Pharma’s Cutting Edge

I was a bit surprised to learn yesterday of FDA’s desire for more cardiovascular safety data before approving Pargluva. We knew from the advisory committee hearing that FDA had concerns about the safety profile of the drug. Two of the eight questions to the committee concerned cardiovascular safety. The preclinical studies suggested no major cardiac toxicity concerns beyond those seen with PPAR gamma agonists such as rosi- and pioglitazone. Cardiac myopathy, a theoretical adverse effect of PPAR alpha agonists at high doses, was not seen preclinically, except for an increased incidence of cardiac hypertrophy in the 6-month rat toxicology study. See the FDA’s toxicology briefing document for details.

The clinical experience with muraglitazar indicated the potential for congestive heart failure and suggested the possibility of excess cardiac mortality. The table above shows mortality reported during muraglitazar clinical trials.

Note that there were 9 cardiovascular-related deaths among subjects assigned to muraglitazar (0.28% incidence) compared with 1 among placebo (0.17% incidence). There were none among the 823 subjects who were assigned to pioglitazone 15 mg or 30 mg daily. Five of the 9 on muraglitazar were at the highest dose tested. Furthermore, 4 of the nine were temporally related to the presence of CHF. On the other hand, three CV-related deaths on muraglitazar were sudden without autopsy and three others were non-cardiac (stroke and PE). Right away you see FDA’s dilemma. Here they have a drug with a cardiac mortality signal suggesting roughly 2x risk over placebo with no mortality observed during active comparator treatment. However, it would not be unreasonable to exclude from consideration the three CV-related deaths that were non-cardiac, since mechanistically the concern is in the heart. So, we’d be left with five muraglitazar events, yielding an incidence of 0.185%, which is very similar to the placebo incidence. Thus, the excess cardiac mortality disappears.

FDA was also likely concerned about an apparent dose-relationship. Doses above those recommended for use are often used off-label, abd FDA will consider toxcity at higher than recommended doses if they believe off-label use to be significant. Below are serious adverse events (SAEs) froma dose-ranging trial of muraglitazar. Sorry if it’s hard to read.

Note the higher incidence of CV-related SAEs with doses of muraglitazar over 5 mg.

Cardiac SAEs at 5 mg were also higher than placebo or active comparator when muraglitazar was combined with metformin or sulfonylurea. Furthermore, broken out by preferred AE term, myocardial infarction occurred three times more often with muraglitazar (all doses) compared with pioglitazone (all doses). And the incidence of CHF was double that of pioglitazone (30 mg) versus muraglitazar (5 mg).

Details of the safety profile are available in the FDA’s medical officer review.

Overall, I can see why FDA would be concerned. But I think two factors probably played most against immediate approval. The first is the efficacy profile of the drug. Frankly, it was disappointing and wasn’t good enough to justify any meaningful increase in risk beyond the PPAR gammas already approved. The second is FDA’s current approach to risk. In the WSJ article cited here, a Deutsche Bank analyst said he doesn’t think this approvable decision reflects on FDA’s current state of mind as regards risk mitigation. I disagree. I think that two years ago this drug would have met with approval accompanied by a rigorous postmarketing committment and surveillance program. Today it received an approvable with a likely approval hinging on further clinical trials before launch. I noted with skepticism commentary that approval could be delayed up to a year. In fact, approval could be delayed for much longer than a year depending on what is asked of BMS. If an outcomes study is required, forget it. That’s several years in the making at a minimum. However, if a surrogate study will suffice (and I can’t imagine which surrogate would be acceptable) a year is possible but unlikely.

Not going to comment on the trial results per se, but I thought this was a good opportunity to point out what I suspect most readers of this page already know: press releases that contain quotes by non-employees are always written by the company. For the uninitiated, this will seem counter-intuitive. After all, the quotes are literally that, set aside by quotation marks and all. But as every PR expert will tell you, it is far too risky to allow someone outside the firm to initiate a quote. The drug firm might have limited control over the results it presents, but it has full control over the quotes that appear in its press release announcing the results. So, the company initiates the quote and then asks the non-employee to endorse it, sometimes allowing for minor edits. If the non-employee insists on major changes that the company can’t live with, the company always has the option of excluding the quote. Legally, the non-employee is bound by confidentiality to avoid comment if this occurs.

I was moved to write this when I read the Lorus release, not because it contained an inordinate number of outside quotes, but because the quotes chosen for publication came across as particularly heavy-handed to me. Here’s the one from the CRO doc leading the study: “Performing such analyses [exploratory subgroup analyses] to define the specific population that benefits from modern oncologic therapies has become standard operating procedure in contemporary cancer drug development and is one more necessary step that will bring us closer to defining the proper role of Virulizin(R) in the management of this disease.” Who actually speaks like that? I’d suggest to Lorus that they invest a bit more in their PR rep.

For investors, this is just another opportunity to remind ourselves of the need to be highly skeptical of company pronouncements.
It’s important to read them carefully, but your gaze should be fixed squarely between the lines.

 I haven’t spent much effort on stock movements for a while, but I came across an interesting pattern developing with AMLN that I thought I’d share. This is a 1-year daily chart of AMLN superimposed with the BTK (Amex biotech index). Notice how closely AMLN tracked the BTK until the beginning of May (red arrow). Then it deviated to the downside, presumably related to institutional short-selling and individual fear over concerns that the company might have trouble getting the desired label for exenatide. By mid-June, however, coinciding with the ADA meeting and presentation of data suggesting that exenatide would fulfill its promises, AMLN rebounded to retrace the BTK (first green arrow). The boost was short-lived. For while the BTK continued its 3-month ascent through August, AMLN stagnated. Then came exenatide’s US approval on 8/22 followed 8/23 by the large stock price movement on heavy volume (second green arrow), with the stock again retracing the BTK, making up for the ground it had lost over the summer. The BTK rise slowed appreciably in September and appears to have topped out short-term with retracement back towards its August low (bottom white support line). But AMLN has shown more resiliency so far this month (upper white trend line). Why? Don’t know. Could be optimism over the launch of exenatide. But if so, I think its misguided. In any case, I read this as a setup for a short-term downward trend in AMLN that will parallel BTK’s recent downward movement. Note that I hold AMLN derivatives.

Unfortunately, you need to be a subscriber to get the story via the link, so here’s a portion of the story (below). The gist is that FTC might be scrutinizing authorized generics more closely. If so, this could lead to a lawsuit test of the practice. If this happens, it would represent an about-face of FTC’s current position supporting the authorized generic practice. As you might know, I am firmly against the practice from a public-health standpoint, as it leads to dis-incentives for independent generic makers to take the risks needed to bring new generics forward quickly. If left unchecked, the practice could eliminate the indpendent generic manufacturer as we know it. –FJC

From FDA News, Oct. 5th edition:

AUTHORIZED GENERICS MAY FACE INCREASED FTC SCRUTINY
Although a growing number of generic drugmakers appear willing to participate in the authorized generics market, the controversial practice may soon face increased scrutiny from the FTC, according to an industry expert.

David Balto, an attorney with Robins, Kaplan, Miller and former policy director in the FTC’s Bureau of Competition, said regardless of whether some generic firms are in favor of authorized generics, the anticompetitive nature of the business strategy is something the FTC is expected to monitor closely.

Congress has already asked the FTC to investigate the competitive effects of authorized generics, Balto noted, citing a May 9 letter by Sens. Chuck Grassley (R-Iowa), Patrick Leahy (D-Vt.) and Jay Rockefeller (D-W.Va.) that asks the FTC to review the practice. The FTC could very well grant the request, said Balto, who noted the agency has undertaken several initiatives to address generic competition issues, including a study on generic drugs in 2002.

The issue of authorized generics remains a polarizing one among generic drugmakers, with some firms electing to stay out of the market and others jumping ship to form partnerships with brand firms. William Kennally, president of Pfizer’s generics subsidiary Greenstone, said a schism has formed between the companies that support the practice and those that don’t.

What can investors and others learn from these repeated failings of Phase 3 clinical trials of cancer vaccines?

If there is only one lesson to take away, it is this. Phase 2 clinical trial designs and endpoints with cancer vaccines have thus far not been adequate predictors of vaccine efficacy. So let’s have a look at the CancerVax Phase 2 study design and endpoints to see why. I’ll tell you up front that I have little prior knowledge of this company’s Phase 2 program. I’m going to read about it and comment on it in “real-time” as I write this.

First, I’ll look for the data. CancerVax’s website has a link to a summary of the program. It says that some of the data have been published. Usually, however, salient details have been released to the press. I check my computer for this using my desktop search (having tried several, I’ve settled on X1 for now). As I’ve been keeping detailed press-release archives since the beginning of 2004, I’m not finding anything on the Phase 2 program there. I’ll check Medline for the publication(s). Note that if I weren’t aware of the publications, I probably would first do a search on ASCO’s meeting abstract database. I find three publications using PubMed that appear promising. All three were published in the second half of 2002, two in JCO and 1 in Ann Surg. Let’s have a look at the paper by Hsueh et al in the JCO.

The study design is found under “Patients and Methods”. Always read this section first when interpreting a study finding. The study population was culled from a database of over over 10,000 patients with AJCC Stage IV melanoma who were clinically disease-free after surgical resection. Now, I don’t know exactly what Stage IV melanoma is, but I can surmise that it is either the most advanced stage or close to it. Typically Stage IV solid cancers have spread to distant sites from the original tumor location. “One hundred fifty patients identified during the database search were enrolled onto phase II protocols for postoperative adjuvant therapy with Canvaxin therapeutic cancer vaccine.” Hmmm…note that, for the first time, we learn that this “study” is actually an agglomeration of Phase 2 studies and maybe something else too. “The patients had no clinical or radiographic evidence of disease before vaccine initiation.” So, the studies were designed to prevent a disease recurrence after a clinical remission period that varied from patient to patient (the amount of variance in this factor is likely important, but we’re not told yet what it is. We’re only told that it must have been at least 30 days since the last prior treatment). “One hundred thirteen patients identified during the database search did not receive Canvaxin vaccine after complete resection of distant melanoma metastases or at any point during their treatment at our cancer institute.” So, in this “study” 150 patients retrospectively identified as having been treated with Canvaxin were compared with 113 patients retrospectively identified who were not.

This is your first RED FLAG. Stop here and think about this a bit. Retrospective Phase 2 studies were conducted, but they were small, too small probably to convince anyone that Canvaxin would be effective in Phase 3. The authors of this paper surmised that if they could combine data from subjects treated with Canvaxin, they might be better able to provide convincing evidence of efficacy. One has to wonder whether they would have published this study had they not. But let’s move on. So the study is essentially a retrospective, uncontrolled treatment comparison. Remmebr, the untreated population has been taken from a cancer treatment database that has nothing to do with Canvaxin Phase 2 studies. The fact that the treated population was “nested” in a Phase 2 program is a red herring. It might as well not have been. This form of evidence is superior only to a case report and a case series in its accuracy for predicting treatment efficacy in a larger population. There are simply too many biases that can influence the findings. We might surmise, for example, that patients who volunteer for a secondary prevention trial with a vaccine might be more diligent about their overall health care and lifestyle, factors that could influence their overall immunity and health. We could stop here, concluding that this study is not worth our effort, but let’s take a look a bit further. Read the rest of this entry »