Replies to post #125342 on Biotech Values

[DewDiligence]

Preview of ESC conference starting this weekend:

http://finance.yahoo.com/news/Data-may-prove-Bristol-Pfizer-rb-951666488.html?x=0&.v=1

Roche’s Dalcetrapib and PFE/BMY’s Eliquis will probably the two most watched presentations.

[DewDiligence]

PCSK9 Blockers: The Next Big Thing?

http://uk.reuters.com/article/2011/08/26/us-cholesterol-idUKTRE77P53O20110826

›By Ransdell Pierson
26-Aug-2011

NEW YORK (Reuters) - A handful of drugmakers are racing to develop a new class of medicines they believe could be the biggest weapon against heart disease since statins were introduced in the 1980s.

The contest is taking place largely out of public view, but researchers and industry analysts say excitement is building over the injectable medicines. They work by blocking PCSK9, a protein whose natural function is to preserve levels of "bad" LDL cholesterol in the bloodstream.

Researchers in Paris, Montreal and Dallas, through experiments with thousands of patients that began in 1999, discovered the gene behind PCSK9 and deciphered its function.

Biotechnology company Regeneron and its big pharmaceutical partner Sanofi are now ahead of the pack in developing a drug that goes after PCSK9. A single injection of their medicine, called REGN727, slashed LDL levels by more than 60 percent for a month in an early trial. Results from mid-stage studies are expected later this year.

"The PCSK9 mechanism is perhaps one of the best examples we have in all of medicine of how the study of genetics can identify new targets for developing new therapies," said Dr. Daniel Rader, a noted heart researcher at the University of Pennsylvania.

Although no serious side effects have been seen with REGN727, larger trials are needed to rule out problems such as liver toxicity or raised blood pressure that have wrecked other promising heart drugs, including Pfizer Inc's experimental torcetrapib.

Rader, who is a consultant to several of the companies developing PCSK9 inhibitors, said most drugmakers are working on once-a-month injections that would likely be self-administered by patients using very small needles. Some drugs might eventually be administered every two to three months, he said.

Amgen Inc, Merck & Co, Alnylam Pharmaceuticals Inc and a partnership between Bristol-Myers Squibb Co and Isis Pharmaceuticals Inc are in hot pursuit, with rival drugs of their own.

The anti-PCSK9 medicines are expected to be used alongside statins, such as Pfizer's Lipitor and AstraZeneca Plc's Crestor, for patients who do not achieve cholesterol-lowering goals with statins alone.

They would also be used on their own for a much smaller group who cannot tolerate statins -- oral drugs with global annual sales of $20 billion that inhibit the liver's production of LDL cholesterol.

In the United States, more than 10 million patients could ultimately be candidates for the new family of medicines. Industry analysts say the products could command $1,000 a month or more because of their potential importance to high-risk patients. Statins cost about $130 a month for branded pills like Lipitor, which is due to lose U.S. patent protection later this year, or far less for other products already available as generics.

BETS ON A MAGIC BULLET

The clearest advantage so far has been seen in Regeneron's new drug. Data from initial studies suggests REGN727 may be able to reduce LDL by another 50 percent when used in combination with statins, which themselves can cut LDL in half.

"Regeneron's anti-PCSK9 antibody really looks like a magic bullet against LDL cholesterol" said Ziad Bakri, a biotechnology analyst with T. Rowe Price. His firm is one of Regeneron's largest shareholders, with a 9.5 percent stake as of the end of June.

Assuming longer-term studies demonstrate the drug is safe and prevents heart attacks and stroke, Bakri estimates it could capture annual sales "in the billions of dollars" if approved.

"Taking advantage of this pathway is a creative leap forward," said Dr. Kristin Newby, a Duke University heart researcher who has no involvement in PCSK9 research.

But she cautioned that other classes of novel medicines have stumbled because of unexpected safety problems.

She cited torcetrapib, a drug to raise "good" HDL cholesterol that Pfizer had expected to reap annual sales of more than $10 billion. Meant to drive down the incidence of heart attacks, the drug instead was linked to deaths and was scrapped in 2006 after costly late-stage trials.

Data from a similar HDL-raising drug being developed by Roche Holding AG will be released on Sunday at the annual meeting of the European Society of Cardiology in Paris. But cutting LDL cholesterol remains the most proven way of reducing heart attacks and stroke, and is the industry's prime focus.

Should PCSK9 inhibitors stumble, it would be a keen disappointment for some of the world's biggest drugmakers.

Amgen, the largest global biotech company, is wrapping up early-stage trials of its PCSK9 inhibitor and will soon advance it into Phase II studies.

"There's a real opportunity to change the paradigm of treating cardiovascular disease with this therapy," said Scott Wasserman, Amgen's global project leader for cardiovascular medicines.

Andrew Plump, head of cardiovascular discovery for Merck, cautions that long-term trials must confirm the value of PCSK9 blockers. But he predicts that when used with statins, they could reduce heart attack and stroke risk 25 to 30 percent beyond the 25 to 30 percent reduced risk seen with statins alone.

"PCSK9 is one of the most interesting proteins in the human body," Plump said. "We didn't know anything about it a decade ago, and the speed at which drug programs have progressed is astounding."

Merck has not disclosed details of its PCSK9 program, but Plump said the company is interested in developing injectable and pill formulations.

Former Merck chief executive Roy Vagelos, who introduced the world's first statin Mevacor in 1987, is helping oversee development of Regeneron's product as chairman of its board.

Two Nobel Prize winners whose research directly led to discovery of statins, Michael Brown and Joseph Goldstein, are members of Regeneron's board, as is Christine Poon, former head of Johnson & Johnson's pharmaceuticals group.

"This is a big, enormous opportunity," Regeneron Chief Executive Leonard Schleifer said in an interview. "It could become one of the biggest drugs in biotechnology."

Regeneron also hopes to benefit from the expertise of partner Sanofi, whose Plavix blood clot preventer has annual sales of more than $9 billion. The companies aim to split any profits evenly from their PCSK9 medicine.

GENE MUTATIONS PROTECT THE HEART

In a series of experiments conducted separately by four research teams, scientists showed that PCSK9 wipes out LDL receptors, proteins that bind to LDL cholesterol in the liver and remove the artery-clogging substance from the bloodstream.

The mechanism is one of many ways the body regulates LDL to make sure there is enough of it to perform vital body functions, although not more than is necessary. But when PCSK9 goes overboard in destroying LDL receptors, LDL rises to harmful levels.

While early studies focused on patients with genetic mutations that triggered sky-high production of LDL, Helen Hobbs and colleague Jonathan Cohen theorized in 2005 that other mutations in PCSK9 might exist and have the opposite effect: of inactivating the gene and thereby leading to lower LDL levels.

They examined the structure of the gene in African-Americans who had low LDL. Their research showed that 2 percent of them had an inherited mutated form of the gene, and that their LDL levels were about a third lower than individuals without the mutation. The two researchers from the University of Texas Southwestern Medical Center went on to show that the subjects were protected from heart disease.

The findings strongly suggested the possible benefits of blocking PCSK9 or its activity.

"We knew what we had right away: the potential for a new way to lower LDL levels in humans," Hobbs said.

Two young women found to have no PCSK9 at all had LDL levels of just 14 to 16 -- one-eighth normal levels. Yet they were deemed to be in good health, suggesting to Hobbs and others that blocking PCSK9 may not pose great safety risks.

"The reaction to Dr. Hobbs' findings was electric among those who understood the field," said Dr. Daniel Steinberg, professor emeritus at the University of California-San Diego. "The science was solid and suggested that blocking PCSK9 could be as important as statins in terms of controlling coronary artery disease."

Steinberg, who has written extensively on PCSK9, said that patients with the protective mutation were shown to have an almost 90 percent reduced risk of coronary artery disease, compared with the general population.

"That's probably because their LDL has been low from birth," he said. Steinberg said anti-PCSK9 drugs could save tens of thousands of lives a year, as statins now do.

Statins actually raise levels of PCSK9, thereby undermining their own effectiveness in reducing LDL. "So if you give a statin, plus a PCSK9 inhibitor, you could get a bigger bang for your buck," Steinberg said.

Patients taking PCSK9 inhibitors might also be able to take lower doses of statins, and thereby avoid their side effects, such as muscle weakness and liver toxicity.

Some studies suggest PCSK9 may help regenerate liver tissue, so drugs that block it theoretically could pose a risk to alcoholics or others with existing liver damage.

Studies will test the liver risk, and also show whether the new medicines affect HDL cholesterol or cause side effects in other organs where PCSK9 is concentrated.

While safety must be established, Alnylam research executive Akshay Vaishnaw is betting on PCSK9 drugs.

"There's no question that this is going to be the greatest intervention, following statins, for treatment of high cholesterol. It's absolutely going to be the next big thing."‹

[DewDiligence]

Phase-2 Dalcetrapib Data Show No BP Elevation

http://www.reuters.com/article/2011/08/28/heart-roche-idUSL5E7JS03120110828

›Sun Aug 28, 2011 10:17am EDT
By Ben Hirschler

PARIS, Aug 28 (Reuters) - An experimental drug from Roche raised "good" HDL cholesterol substantially without increasing blood pressure, the problem that sank a rival treatment from Pfizer , researchers said on Sunday.

The data from a relatively small Phase II trial may increase confidence in the high-risk project, although the key test of whether dalcetrapib saves lives in heart patients will not be known until a large Phase III trial finishes in late 2012, with results likely in 2013.

Dr Thomas Luescher, of University Hospital Zurich, said the new drug was generally well tolerated and did not produce any significant increase in blood pressure. Nor did it impair the flow rate in blood vessels.

After 36 weeks, dalcetrapib had increased high-density cholesterol (HDL) levels by an average 31 percent and no safety problems were seen. The study involved 476 patients who received either dalcetrapib or placebo.

In contrast to another small study of the drug, details of which were released a week ago, there was no difference in the number of adverse cardiovascular events seen between patients on dalcetrapib and those on a placebo. However, neither of the two studies was large enough to detect significant differences in such outcomes.

It is still early days for dalcetrapib, and medical experts remain wary following the high-profile failure of a similar drug from Pfizer, called torcetrapib, in 2006.

Dr Keith Fox from the University of Edinburgh, who was not involved in the Roche-sponsored research, said the limited size of the trial meant it might not reveal all potential problems.

There is also a lack of evidence -- so far at least -- that raising HDL with drugs actually stops heart attacks and strokes [see #msg-63656000].

Nonetheless, the research presented at the European Society of Cardiology annual meeting is encouraging and may also a boost the broader field, which includes another experimental HDL-boosting drug from Merck & Co [anacetrapib].

"I think we can say it is safe and has no untoward effects and it does the job as far as the lipid (cholesterol) profile is concerned," lead researcher Luescher told reporters.

"It's a bit less potent than torcetrapib, which increased HDL by about 60 to 70 percent, but maybe that is even an advantage. It was a bit disappointing that vascular (blood vessel) function wasn't improved -- it wasn't worsened, but it wasn't improved."

NO PROOF YET

Dr Heinz Drexel, a cardiologist at the Private University in the Principality of Liechtenstein who was not involved in the study, said it was encouraging that the problems with the earlier Pfizer drug had been avoided.

But while there is strong evidence from epidemiological studies that low HDL is linked to heart problems, the jury is still out on whether Roche's new drug will make a difference.

"It's promising, but it's no proof that it will reduce outcomes," Drexel said of the latest data.

Industry analysts believe dalcetrapib, which Roche bought from Japan Tobacco , could become a multibillion-dollar-a-year seller if it proves itself in final-stage Phase III tests, which are now under way.

Tim Race of Deutsche Bank said he saw theoretical peak sales of 10 billion Swiss francs ($10 billion) but was adjusting this by 75 percent for risk to 1.2 billion by 2016.

If it succeeds, dalcetrapib would become a major product for Roche and one that would start to diversify its focus firmly beyond cancer treatments, where it is the market leader.

Dalcetrapib and Merck's anacetrapib -- like torcetrapib -- belong to a class of drugs called CETP inhibitors.

Some doctors currently prescribe a different product called niacin, a B vitamin that can boost heart-protective HDL. But niacin is not widely used because it causes uncomfortable facial flushing.

Adding to uncertainty about the role of drugs in HDL, U.S. government researchers reported in May that giving niacin to heart patients already taking a cholesterol-lowering statin did nothing more to prevent heart attacks and strokes.‹

[DewDiligence]

RDY starts phase-2 trial of CETP inhibitor:

http://finance.yahoo.com/news/Dr-Reddys-Announces-Start-of-bw-678710837.html?x=0&.v=1

RDY’s DRL-17822 belongs to the same drug class as PFE’s torcetrapib (defunct), Roche’s dalcetrapib, and MRK’s anacetrapib.

[DewDiligence]

BMY inks CETP drug-development deal with Simcere Pharmaceuticals of Nanjing, China:

http://finance.yahoo.com/news/Simcere-Bristol-Myers-Squibb-prnews-245445739.html?x=0

The companies agreed to co-develop BMS-795311, Bristol-Myers Squibb's preclinical small molecule inhibitor of the Cholesteryl Ester Transfer Protein (CETP). Inhibiting CETP could potentially raise HDL (good cholesterol) levels and help prevent cardiovascular disease. This collaboration is expected to accelerate the delivery of clinical Phase IIa proof-of-concept by leveraging the complementary strengths of a premier Chinese pharmaceutical company and a global biopharmaceutical company.

Under the terms of the agreement, Simcere will receive exclusive rights to develop and commercialize BMS-795311 in China while Bristol-Myers Squibb will retain exclusive rights in all other markets. The companies will together determine the strategic development plan to explore the potential of BMS-795311 to treat and prevent progression of cardiovascular disease. Simcere will run and fund initial development work. Financial terms were not disclosed.

BMS-795311 belongs to the same drug class as Roche’s Dalcetrapib, MRK’s Anacetrapib, LLY’s Evacetrapib, RDY’s DRL-17822, and PFE’s defunct Torecetrapib.