Photo: FDA headquarters surrounded by pill bottles/Taylor Teeden biospace

FDA’s busy March continues, with six target action dates remaining on the calendar. Regulators will spend the next two weeks deciding on investigational treatments for conditions including Duchenne muscular dystrophy, chronic kidney disease anemia and rare metabolic diseases.

Read below for more information.

Orchard/Kyowa Kirinai First FDA approval for metachromatic leukodystrophy

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

If approved, LibMeldy would be the first treatment for juvenile MLD in the United States. The approval marks Kyowa Kirin’s first major regulatory victory since acquiring Orchard in October 2023 for approximately $477.6 million.

MLD is an inherited, life-threatening disease that affects 1 in 100,000 births and is characterized by the accumulation of toxic sulfatide in the brain, liver, kidneys, and other organs. This buildup can cause organ damage and neurological problems, including decreased cognitive, behavioral, and motor skills. MLD patients also suffer from severe seizures and over time lose the ability to speak, swallow, eat, move, and see.

MLD is caused by pathological mutations in the body. Arylsulfatase-A (plot)gene. LIVMERDY, an autologous gene therapy, addresses the underlying mechanisms of MLD by using a patient’s own stem cells to deliver a functioning copy of the gene. plot gene. The European Union approved Livmerdi for the treatment of MLD in December 2020.

In the U.S., LibMeldy, also known as OTL-200, has received FDA Rare Pediatric Disease and Regenerative Medicine Advanced Therapy designations. The company’s Biologics License Application (BLA), which was accepted by regulators in September 2023, received priority review.

LibMerdi’s regulatory bid is supported 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. The results showed that Ribmerdi was able to maintain motor function and cognitive development in treated patients.

ITF awaits verdict on DMD candidate

ITF, the U.S. subsidiary of Italian pharmaceutical company Italpharmaco Group, is proposing the HDAC inhibitor givinostat, which is under investigation as a treatment for Duchenne muscular dystrophy (DMD). The FDA’s verdict is expected on March 21, 2024.

Designed to be administered orally, Givinostat works by blocking histone deacetylases (HDACs), a group of enzymes that affect gene expression in muscles. “The deregulation of HDAC is a major consequence of the dystrophin deficiency associated with DMD,” said ITF Chairman Matt Trudeau. biospace In a previous interview.

Givinostat’s mechanism of action potentially “inhibits pathological overactivity of HDACs, thereby influencing the chain of events that lead to muscle damage, which in turn could counteract disease pathology and slow muscle deterioration.” “There is a gender,” Trudeau explained.

The ITF’s new drug application (NDA), filed in June 2023, includes data from the Phase III EPIDYS trial, which enrolled 179 ambulatory boys aged 6 years and older. Givinostat was administered in addition to steroid treatment. Results from a June 2022 study showed that patients who received HDAC blockers experienced a significantly slower decline in the time it took to climb four flights of stairs than those who received a placebo.

Givinostat also met secondary endpoints, including the wake-up time test and the Northstar Outpatient Assessment, which measures patient function.

Givinostat was initially granted priority review, with an FDA decision expected in December 2023. However, several weeks before the target action date, regulators notified Italpharmaco that the review period would be extended by three months to allow for additional review time.

Merck aims to develop new treatment approaches for PAH

By March 26, the FDA is expected to announce a decision on sotatercept, an investigational activin signaling inhibitor proposed by Merck & Co. to treat pulmonary arterial hypertension (PAH).

Jorg Koglin, senior vice president of global clinical development at Merck Research Laboratories, said in a statement accompanying the BLA approval that sotatercept “has the potential to transform the treatment of patients with PAH.”

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

Merck is supporting its regulatory bid for sotatercept with data from the pivotal Phase III STELLAR trial, a double-blind, placebo-controlled study that enrolled more than 320 patients. Result is, New England Medical Journalit was shown that sotatercept can significantly increase 6-minute walking distance after 24 weeks.

Sotatercept also outperformed placebo on several secondary measures, including pulmonary vascular resistance, improvement in WHO functional class, and time to death or clinical deterioration.

Akebia expects long-awaited decision on CKD anemia treatment drug

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

Vadadustat is an investigational inhibitor of the hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzyme, which is involved in cellular responses to low oxygen levels. Vadadustat mimics the highly physiological effects on oxygen availability, promoting 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 vadadustat met its primary endpoint and key secondary endpoints, but failed on key safety outcomes. Ta. Major adverse cardiovascular events occurred more readily in the vadadustat group compared with darbepoetin alfa.

To demonstrate a more favorable risk-benefit profile, the FDA proposed that Akebia conduct a new clinical trial supporting vadadustat.

Following the denial, Akebia filed a formal dispute resolution request with the FDA in November 2022, arguing for a “favorable balance of benefits and risks for vadadustat,” CEO John said on an investor conference call at the time.・Mr. Butler stated. The FDA then requested additional information to support Akebia’s appeal, but ultimately decided to defer its decision to the new pharmacy in February 2023.

In May 2023, the FDA awarded Akebia a victory, determining that Akebia no longer needed to conduct additional studies to resubmit. Instead, the NDA could be resubmitted to target CKD patients on dialysis and include post-approval data in Japan. The new application would also include a risk of heart- or liver-related side effects in the proposed label.

Esperion aims to expand label for cholesterol drug

Esperion expands the labeling of the bempedoic acid drugs Nexletor and Nexlisette to promote their use to reduce cardiovascular risk in patients with or at risk for atherosclerotic cardiovascular disease. I am proposing to make it possible. The FDA’s decision is expected on March 31st.

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

In March 2023, Esperion announced full data from the Phase III CLEAR trial demonstrating that Necletol reduces the risk of major cardiovascular events (MACE) by 13-15%. Esperion also reported that the drug lowered the risk of heart attack and coronary revascularization by 23% and 19%, respectively.

Esperion CEO Sheldon Koenig called the results a “change in practice” in an accompanying statement. He added on an investor call that if the label expansion is approved, Esperion’s sales could grow significantly and Necletol could achieve blockbuster status.

However, investors were less than impressed, and the biotech company’s stock price fell about 20% in response to the announcement.

Esperion’s partner Daiichi Sankyo was also unimpressed with the data, with the $300 million milestone payment that Esperion claims it would be obligated to pay once cardiovascular risk reduction data was included in Nestletol’s European label. refused. Esperion’s SEC filing states that if Nexletol can demonstrate at least a 20% cardiovascular risk reduction effect, the company will be entitled to milestone payments. The biotech company says it qualifies for the milestone due to a 23% reduction in heart attack risk. Daiichi Sankyo disagreed, arguing that the analysis should focus on the 13% reduction in MACE risk, which missed this milestone.

In January 2024, the two partners came to an amicable end to the payment dispute, with Daiichi Sankyo agreeing to pay Esperion $125 million in two installments.

Regeneron Eyes Follicular Lymphoma, DLBCL Bispecific Antibody Approved

The FDA closes out the month with Regeneron’s BLA, which proposes the investigational bispecific antibody odronectamab for relapsed or refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). It is the target action day. The regulator is expected to announce its verdict on March 31st.

Regeneron supports its application with data from a Phase I study and a pivotal Phase II study presented at the 64th Annual Meeting of the American Society of Hematology in December 2022.

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

The second study tested odronectamab in relapsed or refractory DLBCL, and the investigational antibody demonstrated a 49% objective response rate in CAR-T-naive patients. In this subgroup, 31% achieved a complete response. In patients who had previously received CAR-T therapy, the ORR was 48% and the complete response rate was 32%.

Odronestamab is an investigational bispecific antibody designed to target CD20, which is normally expressed on cancer cells, and CD3, which is found on T cells. Through this mechanism of action, odronestamab can bring immune cells closer to tumor cells, boosting the body’s cancer cell-killing activity.

If approved, odronestamab would be the first bispecific antibody approved to treat both FL and DLBCL.

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