It appears that precision medicine, big data and next-generation sequencing together with breakthrough technologies in immuno-oncology, gene therapy and gene editing have a long way to go before their full impact is fully expressed in terms of the discovery and market approval of new 21st century medicines. The return on research investments was below par this year, as measured by the number of new molecular entities (NMEs) that received the FDA's green light.

In fact, only 21 medicines have made it over the goal line this year, the fewest number approved since 2010. (See NME Approvals, 2004-2016, right, and New Molecular Entities Approved by the FDA in 2016, below.)

Why the slowdown? Certainly, it was not due to a decrease in the number of applications. In posted data from a presentation given at the FDA/CMS Summit earlier this month, Office of New Drugs, Center for Drug Evaluation and Research (CDER) Director John Jenkins noted that 36 NME applications were received by the agency up to Dec. 9, and that was just above the 35 average annual number of NME filings during the past decade. The data did show that five NMEs with decision dates scheduled for this year got the green light early and were approved in 2015. In addition, there was an increase in the number of complete response letters (CRLs) that were issued. According to analysis conducted by BioWorld, 31 CRLs have been issued in 2016, with 12 relating to NMEs. (See BioWorld Today, Dec. 19, 2016.)

In 2015, just two NMEs received a CRL letter. While the number of NMEs this year could have been higher if not for the CRLs and early approvals, the fact remains that innovation continues to be a challenge for the industry. The FDA has done its part "to facilitate and expedite development and review of new drugs" with the introduction of four programs: fast track designation, breakthrough therapy designation, accelerated approval and priority review designation. The industry now has to take advantage. Given the number of high-profile biopharma-related research initiatives that have been launched in the U.S. and Europe during the past couple of years and the recent passage of the 21st Century Cures Act, all the pieces are in place for a much higher run rate of NMEs in the future.

Accelerating approval

The 21st NME to be approved this year was Clovis Oncology Inc.'s Rubraca (rucaparib) therapy for advanced ovarian cancer. The PARP inhibitor targets about 15 to 20 percent of ovarian cancer patients who have the BRCA mutation, and Rubraca received accelerated approval for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have the BRCA mutation as identified by an FDA-approved companion diagnostic, Foundation Medicine Inc.'s Foundationfocus CDxBRCA – it marked the first next-generation-sequencing-based companion diagnostic.

The safety and efficacy of Rubraca were studied in two, single-arm clinical trials involving 106 participants with BRCA-mutated advanced ovarian cancer who had been treated with two or more chemotherapy regimens. Fifty-four percent of the participants who received the drug in the trials experienced complete or partial shrinkage of their tumors lasting a median of 9.2 months.

The approval represents an "example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient's genes," commented Richard Pazdur, director of the Office of Hematology and Oncology Products at CDER.

targeted medicines trending

Rubraca was, in fact, the third targeted medicine to be approved for marketing in this year's crop of new medicines. Venclexta (venetoclax) from Abbvie Inc. received FDA accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. According to the National Cancer Institute, the chromosomal abnormality occurs in approximately 10 percent of patients with untreated CLL and in approximately 20 percent of patients with relapsed CLL. The deletion is pinpointed by way of a companion diagnostic test called the Vysis CLL FISH (fluorescence in situ hybridization) probe kit, developed by Abbott Molecular Inc., of Des Plaines, Ill. (See BioWorld Today, April 13, 2016.)

The new medicine becomes the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and has found to be overexpressed in many patients with CLL.

Accelerated approval was also granted to Genentech Inc.'s bladder cancer immunotherapy, Tecentriq (atezolizumab), the first PD-1/PD-L1 inhibitor approved to treat advanced urothelial carcinoma, the most common type of bladder cancer. Treatment will be directed by the Ventana Medical Systems' companion diagnostic PD-L1 (SP142) assay, which becomes the first test to detect PD-L1 protein expression levels on tumor-infiltrating immune cells by staining and scoring the cells within the tumor microenvironment. (See BioWorld Today, May 19, 2016.)

In all, six medicines received the accelerated approval designation, including Eli Lilly and Co.'s Lartruvo (olaratumab) with doxorubicin to treat adults with certain types of soft tissue sarcoma, There was also Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis, a rare, chronic and gradually progressive liver disease, in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA. The orally delivered drug, binds to the farnesoid X receptor, which is a key regulator of bile acid metabolic pathways. Ocaliva increases bile flow from the liver and suppresses bile acid production in the liver, thus reducing the exposure of the liver to toxic levels of bile acids.

Image is everything

Interestingly, two diagnostic imaging products were approved this year. Advanced Accelerator Applications SA can now market its Netspot, a kit for the preparation of gallium Ga 68 dotatate injection, a radioactive diagnostic agent for positron emission tomography (PET) imaging. That radioactive probe will help locate tumors in adult and pediatric patients with the rare condition, somatostatin receptor positive neuroendocrine tumors, or NETs.

Axumin, a radioactive diagnostic agent for injection from Blue Earth Diagnostics Ltd., was approved for PET imaging in men with suspected prostate cancer recurrence based on elevated prostate-specific antigen levels following prior treatment.

FDA performing well

The statistics presented by Jenkins shows that the agency is meeting its goals. For example, 95 percent of the novel drugs approved in 2016 met their PDUFA goal dates for the approval review cycle. Other data showed that of the 19 NMEs up until Dec. 9, 68 percent were approved under priority review status; 32 percent received breakthrough therapy designation; 37 percent received fast track designation; and 37 percent of the medicines are for rare diseases.

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