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Monthly News Roundup - March 2024

Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on April 2, 2024.

Rezdiffra Approved as First Drug for Nonalcoholic Fatty Liver Disease (NASH)

In March, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Rezdiffra (resmetirom) for adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis. NASH, the term used in the Rezdiffa FDA approval, is now known as metabolic dysfunction-associated steatohepatitis (MASH). Rezdiffra is used in conjunction with diet and exercise.

• Nonalcoholic steatohepatitis (NASH) is a more advanced form of nonalcoholic fatty liver disease (NAFLD), also now known as metabolic dysfunction-associated steatotic liver disease (MASLD). NASH occurs when a buildup of fat in the liver (not due to alcohol use) leads to hepatitis, fibrosis, cirrhosis, and possible liver failure.
• Rezdiffra is a partial agonist of the hepatic thyroid hormone receptor β (THR–β) in the liver. Stimulation of THR‑β in the liver reduces intrahepatic triglycerides and is key to breakdown of liver fat. People with NASH have reduced levels of THR-β receptor activity in the liver.
• Accelerated approval is based on improvement of NASH and liver scarring (fibrosis) with ongoing studies to confirm the clinical benefit of this drug before full approval is granted.
• The Phase 3, placebo-controlled MAESTRO-NASH trial included 966 patients with biopsy-confirmed NASH and a fibrosis stage range of F1B to F3. After 52 weeks in the primary analysis, both primary endpoints were met: NASH resolution with no worsening of fibrosis in 25.9% and 29.9% of the groups taking the 80 mg and 100 mg dose, respectively, vs. 9.7% in the placebo group. Results also showed an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score in 24.2% and 25.9% of those in the 80 mg and 100 mg groups, respectively, vs. 14.2% taking a placebo. LDL-C levels also dropped significantly in the first 24 weeks in the active treatment group.
• The dose of Rezdiffra oral tablets are weight-based and are given once daily.
• Warnings and precautions include liver toxicity and gallbladder-related adverse reactions. Common adverse reactions include diarrhea, nausea, pruritus (itching), vomiting, constipation, abdominal (stomach) pain, and dizziness.
• Rezdiffra is manufactured by Madrigal Pharmaceuticals and is expected to be available in April.

FDA Approves First-in-Class Winrevair for Adults with Pulmonary Arterial Hypertension

This past month the FDA cleared Merck’s Winrevair (sotatercept-csrk) subcutaneous injection indicated for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1).

• Pulmonary arterial hypertension (PAH) is a rare and possibly fatal disease in which the blood vessels in the lungs thicken and narrow causing high blood pressure in the lung arteries. Patients with PAH experience symptoms such as shortness of breath and fatigue leading to possible heart failure.
• Winrevair is the first FDA-approved activin signaling inhibitor therapy for PAH. It works by binding to activin A, a cytokine, to improve the balance between pro- and anti-proliferative signaling to regulate vascular cell proliferation underlying PAH. Clinically, it helps patients to increase their ability to exercise, improve functional class and reduce the risk of clinical symptom worsening.
• Approval was based on the Phase 3, placebo-controlled STELLAR study with 323 patients. Results showed that adding Winrevair to standard of care therapy significantly increased the six-minute walk distance from baseline by 41 meters (134.5 feet) at Week 24. Secondary outcomes also improved significantly, including reducing the risk of death from any cause and lowering PAH clinical worsening events by 84% versus background therapy alone (number of events: 9 vs 42, hazard ratio=0.16).
• Winrevair is administered once every 3 weeks by subcutaneous injection. The starting dose is 0.3 mg/kg with a target dose of 0.7 mg/kg, after verifying acceptable hemoglobin (Hgb) and platelet count. Patients and caregivers may administer Winrevair at home after appropriate training and follow-up from a healthcare provider.
• Warnings include erythrocytosis (elevated red blood cells that may cause blood clots), severe thrombocytopenia (low blood platelets), serious bleeding, fetal harm and impaired fertility. Common (≥10%) side effects include headache, epistaxis (nosebleed), rash, telangiectasia (small, widened blood vessels on the skin), diarrhea, dizziness, and erythema (redness).
• Winrevair is expected to be available from specialty pharmacies by the end of April.

FDA Approves Gene Therapy Lenmeldy for Children with Fatal Metachromatic Leukodystrophy

In March, the FDA approved Lenmeldy (atidarsagene autotemcel) from Orchard Therapeutics, an autologous hematopoietic stem cell (HSC) gene therapy for the treatment of children with metachromatic leukodystrophy (MLD). The first treatment for MLD, Lenmeldy has the potential to restore enzymatic function to stop or slow this fatal disease with a single treatment.

• MLD is a rare and life-threatening inherited disease of the metabolic system caused by a mutation in the arylsulfatase-A (ARSA) gene. This mutation causes accumulation of sulfatides (a type of fat) that destroy the protective layer of the nerves called the myelin sheath. Patients gradually lose the ability to move, talk, swallow, eat and see. Mortality is estimated at 50% at 5 years for late infantile disease and 44% at 10 years for juvenile patients.
• Lenmeldy works by inserting one or more functional copies of the human ARSA gene into the genome of a patient’s own hematopoietic stem cells (HSCs), outside the body, using a lentiviral vector. Cells are then infused back into the patient where they can migrate across the blood-brain barrier into the central nervous system and express the functional enzyme.
• Approval is based on open-label data from 37 pediatric patients with early-onset MLD and followed up for 12 years (median 6.8 years). All children with pre-symptomatic late infantile MLD who were treated with Lenmeldy were alive at 6 years of age, compared to 58% in the natural history group. At 5 years of age, 71% of treated children were able to walk without assistance. Eighty five percent of the children treated had normal language and performance IQ scores, which was not reported in untreated children. Motor function and cognitive skills were also preserved in some early juvenile MLD patients.
• Lemmeldy is manufactured via hematopoietic stem cell (HSC) mobilization in the child followed by apheresis to obtain CD34+ cells for manufacturing. Dosing is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight and the MLD disease subtype. Myeloablative conditioning is performed before infusion of Lenmeldy. Lenmeldy will be given at Qualified Treatment Centers in several states in the U.S.
• The most common adverse reactions (≥10%) include fever and low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, fever, gastrointestinal infections and enlarged liver.
• The wholesale acquisition cost (WAC) of Lenmeldy will be US$4.25 million according to Orchard Therapeutics, making it currently the most expensive drug in the U.S. Officials at Orchard cite the value of therapy to patients and their families, possible caregiver wage loss, and the potential to lower healthcare utilization.

Tryvio Provides New Therapeutic Pathway to Treat Resistant Hypertension

In March, the FDA approved oral Tryvio (aprocitentan) for the treatment of hypertension (high blood pressure) in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other drugs.

• Tryvio is an endothelin receptor antagonist (ERA) and works by targeting endothelin-1 (ET-1), a potent vasoconstrictor involved in the development of hypertension. This unique mechanism is meant to complement other available antihypertensives, including angiotensin receptor blockers, beta blockers, diuretics or calcium channel blockers.
• Approval was based on the Phase 3 PRECISION study in patients with confirmed resistant hypertension. At baseline, 63% of patients reported taking four or more antihypertensive medications. The primary efficacy endpoint was the change in sitting SBP (SiSBP) from baseline to Week 4 ​​(part 1). Results showed Tryvio 12.5 mg once daily was well tolerated and superior to placebo in lowering blood pressure at week 4 (−3.8 mmHg vs. placebo), with a sustained effect at week 40.
• The recommended dosage is 12.5 mg orally once daily, with or without food.
• Tryvio carries a Boxed Warning for serious birth defects and must not be used during pregnancy. Patients should use acceptable birth control prior to, during, and for one month after stopping treatment. Pregnancy testing is required.
• Warnings and precautions include liver toxicity or liver failure, fluid retention, decreased hemoglobin and decreased sperm counts. The most common adverse reactions include edema / fluid retention and anemia.
• Tryvio is from Idorsia Pharmaceuticals and is expected to be available in the second half of 2024.

Tyenne Approved as Second Biosimilar to Actemra

This past month, the FDA approved the biosimilar Tyenne (tocilizumab-aazg), an interleukin-6 (IL-6) receptor antagonist and biosimilar to Actemra (tocilizumab). It is the first tocilizumab biosimilar with both IV and subcutaneous formulations, but does not have an interchangeability designation with Actemra.

• A biosimilar is a biological product that is similar to a reference biologic (in this case, Actemra) and for which there are no clinically meaningful differences in terms of safety, purity, and potency. They can offer cost savings and promote accessibility to biologic drugs. Tyenne is the second tocilizumab biosimilar after the approval of Tofidence (tocilizumab-bavi) in 2023.
• Tyenne is not indicated for all the same uses as Actemra. Tyenne is labeled for the treatment of rheumatoid arthritis in adults, giant cell arteritis in adults, polyarticular juvenile idiopathic arthritis (PJIA) and systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older. Actemra is approved for these uses, plus systemic sclerosis-associated interstitial lung disease, cytokine release syndrome, and hospitalized adult patients with COVID-19.
• Tyenne carries a Boxed Warning for serious infections that may lead to hospitalization or death. Warnings and precautions include risk of serious infection, gastrointestinal (GI) perforation, liver toxicity, and serious allergic reactions, among others.
• The most common adverse reactions include upper respiratory tract infections, nasopharyngitis (common cold), headache, hypertension (high blood pressure), increased ALT liver enzyme, and injection site reactions.
• Tyenne is given as an IV infusion by a healthcare provider or as a subcutaneous injection (injection under the skin). You and your doctor may agree that you can administer Tyenne by subcutaneous injection at home after training. For subcutaneous administration it comes as a prefilled syringe or single-dose prefilled autoinjector.
• Tyenne is manufactured by Fresenius Kabi.

Tevimbra Gains Approval for Esophageal Squamous Cell Carcinoma

The FDA has approved BeiGene’s Tevimbra (tislelizumab-jsgr) as a single treatment for adult patients with esophageal squamous cell carcinoma (ESCC) that cannot be removed with surgery or that has spread in the body. It is used after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor.

• Tevimbra is classified as a programmed death receptor-1 (PD-1) blocking antibody. It works by binding to PD-1 and blocks its interaction with PD-L1 and PD-L2, thereby removing inhibition of the immune response.
• ESCC is a cancer that arises in the epithelial cells that line the upper part of the esophagus and is the most common type of esophageal cancer.
• Approval was based on the RATIONALE 302 trial with 512 patients. Results showed a significant median overall survival (OS) in the Tevimbra arm of 8.6 months (95% CI: 7.5, 10.4) compared to 6.3 months (95% CI: 5.3, 7.0) in the chemotherapy arm (p=0.0001; hazard ratio [HR]=0.70 [95% CI: 0.57, 0.85]).
• The recommended dosage is 200 mg given as an intravenous (IV) infusion over 30 to 60 minutes once every 3 weeks.
• Warnings and precautions include immune-mediated adverse reactions which may involve the lung, intestine, liver, hormone glands, skin or kidney. Complications of allogeneic hematopoietic stem cell transplantation (HSCT), embryo-fetal toxicity, and severe infusion reactions may also occur. Permanent discontinuation of treatment due to a side effect occurred in 19% of patients.
• The most common side effects (≥20%) include increased blood sugar, decreased red blood cell and white blood cell counts, decreased blood sodium, decreased blood albumin, increase in certain liver blood tests, tiredness, muscle and bone pain, decreased weight, and cough.
• Tevimbra, made by BeiGene, Ltd., is expected to be available in the U.S. in the second half of 2024.

FDA Approves Duvyzat for Duchenne Muscular Dystrophy

This past month the FDA cleared Duvyzat (givinostat), a histone deacetylase (HDAC) inhibitor indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. It is thought Duvyzat works by inhibiting HDAC overactivity that can lead to muscle damage.

• Duchenne muscular dystrophy (DMD) is a severe, X-linked genetic neuromuscular disease caused by mutations in the gene that encodes the cytoskeletal protein dystrophin that strengthens and protects muscle fibers. DMD causes progressive muscle degeneration and weakness, eventually affecting the ability to walk. Heart and lung muscle deterioration eventually lead to premature death. The disease primarily affects people assigned male at birth, with symptoms usually first seen between 2 and 5 years of age.
• Approval was based on the Phase 3 EPIDYS trial with 179 males 6 years of age or older. Participants received either Duvyzat twice daily or placebo, in addition to glucocorticosteroid treatment. Patients on Duvyzat showed a significant and clinically meaningful difference in time to complete the four-stair climb assessment compared to placebo at 72 weeks, the primary endpoint, but the results of the four-stair climb assessment worsened in both groups over the study period.
• Warnings for Duvyzat include red and white blood cell and platelet changes, increase in triglycerides (a blood fat), diarrhea, and QTc prolongation (a serious change in heart rhythm). Common side effects (≥10%) include diarrhea, abdominal (stomach) pain, thrombocytopenia (low platelets), nausea, vomiting, high triglycerides, and pyrexia (fever).
• Duvyzat is manufactured by Italfarmaco S.p.A.

Pemgarda EUA Cleared for Pre-exposure Prophylaxis of COVID-19 in Certain Groups

In March, the investigational monoclonal antibody Pemgarda (pemivibart) received emergency use authorization (EUA) from the FDA for the pre-exposure prophylaxis (prevention) of COVID-19 in adults and adolescents (12 years of age and older weighing at least 40 kg). It is given as an intravenous (IV) infusion.

• Patients must meet criteria to be eligible to use Pemgarda. Candidates should not be currently infected with SARS-CoV-2 or have had a known recent exposure to an individual infected with SARS-CoV-2. They should have moderate-to-severe immune compromise due to certain medical conditions (such as blood cancer) or receipt of certain immunosuppressive medications or treatments (such as an organ transplant) and are unlikely to mount an adequate immune response to COVID-19 vaccination.
• Pemgarda is a recombinant human monoclonal IgG1λ antibody that works by targeting the SARS-CoV-2 spike protein receptor binding domain, inhibiting the attachment of the SARS-CoV-2 virus to human ACE2 receptors on host cells. It has broad antiviral activity, including to JN.1.
• The most common adverse events (all grades, incidence ≥2%) observed in participants who have moderate-to-severe immune compromise treated with Pemgarda included systemic and local infusion-related or hypersensitivity reactions (including anaphylaxis), upper respiratory tract infection, viral infection, influenza-like illness, fatigue, headache, and nausea.
• Pemgarda is manufactured by Invivyd, Inc. It is only authorized by the EUA and is not currently approved by the FDA for any use, including treatment of COVID-19 or post-exposure prophylaxis of COVID-19.

Posted March 2024

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