Elan: If You Can’t Beat Them, Be Them

Freud (Anna, not her father) coined the psychoanalytic term ‘identification with the aggressor’ to describe a process wherein an individual identifies with–and emulates–the behavior of someone they experience as a threat, in order to feel less vulnerable. Elan has now displayed that defense mechanism on the grand corporate scale, paying $1 billion to Theravance in exchange for 21% of that Company’s respiratory drug royalty stream from GSK. This takes place in the context of Elan fending off Royalty Pharma‘s attempt to acquire Elan–for its Tysabri royalty stream. The conjecture on the Street is that it is a message to Elan shareholders, reassuring them that Elan will not waste its resources on risk-laden extreme sports, like developing CNS drugs. Elan’s CEO Kelly Martin told Reuters that “This (Theravance deal) was not done because of Royalty whatsoever….Royalty – to myself, to the board, to pretty much every shareholder that we can talk to, frankly – is utterly irrelevant.” Right–the company that Elan had considered acquiring last year, and is now seeking to instead acquire Elan in a hostile takeover, is “utterly irrelevant.” Were Kelly Martin on Anna Freud’s couch, this would be interpreted as a blatant display of denial.

The Not So Divine Comedy of Psychiatric Nosology

There has been considerable recent discussion in the popular press regarding DSM-5, the American Psychiatric Association‘s new version of their diagnostic manual, heavily utilized by mental health providers of all stripes, some much more reluctantly than others. NIR was asked recently how DSM-5 will affect CNS drug development, and our answer is: Very little, if at all. Beyond the bold shift away from the anachronism of Roman numerals, for the most part DSM-5 does not alter the categorization of the disorders most heavily pursued by what is left of the psychopharm industry: Schizophrenia, depression, and bipolar disorder. To the degree to which categories have been altered, the changes obscure, rather than illuminate. For example, Asperger’s Syndrome has now been incorporated into the broad umbrella category of Autism Spectrum Disorder, which means that a poorly defined and unvalidated subgroup has now been collapsed into a broad, poorly defined, and unvalidated large category. Clinically, it’s a terrible idea, and it does nothing for pharma companies who need to parse out ASD subcategories in the hope of identifying groups who are at least slightly less heterogeneous, and who might thus provide a fair test for a new therapeutic agent. The same is true of depression, where the ‘bereavement’ exclusion has been deleted, in order to affirm that the presence of a significant loss does not mean a major depression may not have been triggered or unearthed. But then again, we do not know whether the biology of depression with bereavement is the same as depression that is not preceded by a loss, and woe to antidepressant developers who do not parse the latter from the former.

Which brings us to the larger issue, the disconnect between the observational reliability sought by the producers of the DSM-5, and the biological substrates underlying these disorders. The ability to consistently categorize patients according to their surface manifestations has little, perhaps nothing, to do with defining the biological circuits that must be accessed and modified in order to achieve psychopharmacological benefit–or to put it colloquially, help patients.

Some observers of the psychiatric world have suggested that patients be parsed by symptomatic features which transcend the traditional diagnostic categories inherited from Emil Kraepelin: For example, Roche‘s George Garibaldi has emphasized the treatment of apathy as a clinical phenomenon that has a distinct cost to the patient in terms of functioning, and exists across multiple ‘disorders.’ While an intriguing concept, we do not know whether this parsing strategy will turn out to have any more correlation with underlying biologies than do the usual diagnostic categories.

The NIMH, in conjunction with numerous academic and industry groups, is devoting valiant effort to setting forth on the journey required to identify critical disease biologies; the pathways by which they interconnect and exert downstream effects on observable features and behaviors; and the biomarkers whereby they can be tracked. Over time, those academics and companies wishing to access NIMH funding will have to become conversant in whatever new biologically-rooted nomenclature emerges via the NIMH’s RDoC (Research Domain Criteria) project. But that project is in its relative infancy, and NIMH is not the audience to which the pharma industry in general is attuned. For them, ‘the Agency” does not refer to the NIMH, it refers to the FDA. And the FDA will continue to insist upon a treatment population framework that matches up with what clinicians in the field utilize, the observational paradigm of the DSM, in order to maximize the likelihood that clinicians will know which drugs are validated for which patients. As biomarkers and revised etiological categories gradually emerge, they will first be embraced iwhtin the outer circles of Hell by the NIMH and NIMH’s ‘customers’, academics and smaller companies. Eventually, when relevant biomarkers are available to clinicians in the field, these changes will percolate into the innermost circles of the Inferno–Big Pharma and the FDA. For now, the DSM-5 provides a revenue stream for the American Psychiatric Association, added ambiguity for those contending with Autism Spectrum Disorder, and an extended stay in Purgatory* for those trying to develop new drugs for psychiatric illness.

*Purgatory=CNS drug development metaphor first suggested by Roche‘s Luca Santarelli

Gammagard’s Failure

So far as Baxter’s Gammagard was concerned, there was absolutely no ‘buzz’ of anticipation in the neuroscience community, and we had said in last September’s review of Alzheimer’s that “Our suspicion is that, once again, a small open-label subset of patients will not prove to be predictive of a properly-executed trial.” But while not a surprise, it was  disappointing to see Baxter’s announcement that Gammagard had failed in a “Phase III” trial. While Baxter noted ‘numerical differences’ between groups, it is a far cry from the arrest of decline that had been claimed for some patients in the pilot study.

But there are two silver linings here: First, at least Baxter only ran a 390pt trial, making this a far less expensive failure than were the massive programs for bapi/sola. Secondly, we are spared the prospect of an allocation nightmare that would have raised to an even higher profile the persistent conflict–particularly in the US–around economic class and power. With millions of AD patients, and enough Gammagard for a couple hundred thousand, the process by which recipients would have been chosen–some form of rationing–would have been a potentially mortal blow to what remains of the tattered American ideal of egalitarianism.

Passing for Analysis

Occasionally, the general financial press comes up with a comparison or concept that is amusingly obtuse, but it’s less amusing when one considers the likelihood that this reflects the kind of superficial analysis that can drive investor sentiment, and that such shifts in sentiment influence the availability of capital for even a niche like the neurotherapeutics sector. These two recently caught NIR‘s eye:

(Forbes, 5/3/13): According to ‘ETF Channels‘) Biogen Idec Achieves #169 Analyst Rank, Surpassing United Parcel Service“

It must surely be champagne time at Biogen-Idec today, with another steppingstone in the business plan executed.  We tried to find out what the next benchmark will be, uncover who must Biogen-Idec pass next in the hearts and minds of Wall Street analysts. Who is #168? But apparently one must pay for that kind of sensitive information. We’d rather speculate–FedEx? Carnival Corporation? Smith & Wesson?

But that  reeked of spot-on market analysis compared to this second example, published online by Street.com (‘StreetWire‘ 4/29/13): “ACADIA Pharmaceuticals (ACAD) pushed the Drugs industry lower today making it today’s featured Drugs laggard. The industry as a whole closed the day up 0.8%. By the end of trading, ACADIA Pharmaceuticals fell $0.21 (-1.6%).”

The blurb went on to say: “TheStreet Ratings rates ACADIA Pharmaceuticals as a sell. The company’s weaknesses can be seen in multiple areas, such as its unimpressive growth in net income, weak operating cash flow and feeble growth in its earnings per share.“

Acadia Pharmaceuticals, up over 170% YTD, a “Drugs laggard.” They’d better grow their eps ASAP, or heads will surely roll in San Diego. It’s probably just a coincidence, but the share price did drop the next day. We would prefer to think that a purely computer-generated piece of nonsense like this could not possibly move the stock price, but it probably did. No wonder it is hard to garner support for the kind of longterm perspective  required for genuine investment in neurotherapeutics.

New Ketamine Data

As was discussed at length in December’s NeuroPerspective, the quest for a rapid-acting anti-depressant (RAAD) continues to be one of the most closely watched races in neuropharmacology. A small but intriguing Mt-Sinai sponsored study comparing ketamine with the anesthetic midazolam just reported its results: In the 72 pt trial, there was a response rate (on the MADRS) of 63.8% for the 47 patients who had received IV ketamine 24 hours previously, compared with 28% in the midazolam group. The value of the midazolam control was that there is an unmistakable, immediate psychotropic effect with IV ketamine that is not emulated by placebo, but is mimicked by midazolam. However, the glutamatergic premise behind ketamine’s postulated antidepressant effect would not be mirrored by midazolam, and indeed the much higher rate of response indicates that ketamine’s action is not a nonspecific psychotropic one. The degree of MADRS change was also much greater in the ketamine group, 16.5 points versus 8.8 points. Interestingly since BDNF upregulation is one of the hypothesized mechanisms of action for ketamine, BDNF plasma levels were monitored, and BDNF level changes were higher in treatment responders, but only in the ketamine group. Ketamine is not without its complications, and indeed, the investigators reported changes “in the level of dissociation” during the ketamine infusion, which abated within a few minutes for most, but took up to four hours to abate for others. Even though the investigator referred to this as “very little in the way of psychotic effects,” any psychotomimetic effect is going to alter the perceived risk-benefit calculus, and put more pressure on clinics administering the drug to provide prolonged monitoring. Since this was a single-infusion, single read-out study, no further information regarding the durability of the ketamine response was produced. This is another piece of evidence that supports the RAAD concept. With the consistent report of at least transient and mild dissociative symptoms for ketamine, there will be even more attention given to the Naurex GlyX-13 Phase IIb, now well underway: Thus far, no dissociative/psychotomimetic reactions have been reported with GlyX-13.

Acadia and the FDA

In the upcoming May issue of NeuroPerspective, we will be including some commentary about institutional and regulatory rituals which endure without clear justification–or at the very least,  deserve some reconsideration. This comes in the wake of having recently had the opportunity to spend a couple of days  talking at great length with a former high-profile FDA regulator, where both his intelligence, integrity, and humane desire to do the right thing, and a narrow view of what constitutes the avenues to doing so, were quite salient. Now, the FDA is hardly the only repository of such rituals, indeed no entity epitomizes anachronisms-in-action, or inaction,  more definitively  than the US Congress, but the FDA is of particular relevance to what we do here, so its reliance upon familiar rituals and criteria is highly figural.

But even as we note a history of inflexibility, today some credit looks to be due as well: The FDA has informed Acadia Pharmaceuticals that the single Phase III trial conducted for pimavanserin in Parkinsonian psychosis is sufficient for NDA submission. This is forward-looking and entirely appropriate in its exercise of flexibility: the data are clearcut, and this is a treatment that addresses a need otherwise unmet, at least with any semblance of clinical satisfaction and safety. While it has been noted  that this does not guarantee approval,  unless some unforeseen issue crops up safety-wise, and the likelihood of that, given pimavanserin’s extensive human database, is minimal–the invitation to file infers the strong likelihood of approval, on the basis of the data as it stands. Good for the FDA, good for Acadia Pharmaceuticals, and good for Parkinson’s patients. Win-win-win. We have not had the opportunity to say that often, if ever.

The Varieties of Pharma Disclosure

The variations around corporate disclosure displayed by pharma companies generally fall in a range from amusing to frustrating to baffling. Over the past month, three contrasting approaches crossed our radar, and warrant mention:
1) Acadia Pharmaceuticals waited until the AAN meeting to unveil more detail about efficacy the pimavanserin results in Phase III than had been disclosed in their original PR. The stock price immediately and dramatically responded positively. We understand why a small company wants to have their ‘moment’ at a high-profile professional meeting, but we can imagine anyone who had sold their Acadia stock prior to AAN might feel that this was material information that should have been disclosed right away.
2) Merck‘s drug development group provided a reasonably (for big pharma) full discussion of the suvoxerant Phase III results, which was refreshing. But when it came to the actual NDA filing, Merck (almost certainly not the drug development people, but rather someone in legal/regulatory) refused to disclose when the filing was made, or what the PDUFA date is likely to be. That’s just silly. It is not as if there is a flock of competing orexin-antagonists, or even insomnia alternatives, for whom this might be fantasized as constituting useful competitive information. It’s an evocation of corporate lockjaw based on policy, not pragmatics, and is an anachronism that at the very least, communicates hubris. Secrecy is an outmoded and counterproductive default option–if there is no discernible rationale for withholding information, what is the point beyond ‘that’s how we’ve always done it’?
3) On the other side of the spectrum, Sunovion has for the past couple of years quietly shared data in professional settings in the service of promoting the concept of pre-competitive space, helping others learn from their experience. Some companies pay lip service to the concept of advancing drug development through prudent collaboration and information sharing, Sunovion has consistently ‘walked the walk’, more than any other pharma company that we know.