Sanofi's New Drug Jevtana has FDA Approval

Advanced Prostate Cancer, Sanofi Could See Expansion to First-Line Use
The Pink Sheet Daily. 2010 Jun 21, E Hayes

Sanofi-Aventis gained a fast approval for its chemotherapy Jevtana (cabazitaxel) - just 11 weeks after the final filing in a rolling submission for second-line treatment of advanced hormone-refractory prostate cancer. But the company is also positioned for a quick expansion to the first-line setting.

Cabazitaxel, the successor to the company's soon-to-lose exclusivity Taxotere , was cleared on June 17 for use in combination with the steroid prednisone to treat men with prostate cancer after treatment with Taxotere (docetaxel).

As part of its post-marketing commitments, Sanofi is required to conduct another Phase III study in second-line treatment and a Phase III study in the first-line setting.

However, Jevtana's potential in earlier-stage disease could be limited by its toxicity profile, Leerink Swann analyst Seamus Fernandez noted. Cabazitaxel is linked to severe, potentially fatal side effects that are given a very high profile in FDA labeling, including a boxed warning for neutropenia and severe hypersensitivity.

The side effect profile could be a determining factor, especially given the availability of Dendreon's just approved first-line treatment Provenge , as well as less toxic agents in late-stage development, particularly Cougar/Johnson & Johnson's abiraterone, Fernandez added. On the other hand, Provenge's penetration is likely to be limited by supply constraints, the analyst noted.

Sanofi said it is confident in Jevtana's potential, and has trials getting under way in lung, ovarian and breast cancer.

Taxotere is Sanofi's fourth best-selling product with sales of €2.1 billion ($2.5 billion) in 2009. But the product faces patent expiry at the end of 2010. While sales breakdowns are not available, Taxotere's success clearly has been driven by its application in multiple indications. In addition to prostate cancer, the drug is approved in non-small cell lung cancer, breast cancer, gastric cancer and head and neck cancer.

Targeting Area Of High Unmet Need

Approval of Jevtana was supported by the open-label Phase III TROPIC study of 755 patients, in which Jevtana was shown to improve survival in a very tough-to-treat population. Median overall survival for patients receiving Jevtana plus prednisone was 15.1 months compared with 12.7 months for patients receiving the chemotherapy drug mitoxantrone.

Jevtana marks an important achievement for an area in need of clinical advances. Metastatic prostate cancer ultimately becomes resistant to hormone treatment, and no drugs had been cleared for those who progress on Taxotere. Results were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in March and were considered game-changing.

Room To Maneuver On Pricing

After the glowing reception of the TROPIC results at the ASCO symposium, Leerink doubled its pricing assumption for Jevtana to $5,000 per cycle, with each patient receiving four cycles. Taxotere has a "surprisingly low" price of about $3,000 per cycle, with patients typically receiving six cycles, Fernandez noted.

Leerink estimates that of the 2 million men with prostate cancer in the U.S., about 17,000 could be eligible to take Jevtana. Assuming a $5,000 price, Leerink conservatively projected in a March 9 note Jevtana sales of €270 million ($333 million) in 2016. This estimate is for the second-line prostate cancer indication alone.

Fernandez also noted that Sanofi has a "wide berth to operate in, given pricing that we have seen with Provenge." Provenge came with a whopping sticker price of $93,000 per year, surpassing analyst expectations.

In an interview, Paul Chew, Sanofi's chief science officer and chief medical officer for the U.S., declined to comment on the price, beyond saying it would reflect the 14 years of development time and the value the product brings to patients.

Dendreon had argued that the price was on par with other oncology treatments when the four months of survival made possible by the vaccine were taken into account. If Sanofi applied the same logic, 2.4 months of benefit could equate to a $50,000-plus price, Fernandez observed.

Label Includes Extensive Safety Warnings

While extensive side effects are to be expected with cytotoxic drugs, Jevtana's labeling indicates a high range of potentially fatal outcomes and significant requirements for management that could present a barrier to wider use.

There is potential for severe hypersensitivity, including generalized rash/erythema, hypotension and bronchospasm - as detailed in a boxed warning. Consequently, every time cabazitaxel is administered patients must be premedicated 30 minutes prior to treatment with a corticosteroid, an antihistamine and an H2 agonist. Antiemetic prophylaxis also is advised, and labeling calls for monitoring of complete blood counts on a weekly basis; Jevtana should not be administered to patients with low neutrophil counts.

Many of the side effects associated with Jevtana are familiar with chemotherapy, but labeling spells out the degree of severity (including deaths) of neutropenia and diarrhea.

"Five patients experienced fatal infectious adverse events (sepsis or septic shock)," labeling states. The label advises G-CSF may be administered to reduce the risks of neutropenia complications, recommending prophylactic use in high-risk patients.

In a clinical trial, deaths related to diarrhea and electrolyte imbalance also occurred, and labeling states "intensive measures may be required." Renal failure is another risk that can have a fatal outcome.

Safety data were collected from a randomized controlled trial comparing Jevtana with prednisone to mitoxantrone and prednisone in 371 patients with hormone-refractory metastatic prostate cancer. Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5 percent) Jevtana-treated patients compared to 3 (<1 percent) of mitoxantrone-treated patients. The most common fatal adverse reactions in Jevtana-treated patients were infections (5 patients) and renal failure (4 patients). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of Jevtana.

Patients older than 65 were more likely to experience fatal outcomes not related to disease progression and certain adverse reactions, including neutropenia and febrile neutropenia. Older patients need to be monitored closely, the label advises.

Though the risks associated with cabazitaxel are heavy, they are countered by the significance of the efficacy findings: a survival advantage in a population without treatment options.

Approved With Gleevec-like Speed

FDA approval came well before the Sept. 30, 2010, user fee goal date, and the press statement on the approval included a big endorsement from Richard Pazdur, director of the Office of Oncology Drug Products.

"Patients have few therapeutic options in this disease setting. ... FDA was able to review and approve the application for Jevtana in 11 weeks, expediting the availability of this drug to men with prostate cancer," the statement said.

Sanofi's Chew stressed the value his company places on showing a survival benefit for oncology drugs: "The Holy Grail in drug development is increased survival over standard of care. I believe FDA saw this as a significant advance, the first and only drug to provide significant benefit in second-line treatment of hormone resistant prostate cancer."

The swift approval is certainly outstanding - though it has a few precedents in the oncology sphere, such as Novartis' Gleevec , approved in nine weeks.

FDA noted that Sanofi's own Eloxatin (oxaliplatin) for second-line colorectal cancer was approved in only six weeks (6 'The Pink Sheet,' Aug. 13, 2002). Other examples of oncology drugs that had extremely fast reviews include Millennium's Velcade (bortezomib) and Genenetch's Herceptin (trasztuzumab).


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