Pharma’s Cutting Edge

In a conference call that so stunned a Credit Suisse analyst he was left literally at a loss for words, Alexion Pharmaceuticals  yesterday announced that the annual average wholesale price in the U.S. for Soliris, its newly approved drug to treat the rare disease Paroxsymal Nocturnal Hemoglobinuria (PNH), would be $389,000. 

Wow.

Leonard Bell, Alexion’s CEO, was quick to defend the cost of the drug–interrupting another Alexion executive who started discussing acceptable cost-effectiveness ratios–by referencing the high cost of other therapies for so-called ultra-orphan diseases, such as Pompe (Myozyme, Genzyme) and Hunter (Elaprase, Shire HGT).  But the costs he cited for these drugs (”over $400,000″ and “over $800,000″ annually) appear to be inflated figures, even when considering weight adjustments for adult patients.  Generally speaking, the top end cost for drugs that target around 10,000 patients globally is under $300k a year.  So Alexion seems to be exploring new price territory here. 

This story is sure to be fodder for the WSJ (who more than once roasted Genzyme for their pricing) and, more importantly, for a newly Democratic Congress with drug costs on its mind.

But patients apparently need not worry about the high cost of Soliris.  Alexion, as they reiterated at least five times on the call by my count, has a goal ”that every patient who can benefit from Soliris will have access to Soliris.”  Not the snazziest marketing message, but at least it’s reassuring to patients.  Isn’t it?

It’s ACC annual meeting week, and JAMA and NEJM , among other journals, are providing limited-time free journal articles corresponding to major study announcements from the meeting.  One such published study, actually two studies in one report, from Steve Nissen et al (he’s one busy dude this week) describes Phase 2 experience with Lilly’s investigational PPAR-alpha agonist, LY518674. 

As you probably know, PPARs have been an extremely active target for the drug industry for decades.  Despite the fervent interest in PPARs, the only PPAR modulators marketed in the U.S. are the relatively PPAR-gamma-selective agonists, rosiglitazone and pioglitazone for treatment of hyperglycemia in type 2 diabetes, and the relatively PPAR-alpha-selective agonist fibrates (e.g. fenofibrate, gemfibrozil), which are used to lower triglycerides and raise HDL-C in dyslipidemia to reduce risk of cardiovascular events.  The demise of the PPAR-gamma agonist, troglitazone, has been well documented.

According to CDER, over 50 INDs have been filed for drugs designed as agonists of the PPAR receptors, including dual and pan agonists.  But successful development to market has thus far eluded all comers, due to disappointing efficacy and a variety of clinical safety and preclinical toxicity issues, including rodent neoplasia seen with the PPAR gamma/alpha dual agonists. 

Based on their promise in animal lipid-disorder studies, highly potent and selective PPAR-alpha agonists have been developed to improve upon fibrates.  Lilly has managed to advance its highly potent and selective PPAR-alpha agonist through Phase 2 studies, the first pharma to do so, which is the subject of the Nissen et al. report in JAMA.

I’ll dispense with a review of most of the data in the report.  The bottom-line implications for those still hoping that PPAR-alpha is a good target for treating atherosclerotic combined dyslipidemia is that it’s probably time to give up hope and move on to more promising targets.  LY518674 is plenty potent and selective for PPAR-alpha, so LY518674 tests the PPAR-alpha agonist hypothesis adequately.  It looks like the relatively low potency fibrates have maxed out improvements in apo A1/HDL-C levels that can be effected by alpha agonist treatment. 

Although effects on CV outcomes with fibrate treatment have been generally favorable (see this for review and meta analysis), it’s unlikely that LY or other potent PPAR-alpha agonists will be tested in CV outcome studies.  I say this because of the worrisome dose-related increase in LDL-C with LY that appeared to be correlated with baseline triglycerides in the dyslipidemia study.  This surprising finding, more than anything else in the LY studies, will contribute to an understanding of PPAR-alpha’s role in human metabolism of lipoprotein metabolism, even as it signals what should be the end of the road for potent PPAR-alpha agonists.

I haven’t read the book Science Business by James Pisano that James Robinson reviews in the Health Affairs Blog, but I love the review.  It’s expertly written, concise and informative for those just learning the biotech biz.  Have a look.

The following letter was written by me in response to David Nathan’s February 1st Perspective in the NEJM entitled: “Finding New Treatments for Diabetes: How Many, How Fast…How Good?”  (Subscription req.)  In this essay, Nathan argues that “FDA’s approval process for new antidiabetes medications should take into account their additional and unique contributions, especially when their glucose-lowering efficacy is similar to or less than that of currently available medications.”

In essence Nathan questions the wisdom of allowing approval of new drugs (for chronic diseases, like diabetes) that have not been demonstrated to be better than existing drugs.  My response offers a scientific reason why regulators should not have such discretion; unmade economic arguments are at least as compelling.

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Dr. Nathan throws light on the subject of hurdles for drug approvability in the U.S. Although his arguments are specific to drugs used to treat Type 2 diabetes, the points raised are germane to a number of chronic disease states, where multiple drug classes are currently in use.  Under current U.S. law, FDA lacks authority to restrict approval of new drugs because they might be deemed unnecessary, no matter in whose judgment.  It is a mistake to believe that putting such authority into the hands of FDA today is wise, for the simple reason that traditional pre-marketing studies of new drugs, such as those cited by Dr. Nathan, are incapable of determining which individual patients will or will not benefit from use of drugs.  Rather, these studies aim to show average effects in populations selected to be representative of users; they ask general safety and efficacy questions and yield general guidance only.  Many hope that future pre-marketing approval studies that incorporate highly predictive markers of risk and benefit (i.e. personalized medicine) will allow regulators to tailor approval decisions to specific subsets of patients, but until then it remains for doctors to perform the “N of 1” experiments needed to determine whether a drug benefits an individual or not.  A system for capturing results emanating from these large number of experiments is sorely needed.  In the meantime, clinicians considering prescribing new drugs for conditions like Type 2 diabetes should demand comprehensive monographs from manufacturers that include all relevant preclinical and clinical information.

Carl Nathan of Cornell’s Weill Medical College has published an essay on the above topic in this month’s Nature Medicine.  I can recommend the article for anyone interested in the conundrum of creating medicines to treat diseases orphaned by modern pharmaceutical economics.  Nathan does a particularly nice job of summarizing extant policies, projects and proposals for tackling this tough problem; it’s a valuable reference. 

On the critical side, I wasn’t bowled over by his proposal of relying on a combination of “open-access” drug discovery/development and a utility-based global patent and government reward system (neither idea is new nor an invention of Nathan’s, as he notes) to spur innovation for underserved medical conditions.  I simply find the patent track in particular to be unworkable as described.  That said, doing nothing clearly isn’t an option.