Keeping Track: US FDA Clears Two More Biosimilars, First Non-Injectable Glucagon

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

On the heels of Amgen Inc. and Allergan PLC launching the first two oncology biosimilars in the US, the US Food and Drug Administration approved a pair of new biosimilars just days later: Pfizer Inc.'s Ruxience (rituximab-pvvr) and Samsung Bioepis Co. Ltd.'s Hadlima (adalimumab-bwwd).

Eli Lilly & Co. got the FDA's nod for its glucagon nasal powder Baqsimi as the first non-injectable emergency treatment for severe hypoglycemia.

Meanwhile, Vertex Pharmaceuticals Inc. is eyeing a broad approval for its elexacaftor regimen with the submission of the new drug application.

But it wasn't as good a week for some sponsors. Biohaven Pharmaceutical Holding Co. Ltd. received a complete response letter for its sublingual amyotrophic lateral sclerosis treatment Nurtec (riluzole), while Vanda Pharmaceuticals Inc. signaled that its product Hetlioz (tasimelteon) might also be running into an FDA stop sign in pursuit of a jet lag indication.

Now, here's your news in less brief:

FDA Approves Two Biosimilars On One Day

The FDA approved a pair of biosimilars on 23 July, bringing the total number of biologics cleared under the 351(k) pathway to 23. (See sidebar for the Pink Sheet’s new interactive chart of biosimilar submissions, approvals and launches.)

The 23 July approvals went to the most prolific sponsors of US biosimilars: Pfizer, which received approval for Ruxience, its biosimilar version of Roche’s Rituxan, and Samsung Bioepis, which received the green light for Hadlima, a biosimilar of AbbVie Inc.’s Humira.

First Non-Injectable Glucagon Approval Draws Woodcock's Attention

It's rare that top-level FDA officials chime in on individual drug approvals. But the agency's 24 July release announcing the green light for Lilly's nasal powder Baqsimi (glucagon) as the first non-injectable emergency treatment for severe hypoglycemia was notable enough to warrant a comment from Center for Drug Evaluation and Research director Janet Woodcock.

"There are many products on the market for those who need insulin, but until now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process," Woodcock said. "This new way to administer glucagon may simplify the process, which can be critical during an episode, especially since the patient may have lost consciousness or may be having a seizure."

The FDA simultaneously approved AptarGroup Inc.'s Unidose Powder System, which will be used as the single-use, intranasal delivery device for Baqsimi.

In two open-label crossover studies in 153 adults, Baqsimi demonstrated non-inferiority to intra-muscular glucagon in reversing insulin-induced hypoglycemia. And in a study of 48 pediatric patients, 100% of patients in both treatment arms achieved an increase in glucose ≥20mg/dL from glucose nadir within 20 minutes of glucagon administration.

Lilly, which acquired the drug from Locemia Solutions in 2015, said it will set a US list price of $280.80 for a one-pack and $561.60 for a two-pack. (Also see "Lilly Adds PhIII Intranasal Glucagon To Diabetes Arsenal" - Scrip, 13 Oct, 2015.) The initial user fee date was slated for April 2019, but Lilly submitted additional information requested late in the review cycle, which bumped the goal date back by three months.

At least one competitor is close on Lilly's heels, as Xeris Pharmaceuticals Inc.'s ready-to-use glucagon rescue pen Gvoke is positioned for FDA action this fall. (Also see " Keeping Track: Approvals For Polivy, Keytruda, FDA Applause For Biosimilars" - Pink Sheet, 14 Jun, 2019.) Additionally, Zealand Pharma AS' autoinjectable dasiglucagon is in Phase III development. (Also see "Phase III Data Put Zealand's Dasiglucagon On Track, But Behind Others, For Hypoglycemia Rescue" - Scrip, 19 Sep, 2018.)

March User Fee Date Likely For Vertex's Elexacaftor Regimen

Vertex announced the submission of its triple therapy regimen for cystic fibrosis on 22 July, likely positioning a priority review user fee goal date in March 2020 given the combination's breakthrough therapy designation (BTD).

The regimen specifically consists of elexacaftor (VX-445), a cystic fibrosis transmembrane conductance regulator (CFTR) corrector and a new molecular entity, combined with the components of its double therapy Symdeko, the CFTR corrector tezacaftor and CFTR potentiator ivacaftor. Vertex announced in May that it was opting to include elexacaftor in the regimen over its compound VX-659 primarily due to safety and tolerability considerations. (See sidebar.)

In two Phase III studies of patients 12 and older, the triple combination demonstrated statistically significant improvements on the primary endpoint of percent predicted forced expiratory volume in one second (ppFEV1) compared with the placebo regimen. One study evaluated patients with one F508del mutation and one minimal function mutation (het-min), while the other evaluated a population with two F508del mutations. (Also see "Vertex's CF Three-Drug Combo Excels In Phase III, But Filing Depends On Second Regimen's Results" - Scrip, 29 Nov, 2018.)

Vertex is eyeing a label that could target 90% of the global cystic fibrosis population by adding the het-min patient subpopulation and potentially all patients with an F508del mutation. (Also see "Vertex Selects VX-445 For CF Triple Therapy Due To Safety/Tolerability" - Scrip, 30 May, 2019.)

"The submission of the NDA is a major step toward our goal of bringing this medicine to the largest remaining group of people with CF that still do not have an approved Vertex medicine, as well as toward providing significantly enhanced benefits to patients with two F508del mutations," said Reshma Kewalramani, executive vice president and chief medical officer at Vertex.

The drugmaker noted that the triple combination received a BTD in May 2018.

Biohaven Hits Apotex After Drawing CRL For Nurtec

Apotex Inc. already took a public scolding from the FDA earlier this month after data integrity issues forced the drugmaker to withdraw 31 abbreviated new drug applications from the US market. Now it is taking heat from its industry partner Biohaven.

Biohaven announced 19 July that it received a CRL for its sublingual ALS treatment Nurtec, while pointing the finger at Apotex's Indian subsidiary. According to Biohaven, the only issue raised in the CRL is related to the manufacture of the active pharmaceutical ingredient by Apotex Pharmachem India Private Limited between 2014 and 2016 that was used for bioequivalence testing in 2017.

Apotex failed to provide Biohaven with information about the former's communications with the FDA over the manufacturing issues, Biohaven alleges.

"In the CRL, the FDA stated that it provided recommendations to Apotex regarding the information that would be needed to qualify previous API batches manufactured at Apotex during the time period in question," Biohaven states. "Apotex did not provide Biohaven with notice of the FDA communication, either during the course of its bioequivalence trial or during the submission of its 505(b)2 application for Nurtec (riluzole)."

Apotex did not return a request for comment.

In its release, Biohaven also points to Apotex's massive ANDA withdrawal resulting from its manufacturing woes. (Also see "Apotex Withdraws 31 ANDAs After Failing To Ensure Data Integrity At Two Indian Manufacturing Plants" - Pink Sheet, 9 Jul, 2019.)

"We are doing everything possible to work with the FDA and the API manufacturer to resolve this matter, which we believe to be more technical in nature," said Robert Berman, Biohaven's chief medical officer. "We believe that the quality issues surrounding the Apotex manufacturing facility do not affect the conclusions of our bioequivalence study, but will work collaboratively with the FDA to resolve this matter as quickly as possible."

Keytruda/Lenvima Combo Scores Third BTD

It's now a trio of BTDs for Merck & Co. Inc.'s Keytruda (pembrolizumab) and Eisai Co. Ltd.'s Lenvima (lenvatinib), which most recently nabbed the expedited pathway designation for the first-line treatment of patients with advanced unresectable hepatocellular carcinoma (HCC) not amenable to locoregional treatment, the companies announced on 23 July.

The BTD is based on interim results from the open-label, single-arm Phase Ib trial KEYNOTE-524/Study 116. According to an interim analysis presented in April at the 2019 American Association for Cancer Research annual meeting, the combination demonstrated an objective response rate of 36.7% as assessed by investigators per modified Response Evaluation Criteria in Solid Tumors (mRECIST).

Lenvima first garnered approval for the first-line treatment of unresectable HCC as a monotherapy in August 2018, when it became the first FDA OK for the front-line HCC setting in a decade. (Also see "First In 10 Years, But Lenvima's First-Line Liver Label Could Be Challenged Soon" - Scrip, 17 Aug, 2018.)

The FDA previously awarded the Keytruda/Lenvima combination a BTD in January 2018 for advanced and/or metastatic renal cell carcinoma and in July 2018 for advanced and/or metastatic non-microsatellite instability-high/proficient mismatch repair endometrial carcinoma, although the regimen is not yet approved for any indication.

Vanda Forecasts Potential CRL For Hetlioz's Jetlag Indication

It looks like a CRL might also be on the way for Vanda, which was looking to add an indication to the label of its melatonin receptor agonist Hetlioz for the treatment of jet lag disorder.

In a 22 July statement, Vanda said that the FDA communicated to the company on 19 July that the agency identified deficiencies that preclude discussion of labeling and postmarketing requirements at the current time. Vanda noted that the FDA did not list the specific issues in its communication.

The FDA will likely have a final decision soon, as the supplemental NDA has a user fee date of 16 August. (Also see "Keeping Track: US FDA Receives Submissions Galore As Year Ends" - Pink Sheet, 6 Jan, 2019.)

"Vanda anticipates receiving additional communication from the FDA identifying specific deficiencies in the sNDA," the company said. "Vanda hopes that it will be able to work expeditiously with the FDA to resolve any such deficiencies."

Hetlioz was first approved in 2014 for the treatment of non-24-hour sleep wake disorder. (Also see "FDA OK's Vanda’s Hetlioz for sleep disorder in blind" - Scrip, 1 Feb, 2014.)

Brinavess To Have An Advisory Committee Review …

It's been a long regulatory history for Correvio Pharma Corp.'s antiarrhythmic drug Brinavess (vernakalant hydrochloride, IV), and it will have at least one more obstacle to clear before landing FDA approval: an advisory committee meeting.

Correvio announced 25 July that the FDA accepted the resubmitted NDA for review and assigned a user fee date of 24 December, while noting that the agency is planning to convene an advisory panel to discuss the NDA.

Brinavess, designed for the rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults, has a history with the FDA that goes back more than a decade. The agency first declined to approve the drug in 2008, and it has since faced a slew of other development difficulties. (Also see "Keeping Track: US FDA Closes Out First Half Of 2019 With CRL For Edsivo, But A Burst Of Supplemental Approvals" - Pink Sheet, 29 Jun, 2019.)

… While Lumateperone Advisory Committee Gets Cancelled, For The Time Being

Meanwhile, the FDA cancelled the 31 July Psychopharmacologic Drugs Advisory Committee meeting for Intra-Cellular Therapies' schizophrenia treatment lumateperone, at least for the time being.

In a 23 July statement, Intra-Cellular said the cancellation was related to the submission of non-clinical study information requested by the FDA, and that the agency requires "sufficient time to review this new and any forthcoming information as they continue the NDA review." The company added that the additional information may result in an extension of the current 27 September user fee date. (Also see "Keeping Track: FDA Clears Motegrity And Second Herceptin Biosimilar, But Rebuffs SpecGx's Oxycodone " - Pink Sheet, 16 Dec, 2018.)

But an advisory committee meeting might still be in the cards. Intra-Cellular noted it has a meeting scheduled with the FDA "shortly" and that it will provide an update following the meeting.

Baxter To Launch Ready-To-Use Insulin Later This Year

Baxter International Inc. said on 22 July that it plans to launch its recently approved insulin product Myxredlin (insulin human in sodium chloride injection) "before the end of the year."

The company describes Myxredlin, which was approved on 22 June, as "the first and only ready-to-use insulin for IV infusion in the hospital and other acute care settings."

"When a patient requires intravenous insulin in the hospital, pharmacists have to manually admix insulin for treatment," said Robert Felicelli, Baxter's president of pharmaceuticals. "With the launch of Myxredlin, clinicians will have access to a convenient, reliable presentation of ready-to-use insulin that can help ensure faster delivery to patients, streamlined workflow for pharmacists and nurses, and less waste for hospitals."

A short-acting insulin, Myxredlin's labeled indication is to improve glycemic control in adults and pediatric patients with diabetes mellitus.