FDA Issues Complete Response Letter for Immunotherapy MCNA in Bladder Cancer

Michael J. Berendt, PhD

The FDA issued a complete response letter to Telesta Therapeutics informing the company that its biologics license application (BLA) for MCNA in bladder cancer would not be approved and that an additional phase III clinical trial was needed to adequately evaluate the immunotherapy.

In August 2015, the FDA assigned a priority review designation to MCNA as a treatment for patients with high-risk non-muscle invasive bladder cancer following first-line bacillus Calmette-Guérin (BCG) therapy, with an action date scheduled for February 27, 2016. However, the regulatory agency subsequently called for the BLA for MCNA to be discussed at a joint committee meeting of 2 of its advisory panels: ODAC and the Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC).

At the advisory hearing, panel members voted 18-6 against recommending approval of MCNA. The BLA the panel considered was primarily based on findings from the open-label phase III trial EN3348-301 (Study 301).

In Study 301, 25% of patients treated with MCNA remained disease-free at 1-year, and at 2-years, the disease-free survival (DFS) rate was 19%. However, the primary endpoint of the study was a 1-year DFS rate of ≥40%. Additionally, the FDA, using a responder landmark analysis, calculated a 1-year DFS of 20.9%, also lower than the primary endpoint.

"We are very disappointed with the FDA's decision. Since we began our dialogue with the FDA in February, 2014, we have clearly communicated that we believe that MCNA is a safe and efficacious agent for the treatment of high risk non-muscle invasive bladder cancer patients who have failed frontline BCG therapy,” Michael J. Berendt, PhD, CEO and chief scientist at Telesta Therapeutics, the company developing the immunotherapy, said in a statement. “The FDA decision, at this point, to require an additional clinical trial, is a setback for underserved bladder cancer patients.”

Study 301 included 129 patients who were treated with an induction dose of MCNA at 8 mg weekly. After 3 months of induction therapy, those who remained disease-free went on to receive a maintenance dose from months 3 to 24. In this portion of the study, MCNA was given in 3 weekly installments every 3 months.

Of the patients enrolled, 91 had carcinoma in situ (CIS) with or without papillary disease and 38 had papillary only tumors. Of note, an FDA review of baseline pathology reports found discrepancies between local and central pathology reports, most frequently being that central pathology identified more subjects with CIS and papillary disease. The FDA’s final determination comprised 93 CIS-containing patients and 36 that were papillary only.

Most patients in Study 301 had high-risk disease: 107 were BCG-refractory, 22 were BCG relapsing. The FDA analysis of BCG relapsing/refractory status determined an identical breakdown.

At a median 34.7-month follow-up in Study 301, the median disease-free duration in responders was 32.7 months. The progression-free survival (PFS) rate at 1-year was 87.3%. At years 2 and 3, the PFS rate with MCNA was 79.8% and 77.7%, respectively.

The FDA’s analysis included efficacy results among patient subgroups. Specifically, the 1-year DFS was 17% and 10%, respectively, among CIS-containing and papillary-only patients. In the CIS-containing group, the complete response rate was 27%, with a median response duration of 15.1 months. One-year DFS rates were 19% and 8%, respectively, among BCG-refractory and BCG-relapsing patients.

The safety data considered during the FDA joint-committee session included 129 patients from study 301 and 37 subjects from Study 303 who received at least 1-dose of MCNA. The phase III randomized Study 303 was designed to compare MCNA with mitomycin C in patients with non-muscle invasive bladder cancer; however, the trial was stopped early in November 2012 due to logistic issues.

Ninety-two percent of patients in study 301 had at least 1 adverse event (AE) of any grade, with 14% of patients having serious AEs. There were 3 treatment-emergent deaths, but none related to MCNA instillation.

Hematuria (36.4%), dysuria (32.6%), fatigue (21.7%), UTI (19.4%), pollakiuria (17.8%), and micturition urgency (13.2%) were the most common treatment-emergent AEs with MCNA.

MCNA-related serious AEs included one grade 3 UTI and one moderate hematuria. Two patients withdrew due to MCNA-related AEs (1 asthenia and 1 vomiting).

Fifteen patients (11.6 %) enrolled in Study 301 developed metastatic bladder cancer (MBC), with days from first MCNA instillation to MBC diagnosis ranging from 239 days to 1267 days.

When combining the Study 301 and 303 populations for the overall safety analysis, the most common all-grade AE’s included fatigue (15.7%), malaise (3.6%), chills (3%), pyrexia (2.4%), nausea (2.4%), diarrhea (2.4%), asthenia (2.4%), and abdominal distension (2.4%).

MCNA is an immunotherapy composed of mycobacterial cell wall fragments complexed with nucleic acids. Endo Pharmaceuticals and Bioniche Life Sciences initially developed the treatment as part of a joint collaboration. In 2012, Endo returned global rights for the medication to Bioniche, which later rebranded itself as Telesta in 2014. In June 2015, Telesta, which is based in Canada, received a patent for MCNA in the United States, providing intellectual property protection for the immunotherapy for 16 years.

As part of the submission process for MCNA, Telesta completed a number of upgrades and improvements to its manufacturing facility and operating procedures. These upgrades were completed in February 2015, prior to an FDA pre-approval inspection under their formal review process.

Regarding the next steps, Berendt is hoping Telesta can still move forward with MCNA.

“We will, over the next few months, work closely with the FDA, our advisors and our development partners to analyze the clinical and regulatory path forward in the United States and Europe, as well as the current competitive landscape and the costs and timelines to conduct a second Phase 3 trial for MCNA.”