Vertex's Cystic Fibrosis Drug Kalydeco Could See Speedy Review

High unmet medical need, a genetically targeted patient population and the drug's biological rationale could combine for a faster-than-six-month approval for the novel, disease-modifying therapy.

Vertex Pharmaceuticals' groundbreaking cystic fibrosis therapy Kalydeco (VX-770, ivacaftor) has the potential for quick passage through FDA given the given the disease's high unmet medical need, small, targeted patient population and the biological rationale underpinning the compound.

Vertex announced on Oct. 19 that it has submitted an NDA for VX-770 with a request for priority review. If a six-month priority review is granted, the user fee date would fall around mid-April.

Kalydeco could become the first disease-modifying agent for CF, an inherited orphan disease that affects about 30,000 people in the U.S. The mean predicted age for survival is approximately 38 years, Vertex said.

Whereas currently available therapies only treat the symptoms of CF, Kalydeco targets a malfunctioning protein responsible for the disease.

Quick Reviews For Breakthrough Therapies

FDA has shown a willingness to expedite approval of novel, breakthrough therapies faster than even the six-month target under the priority review clock, with several recent examples seen in the oncology setting and with genetically targeted therapies.

Pfizer's non-small cell lung cancer therapy Xalkori (crizotinib) was approved in August, less than five months after NDA submission. The ALK inhibitor is indicated for treatment of patients who express the abnormal anaplastic lymphoma kinase gene, who can be identified with a companion diagnostic (Also see "Pfizer's Crizotinib Eases Past FDA With Targeted Population" - Pink Sheet, 26 Aug, 2011.).

Earlier that same month, FDA approved Roche/Genentech's metastatic melanoma therapy Zelboraf (vemurafenib) for patients with the V600E BRAF mutation selected by a companion diagnostic; that review took all of 3.6 months (Also see "Zelboraf Approval Hastened By FDA Officials Impressed With Early Efficacy" - Pink Sheet, 22 Aug, 2011.).

Two recent approvals in hormone-refractory prostate cancer also came in well under the six-month target: Johnson & Johnson's Zytiga (abiraterone) was cleared in April after a 4.3-month review, while Sanofi's Jevtana (cabazitaxel) was approved in June 2010 after a mere 2.6 months had passed on the FDA review clock.

Strong Phase III data for Kalydeco, coupled with the drug's disease-modifying approach and a small, genetically targeted population, would seem to create a positive environment for a speedier-than-usual review.

However, it is possible that Kalydeco's novelty could work against it, as well. The first-in-class nature of the CF potentiator could give the agency some pause, as an advisory committee likely would be convened to consider the new molecular entity. As part of user fee negotiations, industry has noted that holding an advisory committee and meeting a priority review goal is difficult - an observation previously made by Office of New Drugs Director John Jenkins (Also see "PDUFA Negotiations Focus On Review Delays; Firms, FDA See Different Causes" - Pink Sheet, 6 Sep, 2010.).

Targeting A Genetic "Gating" Defect

Kalydeco is only the second NDA submitted by Vertex. The company's protease inhibitor Incivek (telaprevir) was approved in May for hepatitis C (Also see "Vertex Prices Telaprevir At $49,200 For Course Of Therapy" - Pink Sheet, 23 May, 2011.).

Vertex is seeking approval of Kalydeco in CF patients ages six years and older who have at least one copy of the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the U.S., approximately 4% of CF patients - or roughly 1,200 people - carry the G551D mutation, Vertex said.

The company said the G551D mutation is the most common "gating" defect among CF patients, whereby the CFTR proteins are present at the cell surface but do not function properly. Kalydeco is designed to keep the CFTR channels at the cell surface open longer to improve the transport of chloride ions across the cell membrane in patients with gating mutations.

A gating defect differs from a more common type of genetic mutation known as a trafficking defect, whereby proteins have trouble reaching the cell surface. The most common of these mutations is the F508del mutation, which is found in more than 80% of the U.S. CF population.

The NDA submission includes data from the Phase III STRIVE and ENVISION studies in adults and children with the G551D mutation, and the Phase II DISCOVER study in patients with the F508del mutation.

In STRIVE, patients treated with VX-770 showed a mean absolute improvement in lung function of 10.6% through 24 weeks and 10.5% through 48 weeks. The mean relative improvement from baseline in lung function was 16.9% through week 48, according to Vertex.

In the ENVISION study of patients ages six to 12 years old, the difference in mean absolute improvement from baseline in lung function was 12.5% at 24 weeks, and this was maintained over 48 weeks, Vertex said (Also see "CF Patients Breathe Easier With Vertex Drug" - Pink Sheet, 23 Feb, 2011.).

The Phase II DISCOVER study was designed primarily to provide additional safety data for VX-770. The trial enrolled CF patients 12 years and older carrying the F508del mutation. Improvements in lung function observed with VX-770 were not considered clinically meaningful.

Vertex also is conducting a two-part Phase II study designed to evaluate multiple combination regimens of VX-770 with VX-809, a CFTR corrector that aims to improve function by increasing the movement of CFTR to the cell surface. The study is being conducted in patients with the F508del mutation.

Both compounds, as well as a third agent known as VX-661, are being developed through a research collaboration with the Cystic Fibrosis Foundation.

In an Oct. 19 note commenting on the NDA submission, J.P. Morgan analyst Geoff Meacham said that given the unmet medical need and the robust ENVISION/STRIVE data, speedy approval of Kalydeco seems likely.

"Our sense from speaking to physicians is that there is a lot of excitement for Kalydeco for G551D patients," he writes. "The big question is the extent of off-label use in patients with 'gating mutations' and to a lesser degree patients with the F508del mutations."

Concerns about off-label use have been known to slow things down at FDA.

-Sue Sutter ([email protected])