Vedolizumab, Empagliflozin And Vintafolide Receive Positive EU Opinions After CHMP Meeting

The three new medicines tackle ulcerative colitis and Crohn’s disease, diabetes and ovarian cancer, respectively, with final approval from the European Commission expected in around two months.

Among the five new molecular entities cleared for marketing by Europe’s top advisory panel, the Committee for Medicinal Products for Human Use (CHMP) after its meeting on March 17-20 were a new integrin-targeted humanized monoclonal antibody, Takeda Pharmaceutical Co. Ltd.’s Entyvio (vedolizumab), for GI disorders; the third SGLT2 inhibitor in development for diabetes, Boehringer Ingelheim GMBH/Eli Lilly & Co.’s Jardiance (empagliflozin); and a targeted ovarian cancer therapy, Vynfinit, from Endocyte Inc..

Second Positive Opinion For Takeda This Year

The positive opinion for Takeda’s humanized monoclonal antibody, Entyvio, for the treatment of ulcerative colitis and Crohn’s disease, is the second new product recommendation received by the Japanese company from European regulatory authorities in the past three months.

Back in January, Takeda and Sumitomo Dainippon Pharma Co. Ltd. received a CHMP positive opinion for use of their atypical antipsychotic lurasidone in schizophrenia; lurasidone is already marketed in the U.S. by Sunovion Pharmaceuticals Inc. as Latuda (Also see "CHMP Rejects Serelaxin But Clears Albiglutide, Riociguat And Lurasidone" - Pink Sheet, 24 Jan, 2014.).

Entyvio, which is directed against integrins expressed on human lymphocytes, is expected to compete with TNF inhibitors such as AbbVie Inc.’s Humira (adalimumab) and MS&D’s (Merck & Co. Inc.) Remicade (infliximab) which are already marketed for gastrointestinal conditions. The positive opinion “brings us closer to providing the first gut-selective biologic agent for ulcerative colitis and Crohn’s disease to patients,” said Trevor Smith, head of Takeda’s commercial operations, Europe and Canada, in a March 21 statement.

The recommendation is also good news for Christophe Weber, who takes up his new position of chief operating officer of Takeda on April 1, 2014. Weber was previously president and general manager of GlaxoSmithKline PLC’s vaccines business.

CHMP said vedolizumab would be indicated for the treatment of adult patients with moderately to severely active ulcerative colitis or Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional or TNF antagonist therapy. Common side effects of the MAb include nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, cough and infusion-related reactions.

Alpha-4, beta-7 integrin is expressed on a subset of memory T-cells that migrate to the GI tract and cause the inflammation that is associated with ulcerative colitis and Crohn’s disease. Vedolizumab binds to the integrin and inhibits adhesion of T-cells to GI mucosa cells, preventing the T-cells moving into inflamed parenchymal cells.

Entyvio was recommended for approval in the U.S. by a joint meeting of FDA’s GI and drug safety advisory committees on Dec. 9 (Also see "Vedolizumab Approval Supported, But Committee Differs on Indicated Population" - Pink Sheet, 9 Dec, 2013.). Later in December, Takeda said the FDA had extended the PDUFA priority review action date for the ulcerative colitis indication to May 20, 2014, to allow the agency time to review a major amendment to the marketing submission. The standard review action date for the Crohn’s indication remained June 19, 2014.

Japanese Phase III studies with vedolizumab - which was initially developed by Takeda U.S. subsidiary Takeda Oncology- started in January 2014 ( (Also see "Takeda Starts Vedolizumab Phase III Trials For Crohn’s Disease, Ulcerative Colitis" - Scrip, 14 Jan, 2014.).

Empagliflozin Cleared For Diabetes

Just over two weeks after receiving a U.S. FDA “complete response” letter for empagliflozin due to manufacturing concerns, Boehringer Ingelheim and Lilly have now received better news from the CHMP (Also see "Manufacturing Woes Result In “Complete Response” For Lilly’s Empagliflozin" - Pink Sheet, 5 Mar, 2014.).

The two companies, which are collaborating on the development of new diabetes agents, received a positive opinion March 21 recommending Jardiance as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Jardiance will be marketed as 10 mg and 25 mg tablets and will likely be the third of a new class of oral diabetes therapies to reach the market, the sodium-glucose co-transporter-2 (SGLT2) inhibitors. AstraZeneca PLC already markets Forxiga (dapagliflozin) and Xigduo (metformin plus dapagliflozin) in Europe, and Janssen-Cilag International markets Inovokana (canagliflozin).

The manufacturing issues do make the expected timing of launches of Jardiance uncertain; re-inspection of a Germany facility where empagliflozin is produced was expected in the first quarter of this year.

Empagliflozin was recommended by the CHMP as a monotherapy when diet and exercise alone do not provide adequate glycemic control in patients for whom use of metformin is considered inappropriate due to intolerance. It was also recommended for use with other glucose-lowering products, including insulin, when these, together with diet and exercise, do not provide adequate glycemic control.

Vintafolide’s Conditional Recommendation

The CHMP recommended a conditional approval for Endocyte’s Vynfinit (vintafolide), for use in combination with pegylated liposomal doxorubicin for the treatment of adult patients with platinum-resistant ovarian cancer.

The committee also conditionally recommended two companion diagnostics, Folcepri (radioactive etarfolatide) and Neocepri (folic acid) that will help identify patients likely to benefit from Vynfinit therapy. Vintafolide is a conjugate of folic acid that targets folate receptors on the surface of ovarian cancer cells and the cytotoxic agent, desacetylvinblastine hydrazide.

“If approved, vintafolide would be the first oncology therapeutic to employ an imaging agent as a companion diagnostic for patient selection,” Endocyte noted March 21 statement. “The positive CHMP opinion is an important step towards personalizing ovarian cancer management for appropriate patients.”

Vynfinit is Endocyte’s lead product, for which the West Lafayette, Indiana-based company entered a worldwide development deal with Merck & Co in 2012 (Also see "Merck Gains Phase III Drug/Companion Diagnostic In Deal With Endocyte" - Pink Sheet, 16 Apr, 2012.). The agent has become part of Merck’s resurgence into the oncology field (Also see "Merck Bets Big On Oncology In New R&D Strategy" - Pink Sheet, 7 Oct, 2013.).

Full approval in Europe, in a disease with limited treatment options, will be conditioned on the companies providing more clinical data at a later date. Phase II clinical data indicated that in combination with pegylated liposomal doxorubicin, Vynfinit improved progression-free survival in patients with platinum-resistant ovarian cancer, compared with treatment with pegylated liposomal doxorubicin alone, the CHMP said. Phase III studies are currently underway to gain U.S. approval.

Vynfinit is a designated orphan product and Endocyte is a registered small-to-medium sized enterprise, so the company received scientific advice from EMA, and also benefited from regulatory and procedural assistance and reduced EMA fees.