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.
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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Praying and Paying for Hope

The FDA’s approval of Sarepta Therapeutics’ eteplirsen for Duchenne Muscular Dystrophy (DMD) turned the spotlight on a decision process that has tapped fundamental fissures within the FDA and the scientific community, fractures that could reverberate in far larger scale in the not-too-distant future.

To quickly recap–Sarepta filed an NDA for this drug, which addresses DMD, a currently untreated, crippling and eventually fatal rare disorder, based on an uncontrolled trial that enrolled just twelve patients (only 13% of DMD patients have the genetic anomaly in the dystrophin gene (exon51) that make them potential treatment responders). The FDA’s Advisory Committee voted 7-3 against approval (albeit with three abstentions, abstention not exactly looking like a badge of honor in this context), but a highly vocal and effective advocacy campaign revolving around the desperate parents of these children finally persuaded CDER chief Janet Woodcock to approve it. One of her subordinate physicians went over her head to appeal the approval, but FDA Commissioner Robert Califf finally announced that he would defer to Woodcock and leave her decision to approve untouched.

NIR has not covered DMD, and thus we have not followed this process in great detail. We are not in position to make informed comments about the quality of the data presented in the NDA, though there is certainly heated debate on the topic. The primary endpoint was the change in dystrophin-positive fibers, reflective-in-theory of improved expression of dystrophin in treatment-responsive patients. But there was no consensus amongst FDA AC members on whether the change in dystrophin levels was enough to be clinically meaningful, whereas a group of DMD researchers sent a letter to the FDA stating that the observed improvement in a walking-capacity secondary endpoint was enough to be clinically meaningful. In other words, this was not just a question of emotion vs. rationality: The interpretation of the endpoints measured was, ultimately, a subjective one when extrapolating to real-world functionality.

With all due respect to the sanctity of the scientific method, there is no immutable and agreed-upon gold standard here, and a stubborn insistence on some ambiguous expression of scientific purity is no more rational and objective than the fervor displayed by parents insisting that they had seen improvement in their children from the use of eteplirsen.

While the intra-agency tumult has not yet subsided, and indeed the main FDA reviewer on the case has resigned, Sarepta‘s valuation skyrocketed as they announced the approval, and their intention to charge an average of $300,000 per patient per year. With perhaps 2600 patients in the US who might be candidates (20,000×13%), 75% market penetration would mean a total health care cost burden of $585 million, which in itself, would be sustainable. Sarepta is required to conduct a post-approval placebo-controlled trial, which had already been open for enrollment. However, now that eteplirsen has been approved, this begs the question–what parent would take a 50% chance that their child would receive saline rather than active drug, thereby guaranteeing that their child would continue to deteriorate? Post-approval efficacy testing is thus even more fraught with obstacles than usual. Eventually, eteplirsen could serve as the standard of care control group against which new DMD candidates can be compared, but that’s not a nearterm scenario. And speaking of which, to what standard will trials for the next generation of DMD treatments be held?

In this instance of a rare, devastating pediatric disorder, using a drug with no apparent safety hazards attendant, it is hard to find serious fault with Woodcock and her decision. But it is not an open-shut case, approval does come at a potential cost. And what about large-scale disorders, where there are safety risks and big-time costs–would the same humanitarian concerns apply?

This is not a purely hypothetical question, we could well face it next year if solanezumab’s next Phase III data mirrors its impact in its previous round of testing. Our view has been, and is, that the best-case scenario for Lilly would be that the sheer size of the trial might provide enough statistical power to beat the magical, and arbitrary, benchmark of p=.05. And that these results might mimic the magnitude of therapeutic effect seen in the previous Phase III, which was a difference of 1.91 points on the ADAS-cog at one year. Given that the general premise has been that a difference of four points begins to augur real-world functional import, it is thus possible that solanezumab will be shown to predictably produce a treatment effect that is not ‘visible to the naked eye.’

This is where the eteplirsen precedent becomes tricky. Without any disease-modifying drugs on the market, even the prospect of imperceptible slowing would create a intense clamor and demand from the families of individuals with Alzheimer’s, particularly those early in the disease process, where it might be hoped that any effect on the disease could extend the time that they can stay independent, and remain themselves. Solanezumab has a relatively more benign safety profile than some other amyloid antibodies, without the vasogenic edema seen with aducanumab, for example. But providing a monoclonal antibody to a large number of elderly individuals is almost surely going to end up with some dire outcomes that could, however unfairly, reflect badly on the regulators. And if, to arbitrarily select some parameters, one million Americans were to receive solanezumab at a cost of $30,000 each (almost certainly undershooting what Lilly or any other Big Pharma would seek for a biologic), that would constitute a healthcare cost burden of $30 billion. That’s a more serious dent in the health care budget, one which would trigger a major debate about the standard that should be set: Must therapeutic benefit be ‘visible’ in order to justify spending $30 billion to get it? Whatever one may think of Woodcock’s verdict, this is a harbinger of the mega-debates yet to come, at a time when thoughtful discourse is in very short supply in the US.

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Allergan Gets It Right

It had seemed for a while that the headlines only reinforced the common public perception that the pharma industry had devolved into a snake pit of self-centered greed. Led by the Three Horsemen of the Pharmapocalypse, Shkreli, Pearson, and Bresch (there are numerous others less adept at getting themselves into the headlines), the corporate ethos has appeared to be one of soaking patients and insurors (the latter group constitutes its own black hole of amorality) to the maximum extent possible, sometimes to the point of extortion (see Mylan; Bresch; EpiPen; parents of vulnerable children). In an election year where the American Sport of Scapegoating  has reached new depths, the search for nearterm gain has attracted the kind of attention that could set the stage for the imposition of governmental controls on an industry seemingly unable to govern itself.

On September 6, Allergan’s CEO Brent Saunders posted an eloquent and bold counterpoint to this theme and ethos, which is worth reading in its entirety:

The overriding message was that pharma/biotech exists within a larger ecosystem, and has an implicit obligation to work within that system in a way that fosters it, rather than undermining it. Specifically, as a statement that is a direct salvo against those for whom the only corporate mission involves the quarterly numbers, Saunders committed to restraining price increases, which “will be limited to single-digit percentage increases.”  He made the implicit social contract explicit: “For our industry to remain a vibrant and important part of the healthcare ecosystem, Allergan commits to this social contract and I encourage others to formulate their own self-policing actions.”

We are now waiting to see if any of Saunders’ peers have the spinal strength to make similar commitments on behalf of their companies. This is not altruism, it is pragmatism: The pharma industry does not exist in an economic or ethical vacuum, and if we do not show the capacity for accountability and self-control, it will be imposed upon us, not a solution that will be optimal for the industry and its future growth.

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Academic Opioid Leapfrogs Field–Perhaps

Nature was the venue (8/18/16) for the publication of a paper from academic collaborators at UCSF, Stanford, UNC, Friedrich-Alexander-Universität Erlangen-Nürnberg, and Parelcus Medical University, a paper that reported the development of a highly refined, selective mu opioid agonist that–in animal models–came close to morphine’s analgesic efficacy while not generating abuse potential on ‘liking’ measures and without morphine’s risk of respiratory depression (RD). Perhaps.
The group screened over three million molecules against a subunit of the mu opioid receptor crystal structure, parsing out those which activated beta-arrestin activity (thought responsible for RD) versus those which were biased towards Gi protein signalling at the mu opioid receptor, believed to be the basis of analgesic activity. Via a number of sophisticated optimization steps, the group developed a prototype drug, PZM21, that fit the criterion of similar efficacy with reduced side effect/abuse risk. In term of selectivity vis-vis other opioid receptor subtypes, the compound lacks nociceptin receptor activity, is a mild kappa opioid antagonist, and has very weak delta-opioid binding. In animal testing, PZM21’s effect in pain models showed efficacy similar to morphine’s; did not trigger sustained respiratory depression, though the paper’s authors failed to mention (and Nature’s peer reviewers overlooked) that the drug had the same RD effect after 15 minutes as morphine* (though morphine’s suppressive action became profound and persistent), and thus at least temporarily separated from vehicle (which raises the question of whether an overdose might in fact be potentially lethal in that timeframe); had less impact on GI motility than morphine; and was not observed to activate reward pathways and behavioral ‘liking.’ This is a unique profile, though this compound has yet to be tested in humans, and thus has a long developmental journey ahead of it. Trevena’s TRV130 is also a biased Gi opioid agonist, and is in Phase III. However, that compound differs from PZM21–it does have kappa opioid agonist activity (which can have aversive affective effects in males)–and it does briefly stimulate respiratory depression (albeit not much more than PZM21)–though there is evidence suggesting decreased abuse/risk.
Though the minefield of human testing remains ahead for PZM21, the animal models used in the analgesia context are more predictive than are models in most neuro-contexts, and the compound differentiates itself on a number of important features that would be relevant to safer, more efficient, less abuse-prone analgesia. We expect that this will be a sought-after licensing asset, though several major pharmas have deleted acute pain relief from their licensing interests; in spite of their flaws, standard opioid analgesics constitute a challenging competitive environment. PZM21 appears, at least preclinically, to address many of the shortcomings that are pervasive in the current offerings. However, the published report somehow overlooked the possibility that the compound may have a window of vulnerability to respiratory depression–a highly experienced neuroscientist suggested to NIR that an animal study be done comparing the potential lethality of PZM21 at 15 minutes post-administration to that of morphine and oxycontin (and we would add, TRV130), in order to ascertain whether the compound has a short-lived but potentially lethal Achilles Heel.
*noted by the LA Times’ Karen Kaplan


Also: TauRx Claims Posthoc Victory Prematurely

A couple weeks back, TauRx released results from the first of three clinical trials (two in AD, one in FTD)  for LMTX, reporting that it failed overall in AD, but they then claimed success based on a subset of patients not receiving concurrent ChEis who appeared to outperform placebo patients (both on and off ChEis). At best, this represents an interesting hypothesis that can only be proven, or disproven, by further prospective testing. Management’s claim that this established LMTX as an efficacious monotherapy was sloppy and specious–other explanations are as likely or more so. These results for the most clinically advanced tau-targeting therapeutic will be discussed in much more detail in the upcoming September/October issue of NeuroPerspective, which covers Alzheimer’s.

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SAGE Therapeutics’ remarkable run with tiny-n pilot studies as predictors of Phase II results continued when SAGE-547 separated remarkably well in a larger (albeit still very small, 21pt study) trial in severe Post-Partum Depression. A single injection provided remission of symptoms in seven of the ten patient SAGE-547 cohort (mean 20pt reduction or more in HAM-D) compared with one patient out of eleven (a mean 8pt HAM-D reduction) receiving placebo. MADRS score changes were similar. The impact was rapid, significant at 60 hours, and just as important, the impact was durable, remaining significant at thirty days. The initial pilot data had been viewed with skepticism by some, but as we noted in our March/April review of depression: “there was some appropriate skepticism about the predictive value of results from four depressed patients receiving an IV infusion of an experimental drug, a set-up for a placebo effect if ever there was one. But the premise for SAGE-547 in PPD has a solid biological basis: SAGE-547 is, after all, a form of allopregnanolone, and women with PPD have been reported to have lower levels of endogenous allopregnanolone than their nondepressed post-partum peers. It has thus been suggested that allopregnanolone may be protective against PPD.”  And so it appears to be, though it remains to be seen what scale of pivotal testing will be required by the FDA. This is not a large patient population (200,000-600,000 US cases annually), but when one considers the locus of PPD’s effect on a critical developmental time period for a newborn, the human impact of the disorder, and the potential of a successful treatment, are considerably magnified.

from NeuroPerspective March-April 2016
Pregnancy and new motherhood are often very different from the idealized, bucolic images conveyed by advertisers, churches, and aspiring grandparents. Indeed, somewhere between 5% and 25% of women experience some degree of post-partum depression. Some of them may have had a history of depression, and because of lingering worries about the safety of perinatal exposure to antidepressants, discontinued their antidepressants during pregnancy. Similarly, women who are nursing may be reluctant to use antidepressants, leaving them ill-equipped to content with their affective disorder. Combine that with the hormonal and experiential upheavals that go along with childbirth and new motherhood, these women can be vulnerable to a dramatic return and exacerbation of depressive symptoms. For a very tiny percentage, this can turn into a psychotic depression, with rare, but on highly-publicized occasion, horrific results.
In June 2015, SAGE Therapeutics announced results from their pilot data in Post-Partum Depression (PPD) and temporarily boosted their market cap by about $420 million. A planned fifteen patient study was cut short after the first four patients showed a complete reversal of their depression, their Hamilton scores nearing zero 60 hours later. SAGE immediately recognized that this radical improvement in PPD symptoms was well-deserving of a placebo-controlled study. At the same time, there was some appropriate skepticism about the predictive value of results from four depressed patients receiving an IV infusion of an experimental drug, a set-up for a placebo effect if ever there was one.
But the premise for SAGE-547 in PPD has a solid biological basis: SAGE-547 is, after all, a form of allopregnanolone, and women with PPD have been reported to have lower levels of endogenous allopregnanolone than their nondepressed post-partum peers. It has thus been suggested that allopregnanolone may be protective against PPD.
SAGE will develop a different, orally bioavailable molecule for PPD, once the signal has been confirmed. That confirmation is hoped to come from a 32pt Phase II placebo-controlled trial that should be completed by midyear.

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Purdue’s Potemkin Village of Addiction-Prevention: Make Them Pay

The Los Angeles Times has published an appalling albeit impressive investigative piece (; by Ruan, Girion, Glover) regarding Purdue Pharma’s handling of fraudulent Oxycontin prescriptions, and the part that this played in the opioid abuse crisis that has burgeoned in the United States. The piece described in detail the activities of  one such ‘pill mill’, which the reporters estimates provided 1.1 million pills to drug dealers, largely affiliated with LA street gangs and organized crime.The article is titled ‘Inside an L.A. OxyContin ring that pushed more than 1 million pills. What the drugmaker knew.’  As it turns out, they knew quite a lot, and looked the other way as millions of pills were diverted to dealers who then resold them to those who had become addicted. The story depicts a corporate culture that masqueraded concern about Oxycontin’s abuse potential; Purdue had even hired a former US-Attorney and a DEA veteran to be part of a team that had the prevention of Oxycontin diversion as its ostensible mission; this group tracked patterns in Oxycontin prescribing that flagged the near-certainty of fraudulent prescription practices on the part of unethical physicians. We are not going to replicate the Times story here, it is well-written and documented, worth reading in its entirety. We will instead cut to the chase: “Crowley (the ex-DEA agent working in Purdue’s anti-diversion ‘effort’) said that in the five years he spent investigating suspicious pharmacies, Purdue never shut off the flow of pills to any store(emphasis ours).
One might well wonder–why set up a group tasked with identifying and responding to illegal diversion of Oxycontin supplies and then make no attempt to effectively intervene? Even though the DEA had specifically pointed to manufacturers as sharing in the responsibility for the prevention of opioid diversion; and even though Purdue had previously been fined $635 million for misleading physicians regarding the abuse risk presented by Oxycontin; the story quotes Crowley as saying “company policy prohibited employees from reporting pharmacies to the DEA without first consulting their distributors.”  Purdue acted as if it was not their problem to solve, as if their hands were tied, albeit by their own Company policy. The obvious explanation is that they hewed towards the letter of the law without doing anything that would actually impede the flow of profits to Purdue’s bottom-line. Those profits were gargantuan: The reporters state that Purdue has “earned more than $31 billion from Oxycontin” (Forbes estimated that the total is $35 billion, but let’s not quibble about $4 billion). It is not as if Purdue is one of those pharmaceutical companies whose outsize profits on one drug are offset by the losses engendered by other research efforts that went-for-naught; Purdue’s business model is totally focused on opioid analgesia. Of the 67 Purdue Pharma-sponsored clinical trials cited on, 64 were for opioid-based analgesics, i.e. Oxycontin, its XR and abuse-resistant progeny, and its chemical cousins. Just three clinical trials were for non-opioids, those three were part of a partnership with Rhodes Pharmaceuticals regarding the clinical development of a new extended-release version of methylphenidate, for ADHD. In other words, Ritalin–not exactly a high-risk, innovative, expensive research endeavor. Neither ethics, legal obligations, or research activities were allowed to detract from Purdue’s bottom line.
Thus Purdue Pharma made tens of billions of dollars in profit on the sales of a drug whose abuse was noted and ignored, with few or no corrective actions taken. Purdue and its legal advisors of course publicly state that their behavior was in accordance with the law, which is the rationale often claimed by those who would prefer to not consider the moral bankruptcy of their position. We do not know whether there are grounds for criminal prosecution here, and our suspicion is that, even if there are, such proceedings would simply punish those who executed the wishes of those who created the policies, who created a corporate culture wherein the human toll associated with opioid addiction was not seen as sufficient reason to compromise their revenue stream. This is the kind of sociopathy one would expect to see on The Wire, not from those controlling a pharma company in Connecticut. The Sackler family, who own Purdue Pharma and to whom the profits flowed, should bear responsibility for the immoral corporate culture Purdue has come to embody. Since they chose to operate on the basis of their pocketbooks, that is where the penalty should be exacted. The largest pharma company fine ever paid was GlaxoSmithKline’s $3 billion penalty, back in 2012, for off-label promotion of its antidepressants and the suppression of safety data for a diabetes drug. But the sheer scope of human suffering, death, and societal harm that can be traced back to Purdue Pharma’s negligence makes GSK’s behavior look philanthropic by comparison. What would be a meaningful penalty in Purdue’s case?
This is NIR’s suggestion: The $31 billion of Oxycontin revenue taken in by Purdue over time is close to what the National Institute for Drug Abuse (NIDA) has for their 2016 budget–if multiplied thirtyfold. The Sacklers should return the $31 billion received for Oxycontin, but rather than having that fine disappear into the maw of the federal budget, let it go to NIDA, which is tasked with addressing and correcting some of the damage done by Purdue. We would not be unreasonably draconian about this; let the penalty be paid over the next ten years. That would in essence quadruple the annual funding available to NIDA, even permitting the funding of late-stage clinical trials for addiction therapies, programs that at present receive virtually no support from the pharma industry or investment community. This would not ‘even the score’, because there is no getting back the lives lost and wasted, but it would be a step in the right direction, and send a clear message that there are rules about sacrificing lives in the pursuit of profit.

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