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FDA Update: Roxadustat AdComm Decision Leads the Week


An advisory committee recommends against approving an anemia drug. Darzalex Faspro receives another indication, Bayer receives approval for Kerendia for chronic kidney disease, and FDA delays its decision on sNDAs for JAK inhibitor therapies for atopic dermatitis.

Advisory committee votes against approving anemia drug roxadustat. The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted on Thursday July 15, 2021, against recommending approval for FibroGen/AstraZeneca’s roxadustat for anemia in patients with chronic kidney disease (CKD). The committee voted 12-2 against approval in patients who are on dialysis and 13-1 against approval in patients who not on dialysis.

Safety issues were the biggest concern raised committee members. “I think we all felt challenged by the unmet need for alternatives in this population, but the safety concerns outweigh the desire to help meet the unmet need,” said committee member Julia B. Lewis, M.D., speaking specifically about patients who are on dialysis. “Those who voted 'no' are concerned about the adverse safety signal.” Lewis is professor of medicine at Vanderbilt University School of Medicine in Nashville.

"While we are disappointed with today's outcome, we believe the scientific evidence supports roxadustat approval in the United States and will work with the FDA as it completes its review of the New Drug Application for roxadustat," Enrique Conterno, chief executive officer of FibroGen said in a statement.

Roxadustat is hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) to market to treat anemia in patients with CKD. HIF-PHI drugs aim to restore production of the hormone erythropoietin and improve iron regulation; currently, the condition is treated by injections of epoetin alpha and darbepoetin alpha.

This application has had a rocky journey. Fibrogen submitted the New Drug Application for roxadustat tablets in December 2019 for the treatment of anemia associated with CKD in both dialysis-dependent and non-dialysis-dependent patients. The PDUFA date was March 20, 2021, which was already an extension from the original PDUFA date of December 20, 2020. This time agency officials asked for an advisory committee to review the NDA.

According to documents from the FDA ahead of the meeting, agency officials believed the data showed roxadustat demonstrated efficacy. The concern, agency official said, was the hemoglobin overcorrection especially in non-dialysis-dependent patients. Although data submitted demonstrated it was effectiveness in increasing hemoglobin levels, roxadustat tends to overshoot targets in patients who are non-dialysis-dependent.

Darzalex Faspro receives another indication. The FDA has approved Janssen’s Darzalex Faspro (daratumumab and hyaluronidase-fihj) in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy.

The approval follows the regulatory submission to the FDA in November 2020 and marks the sixth indication for Darzalex Faspro in the treatment of multiple myeloma. The approval is based on the results of the phase 3 APOLLO study. Results from this study were presented at the 2020 American Society of Hematology (ASH) Annual Meeting and were published in June 2021 in The Lancet Oncology. Investigators found that Darzalex Faspro reduced the risk of progression or death by 37%, compared with pomalidomide and dexamethasone. The most frequent serious adverse reactions were pneumonia (15%) and lower respiratory tract infection (12%). Fatal adverse reactions occurred in 7% of patients.

Bayer receives approval for Kerendia. The FDA has approved a first-in-class nonsteroidal mineralocorticoid receptor antagonist (MRA) to treat chronic kidney disease in patients with type 2 diabetes. Kerendia (finerenone) is approved to reduce the risk of sustained eGFR decline, kidney failure, cardiovascular death, non-fatal myocardial infarction and hospitalization for heart failure in adult patients with chronic kidney disease associated with type 2 diabetes.

The approval of Kerendia is based on the positive results of the pivotal phase 3 FIDELIO-DKD study, presented at the American Society of Nephrology’s (ASN) Kidney Week Reimagined 2020 and simultaneously published in the New England Journal of Medicine in October 2020, and follows Priority Review designation granted by the FDA in January 2021.

FDA grants full approval for Rezurock. Kadmon Holdings has announced that the FDA has approved Rezurock (belumosudil) for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (cGVHD) after failure of at least two prior lines of systemic therapy.

Rezurock is expected to be available by late August 2021. It is the first FDA-approved small molecule inhibitor of ROCK2, a signaling pathway that modulates inflammatory responses and fibrotic processes.

The approval is based on safety and efficacy results from ROCKstar (KD025-213), a randomized, open-label, multicenter pivotal trial of Rezurock in 65 patients with cGVHD who had received two to five prior lines of systemic therapy. The therapy achieved an overall response rate of 75% through cycle 7 day 1 of treatment with 6% of patients achieving a complete response and 69% achieving a partial response. Sixty-two percent (62%) of responders did not require new systemic therapy for at least 12 months following response.

Two JAK inhibitors miss PDUFA dates. Early Friday morning, two companies with supplemental New Drug Applications (sNDAs) awaiting FDA decisions on JAK inhibitors to treat atopic dermatitis announced the agency would miss their PDUFA dates. AbbVie announced its update on the sNDA for Rinvoq (upadacitinib) for the treatment of adults and adolescents with moderate to severe atopic dermatitis.

Rinvoq is a JAK inhibitor that is being studied in several immune-mediated inflammatory diseases. In August 2019, the therapy received FDA approval for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

Eli Lilly and Company and Incyte announced the missed PDUFA date sNDA for Olumiant (baricitinib) for the treatment of adults with moderate to severe atopic dermatitis (AD). Olumiant, an oral JAK inhibitor discovered by Incyte and licensed to Lilly, is approved for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) in more than 75 countries. It is also approved in more than 40 countries for the treatment of adults with moderate-to-severe AD who are candidates for systemic therapy.

In June, AbbVie had also announced that the sNDA for Rinvoq to treat psoriatic arthritis and ankylosing spondylitis would also miss its PDUFA date.

The delays to these applications appear to be part of the FDA’s ongoing assessment of JAK inhibitors. In January, Pfizer released results from the ORAL Surveillance, its post-marketing cardiovascular safety trial of Xeljanz (tofacitinib) in patients with rheumatoid arthritis.

This study compared Xeljanz with a TNF inhibitor and included 4,362 subjects who received study treatments. The primary analyses included 135 subjects with major adverse cardiovascular events (MACE) and 164 subjects with malignancies (excluding non-melanoma skin cancer). For tofacitinib, the most frequently reported MACE was myocardial infarction and the most frequently reported malignancy (excluding NMSC) was lung cancer. In those subjects with a higher prevalence of known risk factors for MACE and malignancy (e.g., older age, smoking), a higher occurrence of events was seen across all treatment groups.

Officials from AbbVie and Lilly both say they are confident in the data for their atopic dermatitis indications.

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