FDA Updates: Week of June 27, 2022

In COVID-19 news, the FDA has declined an EUA request for Zyesami and Pfizer has submitted NDA for Pavlovid. The regulatory agency has accepted several applications, including an sBLA for Eylea in diabetic retinopathy and the NDA for palovarotene for a rare genetic disorder. The FDA also issued a CRL for a UTI therapy and extended the review of diabetes therapy. And finally, Gilead has resubmitted its twice-year HIV therapy.

FDA declines EUA request for Zyesami for COVID-19.

The FDA has declined to issue an emergency use authorization (EUA) for NRx Pharmaceuticals’ Zyesami (aviptadil) for COVID-19 respiratory failure in patients who had received remdesivir and continued to progress. The company had submitted this EUA application using data from a post-hoc subgroup analysis.

Zyesami is a synthetic form of human vasoactive intestinal peptide (VIP) is a substance produced by the body that helps protect cells against inflammatory conditions. Early data had suggested that VIP binds to receptors on Alveolar Type II cells in the lung, the same cells that bind the SARS-CoV-2 virus, which inhibit the replication of the SARS-CoV2 virus.

NRx data from one hospital showed that 16 of 19 COVID-19 patients treated with Zyesami under the Right to Try program recovered. And while the data from an NIH-sponsored ACTIV-3b (TESICO) trial showed a mortality advantage, that study did not meet the primary endpoint. In May 2022, that trial was stopped because it didn’t meet its objectives.

The company indicated in a press release that it will now focus on its bipolar drug candidate, NRX-101. The drug, which is being developed specifically for patients with acute bipolar disorder (requiring hospitalization) and sub-acute (not requiring hospitalization), had been paused during the pandemic.

Pfizer submits NDA for Paxlovid For COVID-19.

Pfizer has submitted a new drug application (NDA) to the FDA for approval of Paxlovid (nirmatrelvir and ritonavir) for patients who are at high risk for progression to severe illness from COVID-19. Paxlovid is currently authorized for emergency use for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older). The submission provides the longer-term follow-up data necessary for acceptance and potential approval.

The submission is supported by non-clinical and clinical data and includes results from the phase 2/3 EPIC-HR study, which found that, compared with placebo, treatment with Paxlovid reduced the risk of hospitalization or death from any cause by 88% in non-hospitalized, high-risk adult patients treated within five days of symptom onset. The results showed an 86% reduction in relative risk.

The submission is also comprised of the most recent analyses from the phase 2/3 EPIC-SR study, which included data from both vaccinated patients with, and unvaccinated patients without, risk factors for severe COVID-19. While the primary endpoint of self-reported, sustained alleviation of all symptoms for four consecutive days was not met, the data were supportive of the efficacy and safety data observed in EPIC-HR for use in patients at increased risk of progression to severe COVID-19 illness.

An integrated analysis of both studies showed an 84% reduction hospitalizations or death, compared with placebo and regardless of vaccination status, in patients with at least one risk factor for progression to severe COVID-19.

FDA accepts sBLA for Eylea in diabetic retinopathy.

The FDA has accepted for review Regeneron’s Eylea (aflibercept) injection supplemental biologics license application (sBLA) for an every 16-week 2 mg dosing regimen in patients with diabetic retinopathy. The target action date for the FDA decision is Feb. 28, 2023.

Eylea is a VEGF inhibitor that is injected into the eye. It is designed to block the growth of new blood vessels and decrease the ability of fluid to pass through blood vessels in the eye by blocking VEGF-A and placental growth factor. In 2019, the FDA approved Eylea for the treatment of all stages of diabetic retinopathy with a dosing regimen of every four or eight weeks after five initial monthly doses. Eylea is also approved for the treatment of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion and diabetic macular edema.

The supplemental application is supported by data from the phase 3 PANORAMA trial investigating every 8- and 16-week Eylea dosing regimens, versus sham, in patients with severe non-proliferative diabetic retinopathy without diabetic macular edema. The submission was further supported by data from the NIH-sponsored Protocol W trial investigating Eylea every 16-week dosing regimen in patients with moderate-to-severe non-proliferative diabetic retinopathy.

FDA issues complete response letter for UTI therapy.

The FDA has issued a complete response letter (CRL) for Spero Therapeutics’ new drug application (NDA) seeking approval for tebipenem HBr oral tablets. Spero was seeking an indication as a treatment of adult patients with complicated urinary tract infection (cUTI), including pyelonephritis, which is a UTI that has traveled to one of the kidneys.

In the CRL, the FDA indicated that Spero’s phase 3 study, ADAPT-PO, was insufficient to support approval and that an additional clinical study would be required. Spero officials said they intend to request a Type A meeting with the FDA to gain further insights as to the pathway forward for regulatory approval.

The CRL was anticipated based on feedback the company had received from the FDA in May 2022, in which the agency said there were potential deficiencies in the application.

FDA extends review of diabetes therapy teplizumab.

The FDA has extended its review of the biologics license application (BLA) for Provention Bio’s teplizumab for the delay of type 1 diabetes in at-risk patients. The extended user fee goal date is now Nov. 17, 2022; the original date was Aug. 17. 2022.

Teplizumab is humanized anti-CD3 monoclonal, and if approved, it will be the first disease-modifying therapy for type 1 diabetes.

In February, the company had resubmitted it application after receiving a complete response letter from the FDA in November 2021, indicating that regulators wanted to see a single, low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in healthy volunteers. Regulators wanted to see data that compared the 14-day dosing regimen for the planned commercial product with the exposure of clinical material used in prior clinical trials.

FDA accepts for priority review Ipsen’s NDA for palovarotene.

The FDA has accepted for priority review Ipsen’s resubmitted new drug application (NDA) for investigational palovarotene for the treatment of patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare genetic disorder. FOP is disorder in which bone develops in areas where it is not normally present, which is called heterotopic ossification. It can cause skeletal muscles and soft tissue to transform into bone.

Ipsen is seeking approval of palovarotene, an oral, selective retinoic-acid receptor gamma (RARγ) agonist for the prevention of heterotopic ossification. The FDA has assigned Dec. 29, 2022, as the Prescription Drug User Fee Act (PDUFA) goal date, which is on track with anticipated regulatory submission timelines.

The palovarotene NDA was initially accepted by the FDA for priority review on May 28, 2021, and Ipsen announced withdrawal of the NDA on Aug. 13, 2021, after a discussion with regulators. Additional analyses and evaluation of data collected from Ipsen’s phase III MOVE and FOP program would be required to complete the review process. It was agreed between Ipsen and the FDA that it would not be possible to complete this within the current NDA review cycle.

Gilead resubmits NDA of long-acting lenacapavir for HIV.

Gilead Sciences has resubmitted its new drug application (NDA) to FDA for lenacapavir for the treatment of patients with HIV-1 infection in heavily treatment-experienced patients.

In February 2022, the FDA had issued a complete response letter (CRL) for lenacapavir, citing chemistry manufacturing and controls (CMC) issues relating to the compatibility of lenacapavir with the proposed container vial. In December 2021, the FDA had placed a clinical hold on trials with lenacapavir. The agency had raised questions about vials made of borosilicate glass and their compatibility with lenacapavir solution. The concern was about the possibility of glass particles forming in the solution of lenacapavir.

The resubmission contains CMC data to support the compatibility of lenacapavir with an alternative vial type made from aluminosilicate glass.

Lenacapavir is a first-in-class, investigational long-acting HIV-1 capsid inhibitor designed to inhibit HIV-1 at multiple stages of its lifecycle and has no known cross resistance to other existing drug classes. If approved, lenacapavir would be the only HIV-1 treatment option administered twice-yearly.