Keeping Track: Submissions Galore, Blincyto Supplemental Approval, And Priority Review For Opdivo/Yervoy Combo

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

A wave of submissions has arrived at the US FDA amid the dawn of spring, as drugmakers filed at least five new molecular entities (NMEs) and new biological entities (NBEs) with the agency.

Amgen Inc.'s Blincyto (blinatumomab) snagged accelerated approval for the treatment of adults and children with minimal residual disease (MRD)-positive acute lymphoblastic leukemia (ALL), becoming the first therapy approved for MRD.

FDA awarded Bristol-Myers Squibb Co.'s Opdivo (nivolumab)/Yervoy (ipilimumab) combination priority review for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).

Additionally, Novo Nordisk AS added safety and hypoglycemia outcomes data from its Phase III DEVOTE trial to the label of its long-acting human insulin analog Tresiba (insulin degludec injection).

Now, here's your news less briefly:

Spring Bursts With New Product Submissions

Sponsors announced the filings of at least five new applications for NMEs/NBEs as the calendar turned from winter to spring:

• AMAG Pharmaceuticals Inc.'s bremelanotide for the treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A first-in-class melanocortin 4 receptor agonist, bremelanotide has a novel mechanism of action that works by activating endogenous melanocortin pathways in the brain, which are involved in normal sexual desire and arousal responses. AMAG originally used desire and the number of satisfying sexual events (SSEs) as the coprimary endpoints. However, the drugmaker performed a post hoc upgrade of a measure of sexual distress from secondary to co-primary endpoint after FDA issued draft guidance on female sexual dysfunction (FSD) in 2016 (see sidebar for related story).

• Sanofi and Lexicon Pharmaceuticals Inc.'s sotagliflozin in combination with insulin therapy to improve glycemic control in adults with type 1 diabetes. Sotagliflozin met its primary endpoint in three Phase III trials, and became the first oral anti-diabetes drug to succeed in a Phase III study of type 1 diabetes patients with inadequate glycemic control. It also has a potential safety edge over safety differentiation from currently available SGLT2 inhibitors, including Invokana (canagliflozin), Jardiance (empagliflozin) and Farxiga (dapagliflozin). (Also see "Third Phase III Success Puts Lexicon/Sanofi's Sotagliflozin On Track For NDA Filing" - Scrip, 12 Jun, 2017.)

• NovImmune SA's emapalumab for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH). FDA previously awarded emapalumab, a fully human monoclonal antibody that inhibits interferon-gamma, breakthrough therapy designation based on preliminary Phase II data presented in December 2015 at the American Society of Hematology annual meeting. The data on children with primary HLH showed improvement in clinical and laboratory abnormalities of HLH, including CNS signs and symptoms. FDA additionally granted rare pediatric disease designation to emapalumab in 2017. A priority review would assign a PDUFA date of Nov. 29 or earlier
• Bayer AG and Loxo Oncology Inc.'s larotrectinib for the treatment of children and adults with unresectable or metastatic solid tumors with neurotrophic tyrosine receptor kinase (NTRK)-fusion proteins who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments. A tropomyosin receptor kinase (TRK) inhibitor, larotrectinib is slated to become the first novel oncology product specifically developed for a tissue-agnostic indication (see sidebar for related story). FDA has previously awarded larotrectinib breakthrough therapy status, orphan drug status and a rare pediatric disease designation. With priority review assumed, larotrectinib would have a goal date of Nov. 26 or earlier. Loxo is in charge of regulatory activities in the US, while Bayer is heading up the worldwide commercialization effort. (Also see "More Deals Like Loxo On The Cards As Bayer Ups Ante In Oncology" - Scrip, 6 Mar, 2018.)

• Catalyst Pharmaceuticals Inc.'s Firdapse (amifampridine) for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS). Deemed a breakthrough therapy in 2013, the neuronal potassium channel blocker has run into setbacks along the way, including FDA refusing to file the initial new drug application (NDA) in 2016 (see sidebar for related story). The initial NDA submission included an indication for congenital myasthenic syndromes (CMS), another rare neuromuscular disorder, but Catalyst is only pursuing the LEMS indication in the new submission, with a decision "not to overcomplicate the review of its NDA submission for LEMS with this second indication," the company explained in a March 29 statement. A priority review would position a user fee goal date of Nov. 29 or earlier.

Blincyto Becomes First Approved MRD Treatment

Amgen's bispecific CD19-directed CD3 T-cell engager Blincyto picked up accelerated approval for a supplemental indication from FDA for the treatment of adults and children with minimal residual disease MRD-positive ALL.

The approval specifically applies to patients in first or second complete remission with MRD greater than or equal to 0.1%.

Accelerated approval is based on results from the single-arm Phase II BLAST study, where Blincyto met the primary endpoint of a complete MRD response, the merits of which were heavily discussed at a March 7 advisory committee meeting. The Oncologic Drugs Advisory Committee ultimately voted 8 to 4 that Blincyto provides a potential benefit for patients with ALL in complete remission who meet the MRD criteria. (Also see "Amgen's Blincyto Has 'Potential Benefit' For MRD ALL, But Approval Chances Remain Unclear" - Pink Sheet, 7 Mar, 2018.)

Amgen has touted FDA's decision as a shift in the treatment paradigm of ALL and in other hematologic malignancies. (Also see "FDA Grants Blincyto Accelerated Approval Based On MRD Response Endpoint" - Pink Sheet, 30 Mar, 2018.)

"Until today, no therapy has been satisfactory in eradicating MRD or approved specifically to treat this high-risk patient population," David Reese, senior vice president of translational sciences and oncology at Amgen, said in a March 29 statement. "This approval not only supports the use of Blincyto earlier in the ALL treatment continuum, but represents a paradigm shift in the management of ALL.

Blincyto is additionally approved for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor (BCP) ALL.

Priority Review Lands Opdivo/Yervoy Combo July Goal Date For mCRC Indication

Bristol's Opdivo/Yervoy combination has scored priority review status for the treatment of adults with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan, putting the user fee goal date at July 10.

The drugmaker additionally announced in a March 27 statement that FDA awarded the immune-oncology (I-O)/I-O combination combo breakthrough therapy status for the indication in February, which would have come later than the Jan. 10 supplemental biologics license application (sBLA) filing date suggested by the PDUFA date. The sBLA is based on data from the ongoing Phase II CheckMate -142 study. (Also see "Breakthrough Status Arrives Late In Development Of Yervoy+Opdivo, Enfortumab Vedotin And Pedmark" - Pink Sheet, 30 Mar, 2018.)

The CheckMate-142 study has already supported a July 2017 accelerated approval for Opdivo as a single agent to treat MSI-H or dMMR mCRC in adults and children ages 12 and older who progressed following chemotherapy with a fluoropyrimidine, oxaliplatin, and irinotecan.

FDA is currently reviewing the Opdivo/Yervoy combination for the treatment of intermediate- and poor-risk patients with advanced renal cell carcinoma (RCC), with a user fee goal date of April 16, 2018. PS122163 The combination is currently approved for the treatment of patients with unresectable or metastatic melanoma.

Novo Adds DEVOTE Data To Tresiba Label, Withdraws SWITCH Data From Consideration

FDA has approved the addition of Phase III data from Novo's DEVOTE trial to the label of its long-acting human insulin analog Tresiba (insulin degludec injection), in which Tresiba demonstrated non-inferiority compared with insulin glargine U100 regarding major adverse cardiovascular events (MACE), the Danish drug maker announced March 26.

In the trial of 7,637 adults with type 2 diabetes at high cardiovascular risk, Tresiba also demonstrated a 40% statistically significant lower rate of sever hypoglycemia compared with insulin glargine U100.

Both the safety outcomes data and the hypoglycemia outcomes data were added to Tresiba's label.

Novo additionally disclosed that it has withdrawn from consideration its supplemental applications with data from its Phase IIIb SWITCH trials, which were submitted in September 2016. The SWITCH trials were designed to compare the safety and efficacy of Tresiba to Sanofi's Lantus (insulin glargine). (Also see "Tresiba Vs. Lantus: Novo Nordisk Scores A Win In Second Head-To-Head" - Pink Sheet, 24 Feb, 2016.)

The company did not explain why it had withdrawn the applications from consideration, aside from that the decision came following discussions with FDA. A Novo spokesman declined further comment.