March 2024 decisions expected from the FDA

Your monthly synopsis of new drugs expected to hit the market

February 14, 2024

Your monthly synopsis of new drugs expected to hit the market

FDA DECISIONS EXPECTED

At Prime Therapeutics (Prime), we’ve positioned ourselves to best prepare our clients to manage new drugs. Our clinical and trade relations teams keep a keen eye on drugs likely to be approved by the United States (U.S.) Food and Drug Administration (FDA).

Drug pipeline for March 2024:

February‒March 2024: donanemab

Eli Lilly is awaiting FDA decision for their immunoglobulin G1 (lgG1) antibody donanemab for the treatment of early symptomatic Alzheimer’s disease. This is the second review for donanemab by the FDA. In January 2023, the Agency issued a Complete Response Letter (CRL) for Accelerated Approval requiring more data in patients (≥ 100) who received the drug for ≥ 12 months. Since that time, final results of the randomized, double-blind, phase 3 TRAILBLAZER-ALZ 2 trial (n=1,736) were published. The trial demonstrated that, among patients with early symptomatic Alzheimer’s disease and amyloid and tau pathology, donanemab administered intravenously (IV) every 4 weeks, slowed the clinical progression of Alzheimer’s disease by 23% compared to placebo.¹ If approved, donanemab will be the third amyloid-targeting disease-modifying therapy (DMT) for early Alzheimer’s disease to gain FDA approval, following aducanumab-avwa (Aduhelm®) and lecanemab-irmb (Leqembi®); however, Biogen recently announced that they will halt marketing of Aduhelm in order to focus resources on Leqembi, which is administer IV once every 2 weeks.²

03/08/2024 glatiramer acetate depot

The FDA is reviewing the 505(b)(2) new drug application (NDA) for Viatris’ glatiramer acetate depot 40 mg, which is administered as a once-monthly intramuscular injection for the treatment of relapsing forms of multiple sclerosis (RMS). The NDA is supported by data from a 12-month, double blind, placebo-controlled, phase 3 trial (NCT04121221) that demonstrated a statistically significant 30.1% reduction in the annualized relapse rate compared to placebo (p=0.0066).³ Glatiramer acetate is also available as brand Copaxone® and generic versions that are administered by subcutaneous (SC) injection as 20 mg once daily or 40 mg three times per week. Safety data from the phase 3 trial were compared with Copaxone’s GLACIER study data and revealed that the annualized rate of injection site reactions was much lower with glatiramer acetate depot compared to once-daily and thrice-weekly Copaxone (2.43 versus 70.4 and 35.2, respectively).4 In addition, compared to data from Copaxone’s GALA trial, the rate of serious adverse events was in 3.7% with glatiramer acetate depot and 4.5% with thrice-weekly Copaxone.

03/14/2024: resmetirom

Madrigal is seeking Accelerated Approval for their thyroid hormone receptor (THR)-β selective agonist resmetirom for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis. Resmetirom treats the underlying cause of NASH by decreasing liver fat, thereby reducing lipotoxicity and inducing NASH resolution. In the double-blind, phase 3 MAESTRO-NASH trial, at 52 weeks, resmetirom (80 mg and 100 mg orally once daily) led to resolution of NASH (26% and 30% of patients, respectively, versus 10% with placebo; p<0.0001 for both doses) and a reduction in liver fibrosis (24% and 26%, respectively, versus 14% with placebo; p≤0.0002 for both doses). The FDA proposed that the two surrogate endpoints used in the trial are reasonably likely to predict clinical benefit and would support Accelerated Approval.5 To date, pharmacologic agents in the pipeline for NASH have failed to achieve FDA approval; therefore, resmetirom could be the first medication available in the U.S. to treat the condition. The FDA has granted resmetirom Breakthrough Therapy and Fast Track designations as well as a Priority Review.

03/18/2024: atidarsagene autotemcel

The FDA is reviewing atidarsagene autotemcel (arsa-cel), a gene therapy by Orchard (a subsidiary of Kyowa Kirin), for the treatment of early-onset metachromatic leukodystrophy (MLD), a rare, genetic, lysosomal storage disorder characterized by progressive loss of motor and cognitive function. An integrated analysis of data from two phase 1/2 open-label, single-arm studies and one expanded access framework were compared to natural history. It revealed that, after a mean follow-up of 6.76 years (range, up to 12 years), a one-time IV treatment with arsa-cel led to a statistically significant and clinically meaningful improvement in severe motor impairment-free survival (sMFS) compared to natural history of the disease.6 Arsa-cel was granted Orphan Drug, Rare Pediatric Disease and Regenerative Medicine Advanced Therapy designations as well as a Priority Review from the FDA. MLD has no cure. Some patients may experience a delay in disease progression following stem cell transplantation. If approved, arsa-cel will be the first pharmacologic treatment available for patients with early-onset MLD.

For more information, see the atidarsagene autotemcel Deep Dive in the January 2024 edition of the Quarterly Pipeline.

03/19/2024: aprocitentan

The FDA is reviewing aprocitentan by Idosia, for the treatment of resistant hypertension. Aprocitentan is an oral dual endothelin receptor antagonist. The phase 3 PRECISION trial demonstrated a significant reduction in blood pressure (BP) after 4 weeks of treatment with aprocitentan 12.5 mg and 25 mg compared to placebo (placebo-adjusted change in systolic BP: -3.8 and -3.7 mm Hg, respectively [p<0.005 for both]; placebo-adjusted change in diastolic BP, -3.9 and -4.5 mm Hg, respectively) when added to background therapy in patients with resistant hypertension.7 If approved, aprocitentan will be the first dual endothelin receptor antagonist to treat resistant hypertension, a condition that lacks therapeutic options. Notably, aprocitentan has not been evaluated regarding its effect on cardiovascular outcomes.

03/21/2024: givinostat

Givinostat is an oral histone deacetylases (HDACs) inhibitor by Italfarmaco that is under FDA Priority Review for the treatment of Duchenne muscular dystrophy (DMD), a rare, X-linked neuromuscular disorder characterized by progressive muscle degeneration and weakness. The double-blind, phase 3 EPIDYS trial demonstrated that HDAC inhibition by givinostat, as add-on to background corticosteroid therapy, slowed disease progression as measured by the time to climb 4 stairs (placebo-adjusted response, 1.78 seconds; p=0.0345).8 If approved, givinostat will be an additional option in the growing armamentarium for DMD. The FDA granted givinostat Fast Track, Orphan Drug and Rare Pediatric Disease designations.

03/26/2024: sotatercept

The FDA has granted a Priority Review to Merck and Bristol-Myers Squibb for sotatercept for the treatment of adults with pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1). Sotatercept sequesters activin ligands, and may reverse vascular remodeling and improve vascular patency. In the double-blind, phase 3 STELLAR trial, the addition of sotatercept to background therapy resulted in a significant improvement in 6-minute walking distance (6MWD) at 24 weeks (median change from baseline, +34.4 meters with sotatercept compared to +1 meter with placebo; p<0.001).9 An interim analysis of the ongoing, open-label extension study, SOTERIA, revealed that response was maintained for up to 1 year with continued treatment.10 In addition, the double-blind, phase 2 PULSAR trial reported a significant improvement in pulmonary vascular resistance (PVR) after 24 weeks with add-on sotatercept (LS mean difference from placebo, -239.5 dyn/sec/cm−5; p<0.001).¹¹ If approved, sotatercept will be a first-in-class activin signaling inhibitor and may be the first DMT to treat PAH. In their final evidence report, the Institute for Clinical and Economic Review (ICER) concluded that the addition of sotatercept to background therapy can improve clinical outcomes with relatively few harms, and sotatercept’s SC administration is less burdensome than many other PAH treatments.¹² It’s efficacy in sicker populations and in those with connective tissue disease remains uncertain, along with durability of effect. Sotatercept carries Breakthrough Therapy and Orphan Drug designations for the treatment of PAH.

For more information, see the sotatercept Deep Dive in the January 2024 edition of the Quarterly Pipeline.

03/27/2024: vadadustat

Akebia is awaiting the FDA’s decision for its oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) vadadustat for the treatment of anemia due to chronic kidney disease (CKD) in dialysis-dependent (DD) patients. The FO2CUS trial demonstrated that vadadustat was non-inferior to the long-acting erythropoiesis-stimulating agent (ESA), IV-administered Mircera® (methoxy polyethylene glycol-epoetin beta) in DD patients with CKD, based on the change in hemoglobin (Hb) from baseline to weeks 20 through 26.¹³ The LS mean difference in Hb was -0.33 g/dL (-0.53, -0.13) with vadadustat, achieving the pre-specified non-inferiority margin of -0.75 g/dL. During weeks 20 through 26, the mean Hb level was 10.1 g/dL with the combined doses of vadadustat compared to 10.4 g/dL with Mircera. This is the second review for vadadustat by the FDA. In March 2022, the FDA issued a CRL based on safety concerns. While the PRO2TECT and INNO2VATE studies showed vadadustat to be non-inferior to IV/SC darbepoetin alfa based on change in mean Hb from baseline to weeks 24 through 36 in DD and non-DD patients with CKD, the PRO2TECT trials revealed a 17% higher rate of major adverse cardiovascular events (MACE) with vadadustat than with darbepoetin alfa in non-DD patients.14,15 Because of this, the resubmission includes an indication of DD patients but not non-DD patients. If approved, vadadustat will be the second oral HIF-PHI agent approved for anemia in DD-patients, following FDA approval of Jesduvroq™ (daprodustat) in February 2023 for use in both DD- and non-DD-patients. Jesduvroq is available only through dialysis clinics; it remains to be seen if the same will be true for vadadustat.

03/31/2024: marnetegragene autotemcel

The FDA is reviewing Rocket’s gene therapy marnetegragene autotemcel for the treatment of severe leukocyte adhesion deficiency type I (LAD-I), a rare genetic disorder of the immune system characterized by recurrent, severe infections. Marnetegragene autotemcel delivers a functional copy of the integrin subunit beta 2 (ITGB2) gene, which encodes for the ITGB2 protein, also known as cluster of differentiation 18 (CD18), that plays a key role in the bodies B- and T-cell immune responses. In a phase 1/2 clinical trial (NCT03812263), a single treatment with marnetegragene autotemcel resulted in a 100% survival rate at 12 months after the infusion in patients ≥ 3 months of age with LAD-1 and no human leukocyte antigen (HLA)-matched sibling donor.16 Significant reductions in all-cause hospitalizations and severe infections were also seen. Marnetegragene autotemcel was given Fast Track, Orphan Drug, Rare Pediatric Disease and Regenerative Medicine Advanced Therapy designations as well as a Priority Review from the FDA. If approved, it will be the first agent indicated for patients with LAD-1, and it has the potential to be a curative option, particularly for those without an HLA-matched sibling donor. Notably, Stelara® (ustekinumab) is also being evaluated for LAD-1 in a phase 1/2 trial.

For more information, see the marnetegragene autotemcel Deep Dive in the January 2024 edition of the Quarterly Pipeline.

03/31/2024: odronextamab

Regeneron’s CD20xCD3 bispecific antibody ondronextamab is under FDA Priority Review for the treatment of adults with relapsed/refractory (R/R) follicular lymphoma (FL) or R/R diffuse large B-cell lymphoma (DLBCL), who have progressed after at least two prior systemic therapies. The ongoing, open-label, phase 2 ELM-2 trial includes patients with R/R FL or R/R DLBCL for ondronextamab treatment. Among those with R/R FL, after ≥ 12 months of follow-up (median, 18 months), interim data revealed an 80% objective response rate (ORR) (primary endpoint) and a 73% complete response rate (CRR).17 Among patients with R/R DLBCL who received ondronextamab, after ≥ 36 weeks of follow-up, ELM-2 reported an ORR of 52% and a CRR of 31%.18 The most common adverse events included cytokine release syndrome, neutropenia, anemia and pyrexia. Ondronextamab holds Fast Track and Orphan Drug designations for both indications. If approved, it will be the second bispecific antibody approved for DLBCL (following Epkinly™ [epcoritamab-bysp]) and the first indicated for FL.

References

1. TRAILBLAZER-ALZ 2 trial. https://jamanetwork.com/journals/jama/fullarticle/2807533.

2. Press release: https://investors.biogen.com/news-releases/news-release-details/biogen-realign-resources-alzheimers-disease-franchise.

3. Press release. https://www.prnewswire.com/news-releases/viatris-and-mapi-pharma-announce-fda-acceptance-of-new-drug-application-filing-for-ga-depot-for-the-treatment-of-relapsing-forms-of-multiple-sclerosis-301894145.html.

4. ECTRIMS-ACTRIMS meeting. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.congrex/abstracts_ectrims2023/147046.pdf.

5. MASTRO-NASH trial. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-presents-phase-3-maestro-nash-data.

6. Press release. https://www.globenewswire.com/news-release/2023/08/31/2735106/0/en/Orchard-Therapeutics-Announces-Presentation-of-Data-Comprising-the-Clinical-Package-for-the-OTL-200-BLA-in-MLD-at-the-SSIEM-Annual-Symposium-2023.html.

7. PRECISION trial. https://pubmed.ncbi.nlm.nih.gov/36356632/.

8. Press release. https://www.businesswire.com/news/home/20220625005001/en/.

9. STELLAR trial. https://www.nejm.org/doi/10.1056/NEJMoa2213558?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed.

10. Press release. https://www.businesswire.com/news/home/20230911038196/en.

11. PULSAR trial. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2024277?articleTools=true.

12. ICER final evidence report. https://icer.org/news-insights/press-releases/icer-publishes-final-evidence-report-on-treatment-for-pulmonary-arterial-hypertension/.

13. Press release. https://www.prnewswire.com/news-releases/akebia-therapeutics-announces-positive-top-line-results-from-vadadustat-alternative-dosing-study-301787853.html.

14. PRO2TECT trials https://www.nejm.org/doi/pdf/10.1056/NEJMoa2035938?articleTools=true.

15. INNO2VATE trials https://www.nejm.org/doi/pdf/10.1056/NEJMoa2025956?articleTools=true.

16. Press release. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-fda-acceptance-biologics.

17. Press release. https://investor.regeneron.com/news-releases/news-release-details/latest-odronextamab-data-relapsedrefractory-follicular-lymphoma.

18. Press release. https://www.globenewswire.com/en/news-release/2023/12/10/2793465/0/en/Updated-Odronextamab-Data-from-Relapsed-Refractory-Diffuse-Large-B-cell-Lymphoma-Pivotal-Trial-Showed-Deep-and-Durable-Responses-and-the-Potential-of-ctDNA-To-Predict-Long-term-Out.html.

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