It has been just over a year since the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed into law. Contained within the act is a breakthrough therapy (BT) designation, intended to expedite the development and review of drug candidates, which has certainly found favor among biopharmaceutical companies.

The agency received almost 100 applications to date according to information published on the website. The Center for Drug Evaluation and Research (CDER) reports that between Oct. 1, 2012 and Sept. 6. 2013 it had 83 requests for BT designation and 26 of them were granted and 34 denied. The Center for Biologics Evaluation and Research (CBER) has had 10 requests to date in FY 2013 and of these eight were denied.

The data on the BT designation show that the bar for granting requests has been set high. To qualify as a breakthrough therapy, a drug must be intended to treat a serious condition and have preliminary clinical evidence indicating that it may demonstrate a substantial improvement on a clinically significant endpoint over other available therapies. (See BioWorld Today, June 26, 2013.)

Fast-Track Advantages Plus Guidance

Candidates deemed breakthrough therapies will get the advantages offered by fast-track designation – i.e., expedited development/review and rolling review – plus intensive guidance on efficient drug development during the investigational new drug process, beginning as early as Phase I.

Most of the companies that reported they have received a breakthrough therapy designation for one or more of their candidate products are large biotechs or pharmaceutical firms. However, Syndax Pharmaceuticals Inc., of Waltham, Mass., broke that mold recently, becoming one of the very few small private biotech firms to achieve such recognition. (See BioWorld Today, Sept. 12, 2013.)

The company received BT designation for its lead product entinostat to treat locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer when added to exemestane in postmenopausal women whose disease has progressed following non-steroidal aromatase inhibitor therapy. Entinostat is an investigational histone deacetylase inhibitor (HDACi) set to begin Phase III testing in combination with exemestane in postmenopausal women with metastatic ER+ breast cancer who have progressed on hormonal therapy.

“We are very honored and excited to have been awarded the designation,” Arlene Morris, CEO of Syndax, told BioWorld Insight.

The decision, she said, was based on data from its completed Phase II ENCORE 301 study, in which entinostat was shown to extend both progression-free survival and overall survival when added to exemestane in post-menopausal women with ER+ metastatic breast cancer whose cancer had progressed after treatment with a nonsteroidal aromatase inhibitor and with a very acceptable tolerability profile.

User Friendly

It was “a very user friendly process with the FDA rendering their decision within 60 days of the submission of our package of data,” Morris added.

One of the benefits that will accrue from having the designation is that it should expedite patient enrollment for the company’s planned Phase III testing of entinostat because physicians and their patients will be encouraged that the drug’s therapeutic potential has been validated in women with advanced breast cancer.

Another important benefit Morris noted is the increased attention the FDA will provide to the company in its ongoing dialog about the forthcoming trial. The designation gives a “special focus” for the agency who flagged it as an important potential therapy that could change practice.

The FDA indicated it plans to expedite the development and review of breakthrough drugs by “intensively involving senior managers and experienced review staff in a proactive collaborative, cross-disciplinary review,” where appropriate.

Syndax will begin enrolling patients for its Phase III study in the first quarter of 2014 and plans for the trial are currently being developed by the ECOG-ACRIN Cancer Research Group, which would conduct the study under the sponsorship of the Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI).

Larger Companies Gain, Too

Among the larger companies to receive BT designation recently is Boehringer Ingelheim Pharmaceuticals Inc., of Ridgeview, Conn., part of Boehringer Ingelheim GmbH, for volasertib, an investigational inhibitor of polo-like kinase (Plk), being evaluated for the treatment of patients aged 65 or older with previously untreated acute myeloid leukemia (AML), and ineligible for intensive remission induction therapy.

“This FDA breakthrough therapy designation provides Boehringer Ingelheim the opportunity to engage in an ongoing dialogue with the FDA to help expedite the development of volasertib as a potential treatment option for these patients with AML,” Sabine Luik, senior vice president, Medicine & Regulatory Affairs, U.S. Regional medical director, said in a release.

Results from a Phase II study, in newly diagnosed patients with AML considered ineligible for intensive remission induction therapy, demonstrated higher rates of objective response and an improvement in event-free survival in patients receiving volasertib in combination with low-dose cytarabine (LDAC) compared to patients receiving LDAC alone. This data led to the start of a Phase III trial, to assess the efficacy and safety of volasertib in combination with LDAC, compared to placebo in combination with LDAC, in patients aged 65 or older with previously untreated AML, ineligible for intensive remission induction therapy. The trial is currently enrolling eligible patients. (See BioWorld Today, Sept. 18, 2013.)

Also last week Genmab A/S, of Copenhagen, Denmark, and Glaxosmithkline plc, of London, received BT designation for Arzerra (ofatumumab) in combination with chlorambucil to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior treatment and are inappropriate for fludarabine-based therapy. The designation was based on the results from an international, multicenter, randomized Phase III clinical trial in more than 400 patients with previously untreated CLL.

Both of Genmab’s lead products, ofatumumab and daratumumab, have now been granted BT designations from the FDA. Daratumumab was granted BT designation for multiple myeloma in May.

In April, Merck & Co. Inc., of Whitehouse Station, N.J., reported that the FDA had designated lambrolizumab (MK-3475) as a BT for the treatment of patients with advanced melanoma. Lambrolizumab is Merck’s investigational antibody therapy targeting programmed death receptor that is currently being evaluated for the treatment of patients with advanced melanoma, and other tumor types. (See BioWorld Today, April 25, 2013.)