Parsley, SAGE, Marathon, and Timing

–with apologies to Simon and Garfunkel, 1966

SIDE A

NIR has long been an admirer of how SAGE Therapeutics has been able to leverage predictive power from tiny pilot studies in Severe Status Epilepticus (SRSE) and Post-Partum Depression (PPD)—but today’s open-label depression results require much more sodium intake. In SRSE, the risk of a placebo response is essentially zero, and in PPD, there is compelling biology linking PPD and allopregnanolone, depletion of the latter heralding the utility of supplementing that hormone. But in Major Depression, if allosteric GABA-A activation truly offers such a rapid avenue to dramatic and immediate relief in MDD, that will require a rather drastic rethinking of how depression, and antidepressants, work. It is not as if we haven’t had GABAergic drugs fail to show benefit in depression before (e.g. benzodiazepines). We are curious about the gender makeup of the 13 patients, and the frequency of somnolence/sedation, not only as a side effect to consider, but as a driver of the placebo effect (’something is happening to me…’). If they can replicate this magnitude of change in the double-blinded, controlled Phase II, that will be very impressive. SAGE’s track record has earned them credibility, but here, science mandates considerable skepticism.

SIDE B

The January/February issue of NP included a satirical sidebar about ‘ToneDeaf
Therapeutics.
’ Unfortunately, Marathon Pharmaceuticals did not get the memo–or the hint. Marathon received FDA approval for deflazacort, a corticosteroid used in the treatment of Duchenne Muscular Dystrophy, but they then marched themselves into a public relations debacle.

1) Marathon announced that the drug will be priced at $89,000 per year. Previously, US families could obtain deflazacort from the UK for about $1600 per year. Marking up a drug more than 50-fold in an environment sensitized to such things by Turing,
Mylan
, and Valeant is like hanging a giant ‘kick me’ sign on one’s hindquarters. Do these companies not learn from the errors of their predecessors?

2) Marathon’s CFO, Babar Ghias, attempted to downplay the pricing issue by telling the WSJ that “Marathon estimates it will keep  only 61% of $89,000….or$54,000.” Most people are not going to see this as ethical or compassionate, it’s like reducing the price of a bottle of water at Coachella from $20 to $13.

3) Ghias stated that the other 39% would go to Medicaid rebates, copay coupons, and discounts, the kind of complicated shell game that makes the pharma industry seem more imbued with scam than science.

4) Ghias was also quoted by the WSJ as saying “more patients will have access to the drug because their health insurers will begin covering its cost now that it has FDA approval.” This is the insurance fallacy, the pretense that drugs covered by insurors have no cost to patients–they do, in terms of the premiums charged, as well as the out-of-pocket costs faced by those with high deductibles.

5) We do believe that a company that works to get US approval for a drug previously not available or validated here deserves to make a profit on the work done–such as Catalyst having to run Phase III trials for Firdapse in Lambert-Eaton Syndrome. But the magnitude of the profit margin has to pass some kind of smell test, and Marathon fails that test even as they claim: “the company showed restraint in how it priced the drug. Other new drugs for so-called orphan diseases, which by definition affect fewer than 200,000 people nationally, have carried price tags of $300,000 annually and higher.”

The $300K price tags the CFO referred to are attached to orphan drugs where there were significant R&D costs and risks borne by the developer, and where the drug often has a life-saving or changing component. Marathon took on limited clinical trial costs and very little risk, and while deflazacort is useful in DMD, it is purely symptomatic, providing some improvement in muscle strength. Referring to the ultra-priced drugs as a marker for ethical execution is a false equivalency, and does not make the case for this pricing.

With the current President having recently said “The (drug) pricing has been astronomical,” Marathon has now put itself in the crosshairs for whatever company-bashing will inevitably come next: They made a bad decision and are only digging themselves deeper in their clumsy attempts to justify it. Marie Antoinette said ‘let them
eat cake
’, and that did not work out so well. Pharma companies think coupons and the hope of insurance coverage provide them with sufficient cover from attack, but they do not: The mob is assembling, carrying torches and an assortment of sharp objects.

 

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The Lunatics Have Taken Over The Asylum

“The lunatics have taken over the asylum
The lunatics have taken over the asylum
The lunatics have taken over the asylum – take away my right to choose
The lunatics have taken over the asylum – take away my point of view
The lunatics have taken over the asylum
The lunatics have taken over the asylum – take away my dignity,
Take these things away from me
The lunatics have taken over the asylum
The lunatics have taken over the asylum – take away my family,
Take away the right to speak
The lunatics have taken over the asylum – take away my point of view,
Take away my right to choose”  

–FB3, 1981

What does this have to do with neurotherapeutics? Nothing and everything. The ten-day-old-and-counting American Administration has yet to announce a executive decision that specifically regulates neuroscience, but when it comes to context, the macro-environment within which we live and work–these have been has been ten days that portend an Age of Unreason the like of which we have not previously seen. To the degree to which the advancement of Science depends upon a cultural acceptance of Science and Rationality, and to the degree to which the willingness of investors and companies to fund the unpredictable process of neuro-research depends upon sustained faith that the economic and political system within which we operate remains predictably adherent to the Rule of Law–the Ground upon which we walk is being rocked by tremors that feel like the advent of a Quake that could rip asunder much of what we have long taken for granted.
In a scientific world where pharma and academia exist in what has become a global venue, the rise of nationalist populism in the US and Europe augurs ill for the collaborative spirit and execution that have fostered the growth of knowledge. The willingness to embrace mean-spirited ignorance and impulses rather than intellectual rigor is a regression that we should not and cannot tolerate, as an industry or as a society.

“The media should be embarrassed and humiliated and keep its mouth shut”  

–Bannon, S.  1/26/17

Don’t think so.

 

 

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ToneDeaf Therapeutics

arf

(from NeuroPerspective Jan-Feb 2017)

(Cambridge, MA 12/8/16):  ToneDeaf Therapeutics, a startup company based in Cambridge, today announced they have obtained seed funding from undisclosed investors with which they will take their cutting-edge Auditory-Reception-Facilitation device, ARF, into IND-preparation. “It is tragic to see the unmet clinical need of pharma executives who have absolutely no idea how they come across to others“, said ToneDeaf CEO Martin Shkreli. “Our mouse studies show that mice utilizing ARF improve by 10% their comprehension of how they sound when communicating with other mice, and we are confident that these results are highly predictive of success in human testing.” ARF utilizes a well validated therapeutic mechanism, improving it (and its IP protection) by constructing the device from an advanced polymer developed by MIT’s Robert Langer*. The polymer promotes improved auditory processing and over time is completely absorbed into the ear canal. Shkreli added “We expect to obtain approval for ARF under 505(b)(2), and we will bring ARF to the Pharma executive market for a very reasonable cost: Coupons will be available for those executives whose health insurance does not fully cover the cost of the device, which will be affordably discounted 95% below the cost of the Wu Tang Clan’s album Once Upon A Time In Shaolin**. Given the burden imposed upon these executives and their companies by their inability to hear themselves as others hear them, we think that no responsible pharma or biotech company will want their executives speaking in public without using ARF. I know mine doesn’t.

*Not really

** for which Shkreli paid US$2 million in November 2014

 

A CASE STUDY

bresch-jpg

 

 

 

 

 

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Mr. Robot and the Amyloid Hypothesis

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 todate.”                     –Aisen, P. 12/8/16  CTAD

Which just shows how low the amyloid bar is, confirmation-wise. The next issue of NeuroPerspective will take a more detailed look at what light Sola 3.0 and Adu 1.25 together shed on the ‘amyloid hypothesis’ and on the treatment of Alzheimer’s. But in the meantime, we have an example of a variant not posited by Mr. Robot, 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. The original AH 1.0 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 the product of the variance produced by the analysis of small cohorts, only a larger trial will tell. And 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.

Perhaps the questioner was referring to AH 2.0, which proposes that amyloid in some non-plaque form (fibril, oligomer, monomer) is the causal key to Alzheimer’s. One counterargument is offered by solanezumab, which produced a dramatic effect upon CSF amyloid, increasing it 500-800 fold, but the weakness of the therapeutic effect in the face of that CSF biomarker does not portend a robust relationship. 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.

AH 3.0 suggests that amyloid is a secondary rather than primary pathophysiological feature; it is not the foremost pathological actor, but plays some facilitative or supportive role. This is consistent with a recent hypothesis that amyloid sets the stage for tau to disperse and cause the bulk of the direct damage. NIR’s own belief is that AH 3.0 is the best current model for understanding the data to this point, one that leaves open the possibility that targeting amyloid could have a clinically meaningful role in AD treatment–-but it is still just a hypothesis.

So the question posed to the sola panel at CTAD 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.

Two other thoughts about the aducanumab titration subsidiary study: Reducing the rate of ARIA 36% comes nowhere close to eliminating the problem. And when patients developed ARIA, it was at the 1 and 3mg dose levels, so ARIA cannot be avoided by stopping at 6mg dosing with APOE4-positive patients, as is currently being done by Biogen in Phase III.

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Sola’s EXPEDITION3 Fails

Back in 2013, NIR used a picture of an ill-fated South Pole expedition in a presentation at CNS Summit. The caption read: “Lilly announced it will run another major Phase III program for solanezumab. Patients must show scan or CSF evidence of amyloid pathology, but have only mild cognitive symptoms. Early intervention? Not really.

Three years later, the top-line results are in, and indeed the EXPEDITION3 trial failed. Solanezumab is being terminated by Lilly, after a total expenditure that surely must have easily  exceeded a billion dollars, with room to spare.

Over those three years, NIR had concluded that Lilly’s task was to power the trial large enough to squeeze a mediocre signal past the threshold of statistical significance. As we said in the NP September/October review of Alzheimer’s: “A key change was the inclusion requirement that amyloid pathology be shown via imaging or CSF assay, thus enhancing the homogeneity of the population, but also meaning that the disease have reached the stage of beta-amyloid plaque. This is a critical conundrum: Patients must be advanced enough to have significant plaque deposits that show on PET-scan, but not so advanced that they have anything more than mild cognitive impairment. Given the very modest treatment effect Lilly gleaned from data-mining the substantially-scaled first two trials, we suspect that even this ‘enriched’ population might be sufficiently advanced in disease progression that nothing more than a minimal treatment effect can be hoped for…..Since EXPEDITION3 powered up and enrolled 2100 patients, it could end up with statistically significant results, but it is very questionable whether a case for clinical significance will be convincingly made based on a signal of very modest impact–less than is seen with cholinesterase inhibitors.”

That is essentially how it turned out: There was a trend towards superiority for the drug group, with a p value of .095. Given that p=.05 is the arbitrary, binary benchmark for statistical ‘truth’, this does save us from a painful debate over whether a clinically meaningless intervention should be approved on the basis of achieving statistical significance.

Lilly will present more complete results on December 8. There are many things that we do not yet know, these are just are a few:

  1. Was the failure due to the aforementioned risk that the treatment population, already showing accumulated plaque, was too advanced in their disease to benefit?
  2. Did solanezumab achieve sufficient brain penetrance to have a shot at neutralizing enough beta-amyloid to change the course of the disease? And is it reasonable to deliver an antibody against a large pool of beta-amyloid monomers, rather than aggregated forms?
  3. Is beta-amyloid central enough to the core pathology of Alzheimer’s to be a viable target for intervention? This treatment failure does not demolish the ‘amyloid hypothesis’, but it does not lend any support to its historical role as the gold-standard for AD targets.
  4. Will reducing the production of beta-amyloid via BACE inhibitors or the inhibition of pyroglutamic beta-amyloid be more efficient and effective than trying to clean up the amyloid mess after the fact? Merck‘s BACEi data next year will be the first major test of this hypothesis.
  5. There has been growing support for the hypothesis that beta-amyloid sets the stage for tau to serve as the toxic blow to the brain. The tau hypothesis has not had a real test in the clinic as of yet, with all due respect to the failed TauRx Phase III trials.

Since Alzheimer’s is unfairly and inaccurately depicted as if it is  a proxy for the ability of clinical neuroscience to deliver tangible benefit to patients, we had hoped that our trepidation regarding solanezumab would prove to have been overblown. Now, we will wait to see Lilly’s more detailed data presentation, and  whether this further shakes their already wavering dedication to neuroscience. They have other AB antibody programs in the clinic, a tau antibody, and a BACEi being developed in partnership with AstraZeneca–we hope that solanezumab’s failure does not wreak  collateral damage within Lilly’s remaining neuroscience R&D portfolio and resourcing.

 

 

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Alkermes, ALKS5461, and the FDA

Alkermes late yesterday announced that the third of the ALKS 5461 antidepressant Phase III trials had yielded positive results for the high dose, utilizing an SPCD trial design and an alternative parsing of the MADRS as the primary endpoint. The good news was the evidence of efficacy; the bad news was that the side effect profile continues to be consistent, meaning that nausea/vomiting (PhII had revealed a high rate of nausea (34%), vomiting (17%), and dizziness (19%)) are not irrelevant adverse event concerns. The great unknowns going FORWARD involve the FDA, on a couple of points:

1) Alkermes is the first company to devise a pivotal trial program largely (but not completely, as they learned to their discomfort in FORWARD-3, devastated by a placebo effect) utilizing SPCD, the Maurizio Fava designed sequential trial process intended to reduce the impact of the placebo effect. There is as of yet no consensus in the field as to whether SPCD reliably delivers as promised, but it is difficult to see any reason why the FDA should not accept the results as valid, other than that  their statisticians will have to adapt to a novel design. Psychiatric drug trials, especially depression, have been chronically undermined by placebo effects, and the trend appears to be worsening. The FDA would be foolish to reject this framework, and we do not think they will be foolish.

2) Alkermes hopes that this clearly successful SPCD FORWARD-5 trial, in conjunction with the almost-positive FORWARD-4 results (also SPCD), and the spectacular but nonreplicable results in Phase II (also SPCD), can be assembled into an NDA filing that will be accepted, and eventually approved by the FDA. This is where it becomes more opaque, and political. To approve based on such a package, the FDA would have to buy into four or five subcomponents:
a) A new trial protocol design (SPCD)
b)  a new parsing of the MADRS using six items they believe most critical (but the high dose also hit on the MADRS-10)
c)  this Phase III averaged MADRS-6 scores across several timepoints, instead of using a single time measure for  establishing change. This is different from what they did with the previous trials.
d) reportedly, retrospectively analyzing FORWARD-4 this way would also have brought the high-dose outcome across the p=.05 threshold. The FDA’s Psychiatry Division does not have any history that we recall of embracing post hoc re-analyses of pivotal trials as constituting success.
AND/OR
the FDA would have to embrace the successful Phase II results as the ‘second confirmatory trial’, perhaps in conjunction with the almost-OK FORWARD-4. The Psychiatry Division has no history of redefining Phase II results as if they were Phase III. The FDA is deeply wedded to the idea of prospectively-established definitions and analyses.

3) Accepting the components in #2 would require a philosophical shift on the part of the FDA, an institutional move towards a degree of flexibility that has not been part of the mindset for Psychiatry or Neurology. The approval of Acadia Pharmaceuticals’ Nuplazid for Parkinsonian psychosis, on the basis of one successful Phase III after a couple of previous failures, has been interpreted as opening the door to such flexibility. Alkermes is not the only company to hold on to this view after mixed Phase III results: Intra-Cellular Therapies hopes that one successful Phase III, plus a very substantial Phase IIb that was successful, might provide critical mass for ITI-007’s filing in schizophrenia, despite the failure to separate in its second Phase III. Axovant hopes that a single Phase III success with RVT-101 in Alzheimer’s, in conjunction with all the data assembled by GSK during the drug’s previous clinical trials, would constitute an NDA filing. Alzheon hopes that a positive Phase III, along with the truckload of data from Neurochem’s failed program, might do the same for their Alzheimer’s drug. There are some false equivalencies that get tucked into these aspirations: Only the Acadia program addressed a relatively undertreated disorder, one that constituted a small to moderate size market, rather than mega-scale. Depression and schizophrenia have lots of treatment options, even Alzheimer’s has a few. The FDA was undoubtedly concerned that Nuplazid would look like a precedent heralding a more open door for drug approvals; they have a basis for conceptually narrowing that window once again, given the fact that none of these disorders was as undertreated as is PDP.

4) Whither the FDA? Sarepta’s drug approval in Duchenne was based on skeletal Phase II findings plus sentiment, and along with Nuplazid’s approval, may represent a Janet Woodcock/Robert Califf shift towards flexibility, and thus could in theory continue. But our expectation is that, when it comes to the FDA, progressive actions are often followed by an almost-equal and opposite regression, as they seek to reinforce their bona fides in safeguarding the public against the Pharma ‘barbarians at the gate’. With the transition to a Clinton Presidency, we would guess that the industry is in for at least a temporary period of heightened scrutiny and criticism (the only industry that damages itself as frequently with tone-deaf PR as much as Pharma does is the tobacco industry) and the FDA will want to look like it is playing its regulatory role. Hence our belief that Alkermes and Intra-Cellular will each be required to run an additional Phase III. This is not the decision we would make if it was up to us–we are satisfied that both drugs work, at least in some patients, and we would argue for adding to prescriber choices in areas that may not be undertreated in terms of choices, but where the choices are frequently unsatisfactory. Axovant and Alzheon do not have the kind of existing datasets that would afford them the benefit of the doubt in this regard.

5) We have been critical of the Alkermes PR style  in the past, and hope that they do not taint their own prospects by getting too publicly cocky about them. The surest way to provoke the FDA would be to take them for granted.

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Cosmetic Changes at GSK

Those–including NIR–who have been watching the GSK plan-for-succession as an indicator of GSK’s motivation to reassume a leadership role in pharmaceuticals, which by definition would include neuroscience, were disappointed by the GSK Board’s decision to anoint GSK’s consumer division head, Emma Walmsley, as the CEO-in-waiting, pending Andrew Witty’s transition to even greater irrelevance. It would be hard to find a clearer indicator of surrender than naming someone whose previous corporate residence was L’Oréal to run what was once one of the pre-eminent pharma companies. On the other hand, this does augur well for alternative approaches to meeting the needs of a graying First World population. As Walmsley reportedly said during her CEO-interview: “While many other large companies are expending huge sums in the frustrating search for treatments that will help older individuals who are losing their cognitive ‘grip’, GSK will maintain its leadership role with the Polident/Poligrip franchise, so that, even as their memories fade, their dentures will remain firmly fixed in place.

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