The gloom had approached nuclear winter hues after the unexpected failure of the TC-5214 Treatment-Resistant Depression program from AstraZeneca/Targacept, which catalyzed AstraZeneca’s radical remodeling of their neuroscience program, and set the psychiatry community to wondering whether depression had become inaccessible as a target for new therapies. But as the first six months of 2012 drew to a close, there were some positive data reports that should start to lift the mood of those trying to push the neurotherapeutics field forward, even as others edge towards the exits. We heard positive late-stage trial results from Forest/Pierre Fabré, Sunovion, and Lundbeck/Takeda, and there is data yet-to-be-announced from two other CNS trials which will have a dramatic impact when publicly disclosed.

The pessimistic wait for results from bapineuzumab and solaneuzumab (formal presentations in October) continue to cast a shadow over the landscape. But ‘bapi’ and ‘sola’ do not define neuroscience, they do not even define the amyloid hypothesis, given that they were administered too late to prove anything in the developmental cycle of Alzheimer’s. There are other events that will prove to be much more important. Below is a noncomprehensive roster of programs that will produce Phase II and Phase III data over the next eighteen months, and from those, there will be ample good news.

Allon Therapeutics Davunetide PSP
CeNeRx TriRima Depression
EnVivo EVP-6124 Alzheimer’s
Targacept TC-5619 Schizophrenia
Targacept/AstraZeneca AZD3480 Alzheimer’s
Acadia Pimavanserin Parkinson’s psychosis
Ceregene CERE-120 Parkinson’s
Naurex GlyX-13 Depression
Catalyst CPP-109 Cocaine addiction
Intra-Cellular Therapies ITI-007 Schizophrenia
Marinus ganaxolone PTSD
Seaside Therapeutics Arbaclofen Autism
Zalicus Z160 Neuropathic pain
Euthymics Bioscience EB-1010 Depression
Biogen-Idec/Knopp Dexpramipexole ALS
JNJ/Pfizer/Elan Bapineuzumab Alzheimer’s
Neuren NNZ-2566 TBI
Adamas Nurelin Parkinson’s
Lilly Solaneuzumab Alzheimer’s
JNJ/Addex ADX71149 Schizophrenia, depression

Apparently the BOD also had some qualms about Targacept’s direction, because the Company today announced that President and CEO Don deBethizy would step down immediately, and the Company will launch a search for a successor. On the one hand, it is regrettable that deBethizy’s departure comes at the lowest ebb for a company that, just a year ago, could be counted as among the most successful of small biotechs, neuro and otherwise. Certainly, the partnerships achieved over the years, and the resources still on hand for Targacept, speak to a strategy that has been well executed in many ways. But as our May comment had noted, there was a level of corporate certainty about the superiority of the nicotinic approach that was unsettling–nothing is that sure in the neuroscience area.
Targacept’s adherence to a single approach is matched by just a handful of its neurotherapeutics peers: Cortex and Ampakines, Prana and metal-binding, Allon and its ADNP/ADNF derived factors, and Addex‘s allosteric mGluR modulators are a few that come to mind as having been so singly focused over a long period of time. So far, it has not turned out well for Cortex; Addex has gone through its own painful period of introspection and change; Prana has taken what seems like an eternity to make limited progress; and the outcome for Allon will be clear by year-end.
One of the many lessons to be learned from the past fifteen years is that nothing is certain in neurotherapeutics. This is the time that Targacept must step back from the focus in which it was formed, shaped, and matured, and decide whether diversification might be prudent– we do not refer to the application of nicotinics beyond CNS. NIR has been suggesting this for a couple of years now, and it may indeed require the perspective of someone who did not come of age in nicotinics to objectively assess what level of prioritization that platform should occupy going forward.

None of the changes will constitute recognized doctrine until codified by the SEC and FINRA, but at the moment, the revised regulations will begin with changes to Sarbanes-Oxley, making the process of going and being public less onerous and costly. That in itself would be welcome, the fact is that many of these small companies barely have any assets to regulate in the first place. But the most appealingly nostalgic element of this DeLorean trip back to the 1990s is the restoration of Sellside Analysts to a sales and marketing role in the IPO process. For almost ten years, there has been a firewall between banking and research, which seemed to be working, until someone looked on the other side of the firewall and found that all the sellside analysts had left. No wonder it was quiet. Now, sellside analysts would be allowed go back to participating in road shows, issuing glowing research reports, and being quoted in the WSJ about the ‘enormous untapped potential of the biotech area’. While good for restauranteurs and high-end hotel chains, it also constitutes welcome news for the biotech industry, even the neuropharm area. The reason being that any life whatsoever in the moribund IPO market at least conjures up the mirage of possible exits for a venture capital industry which, in recent years, has had had all the freedom of movement of James Franco under a boulder. If investors perceive a way out, they will be more inclined to buy in.

This is good news, a way to infuse a hint of liquidity into the private biotech marketplace. But even more welcome are the jobs that will be brought back to the Street, for this is not just JOBS, this is the ‘Sellside Analysts Long-awaited Improved Vocational Access’ Act (SALIVA). It will be fun to see them again cavort and play, out of captivity and in their natural environment for the first time in almost a decade.
Are there CNS companies for whom this will be an avenue to developmental maturation, and not just a source of entertainment? We are quite sure that this resurrection miracle will not mean that the IPO window will be thrown wide open to anyone with a drug and a patent. The hard-earned cynicism of the Street will mean that only companies with both POC and a defined commercial route will be taken seriously. Which points to companies in or preparing for Phase III, with solid Phase IIb data from trials conducted in the US or EU. Some of the names that come to mind as potentially approaching that threshold during 2012 include Adamas, CeNeRx, EnVivo, Euthymics, and Knopp. It is unlikely that a less mature company would reach critical mass, though if a paradigm-changer like Naurex’s GlyX-13 were to definitively succeed in Phase IIa, we can imagine that some of the feverish creativity of yesteryear might start to surface once again. After all, NIR is hardly the only place where people wonder–’If *&%! like Instagram is worth a billion dollars, what would a useful new drug be worth?’

What idiocy. Parents and prescribers do not  utilize stimulant medications because they are afraid that these children will otherwise indulge themselves in the Pleasuredome of unlimited possibilities. There may be a small subset of bright individuals for whom ADHD has served as a vehicle for out-of-the box thinking and accomplishment, but Richard Branson is the exception, not the rule. For most children and adolescents with medication-worthy ADHD, ADHD has not been an exhilarating ride into uncharted creativity, it has been the experience of spinning one’s wheels and only becoming further bogged down.

So, we have to ask: What is going on at the NYTSR? Two stories in three weeks have painted ADHD as a illusory construct built of inadequate and/or overcontrolling parenting, ADHD medications a ruse. Bereft of any counterpoint, these underinformed, indeed ignorant  pieces remind us not of the luminaries who have graced the pages of the NYT over the decades, but of Tom Cruise, discussing the merits of antidepressants.

1) The predictive power of mouse models where amyloid production is hugely amplified has yet to be shown–indeed there have been numerous failures in trying to do so.
2) This does presume the primacy–or at least salience-of the amyloid model, where improving clearance of brain amyloid is seen as a key target. Again, this needs to be proven in humans.
3) Do acute changes establish longterm modification of the disease process?
4) Would bexarotene be safe when given longterm, and at what dose? (and would safe chronic dosing be sufficiently impactful on AB?)

The exciting part of the news is that some of these questions could be rapidly answered (not so much the safety of chronic dosing). The first step would be to see if bexarotene, in human AD patients, alters beta-amyloid biomarkers in what we believe to be the desirable direction. Based on the mice, one would expect to see such a shift quickly. One could first assess a sample population for biomarker changes, and then (if warranted) begin testing for cognitive changes compared to baseline–six months would be a sufficient pilot study for both the initial magnitude and durability of cognitive improvement. IP issues would complicate pharma investment in the US–but this might be a worthy use for some of the additional Alzheimer’s funding recently announced by HHS.

http://www.sciencemag.org/content/early/2012/02/08/science.1217697

We have our doubts about the wisdom of this stripped-down process. Business Development in today’s environment is a kind of speed-reading task, skimming a huge number of external programs, in theory at least, identifying those which deserve a deeper look. Our suspicion is that the breadth of scan will diminish with this approach, scientists tend to be relatively more specialized in certain areas of expertise, and since they are explicitly going to ‘own’ the programs they license, in an environment where many heads have already rolled, we expect that they will stick somewhat ‘close to home,’ with mechanisms and concepts they are familiar with. Some of the same dynamic already exists in pharma’s traditional model, since an inlicensing candidate that does not resonate with the belief-system and priorities of some internal champion within the larger company has no chance of being chosen. But this takes it to the extreme, and eeven as this is presented as providing a more entrepeneurial context for R&D staff, they are going to be asked to carry out tasks that require a generalist’s perspective while also retaining specialist skills in fostering the programs they have chosen. It is not that there are not people with the ability to function in both domains, there are, and we know large companies who have provided BD people with the opportunity to also have a hand-on role in clinical asset development. But that group is more the exception than the rule.

To the delight of AZ’s CFO, overhead costs will certainly plummet, with just 2.5% of staffing remaining within neuroscience. But in the clamor for resources within AZ, those 40-50 survivors will have near-zero clout. We see this ‘Gilligan’s Island‘ of neuro castaways less as the nucleus for a lean and efficient outsourcing operation, and more as a vestigial organ. It is possible that they could eventually turn out to be the seedling for a renewed neuroscience program when the area comes into favor again. For now, and for those looking for a Big Pharma partner, Astra Zeneca will be suitable only for those who have a large enough range of capabilities that all they need is fiscal resources: Not much else will be available from AZ, and there may not be much of even that for neuroscience.

http://online.wsj.com/article/SB10001424052970204740904577192901072611524.html

To summarize his hypothesis: Since experience can have an effect on neural development (we must point out, and vice versa), and since the neonatal neurological/biological assessments available to him in the 1970s did not detect any signal later correlated with the development of ADHD, he concludes ADHD must be the result of experience, rather than any inherent structural anomalies. One of the possible environmental ’causes’ suggested by Sroufe is “patterns of parental intrusiveness that involve stimulation for which the child is unprepared. For example, the child is playing, and the parent picks it up quickly from behind and plunges it in the bath.” Surprise, momentary alarm, annoyance, frustration perhaps….but ADHD?  Talk about unsupported belief systems…

We would not deny the possibility that heritance and experience may interact, but the absence of conclusive biological evidence from 1973 does not establish evidence of absence. Sroufe points out the frequent comorbidity of ADHD with depression and anxiety as if it explains away the former as a manifestation of the latter, whereas contemporary clinicians are very familiar with the way that these disorders so often coexist. Sroufe decries the use of medication as reflecting a “societal view that all of life’s problems can be solved with a pill,” when in fact competent psychologists and psychiatrists are well aware that effective treatment of ADHD is multimodal, often combining medication with therapy.

The fact that a retired professor in Minnesota has such an antiquated and simplistic view of the disorder and its treatment is not in itself a problem. But placing it in such a prominent position in the New York Times, without so much as an opposing viewpoint, gives it an imprimatur of credibility that it does not deserve. The next few weeks will see a flood of letters to the NYT, but what will not be so evident to the naked eye will be the hundreds of families where well-intentioned parents may not realize just how underinformed and misguided this piece was, who may question the need for ADHD meds for their child. One must wonder if–had an opinion piece espousing schizophrenia as the result of a ‘schizophrenigenic mother’, or autism as due to a ‘refrigerator mom’ (two equally discredited anachronisms), been submitted to Andrew Rosenthal (the editor responsible for the Sunday Review), would he have given them the go-ahead without seeking out a responsible counterpoint? Rosenthal was asleep at the switch on this article, and unfortunately, it will  be children and their families who will pay the price for it.

On a ‘per-capita’ basis, Vanda Pharmaceuticals has done less with its resources (they have over $150 million in cash on hand) than any company we know, and that is not easily done, given some of the underperformers in the neurotherapeutics area. Why Vanda management would choose to highlight that fact with this press release completely escapes us.