New study confirms worst fears about Merck’s HIV vaccine

Posted under Biologics, Blog, Companies, Diagnostics, Funding, HIV, HIV/AIDS, Medical Devices, Medical Supply, Merck, NIH, Pharmaceuticals, R&D, Startups, Universities, Videos by John Carroll

Five years ago Merck ($MRK) investigators stunned everyone working in the AIDS research field with the news that they were abruptly halting a study of a prospective HIV vaccine after the data began to make clear that it wasn't only failing to guard against the virus, but appeared to increase the risk of becoming infected. Now researchers have followed up to confirm that the worst case scenario was true.

The sudden about-face on the vaccine forced investigators as well as the NIH to do some serious rethinking about the R&D work being done on HIV vaccines. Not knowing exactly what went wrong, another big trial was scrapped on a similar vaccine. And as The New York Times reports today, further work has been carried out in slow motion, delivering at best mixed results.

The new study tracked the health of 1,836 men enrolled in the Merck trial for a further two years. Almost 10% later became infected, with uncircumcised men and men with high levels of antibodies for the Type 5 adenovirus most at risk. As the vaccine was constructed using a weakened adenovirus 5, scientists speculate that may have boosted the presence of CD4 cells in the blood, creating the kind of "target-rich" environment that HIV thrives on.

But that's conjecture. Investigators still aren't certain what went wrong, only concluding that the result had to be biologic. As a cautionary tale, the Merck trial will continue to serve as a reality check for everyone in the field.

- here's the story from The New York Times

Related Articles:
Study: Further insight into Merck HIV vax infection increase
HIV vaccines: When is a failure actually a success?

UPDATED: New cloud hovers over class of ‘good cholesterol’ drugs

Posted under Blog, cholesterol, Companies, CTEP inhibitors, Diagnostics, Eli Lilly, Funding, HDL, heart disease, heart drug, John LaMattina, Medical Devices, Medical Supply, Merck, Pharmaceuticals, Pipeline, Startups, Universities, Videos by Ryan McBride

Fresh doubts have cropped up for raising "good cholesterol" to combat heart attack risk, after a new study showed that patients genetically programmed to have higher levels of HDL cholesterol didn't appear to be more protected from heart disease than those with low levels. The news comes as Merck ($MRK) and Eli Lilly ($LLY) are spending millions of dollars to develop HDL-raising treatments, aiming to deliver on the blockbuster potential of the CETP drug class.

"I'd say the HDL hypothesis is on the ropes right now," said outside observer Dr. James A. de Lemos, a professor at the University of Texas Southwestern Medical Center, as quoted by The New York Times.

The HDL mechanism took a recent blow last week when Swiss drug giant Roche ($RHHBY) announced that it was nixing development of its contender designed to raise good cholesterol to thwart heart disease because of absent efficacy, following previous failures at Pfizer ($PFE) and Abbott ($ABT). Informed of the new genetic study revealed this week in The Lancet, Merck and Lilly representatives told the Times that the companies were both undeterred and continuing with their massive CETP programs. Yet the findings have dampened expectations for the drugs.

"This will have a sobering effect, it would have to," said John LaMattina, a senior partner at PureTech Ventures and former Pfizer R&D chief, as quoted by Bloomberg. "HDL has always been a controversial area. You have a question that you have to be willing to commit over a billion dollars in order to get the answer, and that is a very daunting commitment."

With billions of dollars in development costs and potential revenues on the line, expect scientists inside and outside of biopharma companies to take heed of the findings and dig deeper into the role of HDL in heart disease. As the Times notes, mouse studies showed that HDL carried cholesterol out of the arteries. But scientists will now look into whether HDL is an indicator or driver of reduced heart-attack risk.

Forbes' Matthew Herper reported that the latest HDL paper might not bring much in the way of new doubt about HDL-raising drugs, which were "already on the ropes" because of conclusions from previous studies. And he noted that The Lancet paper shows a slight 4% reduction in heart attack risk among patients with a mutation to the CETP gene, which might give hope to believers in drugs that target the CETP protein.

- read the NYT's article
- and Bloomberg's report
- see Herper's piece

Related Articles:
Roche abandons potential blockbuster cholesterol drug
Developers spotlight huge potential of new class of cholesterol drugs
Lilly heralds PhII success for mega-blockbuster cholesterol drug contender

Editor's note: Adds analysis of The Lancet paper from Herper's article. 05/20/12.

CETP Inhibitors: Blockbusters that Never Ran?

Posted under Biotechnology and Pharmaceuticals, Blog, Cardiovascular disease, CETP Inhibitors, Companies, Diagnostics, Funding, leadership, Lilly, Medical Devices, Medical Supply, Merck, Pharmaceuticals, R&D, Resverlogix, Roche, Startups, Technology, Universities, Videos by Ben Comer

The news that Roche scrapped development on its CETP inhibitor dalcetrapib, a drug designed to raise HDL cholesterol in the blood, likely presages the shuttering of Lilly’s development program for its CETP inhibitor, evacetrapib, industry experts and analysts say.

Merck’s CETP inhibitor, anacetrapib, will probably receive additional scrutiny as well, although Tim Anderson, senior analyst at Bernstein Research, identified a “bull case” for the product in an analyst note. The argument in favor of anacetrapib, per Anderson, hinges on the drug’s apparent lack of safety problems compared with torcetrapib (Pfizer’s CETP inhibitor that hit a developmental dead end due to safety problems in 2006), and the fact that it lowers LDL cholesterol, whereas Roche’s dalcetrapib only raised HDL. At any rate, Merck’s Phase 3 trial “is not likely to conclude for two or three years, in the best of circumstances,” wrote Anderson.

The CETP inhibitors – those still being developed– are justified by the assumption that raising HDL levels correlates with a lowering of cardiovascular risk. Donald McCaffrey, CEO at Resverlogix, a Canadian biotech firm, says with HDL, it’s all about “reverse cholesterol transport,” or in other words, plaque removal from the arteries. With HDL, “it’s not about the huge numbers, as Roche’s program has just shown. It’s about functional HDL…and whether you can make more of it.” A simple blood plasma test can show that a patient has higher levels of HDL, says McCaffrey, but HDL differs in function and capability. Resverlogix is developing a product (RVX-208) that acts on the “main protein” in HDL, known as ApoA-1 protein. By causing the body to make more of the ApoA-1 protein, more HDL is created, but it’s “empty” HDL. The idea is to “take the garbage out of the arteries, which requires more garbage bags.” With CETPs, the approach is to stop HDL from leaving the system, which causes it to build up. But the HDL build-up in that scenario resembles a garbage dump. That kind of HDL is “not going to go back into that arterial wall and take out any more plaque…it cannot,” says McCaffrey.

Another concern for CETP inhibitor programs is the class-wide effect of increased C-reactive protein (CRP) levels, a “very serious” inflammation marker, according to McCaffrey. “If you’re increasing your HDL, and you’re increasing CRP, that has been deemed a serious problem,” he says. Lilly and Merck’s respective CETP inhibitors have both demonstrated CRP increases; Lilly’s evacetrapib had the largest increase, followed by Merck’s anacetrapib, and then, in third, Roche’s dalcetrapib. McCaffrey claims that RVX-208, his company’s product, decreases CRP levels by 28%. RVX-208 is currently in two Phase 2 trials, both of which are being conducted by the Cleveland Clinic. The ASSURE trial, which aims to demonstrate plaque regression, not just an HDL increase, is expected to be complete by the first quarter of 2013. The drug is being tested in combination with atorvastatin and rosuvastatin – Lipitor and Crestor, respectively – because “we believe they will be the most efficient statins in the generic market.”

McCaffrey agrees with Anderson on the fate of evacetrapib: “I think the board in Lilly’s case is very conservative, so I think they’ll probably shelve [evacetrapib].” As for Merck’s anacetrapib, “they’ll probably continue on, they’re deep into that program and I think they need to find an answer,” says McCaffrey. (Norman Wong, Resverlogix’s chief scientific officer, outlined the problem with CETP inhibitors in a white paper published last November.)

Analysts have long predicted blockbuster sales for the CETP inhibitor class of drugs, and yet, none have made it through to approval. With the closure of Roche’s dalcetrapib program, is there enough blockbuster potential remaining to justify the enormous development costs these drugs require?

Roche abandons potential blockbuster cholesterol drug

Posted under Blog, cardiovascular, cholesterol drug, Companies, dalcetrapib, Diagnostics, Eli Lilly, Funding, Medical Devices, Medical Supply, Merck, Pharmaceuticals, Pipeline, Roche, Startups, Torcetrapib, Universities, Videos by rmcbride

After a review of lackluster efficacy data, Roche has thrown in the towel on developing one of the most promising drug candidates in the company's vast pipeline, dalcetrapib. And the Swiss drug giant's ($RHHBY) failure brings negative attention to similar drugs in development at Merck ($MRK) and Eli Lilly ($LLY) that raise "good" cholesterol to combat cardiovascular disease.

Dalcetrapib has gone down in flames after an interim assessment of a major Phase III trial, called dal-OUTCOMES, indicated that the HDL-raising drug lacked efficacy, Roche announced this morning. The company had hoped to show that adding the drug to the standard of care would benefit patients with coronary heart disease. The dal-OUTCOMES trial and all studies related to the program have been terminated.

Roche's fresh setback could trigger more angst about the prospects of drugs that raise good cholesterol, and analysts expect Merck and Lilly to feel the repercussions from this latest collapse. Pfizer ($PFE) previously ditched its own program in this field because a study showed that more patients on its drug, torcetrapib, died, Bloomberg reported. And Abbott ($ABT) raised doubts last year after reporting lackluster data on the company's own drug to boost good cholesterol.

"We anticipate a negative reaction driven by bad sentiment and we see other programs at risk as this is the second failure in this class following Pfizer's Torcetrapib," wrote Exane BNP Paribas analysts in a note, as quoted by Reuters.

Roche, the world's largest cancer drug provider, had banked on dalcetrapib to provide the company with a grand entrance into the cardio drug arena, and rosy projections of the drug's sales potential were in the neighborhood of $10 billion. The failure of the dalcetrapib program highlights the major challenge of improving on the standard-of-care statin therapies with new cardio drugs.

"Lowering cardiovascular risk beyond that which is achieved with intensive statin treatment is a very challenging goal and while we have always stated that dalcetrapib is a high-risk project, we are disappointed by the fact that this drug didn't provide benefit to the patients in our study," Roche medical chief Dr. Hal Barron stated. The company is dropping dalcetrapib, but it remains "fully committed" to the cardiovascular disease field, he added.

- here's Roche's statement
- see Bloomberg's article
- check out the Reuters story
- and the Wall Street Journal's report

Related Articles:
Roche abstract paints promising picture of a potential mega-blockbuster
Roche targets 'good cholesterol' drug win where rivals failed
Developers spotlight huge potential of new class of cholesterol drugs
How worrisome is the statin-diabetes link?