Concepts for Consideration

 (from NeuroPerspective July-August 2014)

1) Biometheus and the Placebo Response Gene: Biometheus has licensed IP related to a COMT gene polymorphism that they believe identifies patients prone to placebo-response.  As they discussed in BioCentury, the developers have published work showing that this polymorphism–which may lead to elevated levels of dopamine in the prefrontal cortex–was associated with a  doubling of the magnitude of the placebo response in Irritable Bowel Syndrome patients, and claim there is data indicating the same dynamic in pain patients. While NIR has some skepticism regarding the breadth of applicability of a ‘placebo gene’ anomaly–CNS life is rarely if ever that simple and clearcut–any test that could identify those vulnerable to a placebo effect in even a narrow bandwidth of disorders will be welcomed by drug developers.
2) RDoCs Operationalized: The NIMH team that has been working since 2009 on developing psychopathology categories based on observable behavior rather than Kraepelinian conjecture is going to have the opportunity  to see if this approach provides practical benefit in clinical testing. Both Cerecor and Astra Zeneca are focusing upon acute suicidality as a behavioral endpoint in their ‘antidepressant’ trials, and given the challenges in obtaining valid and reliable measures of depression per se,  progress in this kind of objective measure could be very useful in CNS drug development.
3) NeuroProsthetics for Memory: DARPA is providing up to $40 million to groups at UCLA and U.Penn (in conjunction with Medtronic and Neuropace) who are going to map neural activity patterns associated with memory functions in the hope of developing implantable devices that can improve memory in patients with TBI. The UCLA team will begin with patients who have  already had devices implanted for the suppression of seizures.  The grants cover four years, but we are reminded that Functional Neuromodulation  has already fully enrolled their Phase II/III  trial of their DBS device aimed at improving memory in Alzheimer’s patients–which might be considered an early HOC trial for the cognitive neuroprosthetic concept.
4) Inversion and Flags of Convenience: Perhaps it is trite and naive, but there is something unsettling about the notion that corporate ‘citizenship’ can be so baldly based upon, and moved towards, something as banal as an advantaged tax rate.  But that is the current state of affairs, with pharma companies avidly pursuing ‘inversion’, moving (often) to Ireland as blithely as container ships sticking Liberian flags on their stern. This escape hatch will be closed eventually, with legislation that erases the loophole while, hopefully, addressing the disparity between tax rates.
5) Bring Back ‘Friends’: At the very end of 2013, Merck announced their plan to develop ‘innovation hubs’ in four geographical locations–Boston, London, San Francisco, and Shanghai (we are still waiting for some innovation in site choices beyond this comfort zone). JNJ and Pfizer have created hubs in the same locations, GSK has made a thus-far ill-starred stand in Shanghai, indeed only JNJ showed its willingness to bravely venture into new frontiers by adding one in….San Diego. This is an expensive breed of real estate redundancy, and given the cost-cutting emphasis at virtually all Big Pharmas, one might wonder why they aren’t sharing space. They might claim that they have valuable secrets that must be protected, but it is not as if they would have to decorate their cubicles with chemical structures, and if we were conducting industrial espionage in Cambridge or the Bay Area, we would be bugging the local sushi restaurants and wine bars. In any event, the concept of Pharma roommates could offer interesting comedic TV possibilities; consider what could be done with a combination of a anxious nerd, a slightly vacant blonde, a good-natured but not-too-bright jock, a neurotic control freak, and so forth. Anyone familiar with that mainstay of American situation comedy will get the picture, and the pharma industry can only dream of the ROI being enjoyed by the syndicators of Friends. And which pharma company should be played by which character? We are not going there.

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NeuralStem and the ‘Right-To Try’

Colorado has recently passed ‘Right-to-Try’ (RTT) legislation permitting companies to offer experimental treatments for fatal diseases that have not been FDA approved—and the requirement of payment is permitted if the Company so chooses. The criterion is that they have reached Phase II testing, the law based largely on a framework developed by the libertarian Goldwater Institute. The first CNS company to embrace this concept is, not surprisingly, NeuralStem, whose CEO, Richard  Garr, is head of the Goldwater Institute’s Advisory Council on this topic, and who undoubtedly played a role in the RTT legislation design. Garr very quickly (on June 5) told BioCentury that NeuralStem would begin training Colorado neurosurgeons to administer NeuralStem’s stem cells (NSI-566), which are implanted in the spinal cord; that no permission would be sought from the FDA; and the decision of whether to charge for the treatment had not yet been made.
By the next day, Garr had published a comment on his blog that backpedaled somewhat, quoting an earlier statement by FDA Commissioner Margaret Hamburg that expressed support for making treatments available to patients with life-threatening illness, and stating that NeuralStem would not make a treatment available under RTT if the FDA told them not to. We suspect that his BOD, and perhaps NeuralStem’s legal counsel, may have suggested that his initial stance might have come across as unwisely cavalier, given that federal oversight trumps state control of such issues, as Massachusetts Governor Deval Patrick learned when he tried to outlaw Zohydro in March.

NIR has a profoundly ambivalent view of this issue. On the one hand, patients with ALS have but a few years of life expectancy, and the gradual loss of basic motor functions–including respiration–does not imbue those years with much of what is generally considered to be ‘quality-of-life’ (this is not to diminish the value of what their lives can still include). To put it another way, longterm safety issues would be a good problem to have. Such treatment is an option we ourselves would want to have available, our choice to make.

Having said that, there is another side to the argument. On June 15, BioCentury produced a television segment on this issue, NeuralStem’s Garr did not appear–we have no doubt he was asked–which speaks to some newly adopted caution. However, Lucy Walker, a spokesperson for the Goldwater Institute, said in reference to NSI-566: “That drug has an 85% efficacy rate in trials.” Which nicely illustrates the slippery slope on accuracy in this scenario:  NSI-566 is a cell therapy, not a drug, and while NeuralStem has aggressively highlighted interim and sometimes anecdotal clinical status reports for NSI-566 trial subjects, NSI-566 by no means has established a “85% efficacy rate”. But any ALS patient with access to air travel could be forgiven for seeing this as an opportunity to be seized  whatever the cost, if indeed NeuralStem decides to charge for this technically challenging therapy.

Given that NeuralStem has already decided to sponsor clinical trials of its cell therapy in China and Mexico that are not FDA-vetted, they are already–in our view–walking a tightrope with the FDA. Getting out in front of the RTT movement risks NeuralStem being cast as a Rebel Without A Regulator, which may be why one cannot find anything on the NeuralStem website or Garr’s blog that repeats his more brash stance of June 5.

We are reminded of the fetal stem cell era in the treatment of Parkinson’s, when a few US neurosurgeons, operating under their Physician INDs, carried out cell implantations on patients who were able to pay the $50,000 and up rate. In the long run, some of these patients had a serious worsening of their dyskinesias. One can argue that ALS’s time course is so much shorter (and NSI-566 far better vetted) that this is a risk that patients should be able to take if they so wish, but this is a reminder that there are ethical, clinical, and regulatory downsides to this endeavor. We would hate to see the FDA back track on Hamburg’s commendable shift towards espousing easier patient access if they perceive  any mercenary exploitation (we are not claiming that NeuralStem is doing so–but they could easily be seen as pushing the envelope) in response to the loosening of controls at the federal or state level.

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Opioids and the ‘Right’ to Pain-Free Living

(from  NeuroPerspective June 2014, focused on Pain)

Two California counties (Santa Clara and Orange) have filed suit against the pharmaceutical companies with the largest stakes in opioid analgesics (Actavis, Endo, Janssen/JNJ, Purdue Pharma,  Teva Pharma), claiming that they deliberately understated the addictive risks of their products, overstated their safety, and in so doing have not only greatly accelerated prescription drug abuse, but also spurred an upsurge in heroin addiction. There are a few issues here that warrant comment:
1) We do not know what each of these companies provided physicians in terms of information regarding abuse/addiction risk for their products. But we do know that Purdue Pharmaceuticals pled guilty in 2007 to having ‘misbranded’ OxyContin as presenting less abuse risk. Purdue paid $635 million in the settlement, three Purdue executives were also fined $34.5 million.
2) The plaintiffs’ argument falls short in linking the marketing of these abusable prescription opioids to the recent increase in heroin abuse, which has been accompanied by a high-profile increase in deaths from heroin overdose. The fallacy is indicated by figures from the NIH: Their estimates of the number of individuals in the US regularly using heroin (‘in the past month’) was around 160,000 in 1982, decreasing to under 50,000 by 1990. However, the 1990s saw a dramatic resurgence, the number reached 216,000 in 1996, the year OxyContin was introduced. The number blipped up to 325,000 in 1997, but was down to 130,000 by 2000, 123,000 in 2001. It is clear that heroin use, which had been down since the 1970s, was escalating even before OxyContin was launched, and indeed decreased thereafter–one might actually wonder if the availability of prescription opioids and the growth of heroin use may be negatively correlated. By 2002, after a change in the sampling protocol that elevated the reported rates of drug abuse, the number of current heroin users was still under the 1996 level, at 166,000. Other than an anomalous rise to 339,000 in 2006, followed by 161,000 in 2007, this rate of current use did not reach the 1996, pre-OxyContin level again until 2010, when concern regarding prescription opioids had mounted, and abuse-resistant Oxycontin was launched. Indeed, from 1997-2007, during which time the total amount of prescription opioids sold in the US increased by 149%, the NIH figures showed a decrease of 50% in the number of ‘current’ heroin abusers. The number of heroin users has been steadily increasing since then (335,000 in 2012), as public attention to prescription drug misuse increased. Our faith in these numbers is tempered by the fact that these statistics are extrapolated from small datasets and the sampling system changed in 2002. But even with that caveat, the figures do not point to a positive correlation between prescription opioid use/abuse and heroin usage. If anything, the former may substitute for the latter, a reminder that when it comes to drug abuse, the forty-year legacy of the ‘War on drugs’ has been akin to a game of molecular Whack-a-Mole, or as The Economist referred to it recently:”Press down, pop up.”
3) In looking at the shift of opioid prescribing towards what does appear to be an overly expansive pattern of utilization for less-than-severe pain, one might also consider the societal context, particularly in the United States, which has been Ground Zero for prescription opioid use and abuse. From ‘pain-free dentistry’ to ‘trigger warnings’ to an ever-burgeoning emphasis upon political correctness and a reluctance to pay for infrastructure utilized and entitlements received, there seems to be a simmering belief in a right to life with as close to zero personal pain and sacrifice as possible. There is something of an emerging ethos in the US that phenomenological pain, be it physical, emotional, or a combination of the two, should be medicated, adjudicated, or legislated out of existence. This is an unattainable aspiration, and while genuine maltreatment, malfeasance, and misconduct require a response, opioid overuse is a symptom that also speaks to social dynamics that go far beyond the prescription pad.

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When It’s Too Good to be True…..

Affiris‘ announcement that one of the two placebos they used in their AD02 antibody trial outperformed everything–including AD02–in stabilizing cognition and hippocampal volume takes Alzheimer’s drug development to a new level of BizarroWorld surprise. Just to recap: They reported that 47% of the 60 or so (300pts, 5 groups) patients receiving the nonclear (“obscure”) placebo were stabilized over eighteen months, compared with 17% of those receiving the ‘clear’ placebo (which is visually discriminable from the AD02 drug product), and 31% of those receiving the highest dose of AD02 (there was a dose-response relationship in the reported results). Affiris is happily puzzled (actually the CEO did not look as happy as one would expect given his claim of a “breakthrough”, he looked like he was testifying in front of a Congressional committee run by the party he does not belong to) is disclosing very little about the ‘obscure’ placebo, and may be exploring ways to nail down some kind of use patent for it.

There was understandable chuckling amongst some observers about the value of ‘sugar-water’, and indeed we’ve had a few inquiries as to why we had not yet chimed in. The first reason was that having this kind of completely counterintuitive–indeed counterlogical–finding risks reinforcing the not-uncommon belief that CNS R&D is so riddled with such incongruities that its pursuit is economically and strategically unwise. Frankly, we would have been happier had Affiris simply had the AD02 data in hand, reporting a smaller magnitude of effect than hoped for, but dose-related, raising the possibility that going up in the dose of antibody might give them clinically and statistically significant results (we presume that if the high dose AD02 impact in 31% of patients hit p=.05, we would have heard about it).

The second reason is that the placebo now known as AD04 was likely an immuno-active adjuvant, such as is commonly utilized in vaccine trials. Such adjuvants enhance the effects of the co-administered antibody, generally believed to be via stimulating immune cell recruitment via a proinflammatory effect. This was not an ‘inert’ placebo, but it was not expected to have an effect without the presence of an antibody to ‘magnify.’ We wanted to look into the adjuvant issue more carefully. So far as we can tell, there are four classes of adjuvants used in vaccine work: Aluminum salts/gels; squalene adjuvants; a saponin-derivative (QS-21); and virosomes. The one interesting and useful comment that was made during Affiris’ 27 minute press conference was that AD04 is an adjuvant that has not previously been used in Alzheimer’s trials, but has been used in influenza vaccine development. That rules out virosomes (used in testing Novartis/Cytos‘ CAD106) and QS-21 (used with bapineuzumab and solanezumab). Which leaves us with aluminum and squalene. The putative relationship between aluminum and autism has been the crux of actress Jenny McCarthy’s fleeting brush with the world of science, while squalene has been linked to the rare (but age-related, more likely in younger subjects) emergence of narcolepsy.

The bottom line is that neither of these adjuvant classes is inert, they are co-administered with antibodies for an immunological reason. But with all of the work done vis-a-vis inflammation in Alzheimer’s, one would think that if a very nonspecific proinflammatory chemical could have a very salient impact on AD neurodegeneration, that would have already been established.

Perhaps it could be argued that it is the duration of exposure/re-exposure  and monitoring that might be the differentiating factor here: The only intelligent question to be heard from the audience during the aforementioned press conference was in reference to the apparent year it took for AD04 to begin to have a stabilizing effect on cognition or hippocampal volume. For the first year, while the curve was slightly higher than those of the other groups, the slope of deterioration was essentially the same. At twelve months, hippocampal volume stabilized, and the composite cognition score actually went up. This just adds to the mystery.

These are small cohorts of about 60 patients each, which increases the possibility of flukiness. But the usual suspects when it comes to patient populations do not show up here, neither Russia nor India supplied patients, it was a European trial.

When a clinical finding is too good to be true, it generally isn’t (hello, Dimebon). And while we would like to believe that a nonspecific proinflammatory chemical, given long enough, can somehow provide neuroprotection in mild Alzheimer’s, our guess is that in the long run, there will be some other explanation for the performance of the ‘obscure placebo’ in this Phase II trial, rather than clinical efficacy. The sad thing is that this may so erode Affiris’ credibility that they will never get a chance to see if higher dosing of AD02–the actual antibody–might provide a larger magnitude of effect.

All in all, it’s more tragic than comical.




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Valeant Masses Tanks at Allergan Border, Says Prepared to Protect Shareholder Rights

Reading today’s comments by Pershing Square‘s William Ackman  about his plan to remove Allergan directors and replace them with Valeant friendly directors who would support the surrender of Allergan to Valeant, we couldn’t help but be reminded of a recent speech by another statesman dedicated to protecting the rights of the oppressed:

<<“We think Allergan’s board and management are delaying the inevitable, we encourage them to negotiate with Valeant immediately,” Ackman told a conference call with financial analysts Monday.
“If they negotiate immediately, a merger agreement could be signed in a week, this transaction could get done in a matter of months.”
The move by Pershing Square follows meetings it held last week with other large Allergan shareholders as well as hedge funds and risk-arbitrage investors who combined with Ackman held more than half the shares in Allergan.
“They believe the merger makes tremendous sense and it is a highly strategic transaction and creates enormous shareholder value,” Ackman said the investors told him.>>

the Canadian Press 6/2/2014


<<The most recent public opinion surveys conducted here in Russia show that 95 percent of people think that Russia should protect the interests of Russians and members of other ethnic groups living in Crimea – 95 percent of our citizens. More than 83 percent think that Russia should do this even if it will complicate our relations with some other countries. A total of 86 percent of our people see Crimea as still being Russian territory and part of our country’s lands. And one particularly important figure, which corresponds exactly with the result in Crimea’s referendum: almost 92 percent of our people support Crimea’s reunification with Russia.
Thus we see that the overwhelming majority of people in Crimea and the absolute majority of the Russian Federation’s people support the reunification of the Republic of Crimea and the city of Sevastopol with Russia.>>

–Vladimir Putin

Prague Post  3/18/2014

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Saying No to a Bully

William Ackman, who is collaborating with Valeant Pharmaceuticals in the latter’s attempted takeover of Allergan, is often referred to in the press as an “activist investor.” We think of him somewhat differently, particularly in the light of his latest maneuver. Today it was reported that he sent Allergan’s BOD a letter complaining that Allergan’s CEO, David Pyott, is essentially unwilling–and unable–to negotiate with Valeant because he has a “disabling” conflict of interest: That a takeover would mean that he loses his job. That is usually the case in a takeover scenario, and this is the first time that this has (s0 far as we know) been cited as disqualifying the CEO of the smaller company. Ackman further complained that he wasn’t getting access to Allergan’s BOD one-on-one, without Pyott’s participation. It has become clear to us that Ackman is a bully, used to getting his way, and he is taking a  tantrum because his opponent is actually practicing corporate leadership.

Ackman’s commentary regarding Pyott’s “disabling conflict” is ludicrous, and telling. There are no objective parties here. Everyone has an agenda in this negotiation, Ackman after all is one of the buyers, his is not a dispassionate, objective position of authority. And  by our calculation, Pyott’s Allergan equity stake is worth about $40 million at present,  so desperately holding on to the company in order simply to hold on to his job is unlikely to be a prime motivating factor. Painting Pyott as a creature driven strictly by self-interest is an ironic stance for Ackman, whose entire raison d’etre in this context is one of self-interest. We are happy to see some grownups standing up to this oversized bully.

In the parallel takeover drama of the day, we should note that Pfizer’s Ian Read has eschewed the bully role and its tactics, even as Astra Zeneca  rebuffed his latest (and allegedly final) offer for AZ. There have been comments in the press regarding his apparent unwillingness to go full throttle into hostile-takeover mode, as if it reflects a testosterone test failed, forceful determination gone limp. Maybe it is just Pfizer’s reluctance to put its tax-advantaged aspirations at risk, but we would like to think that Pfizer recognizes something that Valeant and Ackman do not: Productive relationships do not start at gunpoint.



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Pretzeled Peristalsis

The current spasm of M&A peristalsis just keeps yielding more data about the twisted logic so popular these days within the pharma industry and its institutional investors.Today’s sampling comes from, a piece written by Hallam and Kitamura, where they cited analyst comments that Pfizer might have to cut at least $2 billion in annual costs, perhaps as much as $3.5 billion, in order for the acquisition of Astra Zeneca to end up accretive to earnings. That concept in itself is fundamentally insane, like a marathon runner amputating his arms to cut down on excess weight. But then the discussion turns to which limbs are optimal for removal:

<<Pfizer may be more likely to cut its own R&D operations than eliminate jobs in the U.K. because of tax benefits, said Fabian Wenner, an analyst at Kepler Cheuvreux in Zurich. Keeping research operations in Britain enables Pfizer to say that products were invented in the U.K., and use the country’s lower tax rate, Wenner said. Pfizer’s tax rate is 27.4 percent, while AstraZeneca’s is 21.3 percent, according to Fazeli. “They want to lower the tax rate for the overall group by implementing transfer pricing, which you can only get when you have sufficient R&D in the lower tax regime,” Wenner said. “It would make more sense to save 15 to 20 percent of Pfizer R&D. It would make sense from a both a political point of view and a tax point of view.”>> (bolding courtesy of NIR)

Just to recap: To keep the British government happy, and to ensure application of the lower UK tax rate, keep R&D in the UK, while cutting it elsewhere–either in Sweden, who has no tax or political leverage in this situation, or within Pfizer itself.

What’s missing from this discussion? There is absolutely no mention of the scientific merit and prospects for any of this R&D, which in this context, is not considered a resource, a corporate asset, but simply as a line item and bargaining chip. Science is nothing more than dollars to be subtracted from someone, somewhere. Besides the unavoidable shot to morale within Pfizer (it’s not how well you do your job, it’s the tax rate we have to pay on it), it is diagnostic of an industry that has lost its way, and now takes guidance from people whose longterm perspective is limited to what they can garner in their year-end bonus.

To AstraZeneca’s credit, they are not rolling over and playing dead, nor do they seem (not that we have any insider knowledge whatsoever) to be simply aiming to get Pfizer’s bid pumped up as high as possible. They have responded to Pfizer’s increased offer by providing their own forecast of how they can grow if they remain independent. We hope they have the opportunity to try.



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