By 
• JOSEPH WALKER

Drug makers are rallying to a class of drugs that, if they succeed, could be the first treatments to target breast and ovarian cancers tied to the genetic mutations known as BRCA 1 and BRCA 2.

Two years ago, the drugs were all but written off after a string of clinical study failures in broader cancer-patient populations. But later research and a closer examination of existing data showed the drugs, known as PARP inhibitors, had a pronounced effect in BRCA patients.

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As many as one in 400 individuals carry an inherited BRCA mutation, which significantly raises the risk of breast and ovarian cancer. And while advances in genomics have led to several drugs targeting genetic variants in tumors, there is still no treatment specifically for BRCA mutations.

In June, researchers presented positive data on  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=AZN.LN" rel="nofollow - AstraZeneca   http://online.wsj.com/public/quotes/main.html?type=djn&symbol=AZN.LN?mod=inlineTicker" rel="nofollow - - AZN.LN  - +1.72%  PLC's drug olaparib, the most developmentally advanced among the class. Adding olaparib after chemotherapy helped ovarian cancer patients with BRCA mutations to live a median of 11.2 months without their cancers growing worse, or 6.9 months longer than study subjects taking placebos in the mid-stage trial. AstraZeneca said it is weighing an early filing for regulatory approval in Europe, which  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=C" rel="nofollow - Citigroup   http://online.wsj.com/public/quotes/main.html?type=djn&symbol=C?mod=inlineTicker" rel="nofollow - - C  - +1.17% says could lead to approval next year.

http://online.wsj.com/public/quotes/main.html?type=djn&symbol=BMRN" rel="nofollow - BioMarin Pharmaceutical  Inc.,  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=BMRN?mod=inlineTicker" rel="nofollow - - BMRN  - +3.39%   http://online.wsj.com/public/quotes/main.html?type=djn&symbol=CLVS" rel="nofollow - Clovis Oncology  Inc.  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=CLVS?mod=inlineTicker" rel="nofollow - - CLVS  - -0.94% and  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=TSRO" rel="nofollow - Tesaro  Inc.  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=TSRO?mod=inlineTicker" rel="nofollow - - TSRO  - +0.62%  also presented evidence of their drugs' activity in shrinking tumors at the June meeting of the American Society of Clinical Oncology. Though the drugs are early in their development and could still fail, the companies are beginning late-stage trials this year that could lead to U.S. approvals in 2017, according to Citigroup. AbbVie Inc., which is also developing a PARP inhibitor, said it is "likely" to start late-stage studies in the next six to 12 months.

BRCA mutations still account for only a fraction of total cancers, so the potential market is relatively narrow. Roughly 15% of ovarian cancer cases involve patients who are BRCA-positive, while the rate is as high as 10% in breast cancer, according to the National Cancer Institute.

By pinpointing eligible patients through genetic screening, companies are betting they can prove a more definitive benefit, helping make the case for premium pricing. Citigroup projects that the drugs would be sold for between $12,500 and $15,000 per month.

"If we can specifically target the patient, there's going to be a better benefit and people are willing to pay more," said Tesaro President and Chief Scientific Officer Mary Lynne Hedley.

In ovarian cancer, the drugs could be one of the biggest advancements since the development of platinum-based chemotherapy in the 1970s, which is now the standard of care, said Jonathan A. Ledermann, professor of medical oncology at the University College London Cancer Institute. Some companies are also testing the drugs in non-BRCA patients in hopes that additional genetic mutations or biomarkers will be identified and expand the overall market.

"PARP inhibitors are simple oral medications that are well-tolerated and have the ability to give long-term benefit" to patients, said Dr. Ledermann, who was principal investigator in the AstraZeneca study.

The drugs work to prevent cancer cells from repairing themselves after being damaged with chemotherapy by stalling production of an enzyme called poly ADP-ribose polymerase, or PARP, that is responsible for DNA-repair. PARP inhibitors are thought to work with BRCA mutations, in particular, because the mutations also interfere with the DNA-repair process, increasing the chances of destroying the cancer cells.

That PARP inhibitors are once again a focus of the pharmaceutical industry underscores how growing knowledge about the molecular underpinnings of cancer can make successes out of drugs that fail in broader populations.

Not long ago, researchers believed the drugs could work in a broader cancer patient population and reach as much as $5 billion in annual sales in breast cancer alone, according to Yaron Warber, a Citigroup analyst.

A drug being developed by Sanofi SA—called iniparib—cast a cloud over the class when the company said in January 2011 that a late-stage study had failed.

Later that year, AstraZeneca said it wouldn't advance development of olaparib for a broader ovarian cancer population after regulators indicated that the drug's benefit during a midstage trial wouldn't be enough for approval.

The string of disappointments nearly sank development of the treatments, as new clinical trials stalled and pharmaceutical giants  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=PFE" rel="nofollow - Pfizer  Inc.  http://online.wsj.com/public/quotes/main.html?type=djn&symbol=PFE?mod=inlineTicker" rel="nofollow - - PFE  - +0.77%  and Merck & Co. sold off rights to their own PARP inhibitors.

"Big pharma struggled with saying, is this a niche population or something better?" says Jane Robertson, AstraZeneca's global executive director of oncology.

The pessimism presented an opportunity for two biotech firms—Tesaro and Denver-based Clovis Oncology—which bought the rights to Merck and Pfizer's drugs, respectively. Deal terms weren't disclosed, but Tesaro's Ms. Hedley said her company exploited uncertainty around PARP inhibitors to enter the niche cancer drug area.

Ultimately, the effect in BRCA patients has become clearer. Using archived blood and tumor tissue samples of patients in the disappointing midstage trial, AstraZeneca was able to determine that over half were BRCA-positive and a subsequent analysis led to the positive study results presented this summer.

BioMarin Chief Executive Jean-Jacques Bienaimé says the renewed interest in PARP inhibitors reflected the growing embrace of niche cancer drugs that command high prices.

"I think those days of getting responses from 40% of patients and giving 60% of patients side effects that they don't' need are over," Mr. Bienaimé says. "What we're doing is the future and I don't see how that's going to change."

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Table. PARP Inhibitors in Development