Keeping Track: Recarbrio Approval Highlights Two-Week Roundup

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

We have two weeks of drug development updates coming your way, so you won't want to miss this edition. Here's your news in brief:

Merck & Co. Inc.'s Recarbrio became the 15^th novel drug/therapeutic biologic approval of 2019, landing a narrow indication for complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI).

A supplemental approval went to Celgene Corp.'s Otezla (apremilast), making it the first US-approved drug to treat oral ulcers associated with Behçet’s disease.

But AstraZeneca PLC’s Farxiga (dapagliflozin) became the second SGLT2 inhibitor to bite the dust on a type 1 diabetes claim this year, as the company announced it received a complete response letter from the US Food and Drug Administration.

Dicerna Pharmaceuticals Inc.'s added some intrigue to the developmental competition in the primary hyperoxaluria type 1 (PH1) space by becoming the second sponsor to announce a breakthrough therapy designation (BTD) for the indication; the recent honor went to Dicerna's RNA interference (RNAi) candidate DCR-PHXC.

Sponsors also made a burst of announcements related to submissions and filings of novel product candidates, including for Novartis AG's crizanlizumab, Seattle Genetics Inc. and Astellas Pharma Inc.'s enfortumab vedotin and Horizon Therapeutics PLC's teprotumumab.

Now, here's your news in less brief:

Approval For Recarbrio Comes With Labeling Safeguards

In becoming only the second novel infectious disease drug approval of 2019, Merck's combination antibacterial Recarbrio (imipenem, cilastatin and relebactam) picked up a narrow approval 17 July for the treatment of adults with cUTI and cIAI caused by susceptible gram-negative bacteria.

Labeling restricts use of Recarbrio to such patients who have limited or no alternative treatment options and includes a statement reading that, "Approval of these indications is based on limited clinical safety and efficacy data." The drug is further contraindicated for patients with a history of known severe hypersensitivity to any of the active ingredients.

A three-drug combination injection, Recarbrio combines relebactam, a beta-lactamase inhibitor, with the penem antibacterial imipenem and the renal dehydropeptidase inhibitor cilastatin, which are the active ingredients in Merck's antibacterial Primaxin. The addition of relebactam helps to restore the activity of imipenem against resistant bacterial pathogens. (Also see "Merck And The 'Strange Business' Of Antibiotics" - Scrip, 17 May, 2019.)

The Recarbrio new drug application was supported in part by previous findings of safety and efficacy for the imipenem/cilastatin combination in the treatment of cIAI and cUTI, while relebactam's specific contribution was demonstrated by data from in vitro studies and animal models of infection. Safety was further studied in a cUTI trial of 298 patients and a cIAI trial of 347 patients. (Also see "Keeping Track: CDER Approves Its First Two Novel Agents Of 2019" - Pink Sheet, 10 Feb, 2019.)

Ed Cox, director of the FDA's Office of Antimicrobial Products, touted the approval as an addition to the toolbox for fighting infectious diseases in the agency's press release, but he also emphasized the drug's narrow indication.

"It is important that the use of Recarbrio be reserved for situations when there are limited or no alternative antibacterial drugs for treating a patient’s infection," Cox said.

Recarbrio was designated a qualified infectious disease product (QIDP) for the indications in 2014, which resulted in a priority review for the NDA. The drug is also under development for patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP), for which it also has QIDP status. (Also see "Merck's relebactam dubbed qualified infectious disease product " - Scrip, 5 Sep, 2014.)

A Merck spokesperson told the Pink Sheet that the drugmaker expects to launch Recarbrio by the end of 2019, and that it will not disclose pricing information until then.

Another Complete Response Letter For An SGLT2 Inhibitor In Type 1 Diabetes

AstraZeneca’s SGLT2 inhibitor Farxiga received a CRL from the FDA for a new indication in type 1 diabetes, the company announced on 5 July, making it the second SGLT inhibitor to be rebuffed for a type 1 diabetes claim this year.

Sanofi disclosed a CRL for Zynquista (sotagliflozin), its dual SGLT1 and SGLT2 inhibitor, in March 2019 for a similar indication to Farxiga: adjunctive use with insulin to improve glycemic control in adults with type 1 diabetes when insulin alone fails to control blood sugar adequately. (Also see "Keeping Track: Thumbs Up For Zulresso And Sunosi, Thumbs Down For Zynquista And IV Meloxicam" - Pink Sheet, 24 Mar, 2019.)

While neither AstraZeneca nor Sanofi disclosed the reasons behind the CRLs, Datamonitor Healthcare analyst Michael Haydock said that “like Zynquista, I suspect that Farxiga will have been rejected largely based on concerns about increased diabetic ketoacidosis risk.” DKA was a key issue in the FDA advisory committee’s divided vote on approvability of Zynquista. (Also see "Sanofi's Sotagliflozin: Risk Of Ketoacidosis Divides US FDA Advisory Committee" - Pink Sheet, 17 Jan, 2019.)

In the pivotal DEPICT clinical program for Farxiga in type 1 diabetes, the drug significantly lowered HbA1c compared with placebo, but DKA events were more frequent in the Farxiga arm. In DEPICT1, the DKA rate was 4% and 3.4% for the two Farxiga dose arms vs 1.9% on placebo at 52 weeks; in DEPICT2, the DKA rate was 4.1% and 3.7% for Farxiga and 0.4% for placebo. (Also see "AstraZeneca’s Farxiga Fails To Get FDA OK As Insulin Supplement In Type 1 Diabetes " - Scrip, 15 Jul, 2019.)

New Otezla Indication Comes As Bristol Looks To Divest Drug

As Bristol-Myers Squibb Co.looks to divest Celgene's drug Otezla ahead of the mega merger, the phosphodiesterase 4 (PDE4) inhibitor picked up a new indication 19 July to treat oral ulcers associated with Behçet’s disease, a chronic and rare inflammatory disorder that affects multiple parts of the body.

The FDA noted in a tweet that it is the first agency-approved treatment for the disease's common symptom.

Celgene reported data from the Phase III RELIEF study in February 2018, where Otezla achieved statistically significant reductions in oral ulcers compared with placebo through week 12.

First approved in 2014, Otezla also carries indications for adults with active psoriatic arthritis and patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. (Also see "Celgene’s Otezla OK’d in plaque psoriasis" - Scrip, 24 Sep, 2014.)

But while Otezla was supposed to be part of the large combined immunology and inflammation franchise resulting from Celgene's merger with Bristol, the latter recently announced it will divest the drug to secure faster approval from the Federal Trade Commission for the merger. (Also see "In Merger Plot Twist, BMS Needs A Buyer For Celgene's Otezla, Raising New Questions" - Scrip, 24 Jun, 2019.)

Dicerna's DCR-PHXC Heats Up PH1 Arena With BTD

There is not yet an FDA-approved drug for hyperoxaluria, although Dicerna's DCR-PHXC became the second to receive a breakthrough therapy designation (BTD) for the treatment of patients with PH1.

In the 15 July announcement, Dicerna describes DCR-PHXC as "the only RNAi investigational drug in development for the treatment of all types of primary hyperoxaluria," which is a family of rare, inherited disorders of the liver that often lead to kidney failure. Featuring Dicerna's GalXC RNAi technology platform, the drug candidate "selectively silences" lactate dehydrogenase A enzyme in animal models, which blocks excess production of oxalate, according to the company.

The drugmaker recently reported Phase I data from the PHYOX1 trial in June, which evaluated DCR-PHXC in patients with PH1 and PH type 2 (PH2). PH1 patients receiving single doses of 3.0mg/kg, 6.0mg/kg and 1.5mg/kg achieved mean maximal reductions of 24-hour urinary oxalate of 71%, 66% and 48%, respectively, while PH2 participants achieved a mean maximal reduction of 42%.

Dicerna initiated its Phase II pivotal trial PHYOX2 in May after reaching an agreement with the FDA to study the primary endpoint of 24-hour urinary oxalate burden in PH1 and PH2 patients, as measured by the time-weighted standardized area under the curve from day 90 to 180.

The pipeline for hyperoxaluria drugs remains slim, with only six total candidates in active development, according to Biomedtracker. However, Alnylam Pharmaceuticals Inc.'s lumasiran, which is in Phase III development for PH1, also received a BTD for the indication in 2018. (Also see "Keeping Track: A Burst Of Breakthroughs, A Priority Review For Keytruda, And Some Supplemental Submissions" - Pink Sheet, 18 Mar, 2018.)

Dicerna separately implied in its July announcement that it might be seeking a BTD for DCR-PHXC for the treatment of PH2 and PH type 3 (PH3).

"In its communication to Dicerna, the FDA also conveyed its determination that PH type 2 (PH2) and PH type 3 (PH3) meet the criteria for a serious or life-threatening disease or condition, based on the Agency’s standards," the release states. "The Company will continue its ongoing dialogue with the FDA regarding endpoints for studies of DCR-PHXC in patients with PH2 and PH3, as part of the Phyox clinical development program."

One of the parameters for receiving the BTD is that the drug is designed for serious or life-threatening conditions.

Novartis' Crizanlizumab BLA Targets Prevention Of Sickle Cell Crises

Novartis’ crizanlizumab is in line for FDA action in January 2020, based on the company’s 16 July announcement of priority review status for the biologics license application for prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). Crizanlizumab would be “the first monoclonal antibody targeting the P-selectin mediated multi-cellular adhesion in sickle cell disease,” Novartis pointed out.

Crizanlizumab received a breakthrough therapy designation for the indication in January 2019, based on data from the Phase II SUSTAIN trial evaluating a once-monthly infusion of the P-selectin-binding antibody. (Also see "Keeping Track: A Week Of Calm As Shutdown Drags On" - Pink Sheet, 12 Jan, 2019.) SUSTAIN is part of the SENTRY clinical program, which also includes the Phase II SOLACE trials in pediatric and adult SCD patients and the Phase III STAND trial.

The BLA is also supported by the SUSTAIN trial, which found that crizanlizumab reduced the median annual rate of VOCs leading to healthcare visits by 45.3% compared with placebo. “Clinically significant reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype or hydroxyurea use,” Novartis reported. The company highlighted “a greater than two-fold increase in the percentage of patients who did not experience any VOCs vs placebo (36%vs 17%)” and a “three-fold longer median time to first VOC vs placebo (4.07 vs 1.38 months).”

Crizanlizumab is poised to be the first drug in a coming wave of candidates for SCD, which has long been an underserved illness. Global Blood Therapeutics expects to complete a rolling NDA submission in the second half of 2019 for voxelotor, an allosteric modifier of hemoglobin structure that also holds a BTD. Voxelotor, a once-daily oral therapy, has the potential to be disease modifying, the company says; the NDA will seek accelerated approval for treatment of SCD. Pfizer and GlycoMimetics’ pan-selectin inhibitor rivipansel is being studied for acute treatment of VOC in the Phase III RESET trial, which completed enrollment in May.

Enfortumab Vedotin Bladder Cancer BLA Aims For Post-PD-1/L1, Post-Chemo Setting

Seattle Genetics and Astellas announced the submission of a BLA for enfortumab vedotin in urothelial cancer on 16 July, setting the nectin-4-targeting antibody-drug conjugate up for a likely March 2020 priority review user fee goal.

Astellas and Seattle Genetics are seeking accelerated approval of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The BLA indication is slightly narrower than enfortumab BTD for locally advanced or metastatic urothelial cancer who previously were treated with checkpoint inhibitors. (Also see "Breakthrough Status Arrives Late In Development Of Yervoy+Opdivo, Enfortumab Vedotin And Pedmark" - Pink Sheet, 30 Mar, 2018.)

The BLA is based on the first of two cohorts in the pivotal Phase II EV-201 trial, the sponsors said. Investigators presented updated data from cohort 1 of EV-201 at the recent American Society of Clinical Oncology meeting, showing a confirmed 44% objective response rate and median survival time of 11.7 months. Most responses occurred within the first cycle of treatment. (Also see "So Far, Still So Good For Seattle Genetics/Astellas’ Bladder Cancer ADC" - Scrip, 4 Jun, 2019.)

The EV-201 trial continues to enroll urothelial carcinoma patients in cohort 2, which includes patients who have not received platinum chemotherapy or who are ineligible for cisplatin. A confirmatory Phase III trial, EV-301, started in mid-2018 and will randomize 550 patients to enfortumab vedotin or chemotherapy (docetaxel, vinflunine or paclitaxel, determined prior to randomization).

Priority Review Likely For Horizon's TED Treatment Teprotumumab

Horizon is eyeing a priority review for its newly submitted teprotumumab BLA with the hope to secure the first FDA approval for an active thyroid eye disease treatment, the company announced 10 July.

The BLA submission for the breakthrough-designated teprotumumab, a monoclonal antibody and a targeted inhibitor of the insulin-like growth factor 1 receptor, is supported by the Phase III OPTIC study, where 82.9% of treatment recipients achieved a 2 mm or more reduction in proptosis (bulging of the eye) compared with 9.5% of placebo recipients. (Also see "Horizon Pharma Sees Mid-2019 BLA For Tepro After Solid Phase III TED Data" - Scrip, 1 Mar, 2019.)

Teprotumumab also holds orphan drug status and fast track designation. A priority review would position a user fee goal date for March 2020 or earlier.

A Slew Of Standard Reviews

The past two weeks also came with a series of standard review announcements from sponsors, including for two novel entities:

• Neurocrine Biosciences Inc.'s opicapone, as an adjunctive treatment to levodopa/carbidopa for "off" episodes in patients with Parkinson's disease. The FDA set a user fee date of 26 April 2020 for the novel drug candidate. The role of opicapone, an oral, selective catechol-O-methyltransferase (COMT) inhibitor, is to "prolong the benefits" of levodopa and help patients maintain a longer "on" time where motor symptoms are better controlled, Neurocrine chief medical officer Eiry Roberts explained in a 10 July statement. The randomized, double-blind, placebo-controlled BIPARK-1 and BIPARK-2 Phase III trials supporting the NDA evaluated opicapone using the primary endpoint of change from baseline in absolute time in the "off" state, as measured by patient diaries. 

• Sanofi's isatuximab for the treatment of patients with relapsed/refractory multiple myeloma. The BLA, which has a user fee date of 30 April 2020, is supported by the open-label, Phase III ICARIA-MM trial, where isatuximab extended progression-free survival in combination with Celgene's Pomalyst (pomalidomide) and low-dose dexamethasone, versus Pomalyst and dexamethasone alone. (Also see "Sanofi Poised To File Isatuximab In Multiple Myeloma, Going Up Against J&J's Darzalex" - Scrip, 5 Feb, 2019.) Isatuximab would be the second FDA-approved CD38-targeting antibody behind Johnson & Johnson/Genmab AS's Darzalex (daratumumab).

• Allergan PLC's Bimatoprost Sustained-Release (SR) for the reduction of intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension. If approved, Bimatoprost SR "would be the first-in-class sustained-release, biodegradable implant for the reduction of intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension," the company said in a 17 July statement. In the two Phase III ARTEMIS trials totaling 1,122 patients, Bimatoprost SR demonstrated non-inferiority with timolol, reducing intraocular pressure by 30% over a 12-week period. The user fee date is scheduled in the first half of 2020, according to Allergan. The company currently has approvals of bimatoprost as a topical solution under the brand name Latisse and as an ophthalmic solution under the brand name Lumigan.

• Six supplemental BLAs to update the dosing frequency of Merck's Keytruda (pembrolizumab). Merck submitted the sBLAs specifically for approval of a 400mg dosing option over 30 minutes every six weeks for the indications of melanoma, classical Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma, gastric cancer, hepatocellular carcinoma and Merkel cell carcinoma. Keytruda is currently labeled for 200mg dosing every three weeks. The sBLAs have a user fee date of 18 February 2020.

• Horizon's Procysbi (cysteamine bitartrate) delayed-release oral granules in in packets. A cystine-depleting agent, Procysbi is currently approved as a delayed-release capsule for the treatment of adults and pediatric patients age 1 and older with nephropathic cystinosis. The new dosage form "would provide patients and their caregivers with the option of opening a packet containing small, compact granules and sprinkling on certain foods and juice (or administering through a feeding tube)," the company explains in an 18 July release. A user fee date is scheduled in 2020, the company added, which will likely be March 2020 or earlier.

Teva Takes Its Advair Competitor Digital

Teva Pharmaceutical Industries Ltd. announced 15 July that it extended the use of its digital inhaler platform to the company’s AirDuo fixed-dose combination of the inhaled corticosteroid (ICS) fluticasone and the long-acting beta2 adrenergic agonist (LABA) salmeterol with FDA approval of AirDuo Digihaler for maintenance treatment of asthma in patients 12 and older. The FDA approved AirDuo with the Respiclick inhaler in January 2017, allowing Teva to offer a non-interchangeable competitor with the same active ingredients as GlaxoSmithKline PLC’s blockbuster Advair Diskus. (Also see "Teva's AirDuo Authorized Generic Priced At A 70% Discount To Advair" - Scrip, 20 Apr, 2017.)

The breath-actuated Digihaler “contains built-in sensors that detect when the inhaler is used and measure inspiratory flow rates,” Teva explained. The data is sent via Bluetooth to a companion mobile app. “Patients can review their data over time, and if desired, share it with their healthcare providers,” Teva said. The app can also be used to schedule reminders to take AirDuo Digihaler as prescribed.

The Digihaler was introduced with the FDA’s approval of Teva’s ProAir (albuterol) Digihaler in December 2018 for treatment and prevention of bronchospasm. Teva made the device available in 2019 through limited "early experience" programs in partnership with healthcare systems to gather real-world experience, with a national US launch planned for 2020. (Also see "Teva Obtains Approval For ProAir Digihaler In The US" - Generics Bulletin, 2 Jan, 2019.) With the recent approval of AirDuo Digihaler, Teva will be able to offer both acute and maintenance asthma treatments with the digital component.

Gadovist Approval Brings Contrast To Cardiac MRI

FDA approval of a new indication for Bayer AG’s Gadavist (gadobutrol) makes the gadolinium-based contrast agent (GBCA) the first contrast agent approved for use with cardiac magnetic resonance imaging (CMRI) for coronary artery disease, the company said. Coronary artery disease is “the most common form of heart disease in the world,” Bayer noted.

The FDA approved a supplemental NDA on 12 July for use of Gadavist in CMRI to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease. The FDA originally approved the GBCA in 2011 for use with diagnostic MRI to assess disruptions in the blood-brain barrier and central nervous system vasculature; Gadavist received its first indication for cardiac care in 2016 for use with magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease.

The new indication rests on two prospective, open-label, non-randomized, blinded-read Phase III studies assessing the diagnostic results of Gadavist-enhanced CMRI for evaluation of significant coronary artery disease.

Janssen Eyes Subcutaneous Formulation Approval For Darzalex

Darzalex recipients may soon have a subcutaneous option for the multiple myeloma treatment, as Janssen Pharmaceutical Cos. announced 12 July that it submitted a BLA for the new formulation.

In the Phase III COLUMBA study, the subcutaneous formulation demonstrated non-inferiority with the approved intravenous formulation on the co-primary endpoints of overall response rate and maximum Ctrough concentration. The BLA also includes data from the Phase 2 PLEIADES study, Janssen said.