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Newly Available: Big Pharma Report Card sample (from CNS 2008) Download pdf Commentary(last updated 10/6/08) Cortex and Respiratory Depression Cortex Pharmaceuticals reported very solid efficacy data from their second trial of CX717 in respiratory depression, showing that the drug both prevents RD and (iunlike naloxone, the current treatment for opioid-induced RD) preserves analgesia. This will allow anesthesiologists to not have to subject patients to unmedicated post-surgical pain if respiratory depression occurs--and it occurs far more often than we had ever thought. The incidence varies by setting, and Cortex reports it may be as high as 17%, we think it can be safely estimated as being in the low double-digits--enough to be a safety, quality of care, and liability issue. Given that the data suggests this risk can be avoided via prophylaxis with CX717, we believe that once commercialized, CX717 (or a second-generation Ampakine) will become the new standard-of-care, because no anesthesiologist or hospital will want to justify a patient exposed to either the risk of death or of physically traumatizing and dangerous levels of pain. Respiratory depression is not something with which NI was familiar when the concept of Ampakine usage therein was first floated last year. But it is familiar to front-line ER docs and surgeons. We witnessed this first hand when speaking with John Greer, who has pioneered the work in this area, at a professional meeting. During the 30 minutes we spoke in front of his poster, three MDs came up at various points, and spontaneously expressed the wish that they had CX717 in their armamentarium. By a rough calculation of the number of crash carts and surgical suites that would have to be equipped with CX717 in the US, NI's estimate a few months back was that just this market alone would be worth $700-800 million annually in the US (due to expirations, restocking would be necessary at least yearly). Cortex and Greer are also looking at the possibility that CX717 might be the first drug to directly address the respiratory issues in sleep apnea, which would jump the annual potential two to three fold, at least. But beyond this, the Ampakine/RD scenario has one additonal, huge area of potential: the licensing company could develop a combination opioid/Ampakine drug which, via any delivery modality, would be differentiated from all other opioid formulations by this safety margin--the impossibility of inducing respiratory depression. In a nociceptive pain market where the gold standard opioids are almost indistinguishable from each other, and major efforts are going into various permutations of altering duration of effect and vulnerability to abuse, this would represent a unique marketing advantage--and one that no generic could approach for many years. There is no competing MOA on the horizon, and indeed the role of AMPA circuits in the respiratory Pre-Botzinger Complex may be uniquely suited to this role. We expect that these very clear, clean data will stimulate a very competitive bidding situation vis-a-vis a partnership for Cortex.
(Excerpt from NI October) The Subprime Grenade and Other Biopharm Reverberations As we were going to press, American governance reached another nadir in its eight year slide. The US House of Representatives put on a stunning display of stubborn myopia on both sides of the aisle: Instead of sticking the pin back into the subprime grenade rolling on the floor, they debated the inane and irrelevant, distracted from the chilling reality of how close to the economic jugular the shrapnel would fly if it were to detonate full-force. But prior to this latest Festival of Microcephaly, NI had tapped into its network of VC and fund manager professionals to glean some informed opinions about how the macro-carnage might alter the financing environment for small biotech/biopharm firms. We heard back from most, but not all; apparently not every window ledge offers decent WiFi or Blackberry reception. The input we received can be boiled down into a not-very-surprising projection: An Already Tight Financing Noose Will Get Even Tighter for Early-Stage Companies: Fallout from the subprime panic will cause a flight away from risk, towards 'quality'. To the degree to which our sources defined it, quality is discerned in the time-honored tradition of earnings or nearterm prospects for same. If this turns out to be the case, there will be less money available for the earlier-stage companies working on novel mechanisms--the innovators. Early-stage companies were already having a difficult time getting money, and the subprime fallout exacerbates that situation. That refers to all sources of money: IPO and secondary offerings, PIPES, venture funding, hedge funds. Those in the VC industry anticipate that the effect will be primarily upon financings for very early-stage ventures: VC interest is going to be attenuated if they foresee a lack of exit potential, or not being able to share some of the risk down the road, if additional investors are not available for subsequent rounds. Debt financing is likely to shrink, and the advent of hedge funds as sources of funding is going to be at least partly aborted by their increased regulation. Without access to funding, companies must turn even more strongly to partnering, or being acquired. The Financial Times published an article suggesting that the subprime crisis will alter the dynamics of partnering and M&A in favor of Big Pharma, BP regaining some of the leverage lost in the past couple of years. Without available financing alternatives, small companies might have to be willing to take lower offers from Big Pharma, BP becoming the financing vehicle of last resort for small firms. But we believe that effect is likely to be situation-specific, not endemic to the entire industry. The pipeline depletion/generic competition conundrum continues to be a factor for all Big Pharmas, which does negate some of their leverage. The scenario is not completely bleak for small companies. There were some optimistic suggestions that, with the demolition and/or identity shifts of the largest investment banks, that the small, 'boutique' investment bank may make a comeback, preferable for a science-heavy sector like biotech. The obvious exceptions to the BP leverage paradigm are the handful of smaller companies whose products offer the prospect of nearterm commercialization and revenue-growth. Less obviously, companies with programs for which there is relatively less competition for first or best-in-class status are in a seller's market when dealing with Big Pharma companies who cannot afford to let a competitor 'get there first.' Whereas in crowded arenas featuring multiple mechanistic approaches, and here Alzheimer's comes to mind, the lack of financing alternatives does give large companies, who can choose from multiple 'horses', increased negotiating leverage. However, this is all taking place within a context of fundamental cost-cutting trends in Big Pharma, most recently evidenced in Pfizer's streamlined pipeline agenda, and GSK's decision to shed 850 R&D positions. It looks like the industry is gradually shifting towards an inlicensing model, with small companies producing the candidates; the larger firms complete development, and bring the products to the market. This brings us back to the moving target of what constitutes "quality." Some in the pharma field have turned to the superficial comfort of the drug development/repurposing/reformulation troika. A drug that didn't quite make it through clinical trials, or has a database from another indication, and/or one which can be tweaked via reformulation; these are perceived as lower-risk bets. Lundbeck's resurrection of sertindole and Teva's revival of pagoclone are of this ilk; these are NCEs, but well-characterized ones, with familiar MOAs. Academic labs are also performing resuscitation on remarkably venerable drugs: A well publicized study done at UNC reported that atypical antipsychotics performed no better than Moban in a pediatric population. Moban? Moban is so ancient that it is sold in corked bottles, the 1961 Chateau Moban is said to be drinking quite well now. But Moban had passed into the fog of time for a reason, and that is true for many, if not most, of these retreads. While there are some reformulations and repurposings which will have a clinical advantage, they are the exception. The assessment of the NRDO companies presented on p.12 documents the fact that, for all the claims of an easier path to commercialization, familiarity is no guarantee of quality, or of success. In a world where prescribers are increasingly required to justify the use of a non-generic drug, both pharmacy benefits managers and the FDA now collude in making the path for proprietary me-too drugs far less certain than it once appeared to be. Not all of the Street's best and brightest burned out their promise by creating Doomsday Derivatives, and those left seeking opportunities for big returns will find that opportunity, albeit with the risk that goes with it, in new drug mechanisms. Alliances and licensings will involve much more sharing of both risk and reward than was the case in the past, but 'novel' remains the avenue to the quality, the superiority, that will be demanded of new therapeutics. Now that the 'Street' can no longer revert to a business model predicated upon increasingly abstruse forms of paper transactions, the survivors will have to figure out how to make a living via the creation of something of tangible value. Having been cut off from the financial equivalent of Internet porn, they will have to figure out how to make real relationships work. In the long run, that may not be a bad outcome.
The Beta-Secretase Strategy (from NI September's Alzheimer's review) Beta-secretase/BACE (also known as memapsin-2) inhibition has been a popular secretase strategy. There have been BACE inhibition programs at Amgen, Lilly, Merck, Actelion, Takeda, and Elan, among others. Merck's candidate reportedly reduces amyloid levels in a non-human primate model, but only reaches sufficient plasma levels when administered along with a hepatic enzyme (CYP3A4) inhibitor. CoMentis' CTS-21666 was acquired via CoMentis/Athenagen’s merger with Zapaq, whose scientific founder was one of several who discovered the beta-secretase (also called memapsin-2) gene. The compound is selective for BACE2, it does not affect BACE1, which may mean myelination concerns would not apply. This beta-secretase inhibitor elicited a deal ($80 million in cash upfront, $20 million equity buy, US co-promotion rights) with Astellas early in 2008. The IV Phase I was apparently clean, and an oral Phase I has been underway, with a Phase IIa expected 2H:08, though that will be Astellas’ call. BACE: A Case of Mistaken Identity? American Life Sciences Pharmaceuticals contends that the BACE hypothesis is an artifact from the Swedish AD mutation in mice, and is not the source of human AB. In their model, human AB is produced in the active secretory pathway, modified by Cathepsin-B, not BACE. This is beta-amyloid with a pyroglutamic alteration at the N-terminal, and they believe that the great bulk of the beta-amyloid at least partly responsible for Alzheimer's, is this form. They have identified a drug (E64d) which was developed in Japan for Muscular Dystrophy, and then dropped following Phase III failure. ALSP states that their preclinical experiments reduce both soluble and insoluble AB more than BACE inhibition does, and produces functional improvement in cognition. With ample clinical safety data already on the record, ALSP believes that Cathepsin-B inhibition is unlikely to be thwarted by some unexpected toxicity, and hopes that they can move quickly into Phase I/II. They are focused upon finalizing NIH grants that will allow them to do so. Germany's Probiodrug has also embraced the pyroglutamic AB model, seeing BACE as a misidentified culprit. They believe glutaminyl cyclase (QC) is the enzyme intrinsic to the pathological modification of amyloid. They have been developing QC inhibitors which, in animal studies, reduce all pathological forms of AB and produced functional improvement. This is early in development, and given the ubiquitous presence of QC, which provides 'durability' for many neuropeptides (necessary for many, pathological in the case of beta-amyloid), the risk of unexpected toxicity looms as a potential problem.
The World According to Amyloid Approximately 40% of the Alzheimer's therapeutics programs we reviewed involve amyloid as the main target. Second is tau--at just 6%. No other mechanism is pursued by more than 4% of these programs. How did this imbalance develop? There has been a closed loop in the exploration of Alzheimer's mechanisms. Alois Alzheimer found amyloid plaque and tau tangles in the brain of a demented patient, and from that posthoc, post-mortem finding, declared these to be the causal elements in the disease. The process by which beta-amyloid gradually moved into pre-eminence over tau may relate to the fact that transgenic models of amyloid pathology were easier to develop, and thus emerged first. Here is where the logic became circular: Animals genetically altered to overexpress amyloid showed evidence of cognitive dysfunction, and it was presumed that this mirrors the process of Alzheimer's as it occurs in humans. No doubt, immersing the brain in beta-amyloid is not a good thing, for animals or for people, but this does not set it atop the pathophysiological pyramid. To some degree, the model ended up driving the theory. This is beautifully exemplified by the questions raised about whether the Swedish mouse mutation, which birthed the beta-secretase concept, emulates the human condition at all. The model was accepted before proven. In forensics, investigators occasionally must establish the cause of death for individuals found in a burned-out building. Most of the time, Occam's Razor applies, and the cause of death is in fact the fire. But on occasion, they find that the individuals were first shot, bludgeoned, garroted, poisoned, or in some other way dispatched; the fire in fact obscured, rather than explained. In the case of Alzheimer's research, the wish for an explanation and a solution led to the first-in-class hypothesis being treated as if it were best-in-class, in spite of evidence to the contrary. To take it to the absurd extreme; igniting laboratory rats does not portend a positive outcome--'Induced Extreme Hyperpyrexia and Mortality in the Icelandic Flammable Rat'--but does not explain much in the way of mortality in wildtype rodents. In the Middle Ages, premature scientific closure was often based on Scripture. In today's environment, premature closure is often based on Funding. Scientists may pursue a path of fiscal less resistance based on the same survival instincts that exist in all of us. But this does raise troubling questions about the conservatism of peer review for grants, and the venture capital system as it has been applied to CNS therapeutics; neither system lends itself to the equitable treatment of divergent theories and their investigation.
Pfizer Blinks (added 9/13/08) The partnership agreement between Pfizer and Medivation provides some interesting information, albeit no certainty as to Dimebon's eventual value in the treatment of Alzheimer's. $225 million upfront, up to $500 million in potential milestones. US costs and profits to be divided 60/40 betwen Pfizer and Medivation, Medivation retaining some co-promotion rights, plus royalties on ex-US sales. The deal tells us: From NI September
NI has commented ad nauseum--and we do not plan to stop because of a little queasiness-- on the growing tendency to shortcut clinical development by skipping the bulk of the once-thought-critical Phase II process. Now, Phase Ib trials are called Phase II's, Phase IIb trials are called Phase III's, and seemingly rational companies are lunging for the Phase III trial goal-line as if that is the ultimate prize. Given the vapid foolishness of some VC's and funds who seem to look at the Roman Numeral and not the quality of the data behind it, it's almost understandable. There is an eventual price that is paid of course, exemplified most recently by Myriad Genetics' highly expensive Phase III dud built on the sand of a dubious Phase II trial. But to be fair, there is another dynamic at work that may be fueling this impulsive, risk-laden behavior: Doing the process right doesn't guarantee anything either. For example, Elan/Biogen-Idec's Tysabri is thus far the single most effective modifier of any neurodegenerative disorder yet devised. It is not without its risks, as is exemplified by two new PML cases that cut, albeit temporarily, yet another half off of Elan's valuation, but this is a risk many patients are willing to take. Part of the recent concern was whether the FDA might overreact and further restrict or even prohibit Tysabri's use. That would have been be folly, and indeed the FDA did respond rationally; but given the FDA's reactive timidity, no one could have assumed that outcome. One can almost (but not really) understand why companies are turning into clinical daredevils. If playing by the rules, at high costs in terms of both time and money, provides no certainty, they figure that they might as well take their chances. Learning from the experience of others is a key to the eventual maturation of adolescents into adults, but for those who fail to learn vicariously, they generally end up learning the hard way. And that's the direction Elan/Wyeth are now heading with bapineuzumab, as is Lilly with their amyloid antibody, Baxter with Gammagard, and Medivation with Dimebon. They must be feeling lucky. The Search for Intelligent Life in Alzheimer's Trial Design and Analysis Bapineuzumab did not hit its endpoints for cognition, and from the point of view of a prospective study, it was an abject failure. However, given that Elan/Wyeth announced many months ago that they were going to initate a 4100pt Phase III trial, the companies conducted a intensive posthoc slicing and dicing of the data which has now produced a hodgepodge of contradictory findings. Their main conclusion was that there was a bifurcation amongst study patients based on whether or not they were 'carriers' of the pathognomonic APOE4 gene. The 65% of the patient population studied who were carriers showed no significant benefit from bapineuzumab, though if one only counted completers, they appeared to have a slightly (2.6 ADAS-cog points) better outcome than the placebo group. The non-carriers showed a difference of 5 ADAS-cog points, which did reach significance. However, this was in comparison to a placebo group whose rate of decline was essentially the same as the drug group until they reached the final third of the 18 month trial, and their late nosedive took them towards the extreme end of the expectable range for the slope of cognitive decline over the 18 month timespan. No dose-response pattern was seen, further adding to the impression that these data represented a 'random walk' which could only be made to look coherent via posthoc data manipulation in extreme form, and a disregard for the seemingly distinct possibility that the contrast was an artifact of the placebo group, not a result of drug effect. There was also a safety signal of note: the incidence of vasogenic edema which appeared related to high doses of the antibody in conjunction with the APOE4 genotype--though 25% of those with vasogenic edema were not APOE4 carriers. On the one hand, most of the patients were asymptomatic, the VE was only detected via MRI. A few patients were symptomatic and required treatment with steroids. It may well be true that asymptomatic VE is not in itself dangerous--but in a real world population of Alzheimer's patients, how reliably can they be monitored to be sure that what was asymptomatic is not worsening? The notion of hundreds of thousands of elderly patients receiving MRI's because of ambiguity around the VE diagnosis seems fiscally untenable. Elan/Wyeth have responded with a plan to give APOE4 patients only a low dose of bapineuzumab, a solution that may lack something in the eyes of a safety-conscious FDA. But no matter: two trials of 'carriers' and two trials of 'noncarriers', totalling 4100 patients, are still planned. This data, even when spun to the max, has gaping holes in terms of patient selection, efficacy, and dosing. It is data that cries out for a Phase IIb trial to answer these questions, not a premature $300 million expenditure on pivotal studies. Given the substantive questions about bapineuzumab, and the wisdom of moving from a very confused Phase II dataset to Phase III, Lilly's handling of Phase II data for its own monoclonal antibody, LY2062430, was surprising, to say the least. This was only a 12 week trial involving 52 patients, and Lilly dealt with those vexing efficacy issues by declaring that they neither expected nor found any cognitive effects in this shortterm study. They stated that this Phase II was intended only to show safety and tolerability, and has done so. That is an interesting twist on the usual nomenclature, given that safety trials in a patient population are generally called 'Phase Ib', Phase II generally implies some interest in efficacy signals, and not just biomarkers. What was even more striking, indeed shocking, was that, based on the biomarkers of beta-amyloid levels in blood and CSF, Lilly declared this antibody is ready for pivotal Phase III testing, to begin in 2009. This is mind-boggling. Having seen Myriad Genetics, Neurochem, Medivation, and now Elan/Wyeth move into Phase III without solid Phase II efficacy data, the first two crashing and burning in tragic style, one might think Lilly would have taken the hint and reconsidered this strategy. But instead, Lilly is dispensing with functional efficacy testing altogether in their haste to reach Phase III with this antibody. We are aware of the pressures upon small companies like Neuorchem and Medivation, pressing them to push the clinical envelope as they try to stretch limited resources and attract more funding. Elan and Wyeth are also making a mistake, but at least they tried to assess efficacy over an eighteen month timespan, even if they have tied themselves into knots trying to spin the data into something positive. But what is Lilly's excuse? It's like watching two teenage drivers who are playing a game of 'chicken': one car zooms off the cliff and bursts into flames, the second driver decides 'that looks pretty cool', and drives off the cliff as well. This pretty much puts to rest the whole concept of Intelligent Design, because there's none to be found here. Vanda Pharmaceuticals and iloperidone (posted 7/28/08) Today's announcement of a nonapprovable letter for iloperidone/Fanapta was not overly surprising. As NI discussed in our June review of Vanda Pharma: Fifteen years and four owners later, iloperidone does not look anywhere as promising as it did in the 1990's. Novartis had partnered with Titan on Hoechst's iloperidone back in 1996, but a huge Phase III program had one arm that failed to show efficacy, and the big problem was that iloperidone was eventually found to have QTc issues nearly identical to, if not worse than, Geodon's. Novartis gave up on it, and licensed the drug to a Novartis alumnus, who founded Vanda. Phase III efficacy results were comparable to Geodon's, but Vanda's aspiration to genomically steer likely responders towards iloperidone, and those likely to have QT problems away from it, have not been reified, at least as of yet. Thus far, the only test that is operational assesses the presence of two versus one intact CNTF-expressing (Ciliary Neurotrophic Factor gene) genes, and thereby parses out the 75% of patients with two intact copies, who are more likely to respond to atypicals (including but no limited to iloperidone) from the 25% with one intact copy, who are treatment-responsive, but not as much. This test is useless in its current form. Based on the data thus far, iloperidone appears to be very similar to Geodon in all respects, other than it appears more prone to rare but worrisome QTc outliers, patients with more pronounced QTc changes, and less prone to akathisia. As is the case with paliperidone, this is another test of the FDA’s self-appointed role as guardian against me-too irrelevancy. The question is no longer whether a first-tier marketing partner will eventuate--we doubt that one will--the question is whether iloperidone will even receive marketing approval." The conference call held by Vanda this morning confirmed that the company does not have the money to carry out the additional clinical trials required by the FDA. Even if they had the money, they do not have the two years needed. The CEO's forthrightness was again on the line when he was asked if there had been any hint of a change in the FDA's requirements vis-a-vis active comparators--stating that Geodon did not need an active comparator trial. That was 2001. If the CEO would care to look at more recent data, the aforementioned lack of FDA enthusiasm for paliperidone is somewhat more pertinent. Vanda has close to $65 million, but a dead lead program in iloperidone, and and lackluster prospects for tasimelteon. Our major question now is how long it will take Vanda to decide that they need to use their cash to acquire/partner something beyond the scant dregs in their pipeline, and whether CEO Polymeropoulos will remain in charge of making that decision. . We would note that at the time of this addendum, the share price for Vanda was US$0.90/share, even though they have US$2.43 per share in cash. While this makes Vanda an appealing nearterm trading play, it speaks volumes about the credibility that has been lost by Vanda's management. We suspect that if Vanda has any future as a redesigned/repositioned company, it will be with a change at the top. GSK and Actelion (on-line comment) The GSK/Actelion deal for almorexant et al in insomnia sounds like lot of Biobucks ($3.2 billion). But the upfront payment of US$147 million is diminished by the fact that Actelion is paying 60% of the Phase III costs for primary insomnia. Taking $100 million as a likely-on-the-low-side guesstimate (Actelion says they will enroll "several thousand" patients, Pfizer and Neurocrine ran close to 7000 subjects in indiplon's pivotal program), that leaves Actelion on the hook for at least $60 million of those costs, making this deal much more backend loaded than it seems on first blush. US$407 million in potential milestones for the first indication is more plush, but the devil is in the details of those "exceptional" sales thresholds. Other than secondary insomnia (secondary to depression, secondary to binary biotech events, and so forth), it's hard to figure out where the additional indications fleshing out the $3.2 billion potential total would be. GSK had its own orexin antagonist GW-649868 in Phase II, but must have decided Actelion's compounds are superior. Biased parties have suggested that almorexant's next-day profile was not as pristine as Actelion has hinted, but GSK must have decided that they can still beat the GABA-A drugs. Speaking of which, with Neurogen's adipiplon biting the dust today, which leaves Neurogen in grim straits, Evotec is now the last major GABA-A contender in Phase II development.
Getting A Handle on Dimebon (On-line comment, addendum 7/10/08) Medivation's Dimebon is a slippery story, one whose substance continues to be perplexing and ambiguous for NI, even given as we are to avidly following and applauding any hints of therapeutic efficacy in the neurodegenerative disease area. The just-released "top-line" results for Dimebon in Huntington's Disease are another case-in-point. In this 90 patient, three month duration trial, Dimebon produced statistically significant results (p=.03) on the Mini-Mental State Examination, or MMSE. It did not produce any hints of effect on the cognitive component of the UHDRS, or on the ADAS-cog. There were a couple of other positive glimmers that were highlighted in the presentation, including a relatively lower rate of falls, 16% compared to 9% (not statistically significant), and a positive trend (undisclosed) on the behavioral component of the UHDRS. While the percentage change was stated on the incident of falls, when percentage changes were inquired about for other measures, Medivation consistently replied that they were only discussing "top-line" data, though they had already disclosed such a percentage on one which happened to look favorable for Dimebon. Besides the selectivity of disclosure, which seems based on spin as much as anything, there are some other issues of note here: First is the relative weighting of the MMSE in the assessment of Dimebon's potential effect on cognition. Medivation's statement that the MMSE is the most widely used instrument in the assessment of neurodegenerative disease is a bit disingenuous: It happens to be the quickest screening test (5-10 minutes), hence once that can be used by a wide range of clinicians as a screening device. As a measure of cognitive change, it is a blunt instrument, indeed it makes the oft-criticized ADAS-cog look compellingly detailed in comparison. The fact that no trend was found on the ADAS-cog (a fact that was disclosed only on direct inquiry) cannot be dismissed simply on the basis of the trial not being 'powered for efficacy.' Medivation previously made much of the consistent results across five different cognitive tests in their Russian Alzheimer's trial, if consistency mattered there in the decision to move into Phase III, why is consistency unimportant in understanding the import of these Huntington's data? Inconsistency can be due to differences amongst the tests used, but as is described below, looking at what these tests measure does not add support to the Dimebon in HD premise. Second, we were struck by the incongruous "enthusiastic yes" from the CEO when asked about Dimebon's readiness for Phase III in Huntington's. Out of the three cognitive endpoints, Dimebon showed effect on one, the least sensitive, nothing on the other two. Leaping from a 90 patient, three-month duration trial into Phase III is not entirely surprising for Medivation, given their history in Alzheimer's, but it still makes no sense, other than presenting Dimebon as being Phase III ready in two indications, rather than none, as is the case. The MMSE data and selective behavioral findings are encouraging, and would certainly warrant a longer-duration Phase IIb study. The fact that preceding Huntington's trials hinting at possible cognitive or behavioral benefit from other drugs (rivastigmine and Namenda) were even smaller and more poorly controlled (if at all) than this one does not make this data yet worthy of pivotal trial status. A parenthetical note: Several observers jumped on Medivation's "mistake" in having cited efficacy as the primary endpoint in filings over time, with safety and tolerability then stated as primary in the current discussion. It's true that this allowed for a better headline, but we will take them at their word that this was unintentional. It doesn't really matter: the data are what they are regardless of whether efficacy was tiered first or second, and the data are inconsistent and preliminary at best. Medivation would have been better served by a more sober and balanced appraisal of these results, so that their comments about their Alzheimer's program could be judged as coming from a more measured perspective. As it is, our spin filter continues to be calibrated at its maximum setting when it comes to Dimebon information. Now we will wait for the ICAD meetings, when Medivation states that more information about Dimebon will be presented. Addendum from a Neuropsych Perspective (added 7/10/08) Looking at the inconsistency of the data of the three tests used by Medivation, where only the MMSE showed benefit, one must consider the particular focus of the tests, which one(s) would be most credible as an outcome measure. The MMSE, where Dimebon's effect was reported as statistically significant, does not have any component which measures executive function deterioration, the 'frontal' signs which are most emblematic of Huntington's-associated dementia. The ADAS-cog has very limited coverage of executive system functioning, but it does cover more cognitive ground than does the MMSE. The literature describes the MMSE as not being particularly useful in HD, because HD patients tend to score at or near the 'ceiling' of the test. In contrast, the literature supports the use of the UHDRS cognitive section, which by design, is aimed at the deficits that crop up most saliently in Huntington's. The three tests which constitute the UHDRS-cog are: The Stroop Test; Symbol Digit Modalities Test; and the Oral Letter Fluency test. All three of these are sensitive to changes in frontal/executive system functioning. In other words, the presence of a perceived benefit on the MMSE is much less important than the lack of benefit on the UHDRS-cog when it comes to assessing the utility of Dimebon in Huntington's. This is the reverse of what would be the case for Alzheimer's, where the early losses in memory functioning are considered paradigmatic for that disease, and the ADAS-cog in particular is intended to tap these areas (albeit inadequately in our opinion), the MMSE does so in a crude snapshot fashion (delayed recall of three objects). The absence of effect on the ADAS-cog cannot be extrapolated as saying anything about Dimebon's benefit in Alzheimer's, since this system is relatively intact in HD, thus there is little deterioration to be prevented. (On-line comment 7/8/08) The Book of Bapineuzumab: Reading between the lines There has been no biotech event more anticipated in 2008 than the unveiling of the Phase II trial for the amyloid antibody bapineuzumab (henceforth referred to as Bap), already launched into a huge Phase III program by Elan and Wyeth. They had promised some information before midyear, and that is what we got, some information, but not much. The details are scheduled to be presented at a conference in late July, so until then, everyone is trying to make sense of what was stated in the press release. Since it seems like everyone else in the bio-universe has offered some comment on this release, here are some comments: 1) The trial failed to show efficacy in the overall population of Bap patients compared to those who received placebo. Given that there were three dose levels, and just 240 enrollees, that in itself is not necessarily huge news. However, for those starry-eyed groupies who thought that the Phase II data might be sufficient for NDA submission—forget it , the data showed nowhere near the magnitude of effect that one would need for that kind of unprecedented submission and approval. 2) The trial sponsors did announce that there was evidence of efficacy in those patients who do not have the APOE4 mutation, long known to be associated with a more rapid and virulent disease course. Elan and Wyeth did not say how many of the trial participants fell into that category, roughly half of all Alzheimer’s patients have the APOE4 genotype. The APOE2 and APOE3 patients constituting the other cohort were reported to have displayed significant effects from Bap compared to placebo patients, in terms of their scores on the ADAS-cog, NTB, MMSE, CDR-SB, and a favorable trend on a Disability Scale. Additionally fMRI data suggested trends towards reduced loss of brain volume and decreased ventricular volume in Bap patients, but only among the non-APOE4 group. 3) In contrast, the APOE4 “carriers” showed no functional/cognitive effects from Bap, though there was a trend towards an increase in ventricular volume—which Elan/Wyeth here seemed to imply might be a potentially positive sign (“However, favorable directional changes were observed on a number of endpoints. Preliminary analyses suggest possible increase of ventricular volume in treated patients versus placebo patients.”) whereas in the non-APOE4 group, the decrease in ventricular volume was cited as possibly positive. In the legendary AN-1792 vaccine trial, Elan/Wyeth claimed that decreased brain volume and increased ventricular space was in fact positive, reflecting the clearance of amyloid plaque. We have not yet fully embraced the concept that this traditional sign of brain atrophy is now a harbinger of good tidings. 4) Both the drug and placebo group showed plenty of adverse events, but only the APOE4 group differed significantly between the drug group and placebo, with the drug group showing a significantly greater likelihood of severe adverse events, as well as increased, dose-related vasogenic edema. The possibility is thus raised, albeit not confirmed, given the tiny (60 patients) size of each dose cohort (32 of which received drug, 28 placebo) , that Bap may have worsened the condition of patients with the APOE4 mutation, or again about half (estimates range from 40-70%) of the Alzheimer’s population. 5) The APOE4 subgroup distinction, and direction of impact, does not easily fit with the mechanistic hypothesis utilized by Elan/Wyeth in this trial. Based on the amyloid model, and after all, this is a beta-amyloid antibody being used, one would think that APOE4 patients would have more beta-amyloid in situ, since they have a faster-moving variant of the disorder. So why would a beta-amyloid antibody make patients with less beta-amyloid better, patients with more beta-amyloid worse? One could hypothesize that patients with more beta-amyloid subject to antibody effect may be more vulnerable to some type of iatrogenic response, at least in terms of the negative physiological effects. not dissimilar to the inflammation that impacted 6% of the AN-1792 population, 6) IF this is so, that would mean that baseline beta-amyloid levels would have to be assayed before starting treatment with Bap, in order to be sure that more advanced cases (more likely with the APOE4 genotype, but not necessarily excluding advanced APOE2/3 patients) would not be given Bap if that might risk exacerbating rather than ameliorating their condition. Furthermore, periodic AB levels would have to be drawn (and obtaining intracerebral measures of both soluble and insoluble AB is not something your local PathLab could do) in order to be sure that the ‘tipping point’ of AB had not been reached. It is unclear, and we believe, unlikely, that simple APOE4 genotyping would be sufficient. Thus, with little of the data actually released to this point, there is more guesswork than we’d like regarding the interpretation of these data. We do know that Bap is unlikely to be useful, or usable, with the whole spectrum of Alzheimer’s patients. Whether the indications of effect (one would think that showing significance in cohorts of perhaps 30-40 patients must mean pretty salient divergences in scores) established by a post hoc review of the data can be replicated in a pre-specified genotype-distinguished group remains to be seen. The spin being put on the fMRI data, whether cortical shrinkage is bad or good, ventricular expansion bad or good, leaves the interpretation of the scan data completely up in the air. It might be bad, might be good, it’s unlikely to be neither. But this speaks to possible safety issues that are going to discomfit the FDA if this pattern continues in Phase III—because the sheer size of the patient population raises the stakes enormously when it comes to any safety risk. We can certainly make the argument that the risk might be acceptable given the dire course of the disease, but this runs counter to the current FDA climate around risk-reward, which is to focus on the former. Elan and Wyeth state that these data justify the decision to launch a $200 million Phase III program. What else are they going to say? Given the ambiguity, cognitive dissonance theory virtually requires them to rationalize that call. In late July we will know more, but at present, our reaction to these results is much more perplexed and concerned than that of the general market, where Elan’s share price rose 10% on the day of the data release. We suspect that Bapineuzumab is not going to be the disease-arresting paragon some had hoped for, and it remains to be seen whether its disease-modifying benefits will outweigh what appears to be some risk of disease-exacerbation in a substantial proportion, perhaps a majority, of the overall population of Alzheimer’s patients.
From NI April 2008 "So if you meet me It is time to acknowledge the underappreciated torment of the Food and Drug Administration. This oft-maligned (by NI, amongst many) bureaucracy has finally earned our sympathy, because it has been placed in an impossible quandary. While the FDA struggles to operate with 550 empty staff positions, unfilled because the federal bureaucracy is unwilling to accelerate its elephantine hiring process, and the salaries that the FDA pale by comparison to the private sector, Congress keeps adding to the mandates for which the FDA is accountable, with enhanced post-marketing surveillance now the new mantra. We agree with the concept, but there is a limit to which any entity can be stretched without breaking, and the FDA is nearing that point. The FDA will now not adhere to the timeliness requirements set by Congress in the PDUFA legislation (not that they ever did), delays will be permitted as strapped resources are shifted to post-market monitoring. Companies crawling through the regulatory minefield can anticipate this process becoming even slower and more convoluted, as the FDA obeys the edict to emphasize safety above all else. The nuances of weighing risk versus benefit will be shortchanged as the FDA tries to avoid further criticism. It is like watching an abusive family system. Familial abuse is passed down the generations, the children of abusive parents are more likely abuse their own offspring, the bullied learn to bully. Here, the abuse is perpetuated across institutional hierarchies, and the FDA, no stranger to the bully role, exhaustedly embraces it all the more. Congress implacably issues demands without providing the resources to meet them. The FDA in turn dishes out the same abuse that it receives, mistreating the companies coming before it, setting arbitrary, sometimes capricious standards, shifting requirements at the last moment and seemingly at whim, often leaving companies in the dark for months as to how they should or can proceed. The only hope that we take from this situation is this: If the FDA can develop a post-marketing surveillance mechanism in which they (and their Congressional masters) have confidence in terms of rooting out safety issues before they bloom in media coverage, that might permit them to reassess the grueling pre-approval process which at the very least delays, if not prevents, the emergence of improved, novel treatment options. If more certain that flaws will be uncovered, perhaps they will then modulate the current overemphasis upon a pre-marketing approval process which aspires to guarantee safety, but is doomed to fail because of the statistical impossibility of effectively identifying all possible rare events. Expecting the impossible from people, and then vilifying them for failing to deliver it, does not tend to bring out the best in them, or from the agencies that they comprise. For NI's part, we intend to lighten up just a bit in our criticism of the FDA (we'll see how long that lasts). Because no matter how stressful it may feel to be on the industry side of the moat, it's better than the Circle of Hell the FDA currently calls home.
From NI April 2008 The cost of running pivotal Phase III trials in a major disorder that will pass muster with the FDA is intimidating to say the least: It is not unusual for CNS Phase III programs to cost over $100 million, occasionally well over that mark. Thus a prudent company will prepare carefully for a Phase III program, sorting out dosing and population subgroup issues before embarking on pivotal trials. Or not. There is a curious, worrisome, and ultimately self-defeating trends towards miniaturization in the Phase II stage of clinical development. Companies are launching compounds into Phase III based on flimsy data from samples that once would have been thought suitable only for pilot Phase IIa studies. To paraphrase the Boomer motto "Fifty is the new Forty"--is Phase IIa the new Phase IIb? And if so, is this just as self-deceiving as the former? Alzheimer's has been a frequent venue for downsized trial refinement. Some recent examples: These mini-Phase II pseudo-vettings are not confined to Alzheimer's. For example: We could go on--there are several other vivid examples of paltry Phase II data enticing companies into catastrophic Phase III programs. One would think that this pattern would have been duly noted, and that this would dissuade companies from following suit. But, as noted above, not only has the trend not abated, if anything, it has worsened. The fact that relatively thorough Phase II trials do not guarantee Phase III success (e.g. Neurocrine'sindiplon) does not in itself justify skipping that step almost entirely. It is akin to predicating game strategy in American football around the plan to heave a 'Hail Mary' pass at the last moment: It is a play that depends on luck more than anything else, is exciting to watch, but usually fails.
(from NI February 2008) Our prediction: Nothing will change. Location, location, location. People hate it the way it is, but they like it the way it is. 2) Frank Baldino's presentation of Cephalon was, in comparison to some past editions, rather restrained, demonstrating the salutory effects of a $425 million fine. However, he did assert that Fentora (the patent-protected revamp of Actiq,which another CEO privately called "heroin on a lollipop") will become an "important new drug" in the treatment of neuropathic pain and back pain. This is unlikely. Even terminal cancer patients suffering excruciating pain sometimes have difficulty obtaining the opioid analgesics they need, as physicians fear being demonized by the DEA or their respective medical boards as irresponsible prescribers. The idea that physicians will be inclined to prescribe an even easier-to-use version of fentanyl for chronic disorders like neuropathic pain and/or back pain strikes us as not being in touch with clinical or regulatory reality. Our prediction: Nothing will change. Baldino will continue to describe this as a major new market opportunity, 3)Tysabri is alive and well. Biogen-Idec presented marketing data for Tysabri, the most important of which is that of the 21,000 patients worldwide now on Tysabri, 6300 have been taking it for more than one year, with no further cases of PML. Biogen-Idecand Elan continue to project a bullish target of 100,000 patients on Tysabri by 2010. Our prediction: They will reach that goal with Tysabri. The FDA will continue to underutilize this post-approval monitoring option, preferring to simply block marketing in most situations. 4)Vanda Pharmaceuticals spent little time discussing their once vaunted genetic testing. When asked, the CEO did describe their first test as able to identify the 80% of schizophrenics most likely to be responsive to antipsychotic treatment, though the other 20% might also be responsive. To put it another way, the test identifies the 20% of the patient population that is less likely to respond to the treatment they are going to get anyways. Our prediction: This test does not have a bright commercial future. 4) It would be hard to be more condescending than Shire Pharmaceuticals' CEO Matthew Emmens was than when he said “When you stop promoting a drug, about six or eight months out physicians forget about their favorite drug and they start to listen to the new one.” This boils down to a portrayal of MD's as a herd of cattle with an attention disorder. Our prediction: Prescribers are not going to flock to Vyvanse, and Shire will resort to the cattle prod of an Adderall XR price boost to nudge them down the chute.
Blackwater On the Potomac (from NI November 2007: added 11/2/07) The concept of 'Shoot first and ask questions later (if at all)' is one that most rational people and systems tend to eschew. It has unfortunately, but apparently, become a frequent operating tactic of Blackwater USA mercenaries...er, security teams...in Iraq, who in response to any perceived, potential threat, have on numerous occasions blasted the jeep or Toyota away--without first confirming that it was in fact a threat rather than a panicked Iraqi family. Pretty appalling by any standard of civilized behavior. NI would never suggest that bureaucratic boondoggling equals Blackwater's amoral disregard-for-life, but there is a parallel between that pseudo-rational decision-making and the defensive stance assumed by our very own FDA. Two recent cases-in-point illustrate the absurdity and institutional cowardice that has come to characterize the FDA. The first was the rejection of Endo/Vernalis' application for a sNDA for frovatriptan in the treatment of menstrual migraine. The drug hit its Phase III endpoints and showed no particular adverse event issues. It has, after all, been marketed for acute migraine for several years now. But the FDA essentially changed the rules and decided that they would not approve Frova, because there might be a safety issue that could show up later. As if any drug ever enters the marketplace with that possibility completely foreclosed. Personalizing Clinical Data (from NI October, added 11/2/07) Merck KGa dumped the SSRI/5HT1a combo drug vilazodone back in 2004 after it failed in Phase II. It has been brought back from the dead by Clinical Data (where do they come up with these clever company names?), which just announced success in a Phase III. The twist here is that they are analyzing the data to see if there is a genetic profile predictive of treatment response, in which case that would then be used in the final Phase III, and the drug and test would ostensibly be marketed together, so that antidepressant choice would be guided by genotype, rather than prescriber habit or which drug rep bought the drinks last time. It's like what Vanda Pharmaceuticals says they will do with iloperidone--eventually--but Clinical Data is actually developing the biomarker algorithm for Phase III, or at least, is trying to.
Commentary on Individual Companies (click on company name)
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