Keeping Track: US FDA Accepts Ertugliflozin, Extends Reviews Of Abaloparatide, New Keytruda Claim

The latest drug development news and highlights from our FDA Performance Tracker.

FDA prolonged reviews of two applications with March user fee goal dates in another week with more news of submissions than approvals. Here's your news in brief:

Goal dates have been moved to June 2017 forRadius Health Inc.'s bone-building abaloparatide for osteoporosis and a new tissue-agnostic indication for Merck & Co. Inc.'s blockbuster immuno-oncologic Keytruda (pembrolizumab) in microsatellite instability-high (MSI-H) cancer.

Merck also announced a late 2017 goal date for a new molecular entity, ertugliflozin, that it is developing with Pfizer Inc. to treat type 2 diabetes. The companies submitted three new drug applications (NDAs) for the SGLT-2 inhibitor, as monotherapy and in two fixed-dose combinations.

Nicox SA announced resubmission the NDA for its ophthalmic formulation of the antihistamine cetirizine after resolution of problems at a contract manufacturer that had drawn a complete response letter (CRL) from FDA.

And Isreali company PolyPid Ltd.'s lead surgical infection product, an extended-release formulation of doxycycline for local delivery known as D-Plex, received a Qualified Infectious Disease Product (QIDP) designation. The company is working towards Phase III trials in prevention of sternal infections after cardiac surgery. Here's your news in less brief:

Merck/Pfizer Ertugliflozin Aims For December Approval

Merck and Pfizer's ertugliflozin may be in line to be the fourth sodium-glucose cotransporter 2 (SGLT-2) inhibitor antidiabetic to reach the US market, but the companies aim to introduce the drug with a range of formulations. FDA has granted December 2017 user fee goals for three NDAs for ertugliflozin-containing products: a single-agent tablet, a fixed-dose combination with the workhorse antidiabetic metformin, and what could be the most commercially attractive combination, a fixed-dose combination with Merck's blockbuster dipeptidyl peptidase 4 (DPP-4) inhibitor Januvia (sitagliptin). (Also see "With VERTIS SITA2 On Board, Merck Eyes Broad Initial Approval For Ertugliflozin" - Pink Sheet, 16 Sep, 2016.)

If approved, the ertugliflozin/sitaglipitin combo would be the third fixed-dose product to combine the SGLT-2 and DPP-4 classes. Boehringer Ingelheim GMBH and Eli Lilly & Co.'s Glyxambi (empagliflozin and linagliptin), approved in 2015, was the first. AstraZeneca PLC's Qtern (dapagliflozin and saxagliptin) became the second with FDA approval on Feb. 27, 2017. Despite combining two drugs already available on the market (Farxiga and Onglyza), Qtern's approval was delayed by a 2015 CRL calling for more clinical data. (Also see "AstraZeneca Diabetes Combo Needs More Clinical Data, FDA Says" - Pink Sheet, 16 Oct, 2015.)

Merck and Pfizer's Phase III VERTIS program for ertugliflozin includes nine trials in more than 12,600 patients with type 2 diabetes. Pivotal studies in the NDAs include the VERTIS MONO study comparing single agent with placebo and metformin and the VERTIS FACTORIAL and VERTIS SITA2 trials, which tested ertugliflozin and sitagliptin in patients on top of background metformin therapy.

As is standard for diabetes drug development, Merck and Pfizer are conducting a CV outcomes trial, VERTIS CV, in 8,000 patients with type 2 diabetes and established vascular disease. Now CV benefit, not just safety, is emerging as a battleground for antidiabetics; FDA approved the first CV benefit claim for SGLT2 inhibitor in December 2016, for Boehringer Ingelheim GMBH and Eli Lilly & Co.'s empagliflozin. (Also see "Jardiance's Label Expansion Will Change Diabetes Management" - Scrip, 5 Dec, 2016.).

VERTIS CV's primary endpoint looks for non-inferiority of ertugliflozin versus placebo on a composite endpoint of major adverse cardiac events (MACE), but the companies expanded the trial to enable testing for superiority in improving CV outcomes. (Also see "ADA: Diabetes Duo Merck & Pfizer Report Positive PhIII Data For Investigational SGLT-2" - Scrip, 11 Jun, 2016.)

Tissue-Agnostic Indication For Keytruda Needs More Review

An indication for Merck's Keytruda to treat advanced microsatellite instability-high (MSI-H) cancers may break FDA's pattern of swift approvals for the PD-1/L1 inhibitor class. On March 8, the user fee goal for Keytruda's sNDA for previously-treated advanced MSI-H cancer, Merck announced that the sBLA "remains under review" at FDA. The application, which seeks accelerated approval, is the first for an immuno-oncologic for a tissue-agnostic indication.

A three-month user fee goal extension is likely. Merck reported that it "has submitted additional data and analyses," which can trigger an extension if substantial information is submitted too close to the goal. That would push the goal date to June 8, 2017.

FDA has designated Keytruda a breakthrough therapy for MSI-H cancer, first for colorectal cancer patients and then for non-CRC patients with the biomarker. Patients with the signature, a measure of DNA mismatch repair, may be "especially responsive" to Keytruda, according to Merck. (Also see "Keeping Track: Immuno-Oncologics And Abuse-Deterrent Opioids Take Center Stage (Again); Jardiance CV Claim Approved" - Pink Sheet, 3 Dec, 2016.)

Radius' Abaloparatide-SC Launch Plans Delayed As FDA Moves Goal Date

FDA needs more time to review information about subcutaneous abaloparatide that Radius Health submitted in response to agency reviewers' information requests, and thus has extended to user fee goal date for the abaloparatide-SC NDA from March 30 to June 30, 2017. "FDA has not requested any additional information" about the product, a novel synthetic peptide that engages the parathyroid hormone (PTH1) receptor, Radius said March 10.

Radius has been gearing up to launch abaloparatide as a daily self-administered subcutaneous injection to treat women with postmenopausal osteoporosis who are at increased risk for fracture. The company's Feb. 23 earnings announcement reported that over 90% of clinical sales specialists had been hired. Nonetheless, the company intends to "enter into a partnership for the potential commercialization of abaloparatide-SC prior to commercial launch."

If approved, abaloparatide would enter a crowded postmenopausal osteoporosis market. The drug would, however, be only the second anabolic therapy to build bone to treat osteoporosis. In the Phase III ACTIVE trial, abaloparatide patients saw an 86% risk reduction for new vertebral fracture compared to placebo, the primary endpoint. The trial also included an arm treating patients with Lilly's approved anabolic agent, the PTH analog Forteo (teriparatide). Teriparatide patients had an 80% risk reduction compared with placebo, but the trial was not powered to compare the two active drugs. (Also see "Will Radius Health's Abaloparatide Data Do The Trick In Osteoporosis?" - Scrip, 18 Aug, 2016.)

NicOx Reveals Zerviate As Name For Resubmitted Cetirizine Eyedrops

Nicox' eyedrop formulation of the antihistamine cetirizine, previously called AC-170, will be known as Zerviate, the company indicated in a March 9 release announcing the resubmission of the NDA for treatment of ocular itching associated with allergic conjunctivitis. Zerviate was developed by Aciex Therapeutics, which was acquired by NicOx in 2014.

FDA issued a CRL for AC-170 in October 2016 citing good manufacturing practices (GMP) issues noted during an inspection of a third-party facility producing the active pharmaceutical ingredient (API) cetirizine. (Also see "Keeping Track: FDA Rejects Mealtime Insulin, Antihistamine; Misses Goal For Another Opioid" - Pink Sheet, 14 Oct, 2016.)

NicOx sees "a potential approval before the end of 2017" for Zerviate. The six-month review goal for Class 2 resubmissions would put the new target for FDA action in September. The company is seeking a US commercialization partner for the cetirizine ophthalmic solution. (Also see "Keeping Track: Ilaris Adds Three Rare Disease Claims; Sirukumab Submitted; Exondys 51's Surprising Approval" - Pink Sheet, 23 Sep, 2016.) The NDA resubmission announcement noted that the company has seen "interest from several parties, with discussions ongoing involving key industry players active in both eye care and general practitioner segments."

User Fee Goal Date Updates

FDA assigns a user fee goal date when it accepts an application for filing, a decision that is due 60 days after submission. Goal dates recently disclosed for previously-announced submissions include:

• Oct. 24 is the official user fee goal date for PTC Therapeutics Inc.'s Translarna (ataluren). The date suggests a standard review for the protein restoration therapy to treat nonsense mutation Duchenne muscular dystrophy. PTC pursued the little-used "filing over protest" pathway to submit the NDA after FDA rejected an appeal of the "refuse to file" letter the agency issued for the company's first try at submitting Translarna. (Also see "Keeping Track: Xermelo, Odactra, Noctiva Approved; Second Submissions For Avelumab And Deutetrabenazine" - Pink Sheet, 4 Mar, 2017.)
• Nov. 6 is the goal for Keryx Biopharmaceuticals Inc.'s submission of a new indication for the oral phosphate binder Auryxia (ferric citrate), which is currently approved to control serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis. The sNDA would extend use of Auryxia to non-dialysis dependent patients (NDD-CKD). (Also see "Keeping Track: Arymo ER Approved, Parsabiv Returns, Merck Surprises With Keytruda Chemo Combo Submission" - Pink Sheet, 14 Jan, 2017.)
• Oct. 23 is the user fee goal for Alexion Pharmaceuticals Inc.'s terminal complement inhibitor Soliris (eculizumab) for a new indication for treatment of patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. There are no approved treatments for this ultra-rare subset of gMG patients. (Also see "Keeping Track: Arymo ER Approved, Parsabiv Returns, Merck Surprises With Keytruda Chemo Combo Submission" - Pink Sheet, 14 Jan, 2017.)

PolyPid's Post-Surgical Doxycycline Qualifies For QIDP

The lead product from PolyPid's surgical site infection program, D-Plex, was selected for FDA's expedited review and incentive program for anti-infectives, the Isreali company announced March 8. D-Plex, which incorporates doxycycline in the company's polymer-lipid encapsulation matrix (PLEX) technology, was named a Qualified Infectious Disease Product (QIDP) for prevention of post-cardiac surgery sternal infection.

PolyPid's PLEX products are designed to be placed during surgical procedures. The matrix forms a protected reservoir that releases the entrapped antibiotic at the target site at a predetermined release rate and duration, according to the company. Products like D-Plex that incorporate already-approved anti-infective drugs will qualify for the 505(b)(2) NDA pathway.

D-Plex is currently being studied in a Phase Ib/II post-cardiac surgery sternal infection trial in Israel. Initial data found "no sternal infection occurred during three-month follow-up in treated patients," PolyPid stated, "and there were no adverse events related to the product." Further data are expected by year-end 2017.

At a recent pre-IND meeting, FDA told PolyPid that, with positive Phase Ib/II results, D-Plex could move directly into a Phase III trial in the US. The company said it intends to seek regulatory approval to conduct a Phase III trial in post-cardiac surgery sternal infection in the US and Europe in the coming year.