Sanofi-Aventis Could Refocus Development For PARP Inhibitor Iniparib

The French pharma is standing by the first-in-class drug, which failed in a Phase III trial in triple-negative breast cancer, saying it conferred a benefit in heavily pretreated patients.

Iniparib, the potential first-in-class PARP inhibitor for which Sanofi-Aventis SA had planned to complete a rolling NDA this quarter, failed to meet the co-primary endpoint of overall and progression-free survival in a pivotal Phase III study of women with metastatic triple-negative breast cancer, the company reported after market close Jan. 27.

The results are particularly disappointing in light of stellar Phase II findings presented at the San Antonio Breast Cancer Symposium in 2009 and published online Jan. 5 in the New England Journal of Medicine (Also see "Sanofi's PARP Inhibitor Plus Chemo May Be A Lethal One-Two Punch In Triple-Negative Breast Cancer" - Pink Sheet, 1 Jan, 2011.).

Despite the divergent outcomes, the designs of the two studies were very similar. "We need to do a complete look at the data, the patient populations, any differences that we can see between the Phase II and the Phase III," Sanofi's U.S. Chief Science Officer and Chief Medical Officer Paul Chew said in an interview. "When we have that data we'll present it at a major scientific meeting."

"We still feel that there is value in iniparib," Chew said. "We're going to look at this data. We're continuing the development in other tumors. And we'll know more soon."

Besides breast cancer, iniparib is in Phase II studies against ovarian, uterine and brain cancers, and a Phase III study in patients with advanced squamous non-small cell lung cancer launched in March 2010.

The bad news on Sanofi's lead pipeline drug "is a clear setback," BernsteinResearch Senior Analyst Timothy Anderson said in a Jan. 27 "quick take" note. Investor expectations for iniparib have been high, says Anderson, who modeled 2015 sales of iniparib at €644 million ($882.8 million) with a launch in 2012.

While the failure isn't likely to affect the financials of a company the size of Sanofi in the intermediate-term, said Anderson, "iniparib has been one of the few, tangible, high-visibility late-stage products in the company's pipeline, and this new uncertainty is likely to weigh on sentiment."

While several regimens are used off-label, there are no approved treatments for triple-negative breast cancer, so called because those tumors are negative for three markers: estrogen receptor, progesterone receptor and HER2.

Can The Triple-Negative Claim Be Salvaged?

Excitement over the Phase II data was based on results that were not a prespecified primary endpoint. Among the 61 women in the 123-patient trial randomized to receive iniparib plus gemcitabine and carboplatin, median overall survival was 12.3 months compared with 7.7 months for women in the chemo-alone group - a 43% reduction in risk of death. Median progression-free survival in the iniparib group was 5.9 months, compared with 3.6 months for chemo, and the overall response rate was 52% compared with 32%.

The iniparib group also fared better on the specified endpoint of clinical benefit - complete or partial response or stable disease of at least six months. Of the women who received iniparib, 56% showed a clinical benefit, compare to 34%.

Iniparib has fast-track status with FDA, and Chew didn't exclude the possibility of completing the oncologic's rolling NDA with the Phase II data in hand, then working on a new confirmatory Phase III. "Once we have these data analyzed, we're going to be talking very soon with the regulatory authorities both in the U.S. and in Europe in terms of what the next steps will be," he said.

The failed study enrolled 519 women with the tough-to-treat disease, who had received up to two previous lines of chemotherapy after their cancer spread. They were randomized to receive gemcitabine and carboplatin chemotherapy either alone or with iniparib.

While the iniparib results failed to reach statistical significance for the combined survival endpoint, a prespecified analysis of patients in the second- and third-line setting did show improvement, Sanofi said, raising the question of a possible claim for heavily pretreated patients. Chew called it "premature to comment on these first looks," however, and wouldn't elaborate on the potential significance of those data.

Iniparib is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor. Its mechanism of action is not well understood, but PARPs are signaling enzymes involved in the repair of damaged DNA, and thwarting their activity results in selective destruction of tumor cells that have a certain DNA defect - a defect hypothesized to be found in the DNA of triple-negative cancer tumors.

Rapidly multiplying cancer cells have frequent disruptions in the DNA that they need to repair, Chew explained. When a PARP inhibitor is paired with chemotherapy agents that induce DNA damage, the effect is to "put a stick in the spokes" of DNA repair in those malignant cells, he said.

"You have a one-two punch if you administer chemotherapies that include or cause breaks in the DNA, then follow it up with another therapy that inhibits the repair. One might expect a potential at least additive benefit."

Among other PARP inhibitors under development are AstraZeneca PLC's olaparib, in development against a number of cancers, with regulatory filings in ovarian cancer and BRCA-associated breast cancers in 2014; Merck & Co. Inc.'s MK-4827, in Phase I in advanced solid tumors; and Pfizer Inc.'s candidate PF-01367338, in Phase II development in a number of cancers. BioMarin Pharmaceutical Inc. announced the launch of a Phase I/II study of its candidate BMN-673 in advanced or recurrent solid tumors Jan.11.

-Shirley Haley ([email protected])