Pharma’s Cutting Edge

NEJM — Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes

Following up Oct 24th’s post reporting on the news of Phase 1 trial suspensions of prasugrel to adjust dosage, we have today’s results of the TRITON-TIMI 38 Phase 3 pivotal trial of prasugrel vs. clopidogrel, published online in the NEJM to coincide with a presentation at the AHA annual meeting.

The editorial accompanying the detailed trial results, written by Deepak Bhatt of the Cleveland Clinic, sums up the study findings and implications nicely and sheds some light on the decision to study the antiplatelet pharmacodynamic effects at lower doses in subgroups of patients with differing baseline risks for serious bleeding:

The degrees of reduction in all these important ischemic events were substantial and robust [~19% in the primary efficacy endpoint, up to 52% for reduction in stent thrombosis with drug-eluting stents]. Beyond  comparing one drug with another, the TRITON–TIMI 38 study validates the hypothesis that greater degrees of adenosine diphosphate–mediated platelet inhibition are indeed associated with a greater suppression of clinical ischemic events. This is a major scientific contribution to our understanding of antiplatelet therapy….

Of concern, however, was the excess in TIMI major bleeding not related to coronary-artery bypass grafting that was life-threatening in the prasugrel group (1.4%, vs. 0.9% in the clopidogrel group; P=0.01), even fatally so (0.4% vs. 0.1%, P=0.002)….Thus, there is a price to pay for greater platelet inhibition and the accompanying reduction in ischemic events: higher rates of serious bleeding. In TRITON–TIMI 38, for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel…..[I]n a “real-world” setting, such as in an elderly patient with multiple coexisting conditions, the risk of major bleeding and even fatal bleeding may be increased to an even greater degree than was seen in TRITON–TIMI 38. Correspondingly,the benefits may also be greater in actual practice….

Bottom line:  Prasugrel more effectively prevents acute coronary syndromes than clopidgrel at its approved dosage, probably by stronger ADP-mediated platelet inhibition at the one size-fits-all dose of prasugrel studied.  However, one-size-fits-all appears to be an undesirable approach to this form of therapy, as evidenced by the significantly higher bleeding risk with prasugrel.  A more personalized approach, perhaps to the level of an individual patient, is necessary to improve on the efficacy of clopidogrel in the real world.  Thus, further clinical study of prasugrel , perhaps in conjunction with a point-of-care theranostic, will be needed to guide its tailored prescription.  That said,  I see nothing in these results that would preclude FDA approval of prasugrel now, without further clinical study, albeit with limitations on its use to low bleeding-risk patients.  Realistically, though, Lilly and DaiichiSankyo must perform additional studies to justify prescription of prasugrel to broader populations of patients and reap the financial rewards they are seeking.

Study Protocols Will be Amended in Two Small Early-Phase Prasugrel Studies

These amendments are strictly protocol-related and do not provide a basis for inferring overall outcomes of other prasugrel trials.–J Anthony Ware

Usually, a company studying an important new drug in a competitive market tries to keep progress of the program sort of, well, secret.  Certainly, Lilly and Daiichi/Sankyo are doing what they can to keep the top-line efficacy and safety results from the Phase 3 prasugel study of nearly 14,000 patients a well-kept secret until unveiled at the AHA meeting in a couple of weeks.  So, why this press release.–for two, small Phase 2 studies that Lilly says shouldn’t be interpreted as inferring anything about the “overall outcomes” of the prasugrel program? 

This disclosure has but a single interpretation; Lilly and Daiichi/Sankyo are essentially saying that this dosage adjustment news is material to investors.  There is no other reason for it that would make any sense.  In  order for the news to be material to investors it must mean that there are implications for the larger program; suspension of two Phase 2 studies for a dosage adjustment amendment, considered in isolation, would never rise to the level of being material news that must be released to investors, especially not right before Phase 3 results are expected.  Granted, these implications apparentlly do not reflect the ”overall outcomes” of the program, but that doesn’t mean they aren’t very important to the program and to the eventual approval and sales of this highly anticipated drug.  By making this announcement Lilly and Daiichi/Sankyo are admitting as much. 

“In analyzing the data and looking over the numerous studies and then considering all the patient populations, we decided it would be prudent to start considering the potential dosages,'’ said Joedy Isert, a spokesman for Lilly. “You want to make sure you provide the right dose to the right patient at the right time.” [from Bloomberg]

What a mess.  I don’t know what Mr. Isert was trying to say, but what he said was not only a cliche without substance, it was also harmful to the company, making Lilly appear derelict in its dose-finding responsibilities.  Not good; get better spokespeople. 

Bottom line–If you’re a Lilly or Daiichi/Sankyo investor on the long side, you have good reason to be concerned.

Disclosure: I do not own equity in either Lilly or Daiichi/Sankyo. 

siRNA passes milestone

              Images courtesy of Alnylam

Researchers from Alnylam Pharmaceuticals, Roche Kulmbach, the Swiss Federal Institute of Technology, UT Southwestern Medical Center at Dallas, and MIT have collaborated on research published online yesterday in Nature (subscription req.) that demonstrates the efficacy and afety of systemically administered synthetic siRNA. 

Despite the hype that has followed siRNA for the last couple of years, accompanying the IPOs of SIRNA Therapeutics and Alnylam Pharmaceuticals, many unknowns remain about the feasibility of delivering systemic synthetic siRNA safely and effectively.  For siRNA proponents and their investors, one of the scariest unknowns was whether siRNA would suppress microRNAs.  microRNAs are ~22nt RNAs that regulate transcription and translation of proteins via a protein complex. known as RISC.   Unlike siRNA, which generally suppresses a single mRNA transcript, microRNAs each affect the regulation of more than one protein, providing a post-transcriptional mechanism for coordinated regulation of important cell growth and survival pathways. 

The concerns regarding siRNAs were brought to light last year, when it was discovered that systemic delivery of synthetic short hairpin RNAs (shRNAs, natural precursors to siRNA) disrupted microRNA synthesis, leading to frequent fatal toxicity.  The cause of toxicity was believed to be saturation of a protein needed for nuclear export of microRNA precursors.  Although it was believed that siRNAs would not cause the same saturation problem, it was not known for certain whether in vivo concentrations of siRNA sufficent to suppress mRNA by upwards of 80% would avoid similar microRNA disruption and its associated toxicity.  This latest work shows that siRNA administration leading to therapeutic effects is not associated with microRNA suppression or severe toxicity in mice.  Because these pathways are largely evolutionarily conserved, it’s expected that the findings will be transferable to humans, although no studies of systemic siRNA administration to humans have been conducted.  Non-human primates have been administered siRNA systemically, with promising results so far.

Bottom line is that this work was a necessary and important step in the progression of systemic siRNA therapy for humans.  Both Alnylam and Sirna (now a part of Merck) are testing synthetic siRNAs delivered locally into the airways and eyes, respectively.  Both also have siRNAs intended for systemic delivery in preclinical testing.  We can now be reasonably assured that both firms will eventually advance systemic siRNAs into the clinic.  Although the first clinical disease targets for systemic siRNA aren’t known for sure, decent bets for Alnylam are hypercholesterolemia and liver cancer, and for Merck are Hepatitis C and Type 2 diabetes.

Ophthotech Raises $36 Million; In-Licenses Two Compounds for Macular Degeneration

The Ophthotech Board will consist of: Henry Simon (SV Life Sciences and former Chairman of the Board of Eyetech Pharmaceuticals, Inc. (”Eyetech”), Axel Bolte (HBM BioVentures), Thomas Dyrberg, M.D., Ph.D. (Novo A/S), David R. Guyer, M.D. (former CEO and co-founder of Eyetech, who will also serve as Ophthotech’s Chairman of the Board), and Samir Patel, M.D. (President and CEO of Ophthotech and former co-founder of Eyetech). The management team consists of former senior Eyetech personnel led by Chief Executive Officer, Samir Patel, M.D. Eyetech developed and commercialized Macugen, the first anti-VEGF therapy for the eye.

Eyetech, formerly an independent biotech with an aptamer targeting VEGF (pegaptinib, Macugen) that is used to treat wet AMD, was acquired by OSI Pharmaceuticals not long ago.  The acquisition price was below the IPO price (details here).  It was a new therapeutic area for OSI, and it didn’t work out.  Despite the assistance from Pfizer’s ophthalmic salesforce, Macugen couldn’t stand up to pressure from Genentech’s anti-VEGF monoclonal antibodies, Lucentis and Avastin.  OSI is now divesting its eye business. As part of the divestiture, OSI has licensed its apatemer targeting PDGF (a related angiogenic peptide) to newly formed Ophthotech.  Ophthotech has also licensed development and marketing rights to Archemix’s aptamer targeting the C5 component of complement (an inflammation factor).  As you’ll read, Ophthotech is staffed largely by former Eyetech execs.  It’s a chance for them to do it all over again.  Perhaps this time around they will not sell out the early public-market investors by dumping the firm below its IPO price, while reserving a tidy sum for themselves.

I read BusinessWeek.  It’s a quick general overview of what’s going on in business, the economy and investing; I can’t imagine that anyone thinks it’s more than that.  I certainly can’t imagine that anyone would use it to make individual stock picks.  Yet, for 10 years Gene Marcial has been providing his “insights” into individual stocks.  I view Marcial’s column the same way I view any investment newsletter–with great skepticism.  How does he select stocks for inclusion?  How does he select the analysts he quotes?  What ties doe does he have to any of these people or their companies (he doesn’t take stock positions in the companies he mentions). 

The reason I’m even discussing Marcial’s column is that he frequently discusses biotech companies.  He makes it pretty clear to anyone who’s been in or around the industry for a while that he knows this industry less than well–that is to say barely or perhaps not at all.  But that’s okay.  If he always chooses his sources like a chop house sommelier chooses the red to match your Kobe, he could still make wise calls and followers of his cobbled together advice might still make out.

But he’s no stock-picking somellier. 

What irks me about the column isn’t even so much that Marcial doesn’t know a thing about biotech but that BusinessWeek sees fit to tout his long-term performance.  Long-term performance?  If he’s a lousy biotech stock-picker, as I claim, why would BusinessWeek tout his long-term performance?  And there’s the rub.  It’s because BusinessWeek lies.  Well…not so much lies as distorts, in a way that inflates Marcials’ picking prowess.  Here’s how:  Marcial’s column is published online on a Thursday afternoon, after the market closes.  By the time anyone can act on the column it’s at least Friday (or Monday if it’s a 3-day weekend).  By the time the market opens on Friday, the “Marcial effect” has occurred and the stock price at open reflects it.  Not surprisingly, when Marcial touts a stock Thurday it frequently bumps Friday.  Not that any individual investor could take advantage of the bump, unless he/she knew that Marcial’s column was about to be published.  Following the bump, the market settles to reflect the stock’s underlying value.  The distortion from BusinessWeek comes from the price they use to reflect Marcial’s total returns.  They use as the basis the stock price at close on Thurday, not the price at open on Friday.  So, the 1-day return is from the close Thursday to the close Friday.

You can see the “Marcial effect” by reviewing Marcial’s 1-day returns compared with broad indices, as BusinessWeek has published in their August 13th issue.  You’ll see that Marcial beats the S&P 500, the DJIA, and the Russell 2000 by 3.8, 3.7, and 3.8%, respectively.  Folks, that’s not a sign of stock-picking prowess, that’s a sign of a direct influence on stock market valuations.  If Marcial really did pick stocks that beat the indices over a 10-year period as BusinessWeek claim, we would expect that his 1-day returns would closely approximate the indices’ 1-day returns.  That’s because a broad selection of stocks will never appreciate measured over any randomly selected 1-day period, because their combined underlying value will never increase significantly over a 1-day period.  So, BusinessWeek’s own published data shows that the “Marcial effect” contributed to nearly a 4% transient bump in the value of his picks.  Read the rest of this entry »