Keeping Track: Biosimilar Submissions Galore (And An Approval), Bayer Gets An Oncology Approval, KemPharm Resubmits Apadaz NDA

The latest regulatory submission news and highlights from our US FDA Performance Tracker.

Biosimilars dominated the news of the week, with the US FDA approving Amgen Inc. and Allergan PLC's Mvasi (bevacizumab-awwb) as the first biosimilar to Genentech Inc.'s Avastin (bevacizumab). Here's your news in brief:

FDA also accepted biologics license applications (BLAs) for biosimilars from three other sponsors, including Sandoz Inc., Pfizer Inc. and Adello Biologics.

On the new molecular entity (NME) front, Bayer HealthCare Pharmaceuticals AGscooped up an approval for its follicular lymphoma treatment Aliqopa (copanlisib).

KemPharm Inc.has resubmitted its new drug application (NDA) for its immediate release opioid Apadaz (benzhydrocodone/acetaminophen), after going through FDA's formal dispute resolution process following the receipt of a complete response letter.

FDA has also accepted Array BioPharma Inc.'s retooled binimetinib NDA, which the drugmaker had previously withdrawn over a lack of efficacy in treating melanoma. Here's your news in less brief:

FDA Approves First Avastin Biosimilar

FDA has given the thumbs up to Amgen and Allergan's Mvasi the first biosimilar to Genentech's vascular endothelial growth factor-specific angiogenesis inhibitor Avastin.

Mvasi – the first biosimilar approved in the US for the treatment of cancer – was approved for all six Avastin indications Amgen and Allergan were seeking:

• Metastatic colorectal cancer, with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment;
• Metastatic colorectal cancer, with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen;
• Non-squamous, non-small cell lung cancer, with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent or metastatic disease;
• Glioblastoma, as a single agent for adult patients with progressive disease following prior therapy;
• Metastatic renal cell carcinoma with interferon alfa; and
• Cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic disease.

Two other Avastin indications remain protected by orphan exclusivity. Its recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum-resistant in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan indication is protected until Nov. 14, 2021. The indication for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum-sensitive in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine is protected until Dec. 6, 2023.

Like Avastin, the label for Mvasi contains a boxed warning for increased risk of holes in the stomach and intestines, surgery and wound healing complications and severe or fatal pulmonary, gastrointestinal, central nervous system and vaginal bleeding.

Mvasi has become the seventh biosimilar approved in the US. Amgen declined to provide pricing and launch plans.

The Oncologic Drugs Advisory Committee voted 17-0 in favor of approval of Mvasi at the July advisory committee meeting. (Also see "Mylan, Amgen Biosimilars Sail Through Advisory Panels, May Diverge From There" - Pink Sheet, 14 Jul, 2017.) It remains under review in the European Union (EU).

FDA Accepts Sandoz's Rituximab Biosimilar BLA…

Sandoz announced Sept. 12 that FDA has accepted the company's BLA for a biosimilar to Genentech's Rituxan (rituximab), becoming at least the second copycat to the CD20-directed cytolytic antibody in the agency's review pipeline.

The user fee goal date for the biosimilar candidate is May 12, 2018 or earlier.

Rituxan was first approved in 1997, and is indicated for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis. Sandoz is seeking all of those indications for the biosimilar.

The Rituxan biosimilar pipeline, however, has become a crowded one. Teva Pharmaceutical Industries Ltd. and Celltrion Inc. were the first to submit a BLA for a Rituxan biosimilar to FDA; their CT-P10 has a user fee goal date of February 2018. Archigen Biotech/AstraZeneca PLC, as well as Amgen/Allergan also have biosimilar Rituxan candidates in Phase III development. (Also see "Celltrion’s Biosimilar Rituximab First In Line For FDA Review" - Scrip, 3 Jul, 2017.)

Although Genentech's initial rituximab product could be facing competition, the Roche subsidiary has launched a subcutaneous reformulation of the biologic. The drugmaker won approval for Rituxan Hycela (rituximab and hyaluronidase) in June for the treatment of follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia. The subcutaneous formulation was touted by ODAC as being a more likeable patient option than the initial intravenous option. (Also see "Genentech's Subcutaneous Rituximab Breezes Through US FDA Advisory Committee" - Pink Sheet, 29 Mar, 2017.)

Sandoz's Rituxan biosimilar was approved in the EU in June 2017.

…And Also Pfizer's Herceptin Biosimilar Application

Staying on the biosimilar pipeline train, FDA also accepted Pfizer's Herceptin (trastuzumab) biosimilar candidate PF-05280014 for review.

PF-05280014 showed no clinically meaningful differences from Herceptin – which is approved for the treatment of HER2-overexpressing breast cancer – in a Phase III randomized, double-blind pivotal trial, Pfizer announced Sept. 10. It will have a user fee date of May 2018 or earlier.

The drugmaker also noted that it filed the biosimilar for approval in the EU.

It has been a bumpy road for Pfizer on the biosimilar front so far, as the company had previously received two complete response letters in its bid to bring the first biosimilar version of epoetin alfa (Amgen's Epogen/Johnson & Johnson's Procrit) to the US market. (Also see "Pfizer’s EPO Biosimilar Stalls In US On Hospira Compliance Woes" - Pink Sheet, 22 Jun, 2017.)

Adello Joins Party With Neupogen Biosimilar Application

In the third biosimilar acceptance announcement this week, FDA has also accepted for review Adello's Neupogen (filgrastim) biosimilar candidate, in what could become the second biosimilar to the leukocyte growth factor on the US market.

Adello announced FDA's acceptance Sept. 11, putting the user fee date at May 11, 2018 or earlier. The drugmaker did not return a request for comment regarding which Neupogen indications it is seeking for the biosimilar.

Sandoz's Zarxio (filgrastim-sndz) is the sole biosimilar on the market to Amgen's Neupogen, which is designed to increase white blood cell counts for a number of conditions. It was also the first biosimilar approved in the US. (Also see " Novartis/Sandoz make US history with 1st biosimilar approval " - Pink Sheet, 9 Mar, 2015.)

Bayer Wins Approval For Second PI3K Inhibitor Aliqopa

Bayer has scored approval for its follicular lymphoma treatment Aliqopa (copanlisib), becoming the second phosphoinositide 3-kinase inhibitor (PI3K inhibitor) to reach the US market.

FDA granted Aliqopa – which previously received an orphan drug designation and a priority review – accelerated approval Sept. 14 specifically for the treatment of adults with relapsed follicular lymphoma who have received at least two prior treatments known as systemic therapies.

Bayer used the surrogate endpoint of objective tumor response rate in the Phase II open-label, single-arm, 142-patient CHRONOS-1 study. Roughly 59 percent of patients had a complete or partial response for a median 12.2 months. Secondary endpoints included duration of response, overall survival, progression-free survival, quality of life, and safety. (Also see "More Than CAR-T: Hematologic Oncology Pipeline Offers Rich Menu Of Possible Approvals" - Pink Sheet, 18 Jul, 2017.)

FDA is requiring Bayer to conduct a randomized, double-blind, placebo-controlled confirmatory trial of Aliqopa that enrolls roughly 520 patients to satisfy accelerated approval requirements. The agency is also requiring a postmarketing trial that enrolls at least 400 patients to assess the risk in patients with hepatic impairment, renal impairment or from interactions with certain other drugs.

Aliqopa becomes only the second FDA-approved PI3K inhibitor, with Gilead Sciences Inc.'s chronic lymphocytic leukemia, follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma treatment Zydelig (idelalisib) being the other. Approval also brings the Center for Drug Evaluation and Research's (CDER's) novel approval count for the year 2017 to 32.

A Bayer spokesperson tells the Pink Sheet that monthly list price for Aliqopa will be $12,600, but declined to comment on the launch plans.

FDA Accepts KemPharm Resubmission For Pain Drug Apadaz

KemPharm is hoping to bounce back from its complete response letter for its immediate release opioid Apadaz (benzhydrocodone and acetaminophen), as the clinical-stage drugmaker announced Sept. 12 that it has completed its formal dispute resolution process with FDA and has resubmitted its NDA for the acute pain medication.

The resubmission was of the Class 2 variety, and KemPharm says FDA is expected to have a decision about approval by Feb. 23, 2018.

KemPharm was initially trying to get Apadaz to market as the first immediate-release opioid with abuse-deterrent properties. FDA's Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committees, however, voted in favor of approving the drug last year, but not with abuse-deterrent properties. (Also see "KemPharm's Opioid Apadaz Will Likely Miss Out On Abuse Deterrence Claim" - Pink Sheet, 5 May, 2016.)

FDA nevertheless handed KemPharm a complete response letter for the opioid, with the agency expressing confusion about some of the studies the company included to demonstrate that Apadaz could deter intranasal abuse of the drug. (Also see "Can KemPharm's Apadaz Meet FDA Opioid Abuse Deterrent Standards?" - Pink Sheet, 14 Jun, 2016.) In November 2016, KemPharm began to appeal the complete response letter through the agency's dispute resolution process. (Also see "KemPharm Seeks FDA Dispute Resolution Over Apadaz's Abuse Deterrence" - Pink Sheet, 16 Sep, 2016.)

Travis Mickle, president and CEO of KemPharm, said in a Tuesday investor call that although the company is optimistic about prospects for approval, there are several more obstacles along the way, including a "failure to reach agreement on the final product label language, a changing environment in the consideration of approvals for opioid product, and even the possibility of a second ad comm to re-review the existing data."

Mickle said the company's appeal focused on the lack of advantages from snorting the opioid.

Even if the drug is approved with abuse-deterrent properties, however, it would no longer be the first immediate-release opioid to have such labeling. Inspirion Delivery Sciences LLC won that honor with FDA approval of RoxyBond (oxycodone hydrochloride) in April. (Also see "RoxyBond Clears US FDA With Abuse-Deterrent Properties, But No REMS Yet" - Pink Sheet, 27 Apr, 2017.)

Scilex Gets FDA Acceptance For ZTlido Resubmission

Also looking to rebound from a complete response letter is Sorrento Therapeutics Inc. subsidiary Scilex Pharmaceuticals Inc., which announced Sept. 12 that FDA has accepted the drugmaker's resubmitted NDA for its postherpetic neuralgia treatment ZTlido (lidocaine patch 1.8%).

FDA deemed the resubmission Class 2, giving ZTlido – a non-opioid lidocaine patch – a user fee date of Feb. 28.

Scilex initially filed the NDA for ZTlido with the agency in September 2015, but the details of the subsequent complete response letter are unclear. The company announced in December 2016 that in a new pivotal trial, ZTlido demonstrated comparative pharmacokinetics and bioequivalence with Endo Pharmaceuticals Inc.'s Lidoderm (lidocaine patch 5.0%).

Scilex announced the 505(b)(2) resubmission to FDA Aug. 30.

FDA Accepts Array's Binimetinib Combo Submission

Array announced Sept. 12 that FDA has accepted the company's NDAs for the combination of binimetinib and encorafenib to treat BRAF-mutant advanced, unresectable or metastatic melanoma, bringing the clinical-stage company one step closer to getting its first product to market.

The NDAs both support an indication for the combination of the MEK inhibitor binimetinib and BRAF inhibitor encorafenib, given in doses of 45mg twice daily and 450mg once-daily, respectively, in a regimen known as COMBO450. Each application has a user fee date of June 30, 2018.

Array submitted the NDAs in July, after initially trying to score an approval for binimetinib as monotherapy for NRAS-mutant melanoma. (Also see "Keeping Track: US FDA Approves Sickle Cell Therapy Endari; Array Submits Binimetinib Again" - Pink Sheet, 10 Jul, 2017.) The drugmaker withdrew the application, however, after a late-cycle meeting with FDA suggested that its modest progression-free survival clinical benefit would not be sufficient for approval. (Also see "Array Withdraws Binimetinib's US Filing On Heels Of Late-Cycle Meeting With FDA" - Pink Sheet, 20 Mar, 2017.)

The pivotal Phase III COLUMBUS trial supporting the binimetinib and encorafenib NDAs found a median progression-free survival of 14.9 months compared with 7.3 months for patients on the vemurafenib monotherapy control arm.