Earning It

They make money the old fashioned way. They earn it.“–Houseman, J.,    Barney, S.  1979

The news that AbbVie is pulling out of its arranged marriage with Shire Pharmaceuticals (because tax law revisions are changing the value of inversion deals) broke yesterday, much to the consternation of the hedge funds that had piled in, seeing this as an easy, indeed lazy route to riches. Similar to the thinking of the principals, whose corporate strategizing was oriented to loopholes rather than the generation of true value.

Good. Having been unable to muster much in the way of corporate creativity or courage on a voluntary basis,  both companies, but particularly Shire, will have to find some in the wake of this change of plan. Reportedly, AbbVie has to pay a breakup fee of US$1.6 billion to Shire for having called off the nuptials. After Shire pays off its legal and banking advisors, that should leave at least a couple hundred million that they could invest in something useful, like drug discovery and development. Having made a fortune in psychiatry via its ADHD franchise (Vyvanse, Adderall, Intuniv), Shire had subsequently built absolutely nothing of value in CNS, indeed they had retreated and regressed. Now, Shire has another shot, using AbbVie’s money. Via licensing/acquisitions, they have the opportunity to make money the old fashioned way–they can earn it.

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Alcobra’s Selective Inattention

Last week, in the October issue of NeuroPerspective, which covered ADHD, we noted the delay in Alcobra’s disclosure of Phase III data for MDX (metadoxine), and stated “ our suspicion is that the analysis of the primary and secondary endpoints for the overall patient population was negative, and that they are seeking evidence of benefit
in the ‘Primarily Inattentive’ subgroup in order to salvage something positive from a failed trial.” This turned out to be at least partly accurate, since they have not yet reported anything on secondary endpoints, but they are indeed working hard at the salvage process.

Basically, the results of the primary endpoint analysis was that the trial failed–though Alcobra termed the obtained p=.15 as a ‘trend’, which is generous, we generally reserve ‘trend’ for that grey area between .05 and .10. However, their emphasis was on a posthoc analysis that excluded four patients in the Combined Inattentive/Hyperactive subgroup who had received placebo, but shown dramatic ‘improvement,’ to an extent that pointed to invalid responses. Removing those four led to a change in the reported value, to p=.03, which is somewhat astounding in itself. This raises the reasonable question of whether the trial failed or the drug failed–it is one or the other.

Unfortunately, Alcobra doubled down on a selective emphasis upon the perceived nuggets of value in the trial, and did not adequately attend to the wider spectrum of implications:

1) Three of the four outlier placebo patients came from the same US site. Alcobra did not break out how many of the trial patients in total came from that site, but we would suggest that it is self-serving to just exclude the dramatic placebo outliers. Invalid inclusion and/or response patterns could be the case for some of the patients who received MDX, whose improvement might not be nearly as much of an outlier compared to historical drug-responders. Alcobra would likely state that since the overall change in the drug group was similar to previous testing, and it was the placebo group that diverged, that the problem is in the latter. Unfortunately, that cannot be safely assumed: If, for example, additional ‘ATM patients” entered the trial at that site and were not screened out, there is no reason to assume that all fraudulent patients received placebo, and that less dramatic improvement in the drug group can be safely attributed to MDX, not patient fakery.

2) Which means that there is absolutely no reason to think that the FDA is going to accept this as one of the two required pivotal trials. Alcobra’s statement that the FDA looks at the “totality of the data”, as if they might set aside those four patients, denies regulatory reality (e.g. Neurocrine Biosciences‘ first Phase IIb in Tardive Dyskinesia, where one site’s onsite ratings had zero congruence with the video ratings–Neurocrine still had to run another Phase IIb, they did not get the go-ahead to enter Phase III based on overtly distorted Phase IIb data). Alcobra kept saying that they would meet with the FDA to assess their next step: The next step would be to run another Phase III trial, while assuming the requirement of a second. Meeting with the FDA would offer the opportunity to finetune the protocol and enrollment criteria to reduce the risk of this being replicated, but not the necessity of repeating the trial.

3) Alcobra’s conference call began with the statement that they would ‘start with the bottom-line’–that the trial results support MDX as providing clinical effect in Adult ADHD. We would disagree: While the results do not prove the converse, that it does not have beneficial effect,  a failed Phase III whose data are suspect does not establish benefit. Their emphasis on finding positive trends in the Combined Inattentive/Hyperactive subgroup where none had been seen before, might reflect the greater statistical power of this larger sample, but given that all of the identified outliers came from that group, we would suggest that some other patients in that category may have received drug but also responded fraudulently.

Alcobra needlessly undercut its own credibility with its press release and conference call, where they selectively inattended to negative ramifications of the dataset as it currently stands. The stock sell-off, of over 50%, reflects disappointment with the results, but also with the spin operation that ensued: One fund manager told me he thought the press release was “disgusting” in its flagrant denial of trial failure, he clearly was not alone.

Metadoxine is not finished, but its all-Israeli pediatric ADHD PhII data due late this year will not undo the damage done, and Alcobra’s management should consider a reset of its PR stance, which cost their credibility dearly.

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The Flying Dutchman sets course for an IND

<<The Flying Dutchman is a legendary ghost ship that can never make port and is doomed to sail the oceans forever. >>  –Pedia, W.

Last November, a disspiriting diaspora of neuro talent from Bristol Myers Squibb  began when BMS decided to disband its CNS research group; hence considerable surprise back in April, when the Ghost Ship signed its iPierian deal, acquiring that Company and its tau antibody program for $175 million upfront, and promises of much more later. But given that there are tauopathies that fall under the Rare Disease category, that seemed the probable angle for understanding a deal that was CNS-based, from a company that had seemingly chosen to exit the brain.

But today, it was announced that BMS is advancing a NR2B antagonist candidate molecule that had been developed within its ‘fully internalized’ alliance with NeurOp. They will be preparing the compound for its eventual IND, in psychiatry, aimed at Treatment-Resistant Depression. Which is not a rare disease.

One can only imagine what would be possible if they hadn’t made most of their crew walk the plank.

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‘Google’s War Against Aging’ (WSJ 9/4/14)

The announcement that Google‘s Life Science spin-off Calico LLC is joining up with AbbVie in an anti-aging R&D effort into which each will put an initial investment of $250 million (and up to half a billion more each) raises some interesting issues and questions. In no particular order:

1) The two major foci cited are neurodegenerative disease and cancer, which gives CNS the kind of high profile that has been missing from several Big Pharma companies. It was somewhat amusing, in a black-humored way, that the WSJ reporters stated that “the drug industry has had a mixed record in its efforts to significantly improve treatment for neurodegenerative diseases such as Alzheimer’s and Parkinson’s.”  Mixed? The drug industry aspires to eventually have a ‘mixed record’, currently the more accurate adjectives include candidates like ‘abysmal’ and ‘horrific.’ Calling it ‘mixed’ is like saying that Vladimir Putin has a ‘mixed’ record when it comes to humility.

2) Entering into a 50/50 partnership with AbbVie is an interesting choice on Calico’s part–and on AbbVie’s, given that their history is one of ‘not playing well with others.’ Calico is not being managed by lightweights, so AbbVie’s penchant for control rather than collaboration is going to undergo a cultural stress test. On the other hand, both Calico and AbbVie have the reputation of being quite secretive, so we expect to hear very little of substance for a very long time. The rumor that AbbVie employees are required to have cyanide fillings that can be remotely-activated if they say anything of informational merit remains just that, a rumor.

3) If  the ‘War against aging’ is operationalized as a life-extension campaign, it may be a misguided goal. While we stand with our Boomer peers in claiming that the Boomer generation is a very special generation that deserves immortality; from a Millennial resource-allocation viewpoint, extending life chronologically would be an unwelcome development. In NeuroPerspective‘s review of Alzheimer’s, we noted that “Success in delaying that (Alzheimer’s) onset…may delay the advent of incapacitating dementia symptoms for a significant portion of the at risk population towards, or beyond, the end of life. If the process can be slowed, fewer people will outlive their functional capabilities, saving them and the society within which they live from the indignities and costs of severe dementia… This assumes, of course, that modern medicine does not further complicate the task by extending the average lifespan beyond its current point, an assumption that may be more safely rooted in the inevitable shift towards the actuarial allocation of finite medical resources, than upon any retreat on the part of medical science itself.”

In other words, extending independent functioning is likely to be a reasonably good thing, extending life span might not be…

4) Finally, the sheer scale of the AbbVie/Calico endeavor has some advantages, but has a potential downside. They will have the resources to attract scientists from almost anywhere, which could put some small-scale, independent R&D projects in jeopardy, as their initiators/sponsors are recruited to Calico tasks. A sidebar in the September issue of NeuroPerspective noted that the hyperconsolidation of resources in a few entities and geographic areas risks losing creativity and innovation–and this is another example of a situation where scale may be counterproductive.


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The Golden Age of Neuroscience

We were surprised and thrilled, as so many were, to find out from the Wall St Journal that the “Golden Age of Neuroscience Has Arrived” (Michio Kaku, 8/20/14). We hadn’t even received an email alert. Apparently, we are now able to “mentally control appliances, surf the Web..control a distant robot or avatar, and even drive a car.”  That is welcome news for NIR, because we have had a very difficult time controlling our avatars manually, let alone operate our Miele dishwasher beyond the one cycle that we understand (‘Turbo’). Kaku went on to say that “one short-term research goal is to create a “brain pacemaker” for Alzheimer’s patients. By pushing a button, a person might be able to remember where they live…” That’s the shortterm goal.  And the longterm objectives? For one, Kaku suggests that “the Internet might be replaced by a Brain-Net, in which emotions, sensations, memories, and thoughts are sent over the Internet….. Instead of using clumsy symbols like :), teenagers would go crazy sending all their adolescent emotions and feeling on a mentalized version of Facebook.” Besides the inevitable bandwidth issues, Kaku overlooks the fact that it is the necessity of using symbols, and occasionally language, that provides teenagers with a paper-thin buffer between their impulses and actions, allowing them to mimic the mediating effect of a not-yet-fully-connected frontal lobe. The spectre of an unfettered flood of adolescent angst and lust permeating the communal ‘Brain-Net’…that’s not a Golden Age, it’s Dante 9.0, a new Circle of Hell. And Kaku’s forecast of a “day when we might wake up and watch a video of the dream we had the previous night” is unappetizing: CNS Summit. Keynote address. No pants. Again.

But we are not going to dwell on these less photogenic images of the new Neuro World. After all, Kaku is a professor of theoretical physics, a discipline whose panoply of invisible and incomprehensible subparticles makes the DSM-5 seem evidence-based by comparison. He may have misread a few quarky details here and there. We prefer to focus on his inspirational closing thoughts, one of which was this: “the promise of this new revolution in neuroscience is profound, holding out the ability to someday alleviate suffering and enhance our true mental potential.” Finally. The Golden Age is here. Somebody call GSK and Bristol Myers Squibb. Our avatars say that it’s time to turn the CNS lab lights back on.

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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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