Novartis AG’s lung cancer treatment Zykadia (ceritinib) can claim the early title for the fastest approval among novel drugs designated as “breakthrough therapies” by FDA.

FDA granted accelerated approval to ceritinib (previously known as LDK378) on April 29, four months ahead of the Aug. 24 user fee goal date. The NDA was submitted in December and was undergoing a priority review ([A#14140129007]).

Ceritinib’s four-month review bested the previous record for first-time approval of a breakthrough-designated product set by Janssen Biotech Inc./Pharmacyclics Inc.’s Imbruvica (ibrutinib), which was approved for treatment of mantle cell lymphoma following a review that lasted four-and-a-half months ([A#14131113009]).

A one-month supply of Zykadia will cost $13,497.

Ceritinib is an oral, anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor. It is approved for treatment of patients with ALK-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to Pfizer Inc.’s ALK inhibitor Xalkori (crizotinib). FDA approved crizotinib in August 2011 following a five-month review Also see "Pfizer's Crizotinib Eases Past FDA With Targeted Population" - Pink Sheet, 26 August, 2011..

For Novartis, the super-speedy ceritinib approval comes on the heels of its announced plans for expansion in the oncology area by acquiring GlaxoSmithKline PLC’s cancer drug business ([A#14140422001]).

Novartis said Zykadia is expected to be available through a number of specialty pharmacies within a few weeks of approval. The U.S. wholesale acquisition cost of a one-month supply at a daily dose of 750 mg will be $13,497, and the company has several patient assistance programs in place for those with and without insurance.

Speedy Approvals Not Guaranteed

The breakthrough therapy program created in the FDA Safety and Innovation Act is aimed at speeding the development of new treatments for serious medical conditions where early clinical evidence suggests they may offer a substantial improvement over available therapies. The designation entitles the sponsor to intensive guidance from the agency, with FDA committing to bring an “all hands on deck” approach.

Through April 18, 150 requests for breakthrough status had been submitted to the Center for Drug Evaluation and Research, of which 42 were granted and 72 were denied.

To date, CDER has approved four novel products (including ceritinib) and two supplemental indications carrying breakthrough status. Since the program is aimed at shortening development time, its benefits have not always been obvious on the review time metrics for some of the earliest products approved because development was well underway at the time the designation was granted.

For example, it took FDA six months – the same amount of time as an old-school priority review – to review Genentech Inc.’s leukemia drug Gazyva (obinutuzumab), which was the first approval under the breakthrough program ([A#14131101002]).

Gilead Sciences Inc.’s hepatitis C drug Sovaldi (sofosobuvir) also didn’t break any speed records, taking a full eight months for its priority review. However, Sovaldi did not receive breakthrough status until late in the review process, and the designation did enable the agency to fully review new data from two studies that supported a broad label for the nucleotide analog NS5B polymerase inhibitor and an on-time approval ([A#00140414006]).

[Editor’s note: This story was updated May 5, 2014 to reflect the correct number of approved supplemental indications carrying breakthrough status as two, not three. Also, an incorrect statement regarding FDA’s review of Vertex’s sNDA for Kalydeco was removed from the story; the review took approximately five months, not two months as reported.]

Benefits Early In Development

In contrast to Gazyva and Sovaldi, Zykadia gained breakthrough status early in development, and this likely aided the drug’s quick path to market.

Novartis announced in March 2013 that it had received breakthrough designation for the compound. At that time, the company highlighted results from a Phase I study investigating the maximum tolerated dose, safety, pharmacokinetics and antitumor activity of LDK378 in 88 patients with ALK+ advanced malignancies. The response rate among patients who had experienced disease progression after crizotinib treatment was 80% Also see "Novartis Counting On Depth Of Insight To Continue Success In Oncology" - Pink Sheet, 29 July, 2013..

Novartis said accelerated approval was based on results from a single-arm, open-label trial of 163 patients with metastatic ALK+ NSCLC who progressed on or were intolerant to treatment with crizotinib. The most common sites of metastases in the patient population studied were brain (60%), liver (42%) and bone (42%).

Patients were given a ceritinib dose of 750 mg once daily. The overall response rate was 54.6%, and the median duration of response of 7.4 months.

Two Phase II, single-arm trials in previously treated and treatment-naïve ALK+ NSCLC are ongoing and fully enrolled. In addition, two Phase III trials comparing ceritinib with chemotherapy in treatment-naïve and previously treated patients are underway.

Press releases from both FDA and Novartis hailed the speed at which ceritinib was able to come to market.

“Today’s approval illustrates how a greater understanding of the underlying molecular pathways of a disease can lead to the development of specific therapies aimed at these pathways,” FDA Office of Hematology and Oncology Products Director Richard Pazdur said. “It also demonstrates the FDA’s commitment to working cooperatively with companies to expedite a drug’s development, review and approval, reflecting the promise of the breakthrough therapy designation program.”

"The approval of Zykadia less than three-and-a-half years after the first patient entered our clinical trial exemplifies what is possible with a highly focused approach to drug development and strong collaboration," said Alessandro Riva, president of Novartis Oncology ad interim and global head for Oncology Development and Medical Affairs. "The dedication of clinical investigators, patients, the FDA and others has enabled us to bring this medicine to patients in need as swiftly as possible."

Novartis’ Zykadia Sets New “Breakthrough” Speed Record For NME Review

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