US Approvals Roundup: Cyltezo Biosimilar, Victoza CV Benefit, Gocovri In PD, Kedrab Rabies Biologic, Gout Combo Duzallo

FDA's clearances showcase the application of formulation technology to reduce problem side effects and improve convenience of available drugs.

FDA approvals in the past week range from a new biosimilar to a novel biologic and a significant new claim for an antidiabetic first approved in 2010, and showcased the application of formulation technology to reduce problem side effects and improve convenience of available drugs.

BI Cyltezo Is FDA's Second Humira Biosimilar Approval

FDA's Aug. 25 approval of Boehringer Ingelheim GMBH's Cyltezo (adalimumab-adbm) ramps up biosimilar competition for AbbVie Inc.'s mega-blockbuster Humira (adalimumab), an anti-tumor necrosis factor antibody with a range of immunology indications.

Cyltezo, previously known as BI 695501, is the second biosimilar of Humira to receive FDA approval. Amgen Inc. 's Amjevita (adalimumab-atto) cleared the agency in September 2016. (Also see "Amgen's Amjevita Approved As First Biosimilar To AbbVie's Humira" - Pink Sheet, 23 Sep, 2016.)

Cyltezo is the sixth biosimilar approved by FDA.

The main trial supporting BI's 351(k) BLA demonstrated equivalence of Cyltezo to Humira in rheumatoid arthritis, but BI has said it also would provide data in Crohn's disease and psoriasis beyond the single trial required for approval. (Also see "Boehringer Ingelheim Limbering Up With Humira Biosimilar" - Scrip, 14 Jun, 2017.)

Victoza Nabs First Cardiovascular Benefit Claim For A GLP-1 Antidiabetic

Novo Nordisk AS's Victoza (liraglutide) added an indication to reduce risk of major adverse cardiovascular events in adults with type 2 diabetes and established CV disease, the company announced Aug. 25, 2017. Victoza is the first drug from the crowded GLP-1 analog class to be able to claim a CV benefit.

Victoza is the second antidiabetic agent to receive a CV risk reduction claim from FDA, following the December 2016 approval of a similar indication for Boehringer Ingelheim and Eli Lilly & Co.'s SGLT-2 inhibitor Jardiance (empagliflozin). (Also see "Jardiance's Cardiovascular Benefit Claim Bodes Well For Other Products Too" - Pink Sheet, 5 Dec, 2016.)

The Victoza approval was foreshadowed by a positive FDA advisory committee review in June. The panel voted 17-2 that Novo's CVOT, the LEADER trial, showed that Victoza reduced CV risk in type 2 diabetes patients. (Also see "Novo’s Victoza CV Benefit Claim Could Be Narrowed With FDA Panel Vote" - Pink Sheet, 20 Jun, 2017.)

Kedrab Approval Brings CBER 2017 Novel Biologic Count To Five

FDA's Center for Biologics Evaluation and Research (CBER) approved Kamada Ltd. and Kedrion Biopharma Inc.'s Kedrab for post-exposure prophylaxis of rabieson Aug. 23, making the plasma-derived immunoglobulin the fifth original biologics license application (BLA) cleared by CBER this year.

While CBER started out 2017, turning in its first novel approval – ALK Abello's sublingual house dust mite allergy immunotherapy Odactra – in March, but the biologics center has picked up the pace recently, clearing CSL Behring's plasma-derived C1 esterase inhibitor Haegarda on June 22, Octapharma AG's human fibrinogen concentrate Fibryna on June 7, and Novo Nordisk's glycopegylated recombinant coagulation factor IX (rFIX) Rebinyn on May 31.

Kamada submitted the Kedrab BLA, while Kedrion holds exclusive rights to commercialize Kedrab in the US. Kamada has sold the human rabies immunoglobulin (HRIG) outside the US as KamRab since 2006. (Also see "Keeping Track: Sandoz Erelzi Is Third Biosimilar To Clear FDA; Expanded Labels For Arzerra, Blincyto" - Pink Sheet, 2 Sep, 2016.) The product is derived from human plasma from donors hyper-immunized with rabies vaccine.

Kedrab is indicated for passive, transient post-exposure prophylaxis (PEP) of rabies infection, when given promptly after contact with a rabid or possibly rabid animal. Labeling specifies that Kedrab should be administered concurrently with a full course of rabies vaccine.

Kedrab is the third human rabies immunoglobulin (HRIG) therapy approved in the US, but the rabies market "has experienced inconsistent supply in recent years," Kedrion and Kamada pointed out.

The pivotal study for the Kedrab approval was a single-center Phase II/III trial comparing Kedrab with another HRIG in 118 healthy subjects. The primary efficacy variable for the non-inferiority trial was rabies virus neutralizing antibody (RVNA) titer, as assessed by rapid fluorescent focus inhibition test (RFFIT), on Day 14.

Adamas Gocovri Earns First Indication For Levodopa-Induced Dyskinesia

FDA approved Adamas Pharmaceuticals Inc.'s extended-release formulation of amantadine, Gocovri, on Aug. 24 for treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications. Gocovri is the first drug with an indication for levodopa-induced dyskinesia (LID), which eventually develops in most PD patients treated with levodopa. LID can be managed by reducing levodopa dosage, but then underlying Parkinson's symptoms return.

Immediate-release amantadine has been used off-label for LID, but the doses high enough to provide symptom relief are also associated with increased adverse events, including sleep disturbance. Adamas developed Gocovri, previously known as ADS-5102, as a "chrono-synchronous regimen" taken before bed that provides high plasma concentrations of amantadine in the morning through mid-day. (Also see "Keeping Track: Merck's Winning Week; Novel Agents Submitted By GSK, Melinta, Portola" - Pink Sheet, 29 Oct, 2016.)

The approval is based on two Phase III trials that used the same primary endpoint of change in Unified Dyskinesia Rating Scale (UDyRS) total score between baseline and week 12. The UDyRS scale was developed and validated with the help of the Michael J. Fox Foundation for Parkinson's Research. In one trial, Gocovri patients saw a 37% reduction in UDysRS score, compared with 12% for placebo. In the other, the Gocovri arm saw a 46% reduction vs. 16% for placebo.

Adamas also highlighted secondary endpoints that showed significant improvements for Gocovri in ON time without troublesome dyskinesia and significant decrease in OFF time compared with placebo. “Gocovri is the first Parkinson’s disease medicine proven in controlled trials to reduce both dyskinesia and OFF time in Parkinson’s disease patients receiving levodopa," Adamas pointed out.

Ironwood Hopes Duzallo Approval Will Unlock Lesinurad Value

FDA approved Ironwood Pharmaceuticals Inc.'s Duzallo, a fixed-dose combination of lesinurad and allopurinol, on Aug. 18 for treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate dose of allopurinol alone.

The Duzallo approval is key to Ironwood's plans for the URAT1 transporter inhibitor lesinurad, which it licensed from AstraZeneca PLC in mid-2016. (Also see "Duzallo Approval Opens Gout Opportunity For Ironwood" - Scrip, 21 Aug, 2017.) FDA approved lesinurad as Zurampic in December 2015 for use in combination with a xanthine oxidase inhibitor (XOI) like allopurinol or Takeda's Uloric (febuxostat); the label includes a box warning that acute renal failure has occurred with Zurampic and was more common when Zurampic was given alone.

AstraZeneca chose not to launch Zurampic, which had been the centerpiece of AZ's acquisition of Ardea Biosciences Inc., citing its lack of strategic fit and less-than-ideal profile. (Also see "Ironwood Buys AstraZeneca's Zurampic As Ideal Linzess Complement" - Pink Sheet, 26 Apr, 2016.) Ironwood conducted only a soft launch of Zurampic, waiting for the more convenient fixed-dose combination Duzallo.

Duzallo was approved on the basis of the same Phase III trials, CLEAR 1 and CLEAR 2, that supported the Zurampic NDA along with a pharmacokinetic study that compared the bioequivalence of the fixed-dose combination of lesinurad and allopurinol with co-administration of separate lesinurad and allopurinol tablets. (Also see "Keeping Track: New Indication For Lucentis; New Lesinurad Application From Ironwood" - Pink Sheet, 6 Jan, 2017.)