Sanofi-Aventis US LLC plans to make its newly approved metastatic colorectal cancer treatment Zaltrap (ziv-aflibercept) available “as soon as possible in the coming weeks,” but with poor expectations for the angiogenesis inhibitor, it may take a long time for the company and partner Regeneron Pharmaceuticals Inc. to see real benefit to their bottom line.

FDA approved Zaltrap Aug. 3 to be used in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. The drug is a recombinant fusion protein that targets vascular endothelial growth factor (VEGF)-A and -B and placental growth factor.

Colorectal cancer is the third most common cancer in both men and women in the U.S., Sanofi reports. The American Cancer Society estimates more than 143,000 new cases will be diagnosed in 2012, and more than 51,000 people will die from it, according to the company. Approximately 60% of colorectal cancer cases are diagnosed at the locally advanced or metastatic stage. “Although survival for early stage disease is relatively high, once colorectal cancer metastasizes to distant organs, five-year survival is estimated to be 12%,” it adds. However, there are numerous treatment options for metastatic colorectal cancer.

Zaltrap must contend with established therapies including Bristol-Myers Squibb Co. and Eli Lilly & Co.'s EGFR inhibitor Erbitux (cetuximab), Amgen Inc.'s EGFR inhibitor Vectibix (panitumumab) and Genentech Inc.'s VEGF inhibitor Avastin (bevacizumab).

Zaltrap showed a 1.5 month survival advantage in the second-line VELOUR trial, with patients on Zaltrap plus FOLFIRI having median survival of 13.5 months compared to 12 months for the FOLFIRI/placebo arm. Progression-free survival was 6.9 months for the Zaltrap arm versus 4.7 months for placebo. “A reduction in tumor size occurred in 20% of patients receiving the Zaltrap plus FOLFIRI combination versus 11% for those receiving FOLFIRI plus placebo,” FDA’s approval announcement states.

The second-line setting is Zaltrap’s best chance for penetration Also see "Survival Benefit May Position Zaltrap To Compete With Avastin In Second-Line CRC" - Pink Sheet, 27 April, 2011..

Avastin showed a 2.2 month advantage in overall survival in an open-label second-line mCRC trial, but it is far more commonly used in mCRC as front-line therapy. In a double-blind study in the first-line setting, bevacizumab had a 4.7 month advantage in OS and a 4.4 month advantage in PFS compared to chemo alone. Erbitux plus chemo had a 1.5 month survival benefit in previously treated patients against chemo alone. In the first-line setting, Erbitux showed a 0.8 month advantage in PFS and no statistically significant difference in OS compared with FOLFIRI alone. For Vectibix, there was a statistically significant advantage for the drug in PFS, but none for OS, in a trial of previously treated patients. Similar results were seen in first-line. [Correction: Vectibix did show a significant advantage in PFS in first-line mCRC patients with wild-type KRAS. This article originally stated it did not meet that endpoint.]

Label ing featuring a boxed warning for Zaltrap is similar to prescribing information for fellow angiogenesis inhibitor Avastin; for both drugs, prescribers are advised to watch out for hemorrhage, gastrointestinal perforation and compromised wound healing.

$150 Million In Sales?

Given the other approved drugs for mCRC, the market for Zaltrap may be more modest than Sanofi or Regeneron would wish.

Deutsche Bank’s Robyn Karnauskas expects worldwide sales of Zaltrap will peak at only about $150 million. Although they have built Zaltrap sales into their model for Regeneron, “our model assigns no value to this asset as REGN will have to start repaying 50% of Zaltrap development expenses in all cancers as soon as this business becomes profitable. Combined Zaltrap expenses were $763M at year end 2011.”

Regeneron will share half of expenses upon profitability, Karnauskas noted. “The reimbursement payment in any quarter will equal 5% of the then outstanding repayment obligation, but never more than REGN's share of the Zaltrap profits in the quarter unless REGN elects to reimburse Sanofi at a faster rate.”

Sanofi said pricing for Zaltrap has not yet been set. The company will put approximately 150 sales reps behind the drug in the U.S.

Aflibercept was approved as Eylea last November for wet age-related macular degeneration Also see "Regeneron Plays It Safe With Eylea, Aims To Undercut Lucentis" - Pink Sheet, 21 November, 2011.. But Karnauskas points out that Sanofi/Regeneron will avoid the off-label substitution problem Genentech has with its oncology/ophthalmology VEGF inhibitors Avastin and Lucentis (ranibizumab), as the Zaltrap formulation cannot be used in the eye.

The drug is also scheduled to undergo a Phase II/III trial in patients with resectable liver metastases.

Market For Sanofi And Regeneron’s Zaltrap Could Be Limited

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