US FDA opens US market to Regeneron/Sanofi mCRC drug Zaltrap
This article was originally published in Scrip
On schedule, the US FDA on 3 August approved Regeneron Pharmaceuticals’ concentrated form of aflibercept, which will be sold as Zaltrap, as an intravenous infusion treatment in combination with FOLFIRI chemotherapy for adults with metastatic colorectal cancer (mCRC) – giving the company a nice win after its disappointment earlier in the week with the rejection of its gout drug in the US.
Tarrytown, New York-based Regeneron markets another version of aflibercept, a fully human fusion protein, consisting of portions of vascular endothelial growth factor (VEGF) receptors 1 and 2, that binds all forms of VEGF-A along with the related placental growth factor, as a treatment for wet age-related macular degeneration (AMD) – selling that product as Eylea, which won the FDA's endorsement last November (scripintelligence, 21 November 2011).
Regeneron has partnered with Paris-based Sanofi on Zaltrap, with the firms co-commercializing the medicine, which is not expected to run into the same off-label issues as Genentech and its parent company Roche face with their products Lucentis (ranibizumab) and Avastin (bevacizumab).
Avastin, which is approved in the US for various forms of cancer, including mCRC, is derived from a protein similar to Lucentis, which is approved for wet AMD and was specifically designed, developed, formulated and licensed for ocular conditions.
Avastin, however, is widely used off-label by the ophthalmology community in treating wet AMD – costing about $50 per dose, versus the $1,950 for Lucentis. Because Avastin must be compounded into smaller doses for the ocular use, Genentech and Roche and their partner Novartis, which markets Lucentis outside the US, have discouraged the use of the medicine in treating AMD – warning that patients are put at risk for infection and contamination with the compounded formulations.
A thorny issue for those companies has been a much-publicized National Institutes of Health head-to-head study, known as CATT, which found that Avastin was just as effective as Lucentis in treating wet AMD (scripintelligence, 28 April 2011, 2 May 2011, 1 May 2012).
But Regeneron officials have insisted that the same type of switch between Zaltrap and Eylea would not be possible due to the differences in the formulations.
In colon cancer, Zaltrap works as an angiogenesis inhibitor, cutting off the blood supply to tumors. It is intended to be used as a second-line treatment in mCRC patients whose tumors are resistant to or progressed after an oxaliplatin-containing chemotherapy regimen.
Dr Debasish Roychowdhury, senior vice president and head of Sanofi's oncology unit, noted that colorectal cancer is one of the deadliest cancers, responsible for more than half a million deaths globally each year.
Dr Edith Mitchell, a clinical professor of medicine and medical oncology at Thomas Jefferson University in Philadelphia, said there are limited treatment options for mCRC patients resistant to or whose disease has progressed after an oxaliplatin-containing regimen.
"The approval of Zaltrap in combination with a FOLFIRI chemotherapy regimen offers another treatment option and is welcome news for metastatic colorectal patients and their physicians," said Dr Mitchell, who was the lead investigator in Sanofi's and Regeneron's pivotal Phase III VELOUR trial, the study on which the medicine’s approval was based.
The results of the VELOUR trial, a multinational, randomized, double-blind 1,226-patient study, showed that patients with mCRC who received the Zaltrap-FOLFIRI combination lived an average of 13.5 months, versus to 12 months for the FOLFIRI plus placebo group.
Zaltrap’s survival benefit, remarked Roth Capital analyst Dr Joseph Pantginis, compares favorably with Avastin.
The VELOUR results also showed that 20% of patients receiving Zaltrap-FOLFIRI had a reduction in tumor size, versus 11% in the FOLFIRI plus placebo arm.
In addition, patients receiving Zaltrap-FOLFIRI had a progression-free survival of 6.9 months, compared with 4.7 months for those receiving FOLFIRI plus placebo.
RW Baird analyst Christopher Raymond said FOLFIRI dominates second-line mCRC, with the chemotherapy treatment regimen, whether used alone or in combination with Lilly's and Bristol-Myers Squibb's Erbitux (cetuximab), accounting for well over half of second-line patients in the US.
"So when combining this label with the solid survival signal seen in Zaltrap's pivotal data, we think [Regeneron] and partner Sanofi have a nice commercial product on their hands," Mr Raymond declared.
The most common adverse effects observed in study participants receiving Zaltrap-FOLFIRI were decreased white blood cell count, diarrhea, mouth ulcers, fatigue, high blood pressure, increased amount of protein in the urine, weight loss, decreased appetite, abdominal pain and headache.
Regulators emphasized that Zaltrap's approved labeling comes with a black-box warning alerting patients and prescribers that the drug can cause severe and sometimes fatal bleeding, including gastrointestinal bleeding, and the development of holes in the gastrointestinal tract. Zaltrap also can make it more difficult for wounds to heal.
Roth’s Dr Pantginis said the boxed-warning appears to be similar to Avastin's.
He pointed out that under a 2003 deal, Regeneron must repay 50% of the development costs for Zaltrap to Sanofi, which had footed the bill during the development process.
Dr Pantginis noted that the development expenses for Zaltrap were $875 million at the end of 2011.
As such, said Baird's Mr Raymond, "it will likely be some time before Zaltrap contributes meaningfully" to Regeneron's bottom line.
Under the partnership, the Paris firm had paid Regeneron $125 million up front, of which $45 million was an investment in newly issued common stock, with the remaining in cash.
Another $25 million was linked to early clinical milestones, while $360 million was hinged on the receipt of marketing approvals for up to eight indications in Europe and the US.
The companies are equally sharing the promotion rights and profits and losses globally.
In a December 2005 amended deal, Regeneron received an additional up-front payment of $25 million from Sanofi for the Japanese rights to Zaltrap.
Mr Raymond noted that Zaltrap's approval makes it the third product Regeneron will have on the US market, with Eylea's win last year and Arcalyst (rilonacept), which gained the FDA's OK in February 2008 as a treatment for cryopyrin-associated periodic syndrome, which consists of two inherited disorders – familial cold auto-inflammatory syndrome and Muckle-Wells syndrome – which affect about 300 people in the US.
Arcalyst is the drug that got the thumbs down earlier in the week for a second indication of preventing gout flares in patients initiating uric acid-lowering therapy (scripintelligence, 31 July 2012).
So Zaltrap's approval was something for investors to celebrate, although shares of Regeneron got only a small bump on 3 August, rising as high as $4.71, or 3.6%, before closing at $136.96, up 49 cents.
Nonetheless, Baird's Mr Raymond said Zaltrap's approval was a "nice complement to what is rapidly becoming one of biotech's best commercial stories."
Dr Pantginis said the key value driver for Regeneron remains its "impressive momentum" behind Eylea's launch, with the drug's sales likely bolstered when it gets ex-US approval and potential labeling expansions in central retinal vein occlusion and diabetic macular edema.
He also projected steady growth for Regeneron based on sustained positive news flow from the broad antibody pipeline, punctuated by Sanofi's expansive ODYSSEY program, which is expected to involve about 10 Phase III studies and 22,000 patients for REGN727, an anti-PCSK9 antibody for cholesterol control.