Pharma’s Cutting Edge

Yesterday, I presented my overview of the US Supreme Court decision in Wyeth v Levine, to join the thousands of other overviews published online in the last couple of days.  Many of those commenting are focusing on the implications of the decision for consumers and lawyers.  You will find less commentary on the likely business policy and practice implications.  That’s where I’d like to take the discussion today.  I’ll begin with some choice snippets from other blogs and end with my own thoughts.

For its part, Wyeth expressed its disappointment on behalf of itself and its customers:

Patients are best served by a national standard for the labeling of prescription medications — set by the medical and scientific experts at the U.S. Food and Drug Administration (FDA). When lay juries are permitted to second-guess the experts at FDA on the benefits and risks of particular medicines, the result is uncertainty for patients and doctors alike about how and when to use prescription drugs.

PhRMA joined Wyeth in its concerns regarding doctor and patient second-guessing of drug labels:

PhRMA is still reviewing the various opinions in the Wyeth v. Levine case. We continue to believe that the expert scientists and medical professionals at the Food and Drug Administration (FDA) are in the best position to evaluate voluminous information about a medicine’s benefits and risks and to determine which safety information to include in the drug label. Healthcare providers and patients rely on FDA-approved drug labeling every day in making critical decisions about whether a medicine is the best treatment for an individual. Unfortunately, patients could ultimately suffer if the Supreme Court’s decision forces healthcare providers and patients to second-guess FDA-approved labeling.

PhRMA’s biotechnology counterpart, BIO, is thus far silent on the case decision.

Over at Overlawyered, Tom Franks sees the decision as an abdication of the SCOTUS duty to protect interstate commerce from the states and disastrous for industry:

[T]he 6-3 decision is the worst anti-business decision since United States v. Von’s Grocery 384 U.S. 270 (1966). Justice Thomas’s confused concurring opinion is especially disappointing, as it declares an abdication of the Supreme Court’s appropriate structural role to prevent individual states from expropriating the gains from interstate commerce. Sell your pharmaceutical stocks now, because the Supreme Court just declared it open season on productive business.

Merrill Goozner ofGoozNews views the decision as conservative:

The duty to warn is one of the oldest precepts in the common law. It’s the height of conservatism to insist on that business obligation, and, from a consumer’s perspective, right.

At the Drug Injury Lawyer Blog, Derek Braslow, sees this as a clear victory for the consumer, one that well leave big pharma scrambling to defend itself from product liability:

The majority opinion in Levine marks a decisive victory for tens of thousands of consumer lawsuits that arise – or will arise – from prescription drug injuries. It is unlikely that Big Pharma will go down without a fight on this issue – indeed, defense attorneys are no doubt hard at work already in crafting arguments to distinguish or marginalize Levine in other cases – but to be sure, the Court’s holding in Levine tips the litigation scale decidedly back in favor of consumer plaintiffs.

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March 6th, 2009 | Category: Drug Safety, FDA, Healthcare Delivery, Legislation, Product Quality, Public Perceptions | Leave a comment

When I reported on the implications of Riegel v Medtronic for device manufacturers in February of last year, I indicated that the related Wyeth v Levine case would have potentially farther reaching implications for the pharmaceutical industry.  Yesterday, the US Supreme Court issued its 6-3 opinion in the case.  Let’s have a look at the arguments made in the case (written briefs can be found here), and the majority and dissenting opinions.  In a future post, I will review what others are saying about the implications of this decision and give my own thoughts on the subject.

The key question presented to the Supreme Court was the following:

Whether the prescription drug labeling judgments imposed on manufacturers by the Food and Drug Administration (”FDA”) pursuant to FDA’s comprehensive safety and efficacy authority under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq., preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use.

 The facts of the case are simple, summarized here by the Supreme Court:

Petitioner Wyeth manufactures the antinausea drug Phenergan [NB. first approved for US marketing in 1955; its label was last updated in 1996]. After a clinician injected respondent Levine with Phenergan by the “IV-push” method [in 2000], whereby a drug is injected directly into a patient’s vein, the drug entered Levine’s artery, she developed gangrene, and doctors amputated her forearm. Levine brought a state-law damages action, alleging, inter alia, that Wyeth had failed to provide an adequate warning about the significant risks of administering Phenergan by the IV-push method. The Vermont jury determined that Levine’s injury would not have occurred if Phenergan’s label included an adequate warning, and it awarded damages for her pain and suffering, substantial medical expenses, and loss of her livelihood as a professional musician. Declining to overturn the verdict, the trial court rejected Wyeth’s argument that Levine’s failure-to-warn claims were pre-empted by federal law because Phenergan’s labeling had been approved by the federal Food and Drug Administration (FDA). The Vermont Supreme Court affirmed.

As a bit of background, I should note that preemption–in this case, the notion that US Federal law regulating drug safety labeling supersedes state failure-to-warn laws when there is a “direct and positive conflict” between the two–has been a tenet held by the industry and the US government for some time, increasingly in this decade.  Indeed, the US government submitted a brief supporting Wyeth in this case.  The trial court in Vermont, however, disagreed with the notion of preemption in the original Levine failure-to-warn case, finding that:

…FDA’s regulation of labeling sets only minimum standards and thus cannot conflict with additional state-law labeling requirements, and that the FDA’s CBE regulation [CBE gives FDA discretion to not take action against a manufacturer that makes a label change prior to FDA approval to strengthen warnings when faced with new safety information] would have permitted Wyeth to strengthen the warnings on Phenergan’s labeling without prior FDA approval [(above summary taken from the Wyeth Supreme Court brief)].

The Wyeth argument is essentially summarized as follows, using selected quotes from their brief strung together:

…[Phenergan] labeling already contained numerous warnings about the risks associated with IV injection of Phenergan [and the] respondent never showed or even contended that Wyeth had any material new information about those risks that FDA had not already taken into account when it approved Phenergan’s labeling. [Therefore,] it would have been impossible for Wyeth to comply with the purported state-law duty to modify Phenergan’s labeling to contraindicate intravenous administration of Phenergan without violating the FDCA.

 

Moreover, enforcement of this state-law duty [as implied by the preceding Vermont Court decision] would nullify the ex ante expert and statutorily mandated balancing of therapeutic benefits and safety risks that FDA performed in approving Wyeth’s Phenergan labeling. It would substitute the ex post judgment of lay jurors whose members consider drug safety through the lens of a single patient’s injury, rather than from the perspective of the overall public health, with the countervailing benefits of the drug to the entire potential patient population in mind. Indeed, counsel for respondent expressly invited the jury to override FDA’s decision, telling them “[t]he FDA doesn’t make the decision, you do.”

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March 5th, 2009 | Category: Drug Safety, FDA, Healthcare Delivery, Legislation, Product Quality, Public Perceptions | Comments (1)

This blog is becoming old enough to start revisiting posts to check for progress of immature technologies.  Yesterday, the WSJ wrote a story (sub req) that discussed, among other emerging technologies, nanobodies from Ablynx, one of the types of next-generation antibodies I briefly wrote about in September of 2005.

With Ablynx making news, now seems a good time to revisit my 2005 list and check on the progress of these engineered antibodies with potential to improve on exisiting monocolonal antibody drugs.  Technologies that first appeared after 2005 or that I did not mention then are not covered here.

Nanobodies (Ablynx):  Derived from naturally-occurring antibodies that function without a light chain, each natural heavy-chain antibody consists of one variable domain and two constant domains. Ablynx’ nanobodies consist of the single variable (VHH) domain.  Compared with traditional monoclonals, nanobodies are touted as less immunogenic, more stable, easier to manufacture, and amenable to oral delivery.  The company has made significant progress signing R&D partnerships and developing its own drugs since my original post. Ablynx’ first clinical candidate was a nanobody against von Willebrand’s factor (ALX-0081), an iv formulation intended to reduce the risks of thrombosis during acute coronary syndromes. They’ve also developed a second anti-vWF for SC administration that has entered the clinic.  Their third clinical candidate is an anti-TNF nanobody partnered with Wyeth.  The company has not yet reported successful oral nanobody delivery, but it claims to have successfully delivered the nanobodies via lung and to have modified the drugs to extend their half-life.

Mimetibodies (Centocor): Unlike most therapeutic antibodies, mimetibodiesare intended to mimic the activity of a peptide, while providing enhanced pharmacological properties. Mimetibodies have the genral structure: [Vn]-Peptide-Linker-Vc-Hinge-CH2-CH3, where Vn is a portion of the N-terminus of a variable immunoglobulin domain and Vc is a portion of the C-terminus of a variable immunoglobulin domain. The greatest potential advantage of mimetibodies over the native peptides is improved pharmacokinetics (generally an extended half-life and receptor interaction).  Mimetibodies are proprietary to Centocor (J&J), and there has been very little published other than patent literature.  Centocor’s patents and applications describe mimetibodies for GLPs, EPO, sRAGE, and melanocortin.

Intrabodies or intracellular antibodies:  A relatively old technology, intrabodies as a new therapeutic modality were probably first proposed by Marasco et al in 1993, who generated intrabodies to function as endogenous inhibitors of subcellular processes in mammalian cells.  As far as I am aware, intrabodies must be expressed in the cells in which they are intended to act, i.e. via engineered-gene delivery.  This limitation has thus far prevented their use in the clinic, and I’m not aware of any companies that have progressed intrabodies past discovery research.  However, their use as a tool to knock down protein function posttranslationally has proved of modest scientific value.

Peptide-conjugated antibodies (Innexus):  When I mentioned this tech in 2005, the direction it would take was unclear. It now appears that Innexus is using peptide linkers primarily to crosslink MAbs to enable higher potency and perhaps improved pharmacokinetics. Its lead drug candidate is crosslinked CD20 for NHL, now in preclinical testing.  The Kentucky company that pioneered this approach, Immpheron, appears to have dissolved.

Bispecific antibodies (various companies): By far the most popular therapeutic use of antibody engineering in my 2005 list was bispecific antibodies. Such antibodies are capable of binding two targets (antigens) with high specificity at the same time.  This too is a relatively old technology, but its therapeutic applications have yet to be fully realized.  Probably the first potential therapeutic exploitation of bispecificity was published by Roche scientists in 1987, in a study that used antibodies specific to both the T-cell receptor (CD3) and a specific B-cell expressed antigen to selectively deplete B-cell clones. The first reported clinical study, of an antibody with specificity for both an ovarian cancer antigen and CD3, was published in 1991.  By the mid-90’s Medarex had entered the clinic with their first bispecific antibody, MDX-210, and followed several years later with MDX-H210, a chemically formed bispecific against Erbb2 and CD64, Hx22-ki4 (CD30 x CD64), and MDX-447 (EGFR x Fc receptor), for prostate cancer, Hodgkin’s lymhoma, and solid tumors, respectively. These were all developed before 2005 and are no longer being developed as far as I know.  Post-2005, several bispecifics were advanced to the clinic.  All of these molecules include a tumor-antigen binding region and a region to bind an immune effector cell antigen, triggering a tumor-specific immune response. Some also attract accessory immune cells (so-called trispecific or trifunctional antibodies–ertumaxomab, Trion Pharma). Micromet has had early promising clinical results with blinatumomab (initially MT-103), a bispecific targeting CD19 (B-cell specific antigen) and the T-cell CD3 complex, aimed at NHL and B-ALL.  In a phase 1 study published recently, a blinatumomab dose as low as 0.005 mg/m2/day eliminated the targeted cells from peripheral blood.  If you think that’s not impressive, consider that Rituxan, the standard of NHL care anti-CD20 MAb, is dosed at 375 mg/m2 per week.  Over four weeks, that equates to roughly 11,000-fold higher amounts of Rituxan being delivered to the patient.  If these results follow through to Phase 2, this will be a treatment to watch for sure. Micromet was partnered with Medimmune on the drug, and I assume that AZ is continuing the collaboration.

Blinatumomab MOA

February 18th, 2009 | Category: Technology | Comments (1)

The promised land in pharmaceuticals was 10 years ago.  Until we see a major technological breakthrough in pharmaceutical development, for now it’s all about working what you have. - David Markowitz

The above quote from David Markowitz, an analyst at Caris & Co., appears in today’s Philly Inquirer in an article by Miriam Hill summarizing analysts’ opinions on the Wyeth/Pfizer merger deal.  Is he right?

Nah. 

First off, I haven’t written about the deal yet, and I don’t intend on saying too much, because frankly, it’s not all that interesting to me.  The Pfizer sponge is sopping up another large company…ho hum…been there before…more than once.  Lots of good folks on both sides will lose their jobs, while senior executives will get even richer, with or without a job afterwards.  Neither company’s shareholders will particularly benefit in the long run, as the combined Pfizer will have a very tough task of growing profits post cost-cutting, because its profit base will be enormous.  Sometime before 2012, the combined firm will reduce its profit base by selling off a major unit (Wyeth’s consumer business, I’m guessing) and spinning out another (vaccines?).  And so it goes.

But back to the quote.  The promised land for Pharma was entered well before 10 years ago, sometime in the early 1980’s in fact, when the drug discovery engine was revved up sufficiently to produce the blockbusters of the early to mid-90’s.  Despite, the dry spell in the land of Promise this decade, the discovery engine, already revved to the max, has been retooled to become more efficient and has been boosted with a goodly dose of in-licensing fuel supplement.  Pharma’s decision-making is still bogged down amidst a large, feather-footed bureaucracy, but some important lessons are being learned.  Arguably the most important lesson of all–that in the absence of accurate nonclinical predictive ability (the technological breakthrough alluded to in the Moskowitz quote) success is a throughput and asset management game–has been learned.  The result is that early clinical pipelines of the nimblest majors are being filled sufficiently for robust volume growth in the decade to come.

Now I know I’ve said nothing about the increasing pressures to curb price increases, and certainly such pressures will counteract the forthcoming proliferation of new drugs to restrain profit growth.  But I think with all important payers now requiring substantial evidence of societal benefit for new health technologies, the industry will be able to price its best medicines more competitively with other health technologies.  In other words, I think that the industry will be held to a slightly fairer standard for “reimbursement” going forward.  Also, as I stated in a recent post, the industry must take advantage of recent regulatory trends to push for longer periods of market exclusivity, thus providing new products with more time to become profitable and encouraging a slightly higher risk tolerance among innovators.

In short, the industry still dwells in the promised land it entered more than twenty years ago.  I advise senior executives of larger companies to resist an urge to merge with other large firms to relieve near-term pressures, understanding that this sometimes means forsaking short-term personal gain.  Once critical R&D and sales mass is reached–and there’s reason to believe it has been reached at every Top 15 firm–there is no compelling business case for a mega merger.  Indeed, going it alone provides a much easier opportunity to grow profits and increase shareholder value.

Alternate views, as always, are welcome to comment right here.

January 28th, 2009 | Category: For Investors, Miscellaneous | Leave a comment