Keeping Track: Thumbs Up For Zulresso And Sunosi, Thumbs Down For Zynquista And IV Meloxicam

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

New molecular entities (NMEs) finally got back into the approval action after a drought of more than a month, as the US FDA gave the nod to Sage Therapeutics Inc.'s Zulresso (brexanolone) and Jazz Pharmaceuticals PLC's Sunosi (solriamfetol) as the fourth and fifth novel approvals of 2019.

But the news for NMEs wasn't all good, as Sanofi and Lexicon Pharmaceuticals Inc.'s type 1 diabetes drug Zynquista (sotagliflozin) was hit with a complete response letter (CRL).

A non-NME wasn't so lucky either, as Recro Pharma Inc.'s intravenous (IV) meloxicam also landed a CRL, marking the second time in 10 months the non-opioid painkiller has run into an FDA stop sign.

Additionally, Aimmune Therapeutics Inc.'s peanut allergy drug AR101 has finally hit the review queue after being held up by the five-week government shutdown, as the company announced that the biologics license application (BLA) will receive a 12-month standard review from FDA.

Now, here's your news in less brief:

Zulresso Approved With Spravato-Like REMS

Sage's Zulresso became the first FDA-backed postpartum depression (PPD) treatment on March 19, as the approval came with a Risk Evaluation And Mitigation Strategy (REMS) similar to that for Janssen Pharmaceutical Cos.'s recently approved treatment-resistant depression drug Spratavo (esketamine).

The REMS for each product has Elements to Assure Safe Use, including that:

• Pharmacies, practitioners, or health care settings dispensing the drug are specially certified;

• The drug is only dispensed to patients in certain health care settings;

• The drug is dispensed to patients with evidence or other documentation of safe-use conditions;

• Patients using the drug are subject to monitoring; and

• Patients using the drug are enrolled in a registry.

The two REMS also list similar procedures for health care settings to become certified to dispense the drugs. Zulresso's REMS, however, comes with a few additional materials, including a patient information guide and materials for training health care settings.

Zulresso's label contains a boxed warning for the risk of excessive sedation or sudden loss of consciousness during administration. Spravato, which was approved March 5, also carries a boxed warning, specifically for the risk for sedation and dissociation after administration, and also for potential for misuse and abuse. (Also see "Janssen’s Spravato Enters US Market With Enhanced REMS And Plans For A Monotherapy Trial" - Pink Sheet, 6 Mar, 2019.)

In two Phase III studies, one in patients with severe PPD and one in patients with moderate PPD, Zulresso achieved the primary endpoint of a significant mean reduction from baseline in the Hamilton Rating Scale for Depression total score at 60 hours compared with placebo. The Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee previously voted by a 17-1 margin that the benefits of the drug outweigh its risks at a joint panel in November 2018. (Also see "Sage's Brexanolone Could Be Transformative, But Only In Controlled Settings, US FDA Panel Says" - Pink Sheet, 2 Nov, 2018.)

Sage has set the list price for Zulresso, a one-time treatment, at $34,000. The launch is expected upon scheduling by the Drug Enforcement Administration (DEA), which is typically 90 days after an FDA approval decision. (Also see "Zulresso Is Sage’s First Step In Postpartum Depression Treatment" - Scrip, 19 Mar, 2019.)

Sunosi Approved With 150 Mg Maximum Dose

In approving Jazz's Sunosi, FDA set the maximum dose in the label at 150 mg, which may have allowed the drug to come with a cleaner label.

A dopamine and norepinephrine reuptake inhibitor, Sunosi was cleared March 20 to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA).

Jazz had initially been seeking approval for doses going up to 150 mg and 300 mg. However, the 300 mg dose provided only an incremental benefit in clinical studies while more severely increasing side effects, such as headache. The company subsequently decided not to seek approval for a 150 mg dose, which resulted in a three-month user fee date extension from December to March.

But the delay may have spared Jazz a black box warning on the label. SVB Leerink Analysts Ami Fadia, Sheldon Fan and Eason Lee write in a March 20 note that, "Our conversation with management confirmed that the company proactively made the request of choosing 150mg as the maximum recommended dose to the FDA last December, which caused the delay of the PDUFA date. We agree that this was a wise move as the 300mg dose may have come with a less favorable label."

The label still contains standard warnings for blood pressure and heart rate increases, as well as for psychiatric symptoms. The other most common adverse reactions listed are headache, nausea, decreased appetite, insomnia and anxiety. Labeling notes that "Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions," although it still includes clinical data for the 300 mg dose.

The Sunosi new drug application (NDA) was supported by four studies from the Phase III TONES clinical development program: one study evaluating excessive sleepiness in adults with narcolepsy (TONES 2), two studies evaluating excessive sleepiness in adults with OSA (TONES 3 and TONES 4) and an open-label, long-term safety and maintenance of efficacy study in the treatment of excessive sleepiness in patients with narcolepsy or OSA (TONES 5). Sunosi demonstrated statistically significant improvements on the co-primary endpoints of the maintenance of wakefulness test (MWT) and the Epworth and Sleepiness Scale (ESS) scores. The Patient Global Impression of Change (PGIc) scale was used as a secondary endpoint.

Jazz said that it plans to launch Sunosi once it receives a scheduling decision the Drug Enforcement Administration. The SVB Leerink analysts are expecting a Schedule IV designation.

Zynquista Draws CRL After Split Advisory Committee

Sanofi and Lexicon's type 1 diabetes drug Zynquista isn't seeing its good fortune from the UK reflected in the US just yet, as the companies announced March 22 that they received a CRL from FDA for their dual SGLT1 and SGLT2 inhibitor.

The companies did not comment on the specifics of the CRL for Zynquista, which previously received a positive opinion from the EMA's Committee for Medicinal Products for Human Use (CHMP) a few weeks earlier. (Also see "EU CHMP Backs Three Conditional Approvals & Several Treatment Firsts" - Pink Sheet, 1 Mar, 2019.)

"We've only just received the letter and have not had any discussions with the FDA regarding the content of the CRL," Lexicon CEO Lonnel Coats said in a March 22 investor call.

Zynquista was the subject of a split FDA panel meeting in January, when the Endocrinologic and Metabolic Drugs Advisory Committee voted 8-8 on the question of whether the drug's risks outweigh its benefits. (Also see "Sanofi's Sotagliflozin: Risk Of Ketoacidosis Divides US FDA Advisory Committee" - Pink Sheet, 17 Jan, 2019.)

The main area of concern centered on diabetic ketoacidosis risk, which was significantly higher among patients receiving Zynquista during clinical trials. (Also see "Sanofi's Sotagliflozin: Risk Of Ketoacidosis Divides US FDA Advisory Committee" - Pink Sheet, 17 Jan, 2019.)

It continues to be a sluggish start to 2019 for novel drug approvals, as FDA has only cleared five such products compared to at least four CRLs. (Also see "Keeping Track: Rebuff Of Iclaprim Creates Early Pileup Of CRLs For Novel Drugs" - Pink Sheet, 18 Feb, 2019.)

Recro Lands Second CRL For IV Meloxicam

The week's CRL news also spilled over to the non-NME front, as FDA issued its second rebuff of Recro's IV meloxicam, a non-opioid pain killer.

In a March 22 announcement, Recro said that FDA's comments in the second CRL "focused on onset and duration of IV meloxicam, noting that the delayed onset fails to meet the prescriber expectations for intravenous (IV) drugs." Additionally, the agency "cited regulatory concerns about the role of IV meloxicam as a monotherapy in acute pain, as well as how it would meet patient and prescriber needs in that setting, given the FDA's interpretation of the clinical trials data," according to the company.

"The company strongly disagrees with FDA's interpretation and its views on the clinical utility of IV meloxicam in the acute pain setting," Recro added, noting that it will request a meeting with FDA to resolve the deficiencies.

IV meloxicam first struck out at FDA in May 2018, when the agency felt that data from ad hoc analyses and selective secondary endpoints suggested an inadequate analgesic effect. FDA also raised questions related to chemistry, manufacturing and controls (CMC), although no CMC issues were identified in the second CRL, Recro added. (Also see "Keeping Track: Thumbs Up For Doptelet And Palynziq, Thumbs Down For Methylene Blue MMX And Meloxicam" - Pink Sheet, 28 May, 2018.) and (Also see "Keeping Track: J&J Esketamine, Sanofi Caplacizumab Lead Off September Submissions; US FDA Says No To Nucala" - Pink Sheet, 9 Sep, 2018.)

Breakthrough-Designated AR101 Gets Standard Review

Despite its breakthrough therapy status, Aimmune's peanut allergy candidate AR101 will get a standard 12-month review from FDA, the company announced March 18.

FDA's review of AR101, specifically designed as a treatment to reduce the risk of anaphylaxis following accidental exposure to peanut, may take until late January 2020, according to the company. The agency previously awarded the product breakthrough therapy designation in June 2015 for peanut-allergic children and adolescents ages 4 to 17. (Also see "Keeping Track: Dueling 'Breakthroughs' For Peanut Allergy" - Pink Sheet, 22 Jun, 2015.) The standard review comes as a surprise, as products with breakthrough status almost always awarded a priority review.

Aimmune added that FDA expects to convene an advisory committee to assess the BLA.

The standard review is another moment of bad luck for the AR101 biologics license application (BLA), which has already been delayed by the five-week government shutdown. Aimmune submitted the BLA Dec. 21, the day before the shutdown began. However, FDA halted its review with the lapse in appropriations, as allergenic products are not covered by user fees, meaning the agency cannot dedicate resources to them during the shutdown. (Also see "US FDA’s Biologics Center Faces Exciting 2019 After Quiet Year For Novel Approvals" - Pink Sheet, 21 Jan, 2019.)

FDA Commissioner Scott Gottlieb also appeared to take a shot Aimmune during the shutdown after the company reported in a Jan.14, 2019 8-K filing that the agency would not review the BLA until the funding lapse ended, even though the application was submitted before the shutdown started. Gottlieb took to Twitter the same day to explain that "for products not covered by a user fee program, like most blood and allergenic extract products, FDA does not have carryover user fee funding to continue reviewing pending or accepting new applications." The commissioner added with a Jan. 15 tweet that "there are also some parties who are using the excuse of the shutdown to advance misleading narratives."

Aimmune said it was under the impression that AR101 was covered by a user fee program. A company spokesperson told the Pink Sheet that "Aimmune did submit the BLA for AR101 under the user fee pathway on December 21, 2018, and paid the fee prior to that, based on our understanding of the regulatory path for the drug." In another Jan. 15 tweet, Gottlieb explained that "sometimes it’s the case that companies will try to file under pathways that aren’t open to them."

Boehringer Eyes Second Rare Lung Disease Indication For Ofev

With a supplemental new drug application (sNDA) submission to FDA, Boehringer Ingelheim GmbH is eyeing an approval for its kinase inhibitor Ofev (nintedanib) to treat patients with systemic sclerosis associated interstitial lung disease (SSc-ILD) in what would be the drug's second indication for a rare lung disease.

Systemic sclerosis is characterized by the thickening and scarring of connective tissue throughout the body, which can cause scarring of the skin, lungs, heart and kidneys, Boehringer says. Ofev received orphan drug designation for the indication in July 2016.

There is not yet a FDA-approved drug for systemic sclerosis. A priority review would position an approval decision for Sep. 18, 2019 or earlier. Clinical trial results will be presented at the American Thoracic Society Congress in May, Boehringer noted.

Ofev was first approved in 2014 for the treatment of idiopathic pulmonary fibrosis, a rare, chronic disease that results in the scarring of the lungs. (Also see "It’s A First (And Second) For IPF: Two Drugs Approved By FDA" - Pink Sheet, 16 Oct, 2014.)