theory offers the prospect of turning off the source of beta-amyloid rather than retrospectively cleaning it up, and there are several other BACEi programs also out there (e.g. Biogen/Eisai, JNJ, Lilly/AZ, Novartis). Whether BACE is the optimal vehicle for doing so has not been proven, and Probiodrug, Lilly, and American Life Sciences Pharma have programs targeting alternative beta-amyloid pathways. Then there are off-the-beaten track strategies that tap into amyloid pathology in divergent ways; Proclara has its cross-motif inhibitor in the clinic, Cortexyme has a lead compound chosen for development, to name but two.
We are not going to review the various alternative mechanistic frameworks available to AD therapeutic programs–we utilized 60 pages to do so in the September/October 2016 issue, and will doubtlessly reach the same volumetric marker of verbosity in next fall’s edition. The field largely, albeit not unanimously, wedded amyloid more than twenty years ago, based on in vitro findings showing beta-amyloid’s effect on cultured neurons. The use of in vitro and animal models to predict the course of the human disease has been an unmitigated disaster, so we are not going to repeat that error with tau. Tau is very much on the ascendancy as an Alzheimer’s target, and there has been work that postulates a tau-centric model for AD that better approximates the human disease than do amyloid-centric models, but it still has to earn its stripes in clinical testing. The same can be said for the pursuit of neuroinflammation as a key pathophysiological factor.
5) The Bottom-Line
For a target that was the consensus choice from 1995-2010, and had tens of billions of dollars devoted to it, amyloid has thus far offered far more disappointment than utility, regardless of how much researchers say that they have learned from the process. The four mAbs with significant clinical data thus far in hand; Bapineuzumab, solanezumab, aducanumab, and gantenerumab, must have totalled over $5 billion in development costs. It seems fair to say that no one has gotten their money’s worth.
from the Sept-Oct 2016 Alzheimer’s/MCI issue
Beyond protection is repair. The competition was once intense in the small molecule neurotrophin stimulant/mimetic area, but that has proven a veritable minefield for the well-intentioned and unwary. At present, the major regenerative activity in CNS is vis-a-vis remyelination, and AD and the other neurodegenerative disorders will be a likely area for extension for anything that passes the initial test in MS.
Neural cell implants
Just as Parkinson’s was for a long time erroneously defined as a disease of the striatum, some have embraced the convenient shorthand that Alzheimer’s is a strictly a disease of the hippocampus. While the hippocampus is an early locus of degeneration, the damage spreads widely, and Alzheimer’s is not an intuitively obvious target for cell therapy. This has not prevented some interesting research from being undertaken: ReNeuron has interest in Alzheimer’s, but chose stroke for its first clinical target. Saneron received a $2.6 million NIH grant to fund their work using human umbilical cord blood cells in animal models of AD. They believe that these cells will provide a beneficial anti-inflammatory effect, without triggering immunoreactivity. StemCells established a collaboration with UC Irvine for the use of their human neural stem cells in Alzheimer’s models, and reported that their hNSCs restored memory in an animal model of AD, but that program, along with all of their cell therapy portfolio, has demised, the Company absorbed by an Israeli medical robotics firm in a reverse merger.
Stemedica International reported that its allogenic mesenchymal stem cells reduced beta-amyloid plaque by 30% in a transgenic animal model. The relevance of plaque load as an endpoint for stem cell therapy is obscure at best. But they received funding for a 40pt Phase II trial, to be run at UC Irvine and Emory, testing one IV administration of these cells in mild-moderate AD–that trial began enrolling patients this past July.
A Korean group (Samsung Medical Center) published a report regarding their stereotactic implantation of mesenchymal stem cells into nine Alzheimer’s patients. The two year followup did not show evidence of any serious side effects, though the authors noted that the rate of decline on the MMSE was more accelerated than is generally expected in an AD population; this may have been due to these patients being relatively more advanced in their disease. The lack of a control group precluded any substantive analysis of the cognitive data obtained.
Another issue that will becloud the use of cells in Alzheimer’s until proven or disproven is whether the disease process may also attack the implanted cells, rendering them as nonfunctional as the patient’s original cells, which has been the fate of some fetal cell implants in Parkinson’s.
Intuitively, the concept of offsetting neurodegeneration by enhancing endogenous stem cell proliferation has appeal. The one neurogenesis-focused company prioritizing Alzheimer’s is Neuronascent, whose founder played a major role in the development of NeuralStem’s depression compounds. Neuronascent has molecules that enhance neuronal differentiation from progenitors, enhance hippocampal neurogenesis and migration of those new neurons, and bring cognition in aged mice back to “young” levels. Alzheimer’s has been first on their menu of indications, but their resources are very limited, National Institute of Aging grants have been slowly funding the work required for IND submission. They raised $1.2 million last year with which to complete NNI-362’s IND-preparation, but they need more funding to actually run a clinical trial.They have refined their explication of the MOA for NNI-362, now describing it as modulating a kinase leading to activation in progenitor cells, deactivation in cells that have differentiated, Otherwise, the status of neurogenesis programs for AD has been bleak, and deteriorating. BrainCells went bankrupt; NeuralStem has turned its small molecule program to depression; NeuroNova was acquired by Newron, its programs upregulating neurogenesis for ALS and PD eventually shut own by Newron due to problems with the ICV catheter system being utilized.
Effective neurogenic interventions could involve mediating the signaling pathway mediated by synaptojanin-1 that controls the proportion of new cells that are glial, rather than neuronal. In a disorder like Alzheimer’s, the likely priority will be to generate more neurons than glial cells, and downregulating the synaptojanin-1 pathway might be a way of steering neurogenesis in the desired direction. An optimal intervention might include both the neurogenic ‘accelerant’ and a guidance factor to steer production towards some ostensibly optimal proportion of neuronal/glial cells.
The Plasma Fountain of Youth
Alkahest is developing an eerily straightforward, yet something of a throwback, neuroregenerative option: Taking blood plasma from the young and infusing it into older adults in the hope of spurring neurogenesis. Regeneration through the absorption of ‘young’ blood is a theme that has percolated through primitive rituals, vampire tales, and some ill-fated experiments of early medicine; but this program comes from work done at Stanford, which sets it distinctly apart from these predecessors. Animal experiments there showed that infusing plasma from young mice into old mice stimulated the generation of new brain cells, and improved cognitive functioning/learning, while injecting plasma from old mice into the young had an opposite and deleterious effect. Work published in Nature Medicine showed that plasma improved synaptic plasticity, operating via CREB, critical to learning/memory. While the Stanford group did try to isolate which particular factors were upregulated via young plasma, and identified a couple of them (GDF11 and B2M), the simplest tactic for turning this thesis into a treatment is simply to infuse plasma itself, utilizing what may be a complex multitude of downstream effects as a whole, rather than trying to parse out and develop critical core components.
This work was spun out as Alkahest, incubated in a JNJ Jlabs facility. An 18 patient, double-blinded Phase II trial was initiated, using four, weekly plasma infusions from individuals under age thirty, in patients with mild to moderate (MMSE 12-24) Alzheimer’s. Last year, Grifols acquired 45% of Alkahest for $37.5 million, and made an additional $12.5 million payment to Alkahest, in return for worldwide commercial rights. The trial is expected to finish some time this year, with most standard cognitive tests utilized as efficacy measures, eighteen weeks into the trial. Expectations must be constrained: It is highly unlikely that marked contrasts will be seen, since this is a tiny, relatively short-duration trial, and it is not known whether (as is the case in other AD trials) these patients may be too advanced in their disease to benefit from the trophic effects of plasma, while it is also not known whether the donors themselves are too old to provide maximally ‘potent’ plasma in terms of the inherent level of regenerative factors. Having stated the caveats, it should be a fascinating dataset to see; if there is a therapeutic product to be had here, this will raise all sorts of practical and ethical issues around plasma supply, and IP regarding the application of the technology. As NIR has commented in the past, one can only imagine the dinner table conversations between middle-aged parents and their teenage offspring: “Yes, you can borrow the car, but there’s something you have to do for us in return…”
Prophylaxis via Lifestyle
Mental activity does appear to confer some protection against Alzheimer’s, which could infer the impact of activity-driven neurogenesis, although it could reflect the confounding effect of a stronger ‘cognitive reserve’, wherein there is farther to decline before reaching clinical dementia. But a paper out of Rush Alzheimer’s Center reported that, even when such factors as SES, social or physical activity, and premorbid cognitive capacity were controlled for, that elderly individuals who were at the 10th percentile of cognitive activity were 2.6 times more likely to develop Alzheimer’s than those at the 90th percentile. But after appraising the impact of diet, drugs, supplements, exercise, and cognitive activity in all of their various permutations, the NIH Consensus Panel report on ‘Preventing Alzheimer’s’ concluded that none have been proven to work. Provisional support was given to cognitive ‘engagement’, walking, and a ‘Mediterranean diet.’ Yet, as was noted earlier, a recent epidemiological study found that the incidence of Alzheimer’s onset is decreasing and emerging later in life, and while causality has not been defined, the usual hypotheses regarding activity level, overall health maintenance, and dietary moderation seem as reasonable an explanation and path forwards as we have at this point. ‘Use it or lose it’ continues to be a benign avenue to slowing deterioration. At the very least, it is a proactive and rewarding way to forestall boredom.
from the May-June 2016 Stroke/TBI issue
The image du jour for TBI has changed once again, even though the song remains the same in terms of the lack of viable treatment options. Twenty years ago, the paradigm revolved around a twenty-something male taking the search for speed and thrill too far. Ten years ago, the new image of TBI came from wartime, the ravages of IEDs upon troops in Iraq and Afghanistan–The Hurt Locker. Now, there is Concussion, a Hollywood film with Will Smith, focused upon the quiet epidemic of sports-related TBI, epitomized by the toll taken by American football upon those who play it. We are not going to pay false homage to the latter by referring to them as another iteration of ‘warriors;’ they are not, but the game they play can have devastating consequences.
Even though the back stories differ drastically, TBI has always been an epidemic hidden in plain sight. NIR reviewed TBI for the first time back in June 1996, and began with this:”In every urban center in the United States, and indeed in most developed countries, there are coma units housing patients who are in persistent vegetative states. These are quiet places, save for the pervasive murmur of the electromechanical devices which preserve the life functions of their residents. They are contemporary cathedrals of a sort, bearing mute witness to our infatuation with steel and speed. Most of the residents of these facilities will never leave; they are for the most part young men who have been in motor vehicle accidents, whose lives have entered limbo, a kind of extraordinarily costly suspended animation……the illusion of immortality that seems to accompany the testosterone storms of male adolescence lingers into early adulthood; by the time they discover that ‘it can happen to them,’ it is too late.”
Much of this remains true, young males still put themselves in harm’s way via thrill-seeking of various sorts. But the public face of TBI has gone through a number of gradual transformations over the years. Instead of the crash of automotive metal and glass, the image switched to the pulverizing shock waves from the explosive devices used to such deadly effect in Iraq and Afghanistan, and more recently to the repetitive concussive blows incurred by athletes in sports that feature levels of physical violence that would be illegal if they happened on a city street, epitomized by football, hockey, and boxing.
There are some significant differences between these phenomena, centered upon the common distinction between acute and chronic. Car accidents and explosive blasts do immediate and obvious damage to brain structures, and a resultant loss of function is immediately apparent, though the longterm profile of functional decrement can take months to fully emerge. Sports-related trauma/CTE, and ‘mild’ instances of blast and accident injuries, have a far more insidious course, with the cumulative effects of chronic CTE only emerging years later. In some ways, the two categories–which are anything but mutually exclusive, an acute injury (or several) can have more subtle but worsening longterm consequences–constitute acute trauma vs. longterm neurodegeneration, akin to the difference between a stroke and Alzheimer’s, where an individual may be robbed of their capabilities in an instant….or over many years. As is discussed in this review, the pathophysiologies of acute and chronic TBI appear to have some significant differences, but while the external manifestations may differ, and the internal pathophysiologies diverge, the impact of both can be devastating.
Acute TBI: The Legacy of War
Head injuries were dubbed the ‘signature wound ‘of the Iraq and Afghanistan wars: As the use of explosive devices grew more common, the incidence of TBI in the US military escalated, and for several years, accounted for 30-35,000 new cases a year. That might seem micro-scaled compared with the estimated 1.7 million TBI cases each year in the US, but it stands out because these men and women were injured in the line of duty, and they knew all too well that ‘it could happen to them.’ The technological advances in battlefield medicine that have saved the lives of so many have also yielded an unintended and grim bounty; a dramatically escalated proportion of wounded veterans with lasting brain injury. 56% of blast survivors were assessed as suffering moderate to severe TBI, while many cases of mild closed head injury (mTBI) never ended up in military hospitals, and likely went unreported, and unrecorded. The soldiers who carried their more severely wounded comrades to safety counted themselves lucky by comparison, but many blast survivors had lingering post-concussive injuries that compromised their cognitive abilities, altered their mood states and personalities, and prevented them from functioning to their full potential. The IED harvest that will never be fully quantified is characterized by occupational dead ends, depressive episodes, rage outbursts, alcohol abuse, and fragmented families. The Department of Defense’s own figures put the total number of US military TBI cases from 2000 to 2015 at 320,000, the vast majority being closed-head injuries, rather than penetrating wounds. There is a high correlation between TBI and PTSD in these military populations; 43.9% of soldiers who experienced TBI with a loss of consciousness also experienced PTSD symptoms. The relationship between TBI and PTSD is still being explored, including work now underway sponsored by Cohen Veterans Biosciences. That nonprofit research organization (which originally began as Orion Bionetworks) is being funded by the hedge fund manager Steven Cohen, who has pledged $275 million to the treatment of mental health issues in veterans.
Private and governmental funding of TBI research has taken on a high profile due to the failure of the pharma industry to display even minimal leadership in this large but challenging therapeutic area. Following a series of program failures in the 1990s, Big Pharma completely wrote off TBI as a drug development target. As with stroke, the major pharmaceutical firms came to see TBI as too difficult and risky to warrant a significant expenditure of resources. War bred an alternative, albeit inadequate, source of funding, and the phenomenon of blast-induced TBI did catalyze governmental support of TBI research. The toll of the battlefield led to a massive expenditure of federal funds from a variety of Department of Defense agencies, totalling $800 million in 2010 alone, probably 80 times or more what the industry as a whole spent on TBI in that same year. The single highest-profile government investment in addressing these military casualties came in the form of a five year, $107.5 million grant by the DoD/VA, funding consortia regarding the identification of biomarkers, the delineation of the clinical course of mild TBI (and PTSD), and the prevention and treatment of these disorders.
Another major collaborative initiative emerged under the aegis of the One Mind for Research program, geared to boosting precompetitive research and collaboration, receiving an initial funding ‘bolus’ of $2 million from JNJ/Janssen. The first initiative pursued by One Mind was to develop a data-integration center for information relevant to TBI research.
Research interest in TBI temporarily burgeoned in response to these high-profile patient populations and the availability of federal research funding. In 2007, NIR covered seventeen programs in our TBI review, in 2012 the number was forty-seven. But in the wake of still more clinical failures, the number has regressed, to thirty-eight programs, and only twenty-one of those are currently active, clinically or preclinically. Only two of these constitute NCEs whose active, primary application is in TBI, a third has yet to have its primary focus defined. The others are either repurposings, secondary interests, or in funding limbo. This should be a source of embarrassment to the pharma industry–but they appear to feel no shame around it.
Chronic TBI: For the Love of the Game Money
It is more than a little embarrassing that, in keeping with the American penchant for celebrity and spectacle, the public profile of TBI in the United States has been raised less by the epidemic of war-related brain injuries than by press coverage of the cumulative neurological toll taken by football. There has been an escalating drumbeat of media coverage of American football players found to be suffering from traumatic encephalopathy leading to early-onset dementia. In a number of cases, an ex-player has suicided in response to their cognitive decline, unable to tolerate the prospect of disability and helplessness, or else overwhelmed by the clinical depression that frequently characterizes CTE. This is neurodegeneration in slow motion, as opposed to the sudden and dramatic ablation of tissue and function seen in major blast injuries. CTE represents the cumulative effect of hundreds, even thousands of mini-traumas, and the brutal reality was best summarized by Lehman et al in their 2012 Neurology review: “The neurodegenerative mortality of this cohort is 3 times higher than that of the general US population; that for 2 of the major neurodegenerative subcategories, AD and ALS, is 4 times higher. These results are consistent with recent studies that suggest an increased risk of neurodegenerative disease among football players.” It is to the discredit of the football industry–which it is–that its executives long resisted attempts to define the risks and toll taken, and indeed withdrew funding from one CTE study because it was to be run by a researcher believed to be critical of how professional football polices itself vis-a-vis TBI. It was only this past March 14, in a Congressional hearing, that an NFL executive finally, publicly acknowledged the link between playing football and CTE. A few weeks later, data presented at the AAN meeting by a Florida researcher (Conidi) showed that 43% of retired NFL players show evidence of traumatic brain injury on diffusion tensor MRI imaging. The functional toll was suggested by neuropsychological testing data ta=hat showed a high prevalence of deficits in specific functional domains, such as executive functioning (50%), attention/concentration(42%), and learning/memory (44.7%).
For those who believe that this is an issue only for the minuscule slice of athletes who play professional football, there is chilling data indicating that the more than one million high school football players in the United States may also be placing themselves at similar longterm risk. A Mayo Clinic review of post-mortem brain studies showed that one-third of men who had played high school contact sports showed histopathological signs of CTE, signs seen in none of those who had not played such sports.American football is not unique in this regard: While there has been a long-acknowledged (and unsurprising) connection with boxing, exemplified by Muhammad Ali’s descent into Parkinsonian immobility (dementia pugilistica), hockey and soccer have been implicated as well. Expanding the potential range of concern is that there is no established baseline for minimum exposure risk, thus there are open questions regarding the millions of youthful participants in these sports at an amateur level, and the undefined but genuine risk they take.
The Societal Scope
Changes in the diagnostic criteria and epidemiological methodology have rendered TBI a moving target when it comes to both incidence and prevalence. Early this year, a Mayo Clinic study concluded that the incidence of TBI is far greater than had been previously estimated: While the CDC had been using an incidence estimate of 341 per 100,000 people, the Mayo estimate, using a broader definition of TBI, was 62% higher; 558 cases per 100,000. Two-thirds of this additional population had TBI symptoms, while the other third was not overtly symptomatic–but 74% of the ‘missing’ cases had actually presented to a hospital/ER. If this is an accurate appraisal, the 1.7 million annual US TBI cases estimated in 2013 might translate into an annual incidence of 2.5-3 million cases per year. This enlarged population cohort involves relatively mild to moderate TBI, the same degree of error would not apply to TBI requiring hospitalization or deaths, estimated to be 283,000 and 52,800 per year in the United States alone.In terms of prevalence, an Australian epidemiological study concluded that, over their lifetime, 5.6-6% of the population suffers a TBI that causes at least 15 minutes loss of consciousness, a more serious level of brain disruption than is generally associated with the milder end of the spectrum.
The traditional breakdown of moderate to severe TBI is that 10% die immediately; while 10% of the remainder are severely injured, less than half surviving; and those who survive are severely disabled. Another 10% are moderately injured, most suffering significant residual disability. Acute care following severe head injury can cost tens of thousands of dollars per day, and for those who survive such injuries but remain in a coma or persistent vegetative state–and there are thousands of these patients in the US–the maintenance care that they require in this twilight state of existential limbo can cost hundreds of thousand dollars per year.
While the great majority of TBI cases are ‘mildly’ injured, ‘mild’ injury is relative,and should not be confused with ‘innocuous’. The longterm cost for head injury patients relates to the jobs they will not be able to obtain or keep, and the safety net of medical and psychosocial services that they will require. The more severely injured can appear demented, and indeed there are pathophysiological similarities (increases in beta-amyloid and tau) which are seen in both TBI and Alzheimer’s. One study estimated that 43.6% of Americans hospitalized for TBI had residual disability a year later. This is a toll for which modern medicine is still very limited in what it can do, and even the most conservative TBI market estimates would provide an effective TBI drug with billion-dollar+ annual revenue potential.
While some sports-related injuries involve acute, catastrophic TBI, the new paradigm involves chronic exposure to repeated neural trauma. A 2011 estimate of sports-related TBIs in the US, utilizing South Carolina hospital and ER data from 1998-2011, concluded that the incidence was increasing, from 19.7 cases per 100,000 people in 1998, to 45.6 per 100,000 in 2011. Our suspicion is that the increase may at least partly reflect a broadening of TBI diagnostic criteria over time. At that 45.6/100,000 rate, one might extrapolate to about 150,000 sports-related cases per year. However, with the evidence suggesting that CTE cases exist and progress in symptomatic ‘silence’ for years and even decades, no one can claim to know with certainty what the true prevalence of TBI is at this point, particularly given that the potential toll of repetitive concussions (CTE) can be cumulative, not linked to a single, signal event, and such cases are particularly liable to slip by screening.
The Clinical Picture
Traumatic Brain Injury is highly heterogeneous, and the nature of an individual’s enduring deficits will vary with the type of injury and its specific impact on brain structures, and their clinical outcome can also depend on the toll taken by other, non-CNS injuries. In terms of closed head injury, patients with moderate-severe damage tend to show some common characteristics. Many of these patients encounter lifelong problems with attentional focus, social skills, and the ability to manage their emotions and/or to organize their lives. They display profound problems with judgment, insight, social appropriateness, attention, memory, and planning.
Post-TBI, an individual’s personality can be altered, even though they may not be aware of this. Particularly if the injury reached moderate severity, these patients may seem like strangers to family and friends, resulting in social isolation and enormous stress upon their familial relationships. Depending on the locus of damage, they may come across as apathetic and dulled emotionally, or they may seem constantly irritable and impulsive, with a ‘hair trigger’ temper. Because the connections between frontal and limbic areas of the brain are often damaged, these patients often have difficulty managing their own emotions. Frontal damage also reduces a patient’s capacity to focus and sustain attention; they become impulsive and easily distracted, unable to manage complex information. Even damage that seems less severe on standard neurological and neuropsychological evaluations can impair an individual’s ability to work up to their premorbid capacity: One epidemiological study noted that only 29% of TBI patients studied were working full time when assessed later, up to twenty years post-injury. Even though the concept of native neural plasticity has broadened in recent years, many significantly injured TBI patients appear to reach a ceiling beyond which further recovery does not occur, often after one to two years, falling short of the previous level of social/vocational functioning for probably two-thirds of these patients.
As was noted earlier, there is a large cohort of mild concussions that are either often ignored altogether, due to a lack of overt symptoms, or else are cursorily assessed and dismissed. It used to be believed that these the effects of such injuries would disappear over time, but that increasingly seems to be untrue, particularly when there is a pattern of repeated head trauma. In the long run, even when the patient may indeed look as though he/she is fully recovered, a careful neuropsychological evaluation, or interviews with wives or co-workers, will often reveal something less benign. Given that many falls, accidents, and sports injuries never end up incorporated into the epidemiological calculations, conservative estimates of TBI incidence almost surely undershoot the mark, as do estimates of prevalence and longterm functional impairment. As data regarding Chronic Traumatic Encephalopathy are now being gathered more systematically, there is an underacknowledged substrate of post-concussion cases wherein an underlying degenerative process may have ben set into motion, manifesting itself overtly only many years later. In the wake of whatever acute symptomatology may (or may not) have been displayed, patients with CTE eventually begin to show a disease course that begins with irritable depression and impulsivity, epitomized by the suicides by former professional football players that galvanized public attention. As CTE progresses, it begins to follow one of several neurodegenerative routes, emulating either Alzheimer’s, Parkinson’s, or ALS, depending on the particular form of the disease. It is not clear what determines the course that emerges for any individual patient.
from the March-April 2016 Depression/Autism issue
Focus on Suicide
There are efforts underway (e.g. NIH‘s RDoCs) to parse out specific behavioral manifestations of psychiatric disorders as more measurable and treatable neurobehavioral domains than are their ‘parent’ disorders. Suicidality is one of these domains, and while it can it can manifest in a variety of conditions, from unipolar depression to bipolar illness to schizophrenia (and others), it is with depression (both unipolar and bipolar variants) that it is most commonly associated. Suicidal ideation became a favored endpoint in a number of ketamine and ketamine-like drug trials, which makes some intuitive sense: As an NMDA antagonist, ketamine might be thought of as a means of disrupting patterns of cognition, and even though it is argued by some that depression in general reflects thinking gone astray, suicidal ideation is a specific and potentially lethal manifestation of cognition ‘in error.’ Just as ECT–amongst its several effects–disrupts learning and memory, perhaps the acute effects of ketamine and its ilk include a similar clearing of the cognitive ‘slate’. One study that looked at neuropsychological functioning assessed just after IV-ketamine administration found that the patients who were treatment responders 24 hours later had performed worse on cognitive testing–perhaps supporting the hypothesis that one must disrupt cognition in order to alter depressive mood in general, suicidal ideation in particular.
AstraZeneca pursued suicidality with IV AZD6423, the successor to the failed (in Phase IIb, albeit with a high placebo response rate) NMDA antagonist AZD6765, but after a 175pt Phase I was completed, that compound was itself replaced with orally-bioavailable AZD8108, for which a 258pt Phase I trial was completed last year. There has been no public announcement, but apparently no gross safety issues have arisen, since it is still cited as in development.
The Mayo Clinic is running a 30pt trial of ketamine in depressed patients with suicidal ideation, that trial wrapping up this year: The MADRS is the primary endpoint, but suicidal ideation is the secondary endpoint. MGH is going to run a ketamine study in suicidal patients, with a suicidality scale as the primary endpoint. A VA study will enroll 40 patients when it is initiated this year. NY State Psychiatric Institute has launched a 70pt study of ketamine’s effect on suicidality, and has fully enrolled a 20pt trial in bipolar depression/suicidality. A Mt. Sinai study that found 53% of previously suicidal patients similar had a complete remission of explicit suicidal ideation 24 hours after a ketamine infusion, compared to 24% of those receiving midazolam. University of Alabama is conducting a 240pt study assessing the potential of plasma microRNA biomarkers for suicidality and ketamine responsivity.
Trials using ketamine to treat suicidal ideation are being done at a number of other US centers and by Canadian, French, and Israeli groups.
JNJ/Janssen is running a 70pt Phase II trial of esketamine in patients believed to be at imminent risk of suicide, both to assess drug effect (4 hours post-administration) and to assess the utility of their measurement strategy for acute suicidality. That trial should be wrapping up in the next few months.
Cerecor ran its Phase II trial of CERC-301 in depressed patients with suicidality, combining two trials into one. That trial was unsuccessful, but they now intend to run another Phase II with a higher dose, emphasizing impact upon depression rather than suicidality.
NeuroRx is developing a combination therapy aimed at suicidality in bipolar depression: A ketamine IV infusion, followed by an oral, fixed-dose combination of lurasidone and d-cycloserine (‘Cyclurad’). It represents something akin to a glutamatergic bolus, followed by glutamatergic maintenance, counterbalanced with an antipsychotic. The data behind the combination consists of a eight patient, open-label, eight-week trial, for which they report a 50% reduction in depressive symptoms, a 75% reduction in suicidal ideation. As is discussed in the Company Spotlight on p.52, there is an unsettling degree of hyperbole and hypercertainty that has characterized the company’s self-promotion.
from the Jan-Feb 2016 Overview issue, Highlights/Lowlights section:
1) Aducanumab: Some time had passed since the most recent Alzheimer’s vaccine hyperbole-fest, so it was almost inevitable that aducanumab would provide Biogen and the Alzheimer’s field in general another opportunity for overreach in the face of ambiguity. It is not that the trial proved failure, it did not, but the questions left unanswered are huge, and little has been definitively established:
a) It does appear clear that target-engagement is achieved, though it requires enough disruption of the BBB that vasogenic edema is frequent and problematic.
b) It seems clear that this mAb does reduce plaque significantly, and there was nothing in these results that pointed towards a negative impact from doing so.
c) Clinical benefit is where the audience bifurcates, with many accepting Biogen’s explanation and enthusiasm for the disclosed data, many others remaining skeptical. There is data that has not been generally released to the public, in terms of results from some of the other neuropsychological tests administered, and the belated 6mg/kg results suggest a very narrow tightrope walk between plaque clearance and vasogenic edema. There was a considerable incidence of VE at higher doses, and while 78% were described as ‘mild to moderate’, this means that 22% were more severe, some requiring hospitalization. It will require a far better understanding of aducanumab’s efficacy at various dose levels, differentiated by APOE genotype, to sort out the risk-benefit profile for aducanumab, and the size of the window for achieving therapeutic benefit with acceptable tolerability.
The trends reported neither prove nor disprove the case for the amyloid hypothesis or for aducanumab. The results provide a highly provisional hint of an efficacy signal, one whose clinical meaningfulness is unclear at best.
2) LRRK2 Safety Alarm: We still think that Genentech going public with their tox findings demonstrated corporate maturity, as was the ensuing collaboration of Genentech, Merck, and Pfizer with MJFF to independently assess other LRRK-inhibitor candidates for pulmonary safety risk. This was a very positive sign of the industry adaptively expanding what is deemed pre-competitive space. The bonus is that the tox finding is not a class-wide phenomenon: Merck (at least) is going to move ahead with its LRRK-inhibiting program.
3) Axovant. After years of drought, the biotech El Nino dropped a foot of fiscal rain across much of the neuro sector, and while this provided sustenance, it also led to some eyeball-rolling from observers who wished that Roivant/Axovant would at least pretend to care about how self-serving their behaviors look.
from the Addictions review, Nov-Dec 2015 issue:
Cocaine and Amphetamines
Cocaine was the glamour party drug of the disco era, falling into disrepute with the advent of smoked ‘crack’ cocaine. There were an estimated 1.9 million cocaine abusers in the US in 2008, and while there has been a decline in cocaine use overall–one estimate was of a 40% drop from 2006 to 2010–cocaine abuse continues to present a major public health problem. While there once was enough cachét to earn cocaine a cameo role in Woody Allen’s Manhattan; even though methamphetamine had a central role in Breaking Bad, ‘meth’ has never been imbued with even a tinge of glamour. Instead, methamphetamine has exploded into a high-profile law enforcement problem, which tore through parts of the American heartland with stunning results. Methamphetamine abuse wreaks extraordinary carnage: No other drug of abuse adds decades of age to a human face in just one year like methamphetamines can.
It should be noted at the outset that, in contrast to opiates, this does not appear to be a context of prescription amphetamine addiction. Even though considerable media attention has been devoted to the overutilization/diversion of amphetamine-based ADHD medications, while this constitutes abuse usually in the service of performance-enhancement, there is no evidence that this has turned into an addiction/dependency issue per se.
In contrast, the abuse of methamphetamine turned into an epidemic of chronic abuse, associated with a slide down the socioeconomic ladder into violence and eroded health. There are signs that this epidemic has crested, and has even begun to recede somewhat: A US survey that in 2006 found 731,000 individuals having used methamphetamine in the previous month, found 440,000 such users in 2012; emergency room visits due to methamphetamine consumption have also ebbed significantly. But there are towns in the American Midwest which have had their social and even law enforcement fabric shredded by methamphetamine abuse.
Amphetamines increase the levels of multiple neurotransmitters, including serotonin, norepinephrine, and dopamine, but it is in terms of their powerful effect upon dopaminergic activity, particularly in the nucleus accumbens, that cocaine and amphetamines are very similar. They also appear to interact with trace amine receptors, though the meaning of that mechanism is not understood. Cocaine is somewhat more specific in its impact, primarily upon dopamine reuptake, (though serotonergic effects via 5HT-3 have been reported) and it is the speed and duration of effect that differentiates cocaine from amphetamines for the most part, though the increase in smoking rather than orally ingesting illegal amphetamines narrowed that gap considerably. The flip side to rapid onset, however, is an equally rapid and intensely valenced cessation of effect, and to rapidly lose that sense of acceleration and expanded mood is aversive in the extreme. Thus freebase amphetamine and cocaine users tend to use these drugs in binge fashion, not stopping until they run out, or simply collapse from exhaustion (or worse).
Negating Reward: Vaccines
Celtic Pharmaceuticals: TA-CD was originally developed by Xenova as a vaccine for cocaine abuse. Like the nicotine concept, the premise has been that the antibody/cocaine bound combination is too large to pass through the BBB, hence reducing the reinforcing impact. A Phase IIa study reported that patients with high antibody titers resulted in a reduced level of cocaine effect and a decrease in the amount of cocaine use self-reported by the patients (self-report is not an optimal measure in this population). In a 114pt Phase IIb study, which unfortunately tested cocaine users also receiving methadone therapy for heroin addiction, TA-CD failed to show efficacy, due to the ‘higher than expected placebo response.’ The Baylor University researcher who designed the vaccine published much more detailed results in 2009. He reported that it was the level of antibody titer which was the key factor in determining effect, and 38% of the 94 subjects who finished the trial had high titers. That 38% cohort produced a 45% proportion of cocaine-free urine samples, compared to a 35% proportion in those with low titers or on placebo. This was marginal at best, and when NIDA ran another trial, it did not show benefit.
A monoclonal antibody aimed at methamphetamine abuse has been developed by the University of Arkansas (ch-mAb7F9). The mAb produced the desired antibody response–which should in theory bind to methamphetamine and prevent BBB entry–in 4 of 32 individuals who received in Phase I. Based on animal testing, it is believed that one infusion might provide attenuation of methamphetamine effects for up to nine months. That program has been spun out as InterveXion Therapeutics, and received $14.5 million in NIDA funding.
Weill Cornell is running a trial testing an AAV delivered vaccine (dAd5GNE) in cocaine addiction. This 30pt trial, with an eight-month treatment duration, is expected to be completed in 2018.
A non-vaccine tactic that has a similar aim involves the upregulation of cocaine degradation, in this case, by increasing its hydrolysis. A mutated form of the enzyme butyrylcholinesterase has been tested in humans, and an IV infusion reduced plasma levels of cocaine by 90% within two minutes. This is being developed as RBP-8000, by Indivior, aka Reckitt Benckiser‘s pharma programs.
A similar program is being brought forward by Teva Pharma, in conjunction with NIDA. TV 1380 combines butyrylcholinesterase with serum albumin, and in recreational cocaine users receiving IV cocaine, was observed to dramatically reduce the maximum concentration and half-life of cocaine, as well as reducing its reward-characteristics. The duration of the effect from a single IM injection was at least one week. A two-dose, 12 week Phase II trial using weekly injections has been completed, but the results have not yet been disclosed.
Vigabatrin/Sabril is an anticonvulsant marketed in the US and EU, Catalyst Pharmaceuticals licensed rights to vigabatrin as an addiction therapy. It was hoped that this irreversible inhibitor GABA-transminase would produce enhanced GABA levels inhibiting dopaminergic ‘bursts,’ hopefully exerting anti-addictive effects. In theory, this was to be an activity-dependent mechanism that avoided the somnolence and dulling expected if GABA levels in the synapse were chronically elevated.Catalyst also hoped that the irreversible inhibition of GABA transminase, once in place, could be maintained with low dosing that might permit up to five years of dosing before reaching the threshold associated with a higher risk of visual field cuts. However, after some initially-promising clinical trials that were conducted in Mexico, US Phase IIb results missed the primary endpoint, though it was also found that the trial was compromised by very poor patient compliance (just 40% of the patients in the cocaine trial actually took their medication as ordered). With funding from NIDA, Catalyst ran yet another Phase IIb trial in cocaine addiction, but that trial showed no benefit. Catalyst subsequently turned its focus to pediatric epilepsies and other orphan disorders.
Embera Therapeutics‘ EMB-001, previously described in detail, combines two off-patent marketed drugs, metyrapone and oxazepam, aimed at modulating HPA activation. Metyrapone is a glucocorticoid synthesis inhibitor that provides decreased CRF activation. It is combined with oxazepam, a benzodiazepine, which increases GABA activity. Embera completed a 45pt pilot cocaine study (two doses and placebo), stating “EMB-001 significantly reduced cocaine craving at many time points during the study and was generally well tolerated over a 6-week treatment period. In addition, objective measures of cocaine use demonstrated decreases in subjects treated with EMB-001 compared to placebo.” Embera received $3.9 million from NIDA to complete their preclinical tox package, and has initiated Phase I, pursuing the smoking cessation indication first.
MediciNova’s ibudilast is in a 140 pt methamphetamine study, sponsored by NIDA and run by UCLA. Addicts are withdrawn from methamphetamine, ibudilast’s impact on craving assessed, along with safety and tolerability. Ibudilast is a glial cell modulator that inhibits Macrophage Inhibitory Factor (MIF) and upregulates GDNF, believed to possibly normalize dopaminergic system functioning. Data is expected in 2017.
As was discussed earlier, orexin-1 subtype receptors interact with dopaminergic neurons in the reward center (VTA) of the brain, and this target is being avidly pursued by a number of companies: Janssen/JNJ, Merck, Sosei/Heptares, AstraZeneca (via Eolas), Eisai, and Minerva Neurosciences. Heptares recently received a $5.5 million NIDA grant to facilitate their program development. They have identified some candidate compounds, and the hope is that their GPCR crystallization technology will enhance their ability to select and optimize a lead for full preclinical development. That grant is to cover three years of work. Eisai’s collaboration with Purdue Pharma will most likely eventually explore addiction as an option for lemborexant, AstraZeneca/Eolas’ partnership is specifically focused upon orexin antagonism in nicotine abuse.
Animal data suggests that 5HT-2c agonists like Arena/Eisai‘s lorcaserin reduces the reward characteristics that lead to the continuation of cocaine intake, but also may prevent relapse. Interestingly, the literature also suggests that 5HT-2a antagonists, like Acadia‘s pimavanserin (NDA filed for schizophrenia) may reduce relapse-rates in cocaine abuse, while not reducing active cocaine ingestion. Eisai/Arena’s interest in expanding Belviq into any addiction disorder appears questionable, and this area will be of little interest to Acadia for the foreseeable future, but it does add some viable compounds for testing these mechanisms in cocaine addiction.
In animals, D3 antagonism appears to inhibit craving for variety of substances, including cocaine. Pierre Fabre Pharmaceuticals has had success developing F17464, but they are currently emphasizing the treatment of schizophrenia. A number of companies discontinued their D3 antagonist programs; Bioprojet had addressed addiction, with a smoking cessation trial that appears to have failed.
A GSK prototype achieved good D3 receptor occupancy, but somewhat disappointing results in a smoking trial, and was discontinued. While that likely reflected internal politics more than mechanistic viability, it is worth noting that animal work indicates that co-administration of GSK’s D3 compound and cocaine led to blood pressure elevation; thus the regulatory path for D3 antagonists in cocaine abuse might not be tenable, due to safety concerns.
BioTie’s nepicastat was a dopamine hydroxylase inhibitor licensed from Roche, which inhibited the breakdown of dopamine to noradrenaline. Based on the premise that slowing dopamine metabolism would attenuate the anxiogenic generation of norepinephrine, NIDA funded a Phase II trial in cocaine dependence, which failed.
Alkermes developed samidorphan/ALKS33, a mu-opioid antagonist, in conjunction with buprenorphine, as ALKS5461. It is believed to act as a kappa opioid antagonist in that combination, and while cocaine abuse was an early target, Alkermes has made a huge bet on it as an antidepressant, wherein it is now in Phase III.
Lorcaserin/Belviq: With a successful Phase II in nicotine addiction on record, Arena/Eisai’s 5HT-2c antagonist obesity drug is being tried in a Phase IIa trial for cocaine addiction, the study being run by Virginia Commonwealth University, funded by NIDA.
Topiramate: A small pilot study done in 2004 indicated that topiramate did improve the likelihood of abstinence over placebo, though animal studies have raised questions as to whether topiramate has any consistent effect upon drug discrimination (and hence, craving). The combination of topiramate with the stimulant phentermine is being tested by a U. Kentucky group as a cocaine addiction treatment. New York State Psychiatric Institute is combining topiramate with Adderall-XR in a Phase II cocaine abuse trial; the use of an amphetamine to treat cocaine abuse raises some interesting questions. That same group is running a trial of amphetamines combined with cognitive-behavioral therapy in cocaine dependency, the same questions apply.
Cannabinoids: CB-2 agonism has been reported to reduce cocaine self-administration and cocaine-induced increases in dopamine within the nucleus accumbens, while avoiding psychoactive effects.
Bupropion, whose dopaminergic effect has been utilized in smoking cessation, is being assessed in cocaine dependency by a Johns Hopkins group, looking at both the initiation of abstinence and the impact upon relapse.
Prior to its acquisition by Gilead, CV Therapeutics was working with an aldehyde dehydrogenase-2 antagonist, CVT-10216. ALDH2 is one of the two major enzymes involved in the metabolism of alcohol, thus blocking this enzyme blocks the intoxicating effects of alcohol by interfering with its processing, and creates aversive effects via the accumulation of acetaldehyde, as does disulfiram. It had been reported that ALDH2 reduces excessive dopamine in the nucleus accumbens, without impacting baseline dopamine. Gilead had continued for a time with preclinical testing vis-a-vis cocaine addiction, but this appears to have been shelved.
In a Phase IIa trial using Provigil, 33% of patients receiving modafinil remained cocaine-abstinent for three weeks or more, versus 13% of those on placebo. Given that the placebo group included more severe users, this has to be taken with some salt, though the researchers attempted to correct for this, and concluded that the effect was significant. A 17pt open-label unpublished study showed 47% produced cocaine-free urine samples (frequency was not reported) over an eight week period, compared to what the investigator cited as a 6.5% historical control comparison. However, a 650pt Phase IIb study vanished without a trace of reported data, and this has demised.
Optogenetics: In vitro testing indicates that mouse neuronal circuits sensitized by exposure to cocaine can be returned to their baseline, changes in synaptic plasticity reversed, via the use of light as a neuromodulator. There is an enormous gap to be bridged from murine brain slices to human brain activity, but it is an intriguing premise.
There are some studies where practical applicability seems unlikely. For example, there is a NIDA-sponsored trial where 120 cocaine addicts are to be treated with Adderall XR and topiramate in combination. Similarly, there has been a trial offering extended release d-amphetamine and buprenorphine to cocaine addicts (“Effects of Sustained Release d-Amphetamine and Buprenorphine on Drug Seeking Behavior in Opioid and Cocaine Dependent Individuals Who Are Not Seeking Treatment”). As noted earlier, while a case can be made for oral amphetamine usage being less of a health risk than IV cocaine use, our view is that offering amphetamines and abusable buprenorphine to addicts who are not interested in treatment is an open invitation for them to ‘game the system.’ While one can well argue that providing a lower-reward substitute is essentially the same model as is used in methadone treatment of heroin addiction, regulatory receptivity may be hard to find.
Parkinson’s: The GDNF Saga (from May/June 2015)
GDNF is the best-known member of a group of neurotrophins that belong to the TGF-beta suprafamily. Back in the 1990s, Amgen demonstrated that infusing GDNF produced functional improvement in a primate Parkinson’s model, including some evidence of cognitive enhancement. Amgen ran a small Phase II trial, injecting GDNF into the putamen, yielding some impressive (albeit inconsistent) anecdotal reports, but a 34pt placebo-controlled study was reported by Amgen in 2004 to have failed. This claim was quite controversial, and indeed turned into an ethical hornets’ nest when, in early 2005, Amgen dropped the GDNF program entirely, and announced that they would no longer supply GDNF to some 48 patients who had been receiving it on an extended, compassionate use basis. Amgen cited what they described as toxicity issues (including cerebellar scarring) in a high-dose primate safety study. This led to a legal skirmish with patients furious at being cut off from a treatment they experienced as being beneficial, their case buttressed by anecdotal reports of durably slowed deterioration, and of a patient who showed signs of interwiring on autopsy. Amgen fended off the legal challenge, but this did lasting damage to Amgen’s reputation in the neuroscience world, and in the PD patient community, wherein there continues to be a simmering undercurrent of anger in the at what they believe was the use of a toxicity red herring to justify a decision made for cost savings.
In 2010, Amgen licensed the use of GDNF to Biovail, whose CSO had previously served as the Amgen CSO overseeing the PD program (which further undermined the credibility of Amgen’s claims regarding patient safety concerns). Biovail’s belief was that it was inefficient perfusion of the parenchyma that compromised the earlier testing, and to address this, they partnered with MedGenesis Therapeutix, whose CED (convection-enhanced delivery) technology infuses payloads under pressure, achieving better brain penetration.
But then, the research-phobes at Valeant had acquired Biovail; this program was anathema to them, and they returned the rights. MedGenesis eventually initiated Phase II testing in Parkinson’s on its own, a trial aimed at enrolling 42 patients, at a single UK site. The placebo-group in this trial is constituted as a delayed-start group, serving as the control for nine months, then transitioning onto the drug themselves, to facilitate enrollment and avoid ethical issues. One as-yet-unanswered question hanging over this approach is whether CED delivery can infuse a sufficiently penetrant and sizable neurotrophic payload into the putamen. The trial utilizes imaging that they hope guarantees that they have provided GDNF where it is needed. Pfizer produced a pleasant surprise last year when they took an option on the MedGenesis program, that option to be exercised (or not) when the Phase II data becomes available in 2016. While Pfizer’s deployment of an option might seem to be a half-hearted commitment, such is not the case here; they have put significant resources into reconfiguring that study, moving it to a new site they consider better-equipped, and preparing sites and investigators (CED neurosurgical delivery of GDNF is not a widely-held skill) for a large-scale Phase III.
The question as-yet unanswered for MedGenesis, and all other neurotrophin programs that involve putaminal delivery, is whether this small delivery ‘locale’ is sufficient to make a clinical difference. There is some evidence–albeit not universally accepted–that axonal transport is impaired in PD: If GDNF, neurturin, or other trophic payloads cannot travel to the substantia nigra, there are those who believe that–regardless of the splendid results in monkeys–this will fail in humans. In other words, boosting penetrance via CED may be necessary, but it remains to be seen if it will be sufficient.
UniQure (the offshoot of Amsterdam Molecular), has a NINDS-funded Phase I trial underway, for AAV2 delivered GDNF (AMT-090), this program in collaboration with UCSF. Uniqure claims exclusive access to the use of the GDNF-gene in this regard, licensed from Amgen. The trial is utilizing convection-enhanced delivery, and is currently enrolling patients in what they describe as an escalating dose safety study, aimed at enrolling 100 patients. The study includes a five-year followup period, and they anticipate completion in 2018. While UniQure’s recent deal with BMS is purely cardiovascular, the $100 million UniQure received upfront guarantees that they have the resources to see this trial through to the end.
NINDS is sponsoring a 24pt study of AAV delivered GDNF in Parkinson’s, this study not expected to report until 2018. Patients will be moderate to severe in their degree of disease-progression, CED is being utilized in the hope of providing better penetrance in the putamen.
In 2011, Lilly partnered with Medtronic to deliver an altered form of GDNF in Parkinson’s. That program never reached the clinic, and appears to have been shelved. Angiochem tried using their conjugate technology to deliver GDNF across the BBB in Parkinson’s, but also appears to have dropped that program.
ArmaGen developed AGT-190, which combines GDNF with an antibody that binds to an insulin transporter site on the BBB, thereby facilitating BBB access. ArmaGen has been conducting preclinical studies in PD. NINDS is sponsoring a 24pt study of AAV-delivered GDNF in Parkinson’s, this study not expected to report until 2018. Patients will be moderate to severe in their degree of disease-progression, CED is being utilized in the hope of providing better penetrance in the putamen. NsGene has been preparing to deliver GDNF-producing cells with its sheath technology, as is discussed later.
Anyone involved with these GDNF infusion programs must have had their anxiety raised when Ceregene‘s AAV delivery of neurturin failed in Phase IIb, as is discussed later in this review. Ceregene had sought to broaden the locus of increased neurotrophic activation by injecting the vector into both the putamen and substantia nigra, amidst concern that the retrograde axonal transport of the neurotrophic factor might be impaired in PD. When this additional feature failed to improve the outcome, it revived the question of how much is needed, and where, in order to achieve disease-modification. If MedGenesis achieves success, that could trigger a renaissance of interest, but that cannot be assumed.
A NIH-sponsored study reported that valproate triggers the release of GDNF and BDNF, and is protective in an in vitro model. However, valproate has been promiscuously thrown at virtually every psychiatric and neurological disorder ever identified, and we suspect that any robust neuroprotective benefit would have already surfaced.
Other members of the same neurotrophin family, considered possible PD therapeutics, include neurturin, perspherin, and artemin. All are protective of dopaminergic neurons. Neurturin was the payload delivered in the Ceregene program, discussed below.
PDGF-C (Platelet-derived growth factor-C) was identified by a NIH group as a trophic factor that provides anti-apoptotic benefit in mouse models of PD and stroke, and is similar to the PDGF-BB variant being delivered in the Newron/NeuroNova program discussed in this review’s section on neuroregeneration.
Genervon Biopharmaceuticals is developing an IV neurotrophic peptide that they call MNTF, which reportedly binds to subunits of the IGF-1 and IGF-2 receptors. They state that they are developing this peptide for multiple neurodegenerative disorders, and claim to have obtained positive Parkinson’s Phase IIa data–from a six patient trial. However, the exceptionally sparse data disclosure consisted of comparing UPDRS scores at 12 weeks with some type of historical dataset, their secondary endpoint comparisons were at two weeks (there was no comment on how they looked after ten additional weeks…) Their presentations tend distinctly towards the hyperbolic, and the notion that this is a one-size-fits-all growth inducer is unlikely to pan out. Given that they sent out a press release expressing frustration with the FDA not granting them accelerated approval following an eight-patient, 12 week ALS trial, their approach to regulatory affairs needs some refinement as well.
MANF (mesencephalic astrocyte-derived neurotrophic factor) was a neurotrophic factor identified by Amarantus Therapeutics’ scientific founder, which they believe reduces apoptosis while fostering regeneration. MJFF funded a rat trial comparing the neuroprotective capacity of MANF with GDNF vis-a-vis dopaminergic neurons. MANF’s distribution in the striatum and frontal cortex exceeded that shown by GDNF. MANF also bettered GDNF in that model, reducing behavioral deficits at 6 weeks by 53% (compared to 20%). However, after a slew of corporate moves, MANF has been relegated to a retinitis pigmentosa program, none of the Amarantus neuroprotectant agenda has remained active.
There is another issue that has surfaced regarding potential obstacles to neurotrophin-centered programs: Increases in alpha-synuclein appear to reduce the availability of Nurr1, and decreases in Nurr1 are believed to reduce the availability of receptors for GDNF and similar neurotrophins, attenuating their impact. This raises the possibility that co-treatment with a Nurr1 agonist, as was discussed earlier in this review, might be necessary for the supplied neurotrophin to work up to capacity.
SCI: All Roads Lead to Rho…(from March/April 2015)
There are a couple of other candidates for the role of inhibitory mediator, through which growth-inhibiting signals from various sources must pass, that offers an attractive target for blocking these inhibitory processes, and Rho has survived to become the leading possibility. As was noted above, activation of the two major Nogo complexes (combined with either p75 or TROY) eventually leads to Rho activation. Rho can also be activated by proteoglycans found in the scar tissue, the aforementioned neurochemical obstacle arising from the extracellular matrix components of scarring. Rho antagonism thus blocks not only the impact of Nogo, but also is involved in pathways triggered by other growth-retarding factors, including proteoglycans and axonal repulsion factors. Rho proteins modulate signal transduction within the growth cone itself, controlling axon growth and cell proliferation. Blocking Rho promotes neuroprotection and axon growth, upstream of nogo, and both in vitro and in vivo studies have shown axonal growth after Rho antagonism. One theoretical downside to the Rho target is the fact that Rho proteins are ubiquitous throughout the body, although no safety/tolerability issues have arisen in the clinical testing done thus far. Rho had initially been the focus of two companies, BioAxone and Migragen. Both took a known Rho-antagonist with very poor absorption, the enzyme c3-transferase, and modified it. Migragen combined CT-3 with a component taken from botulinum toxin, which increased membrane permeability. But Migragen ran out of money and sold their IP to Schering, albeit to be used only for screening.
BioAxone has persevered with the development of Cethrin, a recombinant version of c3-transferase that antagonizes Rho. It is neuroprotective (reducing apoptotic cell death 50% in one model), and reduces TNF-alpha, thus reducing inflammation and scar formation. They claim that it is effective in promoting growth, with at least a 24 hour post-crush window. No significant treatment related adverse events have been seen.
In a 48pt (mean time to treatment was 52 hrs post-injury) open-label PhI/II program using five doses of Cethrin, 43% of the patients showed functional gains of two ASIA grades or more, from a starting point at ASIA A (complete loss of function below the level of injury). Some improved up to Level D, where at least half of the muscles innervated from below the injury have regained significant functionality. In the 12 patients with cervical injuries (thoracic injury patients tended to show little benefit, and were included primarily to assess safety), the mean improvement over twelve months was 27.3 points for the 3mg group, 21.3 points for the 1mg group. Historical control data suggests about 10% of ASIA A patients show this level of ASIA-category improvement, and it usually occurs fairly early in the post-injury period. Motor function and sensory improvement were noted, and no adverse event or tolerability problems were reported. Unfortunately, even when the trial was expanded, no placebo group was added, and the lack of a control group considerably complicated the process of finding partners.
Even though historical control comparisons must be viewed with considerable skepticism, these results are striking, and have long seemed worthy of followup testing. BioAxone originally partnered Cethrin with Alseres, but Alseres failed to carry out the promised PhIIb trial, and BioAxone eventually regained those rights and reconstituted itself, with the goal of going into Phase IIb. That is now going to finally happen, thanks to the long-awaited partnership with Vertex Pharmaceuticals, which provides BioAxone with $10 million upfront. Phase IIb should get underway later this year, funded by Vertex.
Amyloid: The More Things Change….(from January/February 2015)
1)Roche Terminates Gantenerumab Trial: In late December, Roche ended their gantenerumab Phase III in prodromal Alzheimer’s when a futility analysis showed no hope for benefit, a year after an internal review concluded that the program should be continued. This study was planned to go until 2018, and the good news is that Roche had implemented sufficiently stringent controls that they pulled the plug on the program relatively early, before the expectations, and the costs, had further escalated. Secondly, as is noted elsewhere in this review, it calls out plaque imaging as the placebo biomarker that it is: Plaque imaging makes us feel better, because we can measure it, but it has no apparent predictive value when it comes to clinical outcome. Third, it is going to force the Alzheimer’s field to once again address its chronic infatuation with the siren’s song of the amyloid hypothesis; it does not necessarily prove that amyloid is irrelevant to AD pathophysiology, but the burden of proof is on companies that continue to invest in AB monoclonal antibodies to explain how a different outcome can be anticipated from their pet project. Fourth, the rationale that had evolved into a commandment held that vaccine failures had been due to the failure to intervene early enough in the disease process, before too much damage had been done. This trial sought to address that factor by enrolling prodromal patients. The results leave open the question of just how early is early enough, if indeed there is such a thing. And anyone tracking the more recently initiated gantenerumab Phase III in mild Alzheimer’s can now start the countdown; the question is how long it will take for Roche to terminate that trial as well.
2) Biogen-Idec and BIIB037: The gantenerumab collapse relates to this entry, but that is only part of the story. Biogen-Idec has planned and executed better than almost anyone else in the neuro area. So when they make errors, those mistakes are magnified by the contrast. Their mishandling of the announcement of results for BIIB037 would be a faux pas for any company, for Biogen-Idec it was stunningly obtuse.
First of all, the content involved vague but intriguing results for this monoclonal antibody (from Neurimmune)against an undisclosed epitope of beta-amyloid, the Company stating that patients, after 54 weeks of treatment, showed decreased plaque load and improved cognition. Biogen-Idec was sufficiently impressed that they plan to now go directly into Phase III from a trial that was originally labeled as a Phase I. As has been discussed by NIR numerous times in the past, and at several locations in this issue, changes in plaque load have not been established as predictive of anything meaningful to patient outcome, and it is not reassuring that this was apparently central to the BIIB037 ‘go’ decision.
There were also process issues: This news was disclosed at a presentation at the Deutsche Bank BioFest investment conference, and was not accompanied by a corporate press release or SEC filing. Company spokespersons made limited additional comments in response to press inquiries, and when confronted on this, seemed oblivious to the problem, that this was selective disclosure of material information. If anyone doubts that it is material, the Market added $5 billion to Biogen-Idec’s market cap on just that first day, which qualifies as material in our view.
Secondly, in their public description of the trial, Biogen-Idec had disclosed only plans to assess biomarkers; imaging AB plaque load, blood levels of antibodies. It turns out that they were also conducting cognitive testing of some kind, which means they withheld relevant information about the trial protocol. It should be beneath Biogen-Idec to play petty games with this kind of information. We are also unimpressed with their plan to not disclose the full data until a conference sometime in 2015. Private companies can get away with delayed disclosure, but a public company, with this much riding on skimpy and selective disclosure, should not. Perhaps the analysis is not yet complete, but they do have more detail that could have been provided. For example; What were the cognitive testing results that inspired a Phase III ‘go’ decision? What was the rate of vasogenic edema in APOE4 vs. non-APOE4 patients?
Finally, and this is more ambiguous, we always have a moment of vertigo when a company skips doing a real Phase II and just goes directly into a several hundred million dollar Phase III in Alzheimer’s, particularly when they cite beta-amyloid plaque reduction as a key biomarker finding. It has not worked out well in the past, and while Biogen-Idec is in good company (e.g. Merck, Lilly/AstraZeneca, Roche) in choosing to shave off two or three years off the development timeline, the added risk is not to be dismissed, as the freshly minted gantenerumab news once again shows. This is a judgment call, whereas the issues regarding informational omissions, are not judgment calls, they were mistakes. Pretending otherwise does harm to the credibility of a company that has no need to court this kind of self-inflicted damage.