Assorted Interim Comments

1) Scott Gottlieb as FDA Commissioner:
Gottlieb was Deputy Commissioner during the all-too-brief tenure of Mark McClellan, and we have followed his commentaries with interest and generally with agreement over the past decade+. We do believe that he has more appreciation than some for the costs of inaction, the casualties incurred by overcaution and the prioritization of statistical purity. Gottlieb has multiple ties to the pharmaceutical and investment communities, which is a red flag for some observers, but we prefer that the Commissioner know how ‘the sausage is made’, and not enter the regulatory fray with an obstructionist agenda. In terms of balancing attitude and expertise, he is far superior to the other rumored candidate, Jim O’Neill, who even questioned the principle of efficacy testing prior to approval. That would have been a libertarian ideal taken to the absurd extreme. Gottlieb will likely feel some pressure to ‘push back’ against pharma agendas in order to prove his independence, but he is thankfully not an Administration appointee who does not believe in and/or understand his own Agency and role within it (see EPA, HHS, HUD appointees, perhaps State as well). Gottlieb is one of the better picks made by this Administration (not the highest of bars), and we look forward to seeing what pragmatic improvements he can instill at the FDA.

2) Neuren’s trofinetide and Rett Syndrome: Neuren’s Phase IIb showed that trofinetide performed as hoped on three endpoints in this orphan disorder–for which there is no approved therapy, and nothing else that has shown this well in human testing. The investor community appears to have shrugged, for reasons that are unfathomable.

3) Speaking of rare genetic disorders, the AveXis data in Spinal Muscular Atrophy thus far looks highly impressive, and must be worrying Biogen, who already made a serious error in hyper-pricing Spinrazza.

4) Allergan announced Phase II data for Botox in Major Depression, and much of the analyst commentary focused upon it ‘hitting’ statistical significance at the three and nine week timeframes, ‘missing’ it at six weeks. But consider these MADRS changes (compared to placebo) and p values:

Three weeks   -4.2  p=.005

Six weeks -3.9  p=.053

Nine weeks -3.6  p=.049

Setting aside the question of mechanism (one theory being that altering facial musculature impacts a feedback loop mediating subjective mood), and setting aside the question of whether subQ injection of saline is an adequate placebo, or whether Botox functionally unblinds itself due to the specific sensory attributes of botulinum injection: The six week change is barely different from the three and nine week figures, all are relatively mediocre, paling compared to the MADRS change scores reported for vortioxetine, esketamine, and ALKS 5461. The six and nine week p values are almost identical, even though they are on opposite sides of the erstwhile .05 divide. Analysts who treat p values as if they are binary miss the point, the ‘tyranny of .05’, as we have discussed in the past.  In this case, the p values are nearly irrelevant: What is relevant is the mediocrity of the therapeutic impact. Even if this reflects a ‘real’ effect, the world is not waiting for what looks like Viibryd/vilazodone in efficacy, but requires injection. It is not as if Allergan has no good antidepressant options, they have some of the best: Allergan has rapastinel in an extensive Phase III program, and the next-generation version of NRX-1074 is being prepared for testing as an oral rapid-acting antidepressant. Why do they need to squeeze a few more dollars out of the hardest working toxin in the Pharma Biz? The ability to (perhaps) power a study to beat p=.05 does not make it a good idea–ask Lilly. At some point, Allergan will have to accept reality, throw Botox a party, thank it for its services, and buy it a condo in West Palm Beach.

Posted in Big Pharma, Biotech, Muddled Media | Tagged , , , , , , , , | Leave a comment

Jeff Nye

It is with great sadness that we learned of the death of Jeffrey Nye, MD PhD, VP of Neuroscience Innovation at Johnson & Johnson. Jeff was a highly respected and effective voice for neuroscience within JNJ and the field, and will be sorely missed.

Posted in Big Pharma | Tagged , , | Leave a comment

Parsley, SAGE, Marathon, and Timing

–with apologies to Simon and Garfunkel, 1966


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.


The January/February issue of NP included a satirical sidebar about ‘ToneDeaf
’ 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,
, 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.


Posted in BioFollies, Biotech | Tagged , , , | 1 Comment

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.



Posted in Uncategorized | 3 Comments

ToneDeaf Therapeutics


(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









Posted in BioFollies | Tagged , , | Leave a comment

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.

Posted in Uncategorized | 1 Comment

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.



Posted in Uncategorized | Leave a comment