Over the weekend, Naurex announced that it had been acquired by Allergan (Actavis/Forest) for $560 million plus undisclosed milestones; Allergan is focused upon Naurex’s two clinical-stage Rapid-Acting-Antidepressant candidates, IV rapastinel/GlyX-13, and orally-bioavailable NRX-1074. NIR has been following this particular technology since 2003, through its iterations as Nyxis Neurotherapies and then Naurex; in fact the first time we invited Naurex to present GlyX-13 as a ‘Top Partnering Opportunity’ at the TAP conference was back in 2010. We must admit that at first, our reaction to the sale announcement was lukewarm: After all, this has been another year of an open door for IPOs, and if an Axovant could take in $362 million, what might the far-more-promising Naurex portfolio have garnered by going public? Surely a new CNS record could have been set. But Naurex knew that, and the decision to sell rather than go public was based on calculations that were less drama-laden, but more rational:
To take both rapastinel and NRX-1074 all the way through clinical development would have required an enormous investment in infrastructure-building. Naurex has remained a barely-larger-than-virtual company, and while such expansion could have been achieved, receiving $560 million plus undisclosed later milestone payments represents a healthy ROI for its shareholders, particularly as it comes prior to the expense and risk  attached to Phase III trials and the regulatory maze.  These hurdles, yet-to-be-surmounted, are the reason for the divergence between this upfront valuation and that seen for the lower-risk, lesser-potential of Avanir and Auspex, each of which sold for $3.5 billion.
The two other interesting considerations are these: Allergan just announced the sale of its generics business to Teva Pharma, and the acquisition of Naurex makes tangible their intention to keep CNS as a key component of their branded pharma agenda. Given the recent and ill-considered retreats from CNS by several formerly major pharma companies, it can only be good for the neuroscience area to have a company with resources and chutzpah add itself to the licensing/acquisition mix, and their Forest-legacy depression expertise guarantees a highly-competent clinical trial and commercialization process.  But they are not looking to build an inhouse neuroscience research capability, and thus Naurex will spin out its preclinical assets, constituting a glutamatergic platform with potential in cognition and pain, into an independent company. The details on the latter are sketchy, other than Allergan will have right-of-first-refusal for several compounds, but we like the fact that there will be a small company, a ‘NuNaurex’, that will continue with its portfolio building, something that it could not have fostered had all of its energies and resources been funneled into late-stage clinical development. From a neuro ecosystem perspective, it is one of those elusive ‘win-win’ scenarios.

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mAbMEN: It’s Not Over


Eli Lilly: Experimental Alzheimer’s drug shows some benefit  (AP)
Eli Lilly’s Solanezumab Is the Alzheimer’s Drug Equivalent of the Internet Dress                (TheStreet)
Lilly says drug slows Alzheimer’s in patients with mild disease (Reuters)
Lilly’s Alzheimer’s Drug May Slow Patients’ Decline (The Wall Street Journal)
Biogen, Lilly Alzheimer’s Data Spark Street Debate   (Investor’s Business Daily)
 Biogen: Come On, the Results Weren’t That Bad (
 Biogen Alzheimer’s drug data falls flat, Lilly gets slight bump (Reuters)
 Alzheimer’s Trials Offer Few Answers for Investors or Patients (Bloomberg)
 Lilly Alzheimer’s Drug Shows Benefit in Those Who Start Earlier (Bloomberg)
 Promising Alzheimer’s Drugs Disappoint With Incremental Data (Forbes)   

The responses to the data releases for solanezumab and aducanumab were not a model of consensus. As is not unusual, the ramp-up of expectations prior to the solanezumab and aducanumab supplemental data had been unrealistically steep, and the aftermath featured a broad spectrum of divergent responses and interpretations, though the predominant themes were vague disappointment and confusion. When one media outlet has to describe results in terms of “weren’t that bad”, one is not in the presence of definitive success. The expectations were overheated, given the limited nature of what to be unveiled: Biogen’s addition of 52 week data for a dose-level cohort that had enrolled just 30 patients; Lilly’s report of results from an extension of two failed studies for solanezumab, selecting subgroups from those Phase III populations, then comparing outcomes between patients who had been on solanezumab with those who were on placebo until the extension component began, eighteen months later. The number of patients who completed Lilly’s extension study was 626, which might have been impressive, other than for the fact that the trial began with 1314 patients, and the extension component began with 1018. With the attrition rate more than 50% from the beginning of the trial, one must wonder whether the 48% who stayed the course were a representative sample of the subgroups Lilly had selected posthoc, who may or may not have been representative of mild Alzheimer’s (eighteen months later).

Consider the magnitude of change in the Lilly trial. The extension of course did not have a control group, the trial was predicated on the premise that if the drug is disease-modifying, those patients who started on the drug later would remain cognitively ‘behind’ those who started earlier. This is an experimental protocol that has yet to be embraced by the FDA (though Paul Leber played a role in its devise), and it may never be: It can be argued that the two groups are inherently different by virtue of one beginning treatment 18 months later than the other, perhaps having reached a different stage (and slope) of their disease course. Not everyone accepts this divergence as evidence that the disease-course has been modified. But just to take it at face value for the moment, the graph of the results showed the two groups mirroring each other, just slightly separated, for two years on the ADAS-cog. The divergence was statistically significant at all timepoints except the last one, where the p value shot up to .169. That could reflect the shrinkage of the population and/or greater variance in the test results for those who remained.

Even if Lilly’s framing of the results has merit,  the mean difference in ADAS-cog score decline one year into the extension study is just 1.91 points.  The FDA’s general rule of thumb is that a 4 point difference on the ADAS-cog is clinically meaningful. The ADNI group reported that mild AD patients receiving cholinesterase inhibitors declined an average of 9.25 points over two years; another 18 month study found a mean decline (in the placebo group) of 6.44 points. These studies point to a 4-4.6 point annual decline rate for this population, which means (with the caveat that decline rates in Alzheimer’s are not linear, and may vary between genders, with women declining more rapidly) that a 1.91 pt difference is a bit less than one would expect a modal patient to decline in six months.  Similarly,  on the MMSE, Lilly’s slide (we await the imminent publication of the trial report) showed what looked to be less than a one-point difference between the two groups at two years into the extension trial, 3.5 years into the overall study: Three points is considered to be a significant score change on the MMSE, or roughly, just under the decline that would be seen over an eighteen month period. Which would again point to an treatment effect tantamount to ‘six-months worth’ of progression. It is possible that the impact might grow over time, but then again, it is possible that some of this is ‘noise’, perhaps partly due to the notable attrition rate in the study.

Lilly may yet achieve statistical significance in the ongoing ‘Expedition 3’ trial, which uses a traditional placebo-controlled protocol, but even if they do, there is nothing in these results that suggests that clearcut clinical significance is to be assumed. But it is possible that even a minimal clinical effect might be accepted as better than nothing, provided that no safety concerns emerge (the original Phase III data showed just a 1% likelihood of vasogenic edema).

So here is a headline that captures the gist of the findings from the solanezumab data:
Solanezumab May Do Something, But Not Much–But It Might be Better Than Nothing  

We had initially thought that both mAbs had an equally lackluster day today, but that is not the case. First, it looks like 26 patients in total completed all cognitive test sequences in the long-awaited 6mg/12 month group. That is not a cohort size about which much is generally said when it comes to Alzheimer’s. Anomalies in the readout could reflect some outlier patient(s) whose impact would be greatly magnified by the small n. But when Biogen presented the results, they claimed that they fell in line with the preliminary data from last March, which is not completely true. The rate of decline on the CDR-SB did indeed place the 6mg group between the 3mg and 10mg groups, but it was much closer to the 3mg group. The neat dose-response relationship that had initially surfaced in March vaporized: The MMSE score decline for the 6mg group was almost identical to the very limited effect seen from 1mg, while the 3mg and 10mg groups clustered together in an oasis of statistical significance. The impact on amyloid plaque was linear, but since that did not consistently line up with functional effect, this raises more questions than it answers. Finally, the incidence of vasogenic edema in the 6mg group (37%) was nearly the same as in the 10mg group (41%), far above that seen with 3mg (6%). So the hope that the 6mg dose might ‘walk the tightrope’ and somehow provide 10mg dosing efficacy along with 3mg dose adverse effects was not fulfilled, at least not in this trial. While Biogen tried to reassure observers that the vasogenic edema findings were not particularly problematic (“typically resolved within 4-12 weeks”), the fact is that while 78% were “mild to moderate”, this means 22% were more severe. In a trial that enrolls 166 patients and makes brain scans easily available, that is manageable. In a general Alzheimer’s population, perhaps not. For example, if 100,000 patients were to receive aducanumab at the 6mg dose, and if the incidence rate in this trial is predictive, 37,000 could develop vasogenic edema, with 7500 of those cases being severe. That becomes a clinical monitoring and management challenge that could outweigh what looks like a modest-at-best treatment effect: Even the most seemingly efficacious dose (10mg) achieved just a 2.25 point difference on the MMSE decline rate at 12 months, on a test where three points is the minimum considered to be clinically meaningful. On the CDR-SB, where mild Alzheimer’s patients decline 1.4 points annually, the 10mg dose approached that level with a 1.24 point effect, the 6mg dose had just a .76 point impact, close to the ‘six-month’s worth’ noted for the MMSE. Again, these are tiny dose cohorts, and may not mean anything, but today’s additional data only beclouded the issue for aducanumab.
Thus, because of the added concern about vasogenic edema, the aducanumab headline reads like this:

Aducanumab May Do Something, But Not Much–It Might be Better Than Nothing, But Possibly Not 

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Walking It Back on Axovant

NeuroPerspective subscribers are aware that we have not been unreservedly enthused about Axovant; its 5HT-6 drug for Alzheimer’s (licensed from GSK); and their ‘biggest CNS IPO ever.’ There has been a genuine element of fervid overheating here, but unfortunately, the same can be said about our coverage. In specific, we have been highly critical of stock options and salaries being paid to the mother and brother of the CEO. The S-1 described them as “employees”, but provided no substantive detail, and when the CEO was asked about this by the WSJ, the question was, in the words of the WSJ reporter, “swatted away”. That is on Axovant, they should have been more forthcoming in addressing what could easily be perceived as unbridled nepotism.
But it is on us that we did not research the matter more carefully ourselves. As it turns out, the stock options and salaries are not just gifts being paid for by other people’s money: The CEO’s brother is in fact deeply involved in Business Development for Axovant, and the mother, a geriatric psychiatrist of thirty years experience, was at the recent ASCP/NCDEU meeting, actively involved in information-gathering. While one might argue that these professional staff hirings were not conducted  on the basis of an open competition/selection process, it is not as if familial hiring does not happen elsewhere (including NIR). So long as they have the qualifications needed, and are putting in the work, then they are participating in the great drug development enterprise/lottery, and there is no major criticism to be made. Or at least, not with the overly harsh stridency of our comments, which we regret.
So, it is now up to Axovant’s staff to earn their remuneration packages, and up to Axovant to justify the hefty investment made in them and RVT-101. We will be watching with great interest.

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Sages and Mariners

The report from SAGE Therapeutics about their pilot data in Post-Partum Depression (PPD) raised plenty of eyebrows, (and their market cap, briefly, by about $420 million). A planned fifteen patient study was cut short after the first four patients showed a complete reversal of their depression, their Hamilton scores nearing zero  60 hours later. SAGE said that they would run a controlled trial to confirm the signal, and this apparent radical improvement in PPD symptoms is well-deserving of a placebo-controlled study.  At the same time, there was some appropriate skepticism about the predictive value of results from four depressed patients receiving an IV infusion of an experimental drug, a set-up for a placebo effect if ever there was one.

There was an eerie correspondence between these SAGE-547 results and the Severe Status Epilepticus ‘compassionate use’ results that launched SAGE towards credibility and Phase II validation. Four patients were treated, all improved, no patients received placebo. Of course, placebo response is less of a concern in patients who are in Status Epilepticus, but it most certainly is in depression, and it could, in theory, explain these pilot results. But there is biology that suggests that SAGE-547 could be useful in this subtype of depression: SAGE-547 is, after all, a form of allopregnanolone, and women with PPD have been reported to have lower levels of endogenous allopregnanolone than their nondepressed PP peers, and it has been suggested that allopregnanolone may be protective against depression (Hellgren & Akerud, Neuropsychobiology, 2014). The results obtained by ketamine, JNJ‘s esketamine, and Naurex‘s GlyX-13 in major depression (not associated with the post-partum period) also have shown that rapid antidepressant impact is achievable.

Unless it turns out that these four women all belonged to the same New Mother’s coffee klatch, and were comparing notes, our guess is that there is a genuine signal showing itself in this pilot study. Its magnitude probably will not turn out to be as remarkable in its impact on the Hamilton as these results indicated, but one does not have to completely reverse depressive symptoms to achieve something of clinical value.

SAGE states they will develop a different, orally bioavailable molecule for PPD, once the signal has been confirmed. The utility of oral administration is obvious, but SAGE also has a pricing problem: They need to maintain SAGE-547 as a premium-priced compound for last-resort, hospital- based interventions in SSRE, a price-level that would not be sustainable for the much larger PPD population. Thus they need an alternative compound, and will go into their massive chemical portfolio to identify one.

This brings us to Marinus Pharmaceuticals. While Marinus has labored in the shadow of SAGE, their reformulated oral version of ganaxolone is itself a form of allopregnanolone, or in other words, similar to the oral compound  SAGE must now bring forward from preclinical development (SAGE would probably argue that their chemical scaffolds have pharmacokinetic advantages, but that is a secondary issue). With clinical trials already ongoing in epilepsy and Fragile X, it would seem an obvious next step for Marinus to run a pilot study in PPD. The results are unlikely to be as dramatic, the bioavailability of ganaxolone given orally is not going to match that of SAGE-547 given IV, but unless SAGE’s results do reflect purely a placebo effect heightened by the IV administration route, or ganaxolone cannot achieve sufficient bioavailability, a signal might be obtainable.

An oral drug that proves useful in Post-Partum Depression could be an option for prophylaxis in the substantial proportion of women who stop their antidepressants during pregnancy, for fear of harmful prenatal effects. It might also be possible to assay serum allopregnanolone levels to identify women at risk, and thus in need. At present, they are defenseless as they go through the extremes of hormonal disruption; stabilizing/protecting them during the storm would be highly useful, and given that the process  simply upregulates levels of an endogenous neurosteroid, it is likely to be safe.

The bottom line is that this likely to be (again) good news for SAGE Therapeutics. It could potentially be as good or better news for Marinus Pharmaceuticals. Assembling better quality, controlled studies to confirm or disconfirm the signal should be a priority for both companies.

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Mountains and Molehills

First, the Mountain: Denali Therapeutics made their May debut with the announcement that they raised $217 million in a Series A, a very dynamic bit of BioTheatre. Indeed, it is as compelling a headline as we have seen thus far in 2015. It is very good news for the neuroscience sector; the sheer scale is breath-taking; BioCentury referred to Denali’s “mountain of money“, which for the legions of small biotechs who struggle to raise even 10% of this (and for some, 1% has been a challenge), is almost incomprehensible. Denali is being fairly tight-lipped about the specifics of their strategy, but it is fair to partly extrapolate from Genentech‘s principles for their inhouse R&D and inlicensing efforts, given that Denali’s CEO, Ryan Watts, and COO, Alexander Schuth, ran neuroscience and neuroscience partnering for Genentech, respectively.

It is also fair to ask, why now? The availability of ample funding certainly played a role; it could not be assumed that the money would be available at some other point in the future, such windows have a way of eventually closing. The maturation of genomic analysis as a means of explaining variations of biological phenotypes, and the improved ability to track targets and target engagement via protein biomarkers and neuroimaging, also suggested to Denali and its backers that we are on the cusp of a new era for neurodegeneration research–far less of the black box that it has been historically.

Denali cites Alzheimer’s, Parkinson’s, and ALS as three neurodegenerative indications of high interest, with an overriding focus targeting pathways likely common to all of them: Inflammation, axonal degeneration, and cellular trafficking. They cite an emphasis upon biomarker-verified pathways and population enrichment as means by which they will better their chances of success in an area that has been uniformly characterized by failure. This is, unsurprisingly, very similar to the principles by which Genentech’s partnering process operated in recent years, wherein the rational elucidation of relevant pathways for targeting has been highlighted.

We had wondered whether Denali might have licensed any Genentech assets in devising their internal development portfolio, which thus far includes one academic collaboration devised by Fidelity’s FBRI group. That is not the case, at least thus far, though it remains within the realm of possibility that there could be the subject of discussions around collaboration at some point. Genentech had tended to prefer to (at the very least) conduct IND-enabling studies inhouse,based on the expertise and resources  they could bring to those tasks, and with $217 million raised, and more available, Denali can afford to bring in early-stage programs, and they have a long runway available to them. Denali states that they will inlicense from industry and collaborate with academia, but while we have assumed that they tend to prefer discovery-stage and preclinical programs, they are open to clinical-stage alliances as well, provided the assets involved pass their tests regarding biological explication.

Beyond Denali in specific, this particular shockwave has implications for several other components of the neurotherapeutics ecosystem, beginning with what might say about Roche/Genentech, from which some key talent has come, and for Fidelity Biosciences, who played a pivotal role in assembling Denali and the platinum roster of investors who provided it with this munificent Series A–and who have committed to providing more funding in the future.

Genentech has now had major departures to two newcos, with key Genentech people populating Calico and now Denali. Ostensibly, Denali’s formation says little or nothing about Genentech, which retains robust neuroscience capabilities. Genentech is more vulnerable to internal changes at Roche.  Roche has been an exemplary Big Pharma when it comes to supporting neuroscience, but it has been stung by some clinical failures (the bitopertin program in schizophrenia, and one Phase III trial for gantenerumab in Alzheimer’s). Some prominent internal champions of neuroscience are departing from Roche, and we had wondered if this might signal a dimunition in corporate support for neuroscience R&D. Roche is talking about upping the dose of gantenerumab in yet another Phase III, which some would argue is good news, and to the degree to which it indicates persistence, perhaps it is. But it could also divert resources at a time that Roche is reassessing its neuroscience agenda, and for the sake of a mechanistic premise that still behaves more like quicksand than solid ground.

The fact that Fidelity Biosciences played a key role in forming Denali is a welcome signal that Fidelity is not departing from what has been an active role in funding neuroscience drug development, with EnVivo (now Forum Pharmaceuticals) having been the marquee example. Abigail Johnson’s ascension to the helm of the parent company, Fidelity Investments, had been speculated, in some quarters, to augur a loss of the dedication to neuroscience that had been initiated and sustained by her father, Ned Johnson. In terms of absolute dollar amounts, the amount of Fidelity’s participation in the Denali Series A assuredly pales in comparison to their historically full-hearted–and budgeted–support of EnVivo/Forum, but it is much less dire than a 180 degree turn away from the neuro sector would have been.

Axovant: Setting Sights On a Molehill
Then there are companies who are built around the principle of ‘One Man’s Trash, Another Man’s Treasure.’ Opportunism can be a good thing, but Axovant has suddenly bloomed like the radar blob of a tornado expanding near a quiet Kansas town–and there are some warning sirens to be heard. Axovant has been assembled around SB742457, GSK’s 5HT-6 antagonist for the improvement of cognition in Alzheimer’s. The efficacy data from GSK’s most recent Phase IIb trial showed a minuscule impact on rating scales used over a 48 week period (e.g. ADAS-cog decline altered by less than two points, CDR-SB differential that essentially vanishes at 48 weeks). Two earlier, well-sized Phase II studies had shown nothing as a monotherapy, and only an inconsistent, borderline impact as an adjunct, so GSK dropped its development. Not that GSK’s recent judgment calls in neuroscience have been indicators of anything more than rapid-onset spinal atrophy, but the beauty of this asset is definitely in the eye of a few beholders. Which in this case, included a hedge fund executive who set up shell companies in Bermuda (Roivant Sciences Inc., and Roivant Sciences Ltd), which then spun off a neuroscience virtual company (Axovant), to which it licensed SB742457, acquired from GSK for just $5 million upfront (we worry when the number of discrete corporate entities exceeds the number of pharmacological assets). They added some advisors with credentials from legacy projects like Aricept and memantine, and plan to start a single Phase III trial later this year, assuming that success will suffice for NDA filing. This falls into ‘a little is better than nothing’ camp of pharmacotherapeutic aspiration, but  in fact, statistically significant, predictable mediocrity just might make it.

This is molehill territory, aiming to slightly increase the temporary, minimal improvement in cognition provided by cholinesterase inhibitors in Alzheimer’s, without impacting the course of the disease itself. It’s like switching out steel for aluminum in parts of a car frame to eke out a two-miles-per-gallon improvement in gas mileage. And the car only lasts for a year.

But here is the stunning part–Axovant is looking to raise as much as $309 million in an IPO (at the maximum of the price range, with the overallotment), an amazingly heady goal for a nearly virtual newco that is organized primarily around this single asset, plus soon, Arena’s nelotanserin, which has no value attributed at present. The S-1 displays some examples of self-service (e.g. family members getting cheap stock options, Roivant getting paid for providing services to Axovant), the former (and some other features) has already attracted the healthily skeptical attention of Adam Feuerstein at Axovant is hoping that the dearth of cognition enhancers in late-stage, other than Forum and Lundbeck’s drugs, justifies aiming high. The main cautionary note for those who jump on the bandwagon is one of timing: Both Forum and Lundbeck are ahead of Axovant in Phase III execution, and Forum’s nicotinic alpha7 drug (FRM-6124) also showed an efficacy signal, albeit over just three months. Whether that signal will be replicated in Phase III and sustained over a longer duration is not to be assumed, but if FRM-6124 were to reach the finish line earlier and stronger, the opening for one or both 5HT-6 antagonists would narrow considerably.

Is Axovant a scam? No, though some of the built-in rewards for the principals veer towards bad taste. After all, Lundbeck/Otsuka have idalopirdine in Phase III, a 5HT-6 antagonist with its own modest-at-best clinical power, and with companies like Avanir and Auspex being bought out for $3.5 billion each, a transaction that values Axovant at over $1 billion out-of-the-gate is not nearly as ludicrous as it might have sounded in early 2013.

The Neuro Sector
Two years ago, had we predicted that in 2015, the largest Series A round  in CNS sector history would be generated by Denali Therapeutics, a newco dedicated to research in neurodegeneration, a mental status exam would have been called for, given the hallucinatory departure from reality that would have been implied. But in a pharma world where prominent companies have thrown up their hands and exited from neurodegeneration programming while whining that it was ‘too hard’,  here are highly credible scientists and investors saying–’No, it’s not; we now have access to the tools necessary to make it do-able.’ For those companies who have stayed the course, this is validation; for those who have departed, this should sow still more seeds of self-doubt. Axovant is a reminder that healthy evolution can quickly be followed by marriages of convenience, riding the coattails of sentiment change, and the thought of such a hastily cobbled-together enterprise aspiring to be the largest CNS IPO in history is not reassuring to anyone wondering how much of the neuro sector’s recovery reflects a ‘bubble’.

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30,000 is the New 30

’40 is the new 30′, ’50 is the new 30′, and so forth. We have become somewhat innured to the hopeful and/or desperate proclamations of time turned back on itself: 30 seems to be the modal choice of aspiration, epitomizing some idealized waypoint along the human lifespan, a Kodak/jpeg moment of post-adolescent, post-hookup, post-graduate, pre-arthritic, pre-plaque, developmental equilibrium. This conveniently overlooks the thirty-something angst of trying to juggle early professional aspirations and hierarchy-climbing, along with the chaotic demands of love and procreation.

’30’ in the pharma world used to be a billion dollars; the annualized benchmark for blockbuster status, the brass ring to be grabbed and clung to, if at all possible.
Now, an appraisal of deals and financings over the past eighteen months within the CNS sector suggests that there is a new ’30’, a new goalpost in a world where the goalposts are always being moved: 30,000 (plus or minus 5000, but that’s quibbling).  In an environment where going after mega-markets is a task thus far thwarted, such as in Alzheimer’s, or requires somehow leapfrogging a gaggle of generic predecessors, as in schizophrenia or depression, 30,000 has become a sought after hybrid: A big enough patient population to offer some volume of utilization, while small enough to not panic payors into adding yet another tier to their reimbursement schema.

Some examples of the new ’30′: SAGE Therapeutics estimates that there are 25,000 (close enough) cases of severe status epilepticus in the US each year. SAGE-547 in SSRE, just entering Phase III, has thus generated a market cap for SAGE that recently, albeit briefly, surpassed $1.7 billion. Auspex Therapeutics, now in Phase III with SD-809 for Huntington’s (about 30,000 patients in the US), was acquired by Teva for $3.5 billion. Avanir was acquired by Otsuka for $3.5 billion, and Avanir meets criteria by having tried Nuedexta in about 30,000 different clinical indications. Plus or minus 29,980.
With all due respect to the rare (3000) and ultra-rare (300), the sweet spot is 30,000, at least until someone cracks the code for a major disorder, like depression (well underway) or Alzheimer’s (no sign of this happening anytime soon).

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Aducanumab: Less Than Meets The Eye

The beta-amyloid target in Alzheimer’s has become, to put it politely, somewhat tarnished over the past several years. AN-1792, bapineuzumab, solanezumab, gantenerumab, plus several BACE and gamma-secretase inhibitors/modulators, have combined to form a conga-line of clinical disappointments, undulating its way into oblivion. There are a few plucky survivors: Lilly has launched solanezumab into another pivotal Expedition in spite of widespread concerns that it will again be ‘too little, too late;’ Merck’s BACE inhibitor continues in Phase III, as they hold their breath against the fear that the safety issues that have derailed several BACEi peers might yet come to haunt them as well.

And there is aducanumab/BIIB037, Biogen’s (via a partnership with Neurimmune) mAB against beta amyloid plaque (as opposed to soluble AB). The unveiling of the data from a 166pt trial that was powered to address safety, not efficacy, has been a triumph of effectively selective disclosure. Last December 3, Biogen revealed at a Deutche Bank conclave that they had achieved success in a Phase Ib trial, albeit without much in the way of detail. They were not particularly concerned about disclosure standards, and indeed, continued to disseminate more clues about the trial results at other investor gatherings, such as at a Cowen meeting in Boston. Finally, on March 20, they presented more, albeit still partial, data at the AD/PD meeting in Nice. The resultant headlines were bullish, and by the end of the day,  Biogen had added another $10 billion or so to its market cap. To put it in perspective: Biogen’s valuation on December 2, the day before their AD data drip began, was $72 billion. By the end of the day on March 20, it had gained another $39 billion. While Biogen has a wide and impressive range of programs, and is anything but a ‘one-trick pony;’ in NIR’s estimation, most of that rise (perhaps all, since it is in spite of countervailing concerns regarding their EU Tecfidera franchise) can be attributed to this Alzheimer’s news.

Think about that for a moment: $39 billion in added value, attributable to a trial that enrolled a total of 166 patients, wherein the dose-cohort sizes were 30-32, and one of those cohorts (6mg/kg) did even not have its twelve month data reported (though it apparently has been completed). That dose was added later because of safety/tolerability concerns, and a high discontinuation rate, seen with the highest (10mg/kg) dose.

Beyond confirming the power of suggestion, what does the data from this Phase Ib study establish?
1) Target-engagement: It does appear that aducanumab successfully engages with the amyloid plaque target in a clear, dose-related fashion. This is not a minor point; it has been often wondered how many CNS drug failures reflected the inability to get the investigational drug where it needed to be, in sufficient quantity. It is pretty clear that this mAb does reduce plaque significantly, and while we have sometimes wondered whether this might not be a good thing (in theory, might this free up soluble amyloid for further toxic binding within the brain?) there was nothing in these results that pointed towards an iatrogenic effect.
2) Clinical Benefit: This is where the variance in ‘audience’ response broadens. For the most part, the media ‘drank the Kool-Aid’ and asked for seconds. But some Alzheimer’s luminaries who are not amyloid acolytes turned a firm thumbs down, albeit not for attribution. Most of the reported (and that is considerably less than what has been collected) datapoints, i.e. the mean changes in MMSE and CDR-SB scores, (adjusted for covariates like baseline scores and APOE4 carrier status) fell in line with a dose-related curve, the impact upon deterioration rates seeming to rise with higher dosing. But there are factors that mandate caution in taking these numbers at face value and embracing these findings prematurely:
a) There were four dose levels, 1mg/kg, 3mg/kg, 6mg/kg, and 10mg/kg, all infused on a monthly basis. The 6mg/kg dose, which was added after the study was underway, did not separate from placebo at 26 weeks on the CDR-SB or MMSE, unlike the other doses. The 54 week data, not yet reported, may yet show that 6mg takes its projected place between the 10mg/kg and 3mg/kg doses in terms of associated impact on cognition/function. But since it diverges at 26 weeks, that cannot be assumed. Given the high variance on these outcome measures, it also cannot be automatically assumed that it is the 6mg/kg dose’s absence of separation that is the anomaly, given the amount of ‘noise’ in the dataset.
b) There is a lot of data missing, and how that missing data was handled adds to the ‘noise.’ The highest dose (10mg/kg) group was also the one with the highest rate of discontinuations due to adverse events, 31%, whereas only 10% of the placebo group discontinued prematurely. Given that it was the APOE4 group that tended to account for the dropouts in the 10mg/kg group, not surprising since they were the most prone to ARIA (amyloid-related  imaging abnormality, indicating vasogenic edema), this was the dose-group with the highest frequency of earlier-in-the-study clinical data being carried forward to the 54 week readout (LOCF, last-observation-carried-forward). Since this is the more rapidly-deteriorating group,  using LOCF means that their final results were recorded as being better than they would have been had they actually completed the study.  This is in contrast to the placebo group, where E4 patients of course did not receive the mAb, and thus were not preferentially more likely to drop out due to side effects. Instead, their deteriorating course was incorporated into the 54 week data; these two factors in concert would bias the comparison towards enhancing the apparent treatment effect.
c) Speaking of missing data: Where were the results from the other neuropsychological testing components (the NTB and FRCT) with their far more ‘granular’ assessment of cognitive functions? The similarity between the results obtained from the MMSE and CDR-SB is less validating than it might seem: Those two instruments overlap quite a bit, their results tend to be highly correlated, adding to the need for confirmation from these other, more sophisticated psychometric batteries.  Biogen intends to release those results in July, but with all due respect to giving the investigators multiple days in the limelight, there is no excuse for not disclosing and discussing those results along with the MMSE and CDR-SB. After all, the valuation gained thus far by Biogen on the basis of these preliminary results is larger than the annual gross domestic product of some 97 individual countries (International Monetary Fund). The scale is huge, the stakes are high, and Biogen–who we consider to be an exceptionally well-run and effective company–has been  surprisingly cavalier and selective in its dissemination of these trial results.

3) Safety: Vasogenic edema is better understood now than when the first mAb trials reported their results, and it is now known that it tends to be transient. As is not surprising, there was a considerable incidence of vasogenic edema at higher doses. Most cases (92%) emerged in the first five months of treatment; 35% of patients developed subjectively salient symptoms–headache, blurred vision; 78% were described as ‘mild to moderate’, which means that 22% were more severe, some requiring hospitalization.In the APOE4 carrier population, 55% of E4 patients receiving the 10mg/kg dose developed edema. 43% of the E4 patients receiving the 6mg/kg dose did, the incidence was far lower (5%) amongst E4 patients on the 3mg/kg dose. It will require a far better understanding of aducanumab’s efficacy at various dose levels, likely differentiated by APOE genotype, to sort out the risk-benefit profile for aducanumab, and the degree of tightrope-walking that might eventually be necessary to achieve therapeutic benefit with acceptable tolerability. How acceptable this kind of risk will be for a treating physician may reflect physician temperament as much as anything: Some consider this profile quite ‘manageable’, but there are risk-averse prescribers who could find it discomfiting.

The bottom line is that this was a Phase Ib trial with tiny dose cohorts, particularly when broken down by genotype. The antibody gets where it needs to go, and does reduce amyloid plaque levels. Keeping in mind the caveats noted above regarding missing data and high intragroup variance, the trends shown here are in the direction that one would hope to see from a trial. But it neither proves nor disproves the case for the amyloid hypothesis or for aducanumab. It provides a highly provisional hint of an efficacy signal: It could be statistical noise, but if so, it is well-behaved, generally dose-congruent noise. The unreported neuropsych testing data will be useful in assessing the validity of these findings. Biogen, in keeping with the example set by its peers, is planning to go into Phase III later this year. That should not be taken as inferring that this trial provided anything approaching Phase IIb POC. They will roll the Phase III dice, rather than spend two+ years trying to replicate it with a Phase IIb. They are banking on the hope there is something more substantial than noise behind these data.

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