Replies to post #131050 on Biotech Values

[DewDiligence]

Thanks, Urche. I encourage other posters to chime in on this matter, which has at least a modicum of importance for MNTA investors.

For now, I’m keeping the 10%x10%=1% arithmetic in paragraph E of #msg-68940203, but I’m open to changing it if someone can present a persuasive argument for doing so.

[genisi]

Urche on xarelto ACS data

There is also a problem now with dosing. Faced with data that even this small dose of Xarelto is associated with 4 fold major bleeding risk, how are we going to view the higher doses (I think it was 20 mg) approved for other indications such as A. fib?

I think dosing will be a problem only in patients suffering from both AF and ACS.

The biggest problem I see is that even for the lower 2.5 mg BID dose, the "major bleeding risk" is about 4X that for placebo (2.1% vs 0.6%).

No, the 2.1% figure was for both doses. The 2.5mg dose had less bleeding (absolute rates were 1.8%) than the higher dose for the primary safety endpoint (TIMI major bleeding not related to coronary-artery bypass grafting). Also, like you wrote, there was not a significant increase in fatal bleeding (0.3% vs. 0.2%, p=0.66).

The bleeding risk would be tolerated, of course, if the efficacy were high enough. But, the absolute survival benefit of treatment with riva was only 9.1 vs 10.7 for placebo or 1.8%.

This was again for both doses, if you look at survival benefit with the 2.5mg dose, (which is the one I referred to in #msg-68962285 ) as compared with placebo, reduction in the risk of death from CV causes was 2.7% vs. 4.1% (HR=0.66; 95% CI, 0.51 to 0.86; P=0.002), that's a relative reduction of 34%! and the risk of death from any cause was 2.9% vs. 4.5% (HR=0.68; 95% CI, 0.53 to 0.87; P=0.002) that's a relative reduction of 32%. I don't think that

from a clinical viewpoint, that makes little difference

Given the significant reduction in death and the absolute major bleeding rates, I think the 2.5mg rivaroxaban dose has a good risk/reward profile in ACS.

[DewDiligence]

Doctors Attending AHA Reserve Judgment on New Oral Anticoagulants

http://www.reuters.com/article/2011/11/15/heart-bloodthinners-idUSN1E7AD1Y120111115

›Tue Nov 15, 2011 6:50am EST
By Lewis Krauskopf and Bill Berkrot

ORLANDO, Fla., Nov 14 (Reuters) - Cardiologists are not ready to jump to any conclusions about a closely watched group of new blood thinners and said serious questions about their safety still need to be addressed.

Three new medicines that offer potential advantages over older drugs to prevent strokes and other dangerous conditions caused by blood clots will compete in a market worth up to $10 billion in annual sales, according to Wall Street forecasts.

Investors have tried to bet on which of the three will become the dominant player in a race between Xarelto from Bayer and Johnson & Johnson , apixaban [Eliquis] by Pfizer Inc and Bristol-Myers Squibb, and Boehringer Ingelheim's Pradaxa.

Many cardiologists at the American Heart Association meeting this week said they were reserving judgment about whether any one drug is better for their patients. Some said safety concerns and cost could outweigh their benefits.

"I'm more confused than informed," Dr Sanjay Kaul, a prominent heart doctor at Cedars-Sinai in Los Angeles, said after hearing presentations on the medicines at the meeting in Orlando.

"The anti-thrombotic landscape has become more fuzzy for me, and it will continue to be fuzzy for the next few years until we make some sense out of the data."

Kaul was not alone in expressing hesitancy toward the blood clot preventers, and the views of such doctors are valued as an indicator of how widely new drugs may be used.

…Apixaban and Xarelto belong to a class called Factor Xa inhibitors, named for blocking a protein involved in the blood clotting process, while Pradaxa is a direct thrombin inhibitor.

The new medicines aim to replace warfarin or improve upon other older drugs in preventing stroke or dangerous blood clots. But they come with serious bleeding risks and their effectiveness has differed depending on the patients being treated and the dosage strength, complicating the picture.

"It's not clear to me yet that one class of drug is better than the other, let alone that within a class that one drug is better than the other," said Dr James Kirshenbaum, a cardiologist at Brigham and Women's Hospital in Boston.

Xarelto and Pradaxa are approved for use in the United States for preventing stroke in patients with a dangerously irregular heartbeat. Apixaban has yet to be submitted to the U.S. Food and Drug Administration.

Dr Nathaniel Reichek, director of research at St Francis Hospital in Roslyn, New York, expects the FDA will require substantial follow-up study of the drugs for some uses. Reichek conducted some warfarin clinical trials in the 1960s.

MIXED REACTION TO XARELTO

A major part of the promise of these new drugs is that they can replace warfarin, which has been used for decades but is difficult to manage because it requires regular monitoring to prevent life-threatening bleeding.

Doctors said that some patients are stable on warfarin, and they may be more likely to keep up with their prescribed regimen since it is far cheaper.

"Cost is a big issue for compliance," said Dr. Raymond Gibbons of the Mayo Clinic. "We're putting our heads in the sand if we don't recognize that compliance is a major factor."

Wall Street analysts have expected that Xarelto would trail apixaban in the largest market for the drugs -- stroke prevention in patients with an irregular heart beat known as atrial fibrillation -- based on clinical data that shows distinct advantages for the Bristol/Pfizer treatment.

But the meeting's most talked about blood thinner study showed low doses of Xarelto reduced the risk of death by more than 30 percent in patients with acute coronary syndrome (ACS).

Xarelto's rivals failed in this patient group, giving Bayer and Johnson & Johnson a potentially distinct market, although stroke prevention in atrial fibrillation is seen as the most lucrative use for the new drugs.

"It's automatically the biggest market and it still serves a tremendous purpose," said Leon Henderson-MacLennan, a medical consultant with the inThought unit of Wolters Kluwer.

"It's not to say that we're going to give apixaban willy nilly now," Henderson-MacLennan said. "There are other players in this and that's what's coming out of this program."

Other doctors were wary of Xarelto's heightened bleeding risk, including intracranial hemorrhages, in ACS patients. "I'm very concerned about the intracranial bleed," said Dr. Jeffrey Pang of the Sunnybrook Health Sciences Centre in Toronto, saying he was "conservative" on the Xarelto data.

Reichek said "even the strikingly positive" Xarelto data "leave a number of unanswered questions."

Ahead of the meeting, analysts said positive data could provide a "halo effect" for Xarelto in uses beyond acute coronary syndrome. But doctors were wary of attributing success in one trial any more broadly.

"I really think that is a bad idea," said Dr. Raymond Gibbons of the Mayo Clinic. "That is promoted by the pharmaceutical industry subtly, and not so subtly, to improve market share and sales."

"We ought to practice evidence based-medicine, and follow the evidence, and extrapolating the evidence to more and more patients I think is hazardous," Gibbons said.‹