FDA Action Alert: Orchard, ITF, Merck and More

FDA Action Alert_Taylor Tieden for BioSpace

Pictured: FDA headquarters surrounded by pill bottles/Taylor Tieden for BioSpace

The FDA’s busy March continues with six target action dates remaining on the calendar. Over the next two weeks, the regulator will decide on investigational therapies for Duchenne muscular dystrophy, chronic kidney disease anemia, a rare metabolic disorder and more.

Read below for more.

Orchard/Kyowa Kirin Eye First FDA Approval for Metachromatic Leukodystrophy

Orchard Therapeutics is proposing Libmeldy (atidarsagene autotemcel) for the treatment of metachromatic leukodystrophy (MLD), a rare metabolic disease. The FDA’s target action date is March 18, 2024.

If approved, Libmeldy would become the first treatment for early-onset MLD in the U.S. The approval would also mark the first major regulatory victory for Kyowa Kirin since it acquired Orchard in October 2023 for approximately $477.6 million.

Affecting one in every 100,000 live births, MLD is a heritable and life-threatening disease characterized by the toxic build-up of sulfatides in the brain, liver, kidneys and other organs. This accumulation can lead to organ damage and neurological issues such as cognitive, behavioral and motor decline. MLD patients also suffer from severe seizures and over time lose their ability to talk, swallow, eat, move and see.

MLD is caused by a pathological mutation in the arylsulfatase-A (ARSA) gene. Libmeldy, an autologous gene therapy, addresses the underlying mechanism of MLD by using a patient’s own stem cells to deliver functioning copy of the ARSA gene. The European Union approved Libmeldy for the treatment of MLD in December 2020.

In the U.S., Libmeldy, also known as OTL-200, has been granted the FDA’s Rare Pediatric Disease and Regenerative Medicine Advanced Therapy designations. Its Biologics License Application (BLA), which the regulator accepted in September 2023, has been given Priority Review.

Libmeldy’s regulatory bid is backed by data from the OTL-200 clinical development program, which enrolled a total of 39 pediatric patients and used data from 49 untreated natural history controls. Results showed that Libmeldy could preserve motor function and cognitive development in treated patients.

ITF Awaits Verdict for DMD Candidate

ITF, the U.S. subsidiary of Italian pharma Italfarmaco Group, is proposing its investigational HDAC blocker givinostat for the treatment of Duchenne muscular dystrophy (DMD). The FDA’s verdict is due on March 21, 2024.

Designed to be orally available, givinostat works by blocking histone deacetylases (HDACs), a group of enzymes that affect gene expression in muscles. The “deregulation of HDACs is a major consequence of the lack of dystrophin associated with DMD,” ITF head Matt Trudeau told BioSpace in a previous interview.

Givinostat’s mechanism of action can potentially “inhibit HDAC pathological overactivity and thereby impact the cascade of events leading to muscle damage which, in turn, may counteract disease pathology and slow muscle deterioration,” Trudeau explained.

ITF’s New Drug Application (NDA), which was submitted in June 2023, includes data from the Phase III EPIDYS trial, which enrolled 179 ambulant boys aged six years and older. Givinostat was given on top of steroid treatment. Patients who received the HDAC blocker showed a significantly slower decline than placebo recipients in the time it took to climb four stairs, according to a June 2022 readout.

Givinostat also aced its secondary endpoints, including the time to rise test and the North Star Ambulatory Assessment, which measures patient function.

Givinostat was initially granted Priority Review and was due for an FDA decision in December 2023. However, the regulator informed Italfarmaco weeks before its target action date that it would extend the review period by three months to allow additional review time.  

Merck Seeks to Open New Treatment Approach for PAH

By March 26, the FDA will release its decision on Merck’s investigational activin signaling inhibitor sotatercept, which the company is proposing for the treatment of pulmonary arterial hypertension (PAH).

In a statement alongside the BLA acceptance, Joerg Koglin, senior vice president of global clinical development at Merck Research Laboratories, said sotatercept “has the potential to transform the treatment of patients with PAH.”

Sotatercept is a fusion protein therapeutic composed of the extracellular domain of the human activin receptor and the Fc domain of an IgG1 antibody. This structure allows sotatercept to trap TGF-β ligands, thereby helping to restore balance between growth-promoting and growth-limiting pathways. Preclinical models have demonstrated that sotatercept’s mechanism of action can modulate vascular cell proliferation and reverse vascular and ventricle remodeling.

Merck is supporting sotatercept’s regulatory bid with data from the pivotal Phase III STELLAR study, a double-blinded and placebo-controlled trial that enrolled more than 320 patients. The results, published in The New England Journal of Medicine, showed that sotatercept could significantly increase six-minute walk distance after 24 weeks.

Sotatercept likewise outperformed placebo in several secondary metrics, including pulmonary vascular resistance, improvement in WHO functional class and time to death or clinical worsening.

Akebia Anticipates Long-Awaited Decision for CKD Anemia Drug

After a long back and forth, the FDA is set to announce its verdict on Akebia’s NDA seeking approval for vadadustat in anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

Vadadustat is an investigational inhibitor of the hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzyme, which is involved in the cellular response to low oxygen levels. Vadadustat mimics the physiological effects of altitude on oxygen availability and can promote the production of red blood cells and the delivery of oxygen to tissues.

In March 2022, the FDA rejected vadadustat, citing safety concerns. Phase III data for the candidate, released in September 2020, showed that while vadadustat aced its primary and key secondary endpoints, it failed its chief safety outcomes. Compared with darbepoetin alfa, major adverse cardiovascular events occurred more readily in the vadadustat arm.

To demonstrate a more favorable risk-benefit profile, the FDA suggested that Akebia conduct new clinical trials to support vadadustat.

Following the rejection, Akebia in November 2022 filed a Formal Dispute Resolution Request with the FDA, insisting on the “favorable balance of the benefits and risks of vadadustat,” CEO John Butler said in an investor call at the time. The FDA then requested additional information to support Akebia’s appeal, but in February 2023 ultimately decided to defer the decision to the Office of New Drugs.

In May 2023, the FDA handed Akebia a victory when it decided the biotech no longer needed to conduct additional studies for a resubmission. Instead, it could refile its NDA to target CKD patients on dialysis and include post-approval data from Japan. The new application would also include the risk of heart- or liver-related side effects in the proposed label.

Esperion Seeks Expanded Label for Cholesterol Drugs

Esperion is proposing to expand the labels for its bempedoic acid drugs Nexletol and Nexlizet, allowing their use to lower cardiovascular risk in patients with or at risk of atherosclerotic cardiovascular disease. The FDA’s decision is due on March 31.

Bempedoic acid is a non-statin oral drug that lowers low-density lipoprotein cholesterol (LDL-C) via the inhibition of the ATP citrate lyase enzyme. The drug was first approved in February 2020 as Nexletol, becoming the first FDA-approved non-statin therapy to lower LDL-C since 2002.

In March 2023, Esperion presented full data from the Phase III CLEAR study demonstrating that Nexletol cut the risk of major adverse cardiovascular events (MACE) by 13% to 15%. The drug also lowered the risk of heart attack and coronary revascularization by 23% and 19%, respectively, Esperion reported.

In an accompanying statement, Esperion CEO Sheldon Koenig called the results “practice changing.” In an investor call, he added that if the label expansion is approved, Esperion could see major growth in sales and Nexletol could reach blockbuster status.

Investors were not as impressed, however, and the biotech’s shares dropped around 20% in reaction to the readout.

Esperion’s partner Daiichi Sankyo was also unimpressed with the data, refusing to pay a $300 million milestone that Esperion insists it will be owed once cardiovascular risk reduction data are included in Nexletol’s European label. According to an SEC filing from Esperion, it was entitled to a milestone payment if Nexletol could show at least a 20% cardiovascular risk reduction. The 23% decrease in heart attack risk, according to the biotech, qualified it for the milestone. Daiichi Sankyo disagreed, insisting that the analysis should focus on the 13% drop in MACE risk, which fell short of this milestone.  

In January 2024, the partners reached an amicable end to the payment spat, with Daiichi Sankyo agreeing to pay Esperion $125 million in two separate tranches.

Regeneron Eyes Follicular Lymphoma, DLBCL Approval for Bispecific Antibody

Capping off the FDA’s month is a target action date for Regeneron’s BLA proposing its investigational bispecific antibody odronextamab for relapsed or refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The regulator is set to release its verdict on March 31.

Regeneron is supporting its application with data from Phase I and pivotal Phase II trials, which were presented at the 64th American Society of Hematology meeting in December 2022.

One study evaluated odronextamab as a treatment for grade I to IIIa relapsed or refractory FL and found it elicited an 82% objective response rate (ORR), with 75% seeing a complete response. The median response time was 20.5 months. The trial also found that median progression-free survival was 20 months, while median overall survival at the time had not been reached.

The second study tested odronextamab in relapsed or refractor DLBCL, for which the investigational antibody demonstrated a 49% objective response rate in CAR-T-naïve patients. In this subgroup, 31% achieved complete response. In those who had previously been exposed to CAR-T therapy, the ORR was 48%, with a 32% complete response rate.

Odronextamab is an investigational bispecific antibody designed to target CD20, which is typically expressed on cancer cells, and CD3, which is found on T cells. This mechanism of action allows odronextamab to bring the immune cell closer to the tumor cell, facilitating the body’s cancer-killing activity.

If approved, odronextamab would become the first bispecific antibody authorized to treat both FL and DLBCL.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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