Keeping Track: Approvals For Xultophy, Soliqua And Darzalex; NDAs From Intarcia And GSK; Complete Response For Green Cross

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

Type 2 diabetes took center stage in the days before the US Thanksgiving holiday as FDA approved two GLP-1 agonist/basal insulin combinations – Sanofi's Soliqua and Novo Nordisk AS's Xultophy – and received a submission from Intarcia Therapeutics Inc. for an implantable GLP-1 mini-pump. Here’s your news in brief:

FDA's Center for Drug Evaluation and Research (CDER) also approved a new indication for Janssen Biotech Inc. and Genmab AS's multiple myeloma treatment Darzalex. The Center for Biologics Evaluation and Research issued a complete response letter (CRL) for an IV immunoglobulin from Green Cross Corp.

And GlaxoSmithKline PLC and Innoviva Inc. submitted a triple combination therapy for chronic obstructive pulmonary disease (COPD).

Here’s your news in less brief:

Novo Nordisk, Sanofi Insulin Combos Cross Finish Line Together

FDA approved both Novo's Xultophy 100/3.6 and Sanofi's Soliqua 100/33 pen injectors on Nov. 21, obviating the advantage Sanofi had hoped for when it used a priority review voucher to get Soliqua an earlier user fee goal date.

Both approvals are for narrower indications than originally proposed, reflecting the advice of FDA's Endocrinologic and Metabolic Drugs Advisory Committee. (Also see "Novo Nordisk, Sanofi Insulin Combo Products Clear US Regulatory Hurdles" - Pink Sheet, 22 Nov, 2016.) The agency resolved concerns about the difference in measurement between the insulin and GLP-1 components with labeling that reflects dosage based on units, followed by the corresponding number of insulin units and milligrams or micrograms of the GLP-1 agonist delivered in a given dose.

Xultophy, previously known as iDegLira, is a fixed-dose combination of Novo's basal insulin Tresiba (insulin degludec) and GLP-1 agonist Victoza (liraglutide). While the company sought an indication for all adults with type 2 diabetes mellitus, Xultophy is indicated only for adults with T2DM who are inadequately controlled on basal insulin (less than 50 units daily) or liraglutide (less than or equal to 1.8 mg daily).

Soliqua is similarly indicated for T2DM in adults inadequately controlled on basal insulin (less than 60 units daily) or lixisenatide. Sanofi sought an indication for use when both insulin glargine (the company's Lantus) and lixisenatide (the recently approved Adlyxin) is appropriate. Sanofi also sought to market Soliqua in disposable pen injectors at two different dosage strengths, but FDA approved only one presentation, a 3:1 ratio of insulin glargine units to micrograms of lixisenatide.

Risk management for both products reflects the GLP-1 component. Xultophy will be marketed with a Risk Evaluation and Mitigation Strategy consisting of a communication plan about the potential risks of medullary thyroid carcinoma and pancreatitis. Victoza is also subject to a REMS. Soliqua was not approved with a REMS, but is subject to a post-marketing requirement to assess a signal of risk of development of anti-drug antibodies that could potentially neutralize the function of lixisenatide. The study requirement was initially applied to lixisenatide with the July 27, 2016 approval of single-agent Adlyxin.

New Darzalex Claim Speeds Through FDA

FDA took only three months to approve expanded indications for Johnson & Johnsonsubsidiary Janssen Biotech and Genmab's Darzalex (daratumumab) that move use of the CD38-binding antibody earlier in the multiple myeloma treatment paradigm. The supplemental biologics license applications (sBLAs) had priority review user fee goal dates of Feb. 17, 2017.

FDA issued two approval letters for Darzalex on Nov. 21, for combination use with the proteasome inhibitor (PI) bortezomib (Millennium Pharmaceuticals Ltd.'s Velcade) and the steroid dexamethasone and for use with the thalidomide inhibitor immunomodulatory drug (IMiD) lenalidomide (Celgene Corp.'s Revlimid) and dexamethasone. Both regimens are indicated treatment of patients with multiple myeloma who have received at least one prior therapy. (Also see "Expanded US Approval Set To Take Janssen’s Darzalex Higher" - Scrip, 22 Nov, 2016.) Darzalex was initially cleared under accelerated approval in December 2015 for multiple myeloma patients who have received at least three prior lines of therapy including a PI or IMiD or who are PI and IMiD double refractory.

The trials supporting the relapsed MM approvals, the CASTOR and POLLUX studies, also earned breakthrough therapy designations (BTDs) for Darzalex in July 2016. (Also see "Keeping Track: Janssen Gets A Breakthrough Therapy Status, FDA Awards Two Orphan Drug Designations, Portola Lands A CRL" - Pink Sheet, 19 Aug, 2016.)

The sBLA submissions also included data from a Phase I study of daratumumab, pomalidomide, and dexamethasone in patients who have received at least two prior therapies including a PI and IMiD. FDA assigned the pomalidomide combination a standard review, with a user fee goal on June 17, 2017. (Also see "Keeping Track: FDA Rejects Mealtime Insulin, Antihistamine; Misses Goal For Another Opioid" - Pink Sheet, 14 Oct, 2016.)

Intarcia's ITCA 650 Aims To Be First Continuous Subcutaneous GLP-1 Agonist

Intarcia's ITCA 650 formulation of the GLP-1 agonist exenatide to treat type 2 diabetes is the first product using the company's Medici Drug Delivery System for once- or twice-yearly delivery of chronic medications to be submitted for FDA approval, the company emphasized in its Nov. 21 NDA submission announcement.

The subcutaneous delivery system features stabilization technology that keeps proteins, peptides and other molecules stabilized at or above human body temperature for three years or more, an osmotic mini-pump placed under the dermal layer of skin, and placement technology to guide a simple in-office procedure.

AstraZeneca PLC markets exenatide in its injectable Bydureon and Byetta lines for twice-daily and once-weekly self-injection.

The ITCA 650 NDA includes two mini-pump formulations, a 20 mcg/day three-month introductory dose and a 60 mcg/day six-month maintenance dose. The product was tested in four Phase III studies, FREEDOM-1, FREEDOM-1 HBL, FREEDOM-2 and the cardiovascular outcomes trial FREEDOM-CVO, that enrolled more than 5,000 subjects. The trial program demonstrated superior efficacy against placebo and Merck's oral DPP-4 antidiabetic Januvia (sitagliptin), Intarcia said.

The ITCA 650 NDA submission comes after multiple delays. (Also see "Intarcia Raises $215m As NDA For ITCA 650 Slips To Fourth Quarter" - Scrip, 16 Sep, 2016.) With a standard review, Intarcia can expect FDA action by September 2017.

GSK FULFILs Promise To Submit Triple COPD Combo Ahead Of Schedule

GSK and its partner Innoviva announced the submission an NDA for its once-daily closed triple combination therapy for COPD on Nov. 21, 18 months ahead of its original submission target in the first half of 2018. The product combines the inhaled corticosteroid (ICS) fluticasone furoate, the long-acting muscarinic antagonist (LAMA) umeclidinium, and the long-acting beta2 agonist (LABA) vilanterol in GSK's Ellipta dry powder inhaler.

The NDA is based on the FULFIL trial, one of two Phase III trials of the triple combo. In June, GSK reported that after discussions with FDA it had decided to move the NDA submission forward based on FULFIL and data from studies of the three components alone and in combination.

The FULFIL trial measured improvement in lung function and health-related quality of life compared with AstraZeneca's ICS/LABA Symbicort Turbohaler (budesonide/formoterol). An ongoing Phase III, the IMPACT trial, is testing the ability of FF/UMEC/VI to reduce the rate of exacerbations compared with two once-daily dual therapies, GSK's FF/VI product Breo and UMEC/VI combo Anoro.

FULFIL data was presented at the European Respiratory Society International Congress in September. The study met both co-primary endpoints, measuring lung function by change from baseline in FEV1 at 24 weeks and QoL using the St. George's Respiratory Questionnaire. A subset of patients received treatment for up to 52 weeks, and also met those endpoints. FULFIL also found a statistically significant and clinically meaningful reduction in the annual rate of moderate to severe exacerbations with the closed triple therapy compared to Symbicort.

Green Cross Must Rectify Manufacturing Deficiencies For IVIG-SN

Asian plasma protein manufacturing giant Green Cross' first immunoglobulin product submitted in the US received a complete response letter from FDA, the company announced Nov. 23. The issues "pertain only to chemistry, manufacturing and controls (CMC)," Green Cross said, and the company has a clear idea about what is needed to obtain approval.

Green Cross' I.V.-Globulin SN (IVIG-SN) is a plasma-derived human immunoglobulin G for IV administration for treatment of primary immunodeficiency disease (PID).

The company said its North American growth strategy will remain intact despite the delay because it originally expected to full advance into the US market in 2019, when Green Cross' new plant in Montreal, Canada starts operating at full capacity. Green Cross already markets IVIG-SN in Asia, South America and the Middle East. (Also see "US Approval Delay For Green Cross But Long Term Strategy Intact" - Scrip, 24 Nov, 2016.)

The Green Cross CRL is the second CRL for a an IVIG product issued by CBER this year. In July, ADMA Biologics Inc. received a CRL for RI-002, its IVIG for primary immune deficiency disease. (Also see "Keeping Track: Novartis, Calardius Pick Up Speed; ADMA Stumbles" - Pink Sheet, 5 Aug, 2016.)