Biosimilars For Avastin, Herceptin To Cap Off Busy July For ODAC

Pfizer's Mylotarg attempt to return to US market is first up for FDA's Oncologic Drugs Advisory Committee, followed by Novartis's CAR-T therapy. ODAC will then give half-day review to Amgen's and Mylan's biosimilars, suggesting FDA is increasingly comfortable with the product category.

Amgen Inc.'s proposed biosimilar to Roche's Avastin (bevacizumab) and Mylan NV's proposed biosimilar to Roche's Herceptin (trastuzumab) appear set to sail through the US FDA's Oncologic Drugs Advisory Committee, as the panel is devoting just half a day to each biologics license application.

The panel will discuss the biosimilar applications on the last day of a three-day meeting July 11-13. The committee will devote the first day to reviewing Pfizer Inc.'s Mylotarg (gemtuzumab ozogamicin) for use in combination with danorubicin and cytarabine for the treatment of adult patients with previously untreated, de novo acute myeloid leukemia. The review comes seven years after Pfizer voluntarily withdrew the therapy from the market because of reports of deaths related to veno-occlusive disease. (Also see "Pfizer Pulls Mylotarg For Safety 10 Years After Accelerated Approval" - Pink Sheet, 28 Jun, 2010.)

On July 12, the committee will discuss Novartis AG's BLA for its chimeric antigen receptor T cell (CAR-T) therapy tisagenlecleucel-T suspension, also known as CTL019, for patients three to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia. FDA announced the meetings in a Federal Register notice set for publication June 7.

FDA has indicated that it would hold an advisory committee review for the first biosimilar to a given reference product and may skip reviews for subsequent biosimilars to the same product. Samsung Bioepis Co. Ltd.'s Renflexis (infliximab-abda), the second US biosimilar to Janssen Biotech Inc.'s Remicade (infliximab), was the first biosimilar to be approved without a panel review. (Also see "Samsung’s Renflexis: Second US Biosimilar To Janssen’s Remicade, With A Few Firsts" - Pink Sheet, 21 Apr, 2017.)

Advisory committees have been giving overwhelming approval endorsements for biosimilars. And the last application to go before a panel, Pfizer subsidiary Hospira Inc.'s proposed biosimilar of Amgen's Epogen (epoetin alfa), was the first to get a half-day review, receiving a 14-1 vote for approval from ODAC. (Also see "Biosimilar Advisory Committees Getting Smoother, Even As Worries Stay The Same" - Pink Sheet, 25 May, 2017.)

September Action Dates But Biosimilar Launches Uncertain

Amgen was the first to submit an application for a proposed biosimilar to Avastin. The product, ABP 215, which Amgen is developing in partnership with Allergan PLC, has a user fee goal date of Sept. 14. A launch may be delayed by patents. Roche says primary patents covering Avastin expire around 2020.

Avastin and Herceptin are Roche's top selling products with sales of CHF6.783bn ($6.73bn) and CHF6.782bn, respectively, in 2016.

Mylan and its partner Biocon Ltd. could be the first to launch a biosimilar of Herceptin, a backbone therapy for the treatment of women with HER2-positive breast cancer. Their product, MYL-1401O, has a user fee date of Sept. 3. Mylan announced in March that it had reached a patent settlement agreement and a licensing deal with Roche that clears the path for Mylan to commercialize trastuzumab globally (excluding Japan, Brazil and Mexico) but the effective launch dates under the agreement are confidential. (Also see "Mylan Clears Runway For US Herceptin Biosimilar Launch" - Scrip, 13 Mar, 2017.)

Many other companies expect to follow in their path. There are as many as 19 different formulations of trastuzumab in development.

Potential Safety Issues For CAR-T Therapy

Novartis is positioned to be the first to launch a CAR-T therapy. The company announced on March 29 that FDA had accepted its CTL019 application for review, giving it a user fee action date of Sept. 29 or earlier. The drug was given priority review and has a breakthrough therapy designation pending.

The product is designed to target cancer cells expressing CD19. The individualized therapy involves reengineering a patient's T cells to attack cancer cells and other B cells that express the chosen antigen. Given the individualized nature of CAR-T therapies, they are expected to require more expensive manufacturing and distribution than traditional small molecule or antibody therapeutics.

Kite Pharma Inc.'s CAR-T therapy axicabtagene ciloleucel (KTE-C19), which also targets CD19, is second in line with a user fee date of Dec. 1 or earlier. Kite's filing is for treatment of patients with relapsed or refractory aggressive non-Hodgkin lymphoma who are ineligible for autologous stem cell transplant.

While the class has shown impressive efficacy in some patients, it has unique safety issues. Kite reported in its earnings call in May that an extremely ill non-Hodgkin lymphoma patient died from cerebral edema two days after infusion of its product in a 30-patient safety extension of the Phase II trial supporting its BLA. (Also see "Too Sick For CAR-T? Kite Reports Cerebral Edema Death" - Scrip, 8 May, 2017.)

Juno Therapeutics Inc. announced in March that it was ending development of its CD19-targeting CAR-T therapy JCAR015 after a pivotal clinical trial was placed on hold multiple times due to severe neurological side effects and five cerebral edema deaths in adults with relapsed or refractory acute lymphoblastic leukemia (ALL). It is focusing instead on a new CD19-targeting CAR-T. (Also see "Juno Ends JCAR015 Development In ALL, Cementing Third Place CAR-T Position" - Scrip, 1 Mar, 2017.)

Novartis has been touting the blockbuster potential of CTL019. At a meet-the-management event last month, the company said it expects to file for approval of the drug for diffuse large B-cell lymphoma in the second half of the year, a substantially larger indication than pediatric/young adult ALL. (Also see "Novartis' CAR-T CTL019 Back On The Blockbuster Hit List" - Scrip, 1 Jun, 2017.)

Will New Safety And Efficacy Data Revive Mylotarg?

Safety considerations are likely to be a primary focus of the Oncologic Drug Advisory Committee's consideration of Mylotarg, an antibody-drug conjugate comprised of an anti-CD33 monoclonal antibody and calicheamicin, for treatment of adults with acute myeloid leukemia (AML).

The therapy was approved in May 2000 under the accelerated approval pathway. When it was withdrawn in 2010, FDA said the rate of veno-occlusive disease, a serious liver condition that was a concern at the time of the drug's approval, had increased in post-market reporting. The agency also said a confirmatory trial and years of post-marketing experience had not shown evidence of clinical benefit in patients with AML.

FDA accepted Pfizer's BLA in January, which gives it a user fee date in September.

There is a high unmet medical need for therapies to treat AML. The five-year survival rate is only 26% and the standard of care has been the same for decades. The standard treatment for newly diagnosed patients consists of a chemotherapy regimen (seven days of standard-dose cytarabine and three days of an anthracycline antibiotic or an anthracenedione) followed by stem cell transplant.

Several big pharma companies have AML drug candidates in late stage development, including Celgene Corp., Roche, and Takeda Pharmaceutical Co. Ltd. (Also see "AML Pipeline Update: Pharmas Pursue Big Breakthroughs In Niche Spaces" - Scrip, 6 Jan, 2017.)