Amgen's Acquisition Of Dezima And CETP Drug Like Pfizer's '03 Buy Of Esperion. Will History Repeat?

In 2003, Pfizer purchased Esperion Therapeutics for $1.3 billion for access to Esperion’s experimental medicine, ETC-216, an early-stage synthetic, biological drug that mimicked the beneficial effects of HDL and in so doing potentially could reverse atherosclerosis. At the time the deal was viewed positively by industry analysts as it put Pfizer in a position to have three blockbuster medicines in its cardiovascular pipeline: Lipitor, ETC-216 and the CETP inhibitor torcetrapib. As enunciated by Pfizer’s research head, ETC-216 would be used by patients in an emergency setting, followed by long-term treatment with a combination of Lipitor and torcetrapib, the latter of which dramatically raises HDL-cholesterol – the so-called good cholesterol. In justifying the deal, Pfizer claimed “we feel all these drugs are complementary, and that patients will need a variety of treatment options.”

Well, we know how that worked out. As part of its billion-dollar clinical development plan, Pfizer ran a cardiovascular outcomes trial (CVOT) comparing torcetrapib + Lipitor to Lipitor alone in order to demonstrate that the unprecedented LDL-cholesterol (LDL-C) lowering and HDL-C effects of the combination translated to far fewer heart attacks and strokes than seen with Lipitor alone. Shockingly, this CVOT, known as ILLUMINATE, showed that the combination was inferior to Lipitor alone. In 2007 Pfizer stopped all efforts on its CETP program and in 2008, it abandoned HDL research altogether, divesting Esperion. This company was reacquired by its founder, Roger Newton, and relaunched.

Over the past few years, cholesterol R&D has moved from elevating HDL-C programs to more effective approaches to lowering LDL-C. One mechanism in particular, PCSK-9 inhibition, has generated the most interest in the field as these drugs, when combined with statins, lower LDL-C to unprecedented levels driving the LDL-C of patients to as low as 25 mg/dL. The first two such agents, Praluent ( Sanofi /Regeneron) and Repatha ( Amgen ) have recently been approved by the FDA for patients with high LDL-C who are unable to get to low enough levels with only diet and statins. But the full promise of these drugs has yet to be realized. Will getting a heart disease patient’s LDL-C to 40 or lower (well below the current American Heart Association guideline of 100) reduce the incidence of heart attacks and strokes? To answer this question, CVOTs are well underway at both Sanofi/Regeneron and Amgen for their respective drugs and it is anticipated that these results will be available in the next two years. If lower LDL-C is truly better, then the positive CVOT results envisioned with PCSK-9 inhibitors will revolutionize the treatment of heart disease.

Given all the excitement around PCSK-9 inhibitors, CETP inhibitors tend to be ignored. However, despite the cloud that hovers over this area of research due to torcetrapib, two companies -- Merck and Lilly -- have stayed the course. Both believe that they have a CETP inhibitor free of torcetrapib’s safety limitations. But people are not banking on the HDL-C elevating properties of these compounds for meaningful clinical results. Rather they are resting their hopes on the enhanced LDL-C lowering capacity of their CETP inhibitors, which when combined with atorvastatin (generic Lipitor), will provide superior results to statin single therapy. In fact, Merck has its own CVOT underway with its compound, anacetrapib. Known as REVEAL, this trial has enrolled 30,000 patients and is scheduled to read out in 2017.

Against this backdrop, Amgen has announced that it is acquiring the Dutch biotech firm Dezima for $300 million upfront and potential milestones of $1.25 billion. The key to this deal is Dezima’s CETP inhibitor, TA-8995. This compound is years behind Merck’s anacetrapib and Lilly’s evacetrapib in development. The only claim to fame for TA-8995 is its high potency – it requires a smaller pill than anacetrapib or evacetrapib. But whether this translates to better clinical efficacy remains to be seen.

So, if TA-8995 has no discernible benefits, is years behind Merck and Lilly and will undoubtedly require a very expensive CVOT ($500 million?) to demonstrate at least equivalence to the leaders, why did Amgen make such a large investment? Here’s what Amgen’s research chief, Sean Harper had to say:

“TA-8995 has demonstrated dramatic LDL-lowering. With a portfolio of TA-8995 and Repatha, our recently launched LDL-C lowering PCSK-9 inhibitor, we will be able to offer more treatment options with different mechanisms of action and modes of administration across varying LDL-C levels and risk profiles.”

Sound familiar? This is the same reasoning that Pfizer used in buying Esperion 12 years ago. Maybe Amgen’s gambit will be successful. But it is going from being in the first wave of an exciting new area of LDL-C lowerers to investing perhaps $1 billion in a CETP inhibitor clinical program that, if successful, will be third to market. Couldn’t Amgen have found better uses for a billion dollars?

(The author is the former head of Pfizer R&D and still holds stock in the company.)

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