An Unholy Trinity of Bad News

An Unholy Trinity of Bad News

In descending order of Disappointment to Disgust:

1)SAGE Therapeutics  and Brexanolone in SRSE:

When asked this year what nearterm clinical trial results inspired the most confidence for us, we often mentioned the SAGE Therapeutics trial of SAGE-547/brexanolone in Super-Refractory-Status-Epilepticus. After all, in a pilot study of four patients who had not responded to multiple attempts to wean them from anesthetics, brexanolone had allowed three of them to be weaned without relapsing into continual seizure activity. Seizures are, compared to most neurological signs and virtually all psychiatric signs, objectively verifiable, and there was a seemingly sufficient biological ‘explanation’ for brexanolone’s efficacy in SRSE. Because of this, we sipped the Kool-Aid around the concept that this tiny pilot study was more predictive than most.

So much for confidence. Brexanolone underperformed, placebo overperformed, the two treatment conditions were identical in their impact upon anesthetic weaning. Admittedly, SRSE is a heterogeneous disorder with multiple causes and comorbid conditions, and the standards of care for different clinical settings can differ. But still, in a population that heretofore had been considered pretty intractable, being tried on their third epilepto-suppressive option after failing the first two, we never expected that the third option would produce a 42% remission rate on its own, without brexanolone. We do not see any changes in enrollment criteria between Phase II and III that would appear problematic, there is the variability incurred by the reliance upon multiple clinical trial sites, and perhaps data-mining could eventually provide a better explanatory hypothesis. But SAGE is abandoning the SRSE indication, it is Post-Partum Depression coming up next, with a back story of very impressive pilot data that is less reassuring than it was in SRSE. The rationale for PPD remains pretty solid and warrants some optimism, whereas the hopes for brexanolone’s efficacy in Major Depression are on much softer biological ground; the endpoints for both are ‘squishy’. 

2) Axovant and Intepirdine:

On the other hand, we were never enamored of the RVT-101/intepirdine thesis in Alzheimer’s. As we said in NeuroPerspective’s Alzheimer’s review last month:

“…the premise is that an earlier, mediocre differentiation from the control group can be buttressed and enhanced via a higher-powered trial. Our view is that the higher-powered trial may provide intepirdine’s results with statistical significance, though the idalopirdine outcome is a cautionary note that trial size does not guarantee a better statistical profile. But even if it does accomplish this for intepirdine, GSK’s data points to a clinically mediocre, arguably meaningless effect.”

As it turns out, the close-up focus provided by powering up the trial by enrolling over 1300 patients did not reveal subtle benefits, but instead highlighted the flaws; brexanolone failed where it counted. Which saves the field from having to contend with, as it almost did with solanezumab, the cynical calculations weighing statistical significance versus clinical meaninglessness. That is an ethico-statistical conundrum that will likely come up again, with aducanumab, if not before.

3)Allergan Cooks Up An Imaginary Casino

NIR has republished several of Brent Saunders’ eloquent comments regarding the relevance of social responsibility to the longterm viability of the pharmaceutical industry, the implicit ‘social contract’ he admirably invoked in limiting annual price increases for marketed products. And Allergan has executed some of the most promising partnerships/acquisitions in the CNS sector: e.g. Naurex, Heptares, and Lysosomal
Therapeutics
. But they just squandered much if not all of their accumulated good will with one of the most bone-headed, tone-deaf tactical decisions we have ever seen: Transferring their Restasis IP to an American Indian tribe in the hope of protecting their IP from a patent challenge. It is the kind of brazenly cynical maneuver that draws Congressional attention and public derision. For NIR, watching a Company that seemed to be feeling its way towards an intelligent balancing of business and ethical obligations pursue this kind of brazen end-around is like seeing surveillance video of Santa Claus brewing meth in an RV out in the New Mexico desert–we had believed that they were better than that.

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Notes from a Field Trip to the Medical Tower of Babel

NIR subscribers of long duration are well aware that we believe in first-hand data collection–who will forget the 1999 issue wherein we recounted our participation in the first cat-to-human brain transplant? (It didn’t take….sorry about that, Whiskers) Or last year’s cardiac cath lab beach party ?

In any event, it was time for another field trip, so we decided to see how things might transpire for emergency surgery in the service of addressing an appendix that had ruptured (just for an extra soupcon of challenge). We have thus just spent nine days in what turned out to be a complicated inpatient stay, the details of which will be recounted in excruciating detail in our other publication, GastroPerspective. But there are a couple points that could be made of potential CNS relevance, of which we have chosen just one: Getting rid of Psychiatric hospitals was Really Dumb.

Where did they go?..or, What, they’re gone? Pretty much, save for handfuls of corporate, academic, and and legacy units that are completely unsuited for the scale of the task. We are not just talking about Deinstitutionalization as practiced in the 1970s. That grand experiment in top-down social engineering was billed as a humane advance, but in general, because most states neglected to build a safety net sufficient to the task, or more accurately, did not find an alternate source of funding once the federal government stepped away (not irrelevant to today’s Health Care debate),  it turned the chronic schizophrenic population into a nomadic tribe sometimes shipped across state lines by the last municipality that had neither the expertise nor resources to provide them with the comprehensive services they needed. So bus tickets filled in for resources–let them be somebody else’s problem.

But we are also referring to a second-generation culling of inpatient services, from 1995-2005, that was market-driven, not governmentally mandated (again relevant to today’s debate). The first stage had closed many of the huge state hospital ‘snake pits’, the second involved the gradual strangulation of small private psych hospitals and Units by insurors who found it easy and profitable to ‘just say no’, systematically discriminating against Psychiatry, Neurology, and Substance Abuse patients, all of whom tend to be customers without a voice.

What does the Health Care Matrix offer these patients when they, cycling through illnesses that often ebb and flow, hit a point of crisis? For the most part they end up in the ERs and Med/Surg units of community hospitals. Where, after triage, if hospitalization is the only viable option, they are mainstreamed into the larger body of individuals with medico-physical afflictions. Which means the same Unit houses patients with infectious diseases, those recovering from major surgeries, patients in drug withdrawal, those in psychotic decompensation, Alzheimer’s patients with a medical issue, individuals with a toxic delirium, and so on. Because Cardiology and Oncology have been able to define themselves as high-return Cost Centers, those patients sometimes have the luxury of dedicated units, and of course Maternity has a sacrosanct space, because that is a population with PR clout beyond measure. This means that the hospitalists and nursing staff working on Med/Surg units have to function as extraordinarily broad-spectrum clinicians, a feat many pull off to a remarkable degree. But in conversation with some, they admit that the overscaled yet compressed heterogeneity of the populations they have to juggle makes a difficult job doubly so. And it feels like the proverbial Bedlam for many of the patients within it.

So the irony is; as science shifts the practice of medicine towards what in theory is ‘personalized’ and ‘precise’, in many therapeutic areas, economics has driven real world practice to a depersonalized, ever-more-imprecise model, tossing this myriad melange of patients together in the hope that the generalists running these units can somehow figure it out. They do the best they can, but it is like serving as a translator in a Medical Tower of Babel for the 21st Century: There is a price paid by the staff and patients beset by the deluge constantly dumped upon them.

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Pharma Shrugged

We take issue with the commonly-held view that pushing a drug price as much as the market will bear is a fiduciary and ethical obligation: Draining every possible penny from the health care ecosystem jeopardizes the longterm health of that system; considering the ongoing viability of the industry is a pragmatic necessity. There is a desperate need for some rebalancing of the dynamics between longterm and shortterm agendas, because the current system is a carnival of myopic self-interest.

Speaking of which: Neurocrine is pricing Ingrezza at $128,000 per year, for now. Chronic schizophrenics tend to not have platinum-plated health insurance, if anything. This comes in the wake of Marathon‘s aborted sprint to $89,000, and Acadia‘s lunge for $24,000, and Biogen‘s mind-boggling $750,000 for the first year of Spinraza (albeit a life-saving and changing drug). Did these CEOs make some sort of perverse side bet on who could gouge the loudest? The next time a CEO gurgles some nonsense about coupons and discounts, they should be asked if they will throw in a toaster and VitaMix to seal the deal. It validates every negative stereotype about the pharma business, which is not in the best interests of the industry or the companies in it. Hebrew National used to run an ad about their kosher hot dogs that included the tag line: ‘We answer  to a higher authority.’ Even from a secular viewpoint, we all do, and it isn’t Ayn Rand.

(from NeuroPerspective, May-June 2017)

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Pfallergan Round II?

<<Trump Executive Order Could Revive Allergan-Pfizer Merger

-Emily Stewart   TheStreet.com    April 22,  2017

The Trump administration’s executive order on tax regulations could revive the defunct Allergan-Pfizer merger. The White House on Friday unveiled a new executive order instructing the Treasury Department to find and review tax regulations since the beginning of 2016 and make recommendations on modifying or repealing any they see as overly complex and burdensome. The order could potentially open the door for pharmaceutical giants Allergan and Pfizer to take another whack at the $160 billion deal squashed by Obama regulations in 2016.>>

NIR has obtained a copy of new correspondence between Pfizer and Allergan. To put it in context, we are first reprinting the farewell note sent by Pfizer CEO Ian Read to Allergan just over one year ago.

4/6/16

My Dearest Allergan:

The last few months have felt like a dream–you and I idling away the hours by the Irish Sea, picking out a spot for our new corporate cottage, singing the names of the staff we were going to keep, whispering the names of those to be laid off. Now we will have to comfort ourselves with what might have been. I particularly regret having left it to our corporate counsel to let you know the sad news–that it’s over. I should have had the courage to tell you myself. It probably felt terribly sudden and cold, it’s not how I wanted it to be, but I think you know it’s best for both of us.

You may be wondering–Was it all about the money? Is that why I am leaving you?  No, of course not. Well yes, that’s a big part of it, but not all. We come from different backgrounds, you and I, very different cultures. You being from Southern California, er I mean, Ireland, me from….well I’ve lost track at this point–it’s all very confusing. I’m not sure who I am now, and I don’t want to burden you with it all. To be honest, I’m not sure I ever really got over Astra, she still haunts me. I have a lot to think about, as does my Board–two failed engagements in two years, I just don’t seem to be good at the relationship thing.

As the Pfizer counsel probably mentioned, I am sending you some money–I know it’s not much, but at least it will help you with a fresh start.

There’s just one more thing. You deserve honesty, and you shall have it:  When you smile, your mouth kind of changes shape, but your eyes don’t move at all. Nothing. Nada.  It sort of creeps me out. You might want to dial back on the Botox, I think you may have overdone it.

Cordially,

Ian Read

CEO

Pfizer

4/22/17

My most precious and even more succulent Allergan:

It has been too long and I have only myself to blame. After the anguishing end of our engagement, word had come of your dalliances with the dashing Naurex, the suave and debonair Heptares, and even a tequila-fueled hookup with Merck. I thought that you had moved on, but perhaps you were trying to escape from the prison of your own sadness, much as I did here at Pfizer; culling here, trimming there, but bereft of the sense of tax-advantaged meaning that I thought I had found with you. I still recall with such clarity the tantalizing rise-and-fall of your revenue growth curve.

I am not proud of how I ended our betrothal, I can only attribute it to angst and some pointed directives from my Legal Department. But thanks to a new decree, we may have an opportunity for a fresh start, to once again explore a corporate life together. I have even written a song for you that captures how the loss of our fiduciary union still stings me to the very core of my being:

Every breath you take

Every move you make

Every bond you break

Every step you take

I’ll be watching you….

Oh can’t you see

You belong to me

My poor heart aches

With every step you take….

Since you’ve gone I’ve been lost without a trace

I dream at night I can only see your face

I look around but it’s you I can’t replace

I feel so cold and I long for your embrace

I keep crying baby, baby, please*

Longingly,

Ian

*Not actually written by Ian Read. (Sumner, Gordon  1983)

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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.

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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.

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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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