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Missed Opportunity: Would PGx Have Helped Sanofi-Aventis Avoid Phase III Failure for Iniparib?

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Originally published Jan. 31.

By Turna Ray

The disappointing outcome of a Phase III breast cancer trial involving a Sanofi-Aventis PARP inhibitor is the latest example of big pharma pursuing the broadest possible population for a drug candidate, despite a substantial body of knowledge suggesting that pharmacogenomic strategies may have improved the drug's chances of success in best responders.

Sanofi announced last week that a Phase III trial for iniparib, an investigational oncologic for triple-negative breast cancer, failed to meet the pre-specified criteria for overall survival and progression-free survival. The news of the study results didn't have a negative impact on Sanofi's stock, but did appear to depress the stock price of molecular diagnostics developer Myriad Genetics, whose BRCA test has been shown to identify patients likely to respond to PARP inhibitors. Despite the fact that Sanofi did not use BRACAnalysis to select patients for the Phase III trial, Myriad's shares fell more than 11 percent the day Sanofi announced the results.

In response, Myriad CEO Peter Meldrum tried to correct market perceptions by publicly stating that if Sanofi had used its BRCA mutation test to stratify patients in clinical trials, the outcome may have been more positive.

Currently, there is no publicly announced companion diagnostic collaboration between Sanofi and Myriad for iniparib. So far, the only link that currently exists between Sanofi and Myriad is the mechanistic association between their respective drug and diagnostic products.

The PARP1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer tumors. However, in patients with mutations in the BRCA gene, when PARP inhibitors like iniparib destroy the PARP1 enzyme, tumors are unable to repair DNA damage and die. As such, Myriad's BRACAnalysis test can be used in drug trials to identify which patients have BRCA1/2 mutations and therefore would respond to PARP inhibitors.

According to Rebecca Chambers, Myriad's director of investor and public relations, the diagnostics firm plans "to reach out to Sanofi to determine if they are interested in using the BRACAnalysis test to do a retrospective analysis of their patient population."

Several of Sanofi's pharma competitors have already inked Rx/Dx deals with Myriad for their investigational PARP inhibitors. Abbott is using Myriad's BRACAnalysis to stratify breast cancer patients for its investigational PARP inhibitor veliparib in Phase III clinical trials. Myriad also has a similar deal with AstraZeneca to use BRCA mutation testing in clinical trials for the PARP inhibitor olaparib in ovarian cancer (PGx Reporter 06/30/10).

"We are open to working with Sanofi and all other companies who are developing PARP inhibitors," Chambers told PGx Reporter this week. "We continue to believe in the potential of PARP inhibitors and the companion diagnostic opportunity for Myriad and the BRACAnalysis product. We believe Sanofi’s results demonstrated the necessity of determining whether a woman has lost BRCA function and therefore is a likely responder for this class of drugs."

Sanofi isn't unique among drugmakers in holding off on taking a personalized medicine approach that would limit a drug's indication to a smaller subset of patients, and choosing instead to first pursue the largest possible indication.

Genentech, which has traditionally been very proactive in the personalized medicine field, only acknowledged the possibility of using a biomarker strategy to keep Avastin on the market as a metastatic breast cancer drug in best responders after it received notice that the US Food and Drug Administration was planning to revoke the drug's approval due to low efficacy and high toxicities. However, in Genentech's appeal to the FDA to keep Avastin on the market as a breast cancer treatment, the firm presents the biomarker strategy as a secondary point to its arguments for keeping the drug on the market for all comers (PGx Reporter 01/26/11).

Amgen has also been criticized for first pursuing a broad indication for its colorectal cancer drug Vectibix, even though it had preliminary data suggesting that patients with KRAS mutations would not respond to the drug (PGx Reporter 12/02/09). Amgen has responded to the criticism by saying that at the time it filed for Vectibix's approval in the US and in Europe, it may have had early hints about the impact of KRAS mutations on drugs response, but the data were not mature enough to justify modifying the drug's indication in regulatory filings (PGx Reporter 02/24/10).

Absent a business deal between Sanofi and Myriad, analysts are guessing that the PARP/BRCA connection will turn out to be a positive for the test developer in the long run.

In the view of Peter Lawson of Mizuho Securities, though the news of Sanofi's negative Phase III studies with iniparib may have negatively impacted Myriad initially, it may turn out to be a positive for Myriad in the long run. "Sanofi did not select patients for BRCA status in the trial – instead selecting triple negative patients, which in fact highlights the important of BRCA stratification of patients," Lawson wrote in a note.

Since Myriad's patents on BRCA gene mutations make it the only company with a commercially available BRCA test, drug developers that hope to use a companion test to gauge such gene alterations in drug trials will have to work with Myriad.

However, there hasn't been any indication from Sanofi that it is interested in speaking with Myriad about an Rx/Dx strategy for iniparib. Sanofi did not respond to questions ahead of press time. However, it's clear from a published Phase II study involving iniparib that Sanofi is well aware of the mechanistic relationship between BRCA mutations and PARP inhibitors.

In the Phase II trial, when iniparib was added to chemotherapy, patients had an overall response rate of 5.9 months compared to 3.6 months with just chemotherapy, and a median overall survival of 12.3 months versus 7.7 months. In the study, published in the New England Journal of Medicine and led by Joyce O'Shaughnessy of the Baylor Charles A. Sammons Cancer Center, investigators did not stratify patients based on BRCA mutation status, but they did discuss in the article how "dysregulation of BRCA1 … has been attributed to a number of mechanisms, including BRCA1-promoter methylation and overexpression of the negative regulators ID4 and HMG.

"Minimal antitumor activity of iniparib was observed in crossover patients whose disease had progressed on chemotherapy alone," O'Shaughnessy and colleagues wrote in NEJM. "These data are analogous to the decreased benefit of olaparib in patients with BRCA1/2-associated metastatic breast cancer whose disease was platinum-resistant."

In the Phase II study, participants were enrolled based on whether they met the criteria for having metastatic triple-negative breast cancer, which means their tumors were estrogen-receptor-negative, progesterone-receptor–negative, and had no overexpression of the HER2 protein.

Although there appeared to a be a recognition of greater response in patients with BRCA mutations in the article reporting Phase II results, Sanofi did not apply these PGx lessons to the Phase III trial.

Sanofi's Phase III study enrolled 519 women with metastatic triple-negative breast cacner from 109 US sites. Patients in the study were randomized to receive a standard chemotherapy regimen comprising gemcitabine and carboplatin with or without iniparib. Study participants had received up to two previous lines of chemotherapy in a metastatic setting.

Although iniparib did not reach statistical significance for the co-primary endpoints of overall survival and progression-free survival, Sanofi noted that "the results of a pre-specified analysis in patients treated in the second- and third-line setting demonstrate an improvement in overall survival and progression-free survival, consistent with what was seen in the Phase II study." Additionally, the company reported that the study results suggest that the addition of iniparib does not significantly increase the toxicity seen with gemcitabine and carboplatin.

Sanofi plans to publish the full results from the Phase III study at an upcoming oncology conference, and said it will discuss the results with health regulators in the US and in Europe. "We are conducting in-depth analysis to gain further insight into these Phase III results," Debasish Roychowdhury, senior VP and head of Sanofi's oncology division, said in a statement.


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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