Biotech Values

[AlpineBV_Miller]

Torcetrapib combo, Esperion, and Pfizer

I've hesitated to post here for a couple of reasons, the most important of which is my desire not to dilute what my Subscribers pay for. Comments on a big pharma and a company we covered positively from $6 to the $35 buyout seems outside of those bounds, so...

I am one of the few people who think the torcetrapib trials will fail to show a clinical benefit on morbidity and mortality. Will the trials show a benefit on IVUS (intra-arterial ultrasound)? It depends on how badly the investigators want the trial to succeed given that IVUS is notoriously subjective outside of the hands of a handful of people trained by Dr. Nissen. Will the trial show some statistically significant results? Probably, given the enormous n, though I think it interesting the trial data are delayed over a year.

Why do I think the drug won't have a benefit to morbidity and mortality? The short answer is that durable regression of atheroscerotic plaque requires reverse lipid transport (RLT). CETP-inhibition increases HDL, but has not been shown to promote meaningful RLT. The Phase II study recently released by Pfizer implies it does, but the study (purposefully, in my opinion) does not look at excreted lipids. Lipid mobilization in the body is a necessary part of RLT, but it is only an intermediate step. No excretion, no RLT.

I invite those interested in HDL and RLT science to take a look at our April 2002 issue. It is available on our website (BiotechMonthly.com) for no cost (Free Issues), so I do not believe am crossing any boundaries by suggesting that since I gain no revenue for directing people to it. And you won't get any spam from us. Please keep in mind the issue is almost four years old, so much of the rest of it will be dated. There is enough in there on HDL and RLT to still be of interest.

The decision to combine torcetrapib with Lipitor is mostly as PGS suggests. Primarily, it is to extend the patent life of Lipitor beyond the end of this decade. The recent successes of Vytorin (Zocor + Zetia) points to a shift in prescribers' opinions on combination drugs. If my friends who analyze big cap pharma are correct, Vytorin was the only statin to show sales growth in the last quarter. That trend will be exacerbated next year when Zocor goes off patent.

All statins have unfavorable side effect profiles. These side effects are cumulative and present in a large part of the population. The higher the dose, the worse the problem. If doctors can combine a low-dose statin with another drug and reach target lipid levels at lower toxicity, that combination will be a huge seller.

That's the beauty of Vytorin. While a smaller number of patients see more liver toxicity with Vytorin than they would with Zocor, most patients do better on the drug since Zetia has a better side effect profile. There are additional benefits from Vytorin, including a better effect on HDL than with Zocor alone.

Esperion's lead drugs were for acute care (IV), but their oral formulation (which we unabashedly called their "oral wonder drug") was less than six months from the clinic when they were acquired. This drug reduced LDL and boosted RLT in preclinical studies. In the last communications we had with Esperion personnel, the program was going to be slow-tracked into targeted populations (diabetics and those with genetic lipid abnormalities) while Pfizer focused on the torcetrapib trials.

For those who don't know, Lipitor wouldn't exist were it not for the Esperion management team. They rescued the drug from the dung heap and championed it through approval (before founding Esperion, of course). We found them to be an exceptionally gifted team. I mention this because they were convinced CETP-inhibition would not work. Their views were borne out by the results of an anti-CETP vaccine developed by Avant and an oral CETP-inhibitor by (I think) Japan Tobacco that have already failed clinical trials.

Assuming Pfizer kept their committment to the Esperion management team on the ESPR oral drug, if the torcetrapib trials fail there will be JUST enough time to get the ESPR drug into pivotal trials and on to the market before the Lipitor patent runs out. Because the ESPR drug was designed to significantly reduce LDL, that much faster surrogate endpoint pathway is available. Torcetrapib has no meaningful effect on LDL, and the FDA refuses (and rightly so) to use an increase in HDL as a surrogate marker for efficacy. Pfizer would be down in such a scenario because they would have to do a gaggle of marketing trials to catch the ESPR drug up to Lipitor, but they wouldn't be out of the game.

David Miller
BSR, LLC

(I have no position in any of the companies mentioned)