Pharma’s Cutting Edge

When I reported on the initial Galvus approval delay in November, I promised a follow-up story.  Yesterday, Novartis reported that FDA took the action of granting the Galvus NDA approvable status.  Novartis had obviously expected this decision for a while, since label negotiations never occured, but the company chose to make the announcement after the decision was made official by FDA on the 23rd. 

The approvable letter wasn’t disclosed by the company, but Novartis shared FDA’s general reasons for the decision in their presentation to investors.  Seems that FDA remains concerned about the skin lesions Novartis observed in its 1-year monkey tox study, despite the lack of similar lesions being observed in humans.  It’s asked the company to conduct further clinical study or studies to investigate the finding further, specifically requesting a clinical study in patients with renal impairment. 

Reading into FDA’s decision, and aided by Novartis’ mostly frank responses to investors on its conference call, it appears that FDA believes there is reason to think that the finding might be dose-administered and metabolite-related and therefore unmasked by studying the drug in a population with higher average steady-state Galvus metabolite concentrations than the population originally studied.  Of note, Novartis indicated that about 900 study subjects with mild to moderate renal impairment received at least one dose of Galvus in its Phase 2 and 3 program, including 600 who received Galvus for at least six months.  This is a decent safety exposure, especially given that the parent drug is not renally cleared, but it’s not large enough to rule out a potentially clinically important incidence of a rare adverse drug reaction.

During the conference call, Novartis’ Head of Global Development, James Shannon, stated that the FDA division reviewing the drug, the DMEDP, has been under much criticism and public scrutiny lately.  Although he stopped short of suggesting that this criticism influenced the DMEDP decision, it’s unreasonable to expect that such criticism would not influence the division to err on the side of caution.  Regrettably, FDA remains as politically  and publically vulnerable as any federal agency, installation of a ‘permanent’ head notwithstanding.

Despite the allure of chalking up FDA’s approvable decision on Galvus to a case of the cautious pneumonia, it’s impossible to understand the logic behind FDA’s decision and to speculate intelligently on what Novartis will have to demonstrate to gain U.S. marketing approval for Galvus without answers to some key questions.  What was the incidence and PK-relationship, including the active metabolite, of the monkey skin lesions?  Why wasn’t an advisory committee used to debate the importance of this unusual (perhaps unprecedented) preclinical finding before FDA made its decision?  Did FDA have an internal immuno- or derm-tox review of the skin findings performed?  If so, what were the reviewer’s conclusions?  If FDA believes the skin finding to be a pharmacological effect of DPP-IV inhibition, why hasn’t it alerted prescribers and users of Merck’s Januvia, the first drug product in this new class?  If FDA believes the finding to be specific to Galvus, and possibly specific to its metabolite, what incidence of the finding in renally impaired humans is it willing to accept to allow approval, perhaps with population warnings?  Outsiders are unlikely to have any answers to these questions for quite a while.

Based on the title of Schwarz Pharma’s February 15th press release: “Positive Results with Lacosamide in Diabetic Neuropatic Pain in Phase III trial” I was expecting to read of a favorable result of a typical double-blind, placebo-controlled trial of an antiepileptic drug used in patients with painful diabetic neuropathy.  I was pleasantly surprised to see the subtitle:  “Preliminary results from a phase III withdrawal-design trial with lacosamide in patients with painful diabetic neuropathy show that lacosamide was statistically significant over placebo in reducing pain scores. SCHWARZ PHARMA plans for regulatory submission during the second half of 2007.” 

“Cool,” I thought, ”A little creativity used to test a notoriously stubborn subjective endpoint.”  Here’s the release’s capsule summary:

106 patients with painful diabetic neuropathy were treated in this multi-center, double-blind, placebo-controlled phase III study. All patients began the trial receiving their optimal dose of lacosamide (< 400mg/day). During the 16 weeks treatment duration, lacosamide was withdrawn and re-introduced in a blinded fashion at pre-defined time points. Overall, patients showed consistently higher average pain scores while taking placebo than when re-exposed to lacosamide.

The potential benefits of withdrawal designs are several-fold and include the following:  They allow all study subjects to receive a promising new treatment for at least part of the study period.  They can be used to identify and enrich the re-treatment period with responders to reduce the likelihood of futile long-term treatment.  When endpoints are reversible and tolerable, they can provide a robust test of cause and effect in individuals. 

The lacosamide trial offered all subjects the opportunity to receive lacosamide.  That’s it.

Subjects were all given lacosamide prior to withdrawal; there’s was no reported attempt to distinguish responders from non-responders prior to or during withdrawal.  Therefore, there was no no enrichment in responders in the re-treatment phase, a lost opportunity to increase efficiency in that phase.  Also, since withdrawal itself was not randomized (i.e. genuine vs. mock withdrawal), there was a missed opportunity to perform controlled tests of the withdrawal/re-introduction of lacosamide.  It’s a high hurdle to pass, for sure, but it’s a very convincing case for the clinical use of lacosamide over other drugs (like Lyrica or Cymbalta, for example) among patients with characteristics similar to those of the lacosamide-responder study population who show a subjective response to the drug in the “real world”.  The higher cost of such a randomized withdrawal design can be offset by enrichment in the re-treatment phase.

As it turned out, then, this was just another Phase 3, double-blind, placebo-controlled study of an antiepileptic in diabetic neuropathy.  But at least it looks like this antiepileptic from Schwarz Pharma has a decent chance to see the light of day.

Today, the UK’s Office of Fair Trading (OFT) issued its commissioned report of the UK’s pharmaceutical pricing scheme.  Before you say, “so what?” consider that UK drug prices are directly referenced by countries representing 25% of the world’s pharmaceutical sales.  Still uninterested?  Thought not.

You will not be shocked to learn that the OFT believes UK’s current pricing scheme results in government money wasted on drugs.  Can you imagine them concluding that the UK is getting exceptional value for the money it’s spending on drugs?  I’ve never seen a report from any government’s office concluding that its government was getting a bargain.  The UK’s damage according to OFT?  About 500 million pounds in 2005, or about 4.5% of what the UK spent on drugs that year.

If you don’t have to read the entire report, consider yourself lucky and just read the Executive Summary, which certainly provides the salient points.  For now, though, take look at this snippet from the Executive Summary, which provides the government’s “compelling argument” for price controls on pharmaceuticals:

A major reason for the existence of a UK-wide drug pricing scheme is the difficulty the NHS [UK’s National Health Service] has in ensuring drugs are prescribed in a way that delivers value for money.  Informational and incentive problems result in a situation in which prescribers are often not sensitive to or even aware of the prices of the drugs they prescribe. This is particularly the case in primary care, which accounts for some 75 per cent of pharmaceutical expenditure in the NHS. Evidence we have collected from a survey of 1000 GPs suggests they have weak knowledge of the prices of some of the most widely-prescribed drugs in the UK.

Moreover, under current arrangements, there are high levels of prescribing for some products that cost much more than available substitutes but deliver very similar benefits to patients. This raises a major question as to whether value for money is being secured. Neither are patients price sensitive: they contribute through prescription charges to less than five per cent of expenditure on prescription pharmaceuticals – a lower rate than in almost all other countries in the world.

These demand side problems provide a compelling argument for some form of pricing scheme.

Let’s review this rationale, in case it wasn’t entirely clear:  Doctors don’t know what drugs cost and they are not incentivized to consider costs when prescribing.  Patients also don’t know what drugs cost since they pay only about 5% of their actual cost out of pocket.  This information asymmetry (an economist’s catchphrase that means exactly what you might think) leads to demand-side imbalances that maintain artifically high drug prices.  And the solution to this demand-side imbalance??  Well, it’s price controls, of course.  If you’re scratching your head, do not be concerned, it means only that you are a creature of logic.  Sadly, it would seem you have few kin among those recommending health policy in this UK office.

Every so often, I like to pick apart a company press release for analysis.  Primarily I do this for the educational opportunity, not only for my readers but also for me.  It’s a good way to catch up to what’s happening in a hot therapeutic area if nothing else.  I’ve chosen Human Genome Sciences and GlaxoSmithKline’s Announcement   of their initiation of a Phase 3 clinical trial of LymphoStat-B (belimumab) in Systemic Lupus Erythematosus (SLE).  I have no financial stakes in either company.

HGS is a hot biotech company that was one of the pioneers (along with Incyte, Millennium et al) in decoding the human genome’s expressed sequences.  They’re now trying to become a therapeutics company and are partnered since August 2006 with GSK in the development and eventually the marketing of LymphoStat-B.  The drug is a recombinantly expressed human monoclonal antibody, developed by HGS in collaboration with Cambridge Antibody Technologies (now part of AstraZeneca), that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS.  BLyS is a naturally occurring protein discovered by HGS that is required for the development of B-lymphocyte cells into mature plasma B cells.  In autoimmune diseases, such as SLE, elevated levels of BLyS are believed to contribute to the production of autoantibodies.

SLE is a chronic, often debilitating disease, that affects primarily younger women. In the US, about 1.5 million people have some form of lupus; a major organ is involved in about 35% of these people. Although improved care of SLE has resulted in extensions of lifespan, current therapies are inadequate to prevent substantial morbidities, including endstage organ failure, most commonly kidney failure, from occurring in substantial numbers of patients.  The subset of SLE patients with major organ involvement and active serology (i.e. autoantibodies in the blood) are the people who might eventually benefit from treatment Lymphostat-B.

The US FDA has a published a draft clinical guidance for development of drugs to treat SLE, and I’ll refer to this in my comments on the announcement.

Here’s the meat of the press release, re-ordered a bit to enhance comprehension and with my commentary offset by brackets in italics:

LymphoStat-B was generated by HGS through a collaboration with Cambridge Antibody Technology. It has received a Fast Track Product designation from the FDA for its potential use in treating SLE and has been selected for participation in the FDA’s Continuous Marketing Application Pilot 2 Program. The FDA has provided a Special Protocol Assessment agreeing to the LymphoStat- B Phase 3 clinical development program in patients with active SLE. [[I’m providing links to FDA descriptions of these programs in lieu of an extensive discussion.  See also my paper on the Fast Track Effect.  Basically, HGS took advantage of FDA’s willingness to give feedback and prior assurances to innovators of potentially life-altering medicines.  HGS can now be reasonably sure that if Lymphostat-B proves to be effective and safe in Phase 3 that they will be able to make certain pre-specified claims about the drug in their promotions.]]  Agreement has also been received from the European Agency for the Evaluation of Medicinal Products (EMEA) on the major components of the LymphoStat-B Phase 3 clinical development program, including the primary efficacy endpoint measures, target patient population, and dose selection. [[Seeing that they were falling behind the FDA in the quantity and quality of pre-submission advice being offered to applicants, EMEA improved its scientific advice program formally in April 2006.  Product claims made in European countries are still subject to much more political influence than in the US, but HGS can be reasonably sure that its Phase 3 study designs will allow for EMEA approval of marketing in member states assuming the drug is safe and effective.  Generally speaking, sponsors should avail themselves of both FDA’s and EMEA’s scientific advice opportunities whenever they make key product-development decisions (such as the Phase 3 decision).  I’ve met more than one small-firm chief that seemed offended at the idea of taking FDA’s scientific advice.  Offended or not, just get the advice and take it very seriously.]] Read the rest of this entry »