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Supplemental New Drug Application in Residual Function Mutations

The FDA set a target review date of February 7, 2016 for its decision regarding a supplemental New Drug Application for the use of KALYDECO in people ages two and older with one of 23 residual function mutations. The sNDA was based on preclinical data for ivacaftor in certain residual function mutations, the established clinical profile of KALYDECO and on previously reported data from an exploratory Phase 2a study. Eight of the 23 mutations proposed for approval in the sNDA were represented in the Phase 2a study. More than 1,500 people with CF in the U.S. ages two and older have the mutations represented in the sNDA.
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Source: press release, 1/27/16. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=952025

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October 7, 2015

Supplemental New Drug Application for Use of KALYDECO® (ivacaftor) in People with Cystic Fibrosis Ages 2 and Older who have One of 23 Residual Function Mutations Accepted for Priority Review by U.S. FDA

-More than 1,500 people with CF are ages two and older and have one of these 23 residual function mutations in the U.S.-

BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the U.S. Food and Drug Administration (FDA) has accepted for review a supplemental New Drug Application (sNDA) for the use of KALYDECO® (ivacaftor) in people with cystic fibrosis (CF) ages 2 and older who have one of 23 residual function mutations. The FDA granted Vertex's request for Priority Review of this sNDA, and a target review date of February 6, 2016 was set under the Prescription Drug User Fee Act (PDUFA) for the FDA's decision on the sNDA. The submission was based on preclinical and clinical data showing the effect of ivacaftor on CFTR function in certain residual function mutations.

"Given the severity of cystic fibrosis, we are committed to getting KALYDECO to more people as quickly as possible," said Jeffrey Chodakewitz, M.D., Executive Vice President and Chief Medical Officer at Vertex. "Based on the established safety profile of KALYDECO and our increasing understanding of the biology of these specific residual function mutations and their response to ivacaftor, we believe that people with these mutations would benefit from treatment with this medicine."

The sNDA was based on preclinical data for ivacaftor in the 23 residual function mutations, the established clinical profile of KALYDECO and on previously reported data from an exploratory Phase 2a study in 24 people with residual function mutations. In 19 of the 24 patients enrolled in this study, 8 of the 23 mutations proposed in the sNDA were represented.

CF is caused by defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) proteins resulting from mutations in the CFTR gene. The defective or missing proteins result in poor flow of salt (chloride) and water into and out of the cell in a number of organs, including the lungs. Chloride transport is a marker of the function of the CFTR protein at the cell surface. KALYDECO is currently approved to treat people with CF ages 2 and older who have one of 10 mutations in the CFTR gene (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H). As with the mutations for which KALYDECO is currently approved, the 23 residual function mutations in the sNDA are known to have some CFTR protein at the cell surface and have shown in vitro increases in chloride transport in response to ivacaftor in cells expressing the CFTR form produced by each mutation, characteristics associated with clinical response to KALYDECO. Similar to the R117H mutation for which KALYDECO was previously approved, these 23 mutations result in a moderate loss of CFTR chloride transport, and people with these mutations generally have progressive lung function decline and other complications of CF.

There are more than 1,500 people ages 2 and older with CF in the United States who have one of the 23 residual function mutations included in the sNDA. The 23 residual function mutations included in the sNDA are: 2789+5G- > A, 3849+10kbC- > T, 3272-26A- > G, 711+3A- > G, E56K, P67L, R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, and D1270N.
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Source: press release, 10/07/15. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=935666

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
KALYDECO (Ivacaftor) (VX770)Medical GeneticsCystic FibrosisCFTR protein potentiatorCFTR protein

Mechanism of action: KALYDECO (Ivacaftor) (VX770), an investigational oral potentiator, is designed to act directly on the malfunctioning CFTR protein to help restore the balance of salt and water.

Phase of Development: Filed

Event Type: Regulatory FDA: PDUFA DATE

Dates: 2016-02-07

Results:

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February 5, 2016
Vertex Receives Complete Response Letter from U.S. FDA for Use of KALYDECO® (ivacaftor) in People with Cystic Fibrosis Ages 2 and Older with One of 23 Residual Function Mutations
BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that it received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) for its supplemental New Drug Application (sNDA) for the use of KALYDECO® (ivacaftor) in people with cystic fibrosis (CF) ages 2 and older who have one of 23 residual function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The FDA determined that it cannot approve the application in its present form. Vertex plans to meet with the FDA to determine an appropriate path forward.

"Our intention with this submission was to rapidly bring KALYDECO to additional people with CF who we believe may benefit," said Vertex Executive Vice President and Chief Medical Officer, Jeffrey Chodakewitz, M.D. "We chose to pursue this approach given our strong belief in the science of CF and in the well-established safety of KALYDECO across many different groups of people with CF. We are disappointed by this decision and look forward to discussing with the FDA the next steps to bring KALYDECO to people with CF who have these residual function mutations."

The sNDA is based on preclinical data for ivacaftor in residual function mutations, the established clinical profile of KALYDECO and on previously reported data from an exploratory Phase 2a study. In 19 of the 24 patients enrolled in this study, eight of the 23 mutations proposed in the sNDA were represented.

CF is caused by defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) proteins resulting from mutations in the CFTR gene. The defective or missing proteins result in poor flow of salt (chloride) and water into and out of the cell in a number of organs, including the lungs. Chloride transport is a marker of the function of the CFTR protein at the cell surface. KALYDECO, which received the FDA's Breakthrough Therapy Designation in 2013, is currently approved in the U.S. to treat people with CF ages 2 and older who have one of 10 mutations in the CFTR gene (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H). As with the mutations for which KALYDECO is approved, this group of 23 residual function mutations is known to have some functional CFTR protein at the cell surface. This submission was also based on observed in vitro increases in chloride transport in response to ivacaftor in cells expressing CFTR. The presence of CFTR protein at the cell surface and increases in chloride transport are characteristics associated with clinical response to KALYDECO.

There are more than 1,500 people ages two and older with CF in the United States who have one of the 23 residual function mutations included in the sNDA. The 23 residual function mutations included in the sNDA are: 2789+5G- > A, 3849+10kbC- > T, 3272-26A- > G, 711+3A- > G, E56K, P67L, R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, and D1270N.
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Source: press release, 2/05/16. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=953584

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