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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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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