FDA decisions to watch in 2024   

March 5, 2024
This year, the agency will decide on groundbreaking treatments for conditions like Alzheimer's, NASH, pulmonary hypertension and more

In 2024, the FDA is set to make crucial decisions on a range of therapies targeting diseases from early Alzheimer’s to rare genetic conditions. Key candidates include Eli Lilly’s donanemab for Alzheimer’s, Madrigal's resmetirom for NASH, and Merck’s sotatercept for pulmonary arterial hypertension, among others. Here's a look at important regulatory action dates to watch.

1. Eli Lilly’s donanemab  

Indication: Early Alzheimer’s disease 
PDUFA date: First quarter 2024 

Eli Lilly's donanemab, a beta-amyloid targeting antibody, aims to reduce amyloid plaques and slow disease progression in early Alzheimer's disease. Following the pathway of previously approved therapies like Eisai and Biogen’s Leqembi, donanemab represents another promising advancement in Alzheimer’s treatment. 

Eli Lilly was forced to seek traditional approval for the anti-amyloid biologic after the FDA rejected the company's bid for accelerated approval back in January 2023. According to Lilly, the CRL was due to the limited number of patients with at least 12 months of drug exposure data provided in the submission. 

The recent phase 3 trial of donanemab showed that the treatment significantly slowed cognitive and functional decline in patients with early symptomatic Alzheimer's disease. Despite the excitement, experts caution that treatments like donanemab come with risks, including potentially serious side effects such as amyloid-related imaging abnormalities.

UPDATE: On March 8th, 2024, Eli Lilly announced that FDA postponed its approval decision for donanemab, after the agency decided to convene an unexpected advisory panel to examine the drug's phase 3 trial results for safety and efficacy concerns, particularly regarding its unique trial design and limited-duration dosing regimen. 

2. Madrigal Pharmaceuticals’ resmetirom  

Indication: Non-alcoholic steatohepatitis 
PDUFA date: March 14, 2024 

Resmetirom, a selective agonist of the thyroid hormone receptor-beta (THR-β) that was granted priority review by the FDA, has the potential to become the first and only medicine approved for nonalcoholic steatohepatitis (NASH).

The drug has shown significant promise in treating NASH and liver fibrosis, according to the MAESTRO-NASH trial. Recently shared results from the phase 3 trial demonstrated that both doses of once daily oral resmetirom were superior to the placebo in achieving NASH resolution and improving liver fibrosis. The approval could encourage the screening of individuals at high risk for NASH in primary care, especially those with stage F2 or higher fibrosis. 

UPDATE: On March 14, 2024, the FDA approved resmetirom, branded Rezdiffra. 

3. Merck’s sotatercept 

Indication: Pulmonary arterial hypertension 
PDUFA date: March 26, 2024  

Sotatercept is a drug being tested for pulmonary arterial hypertension (PAH), focusing on correcting a specific signaling pathway imbalance that contributes to the disease. PAH is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation. While other drugs on the market treat symptoms of the condition or slow its progression, sotatercept has the potential to stop it. 

Merck snatched up the drug in its whopping $11.5 billion acquisition of Massachusetts-based Acceleron Pharma back in 2021. 

Results from the STELLAR phase 3 trial show the activin receptor type IIA-Fc fusion protein can significantly lower pulmonary artery pressure and improve heart function, offering a new way to treat PAH. It's given as an injection every three weeks, potentially easing the treatment burden for patients.

UPDATE: On March 26, the FDA approved sotatercept, branded Winrevair, as the first activin signaling inhibitor therapy for PAH.

4. ImmunityBio’s Anktiva  

Indication: BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ 
PDUFA date: April 23, 2024 

Anktiva, a novel IL-15 superagonist complex, is being tested in combination with Bacillus Calmette-Guérin (BCG) for the treatment of patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without Ta or T1 disease. The drug’s development pathway highlights a significant advancement in bladder cancer treatment, potentially offering a new standard of care for this challenging condition. 

NMIBC with CIS refers to a specific type of bladder cancer that remains at or near the surface of the bladder's lining without invading into the bladder's muscle layer. CIS is a high-grade form of NMIBC characterized by flat, high-grade cancer cells that are confined to the inner surface of the bladder. This condition is termed 'BCG-unresponsive' when the cancer does not respond to BCG therapy, the standard treatment for high-risk NMIBC. Patients with BCG-unresponsive NMIBC CIS are at a higher risk of disease progression, including potential muscle-invasive disease, and typically require more aggressive treatment options.  

This is ImmunityBio's second run at an FDA approval for Anktiva. The agency rejected the drugmaker's application last May, after identifying deficiencies during an inspection of the company's CDMOs. The agency also provided recommendations regarding additional chemistry, manufacturing, and controls issues, as well as assays that needed resolution. ImmunityBio resubmitted its BLA in October 2023.

5. Geron’s imetelstat  

Indication: Transfusion-dependent anemia in patients with lower-risk myelodysplastic syndromes
PDUFA date: June 16, 2024 

Imetelstat is a potentially first-in-class telomerase inhibitor that could, according to Geron, “change the course of blood cancers.” It is designed as a treatment for transfusion-dependent anemia in patients with lower-risk myelodysplastic syndromes (MDS). In the phase 2 IMbark study, Imetelstat demonstrated significant clinical benefits, including a robust symptom response rate and a potential overall survival advantage for patients with intermediate-2 or high-risk myelofibrosis.  

Lower-risk MDS are a group of blood disorders characterized by inadequate production of healthy blood cells in the bone marrow, with a lower risk of progressing to acute myeloid leukemia (AML). These syndromes are classified as 'lower risk' based on factors such as fewer cytogenetic abnormalities, fewer immature blood cells in the bone marrow, and less severe blood cell deficiencies. Treatment focuses on managing symptoms and improving quality of life, potentially including blood transfusions and medication to increase red blood cell counts. 

6. Verona Pharma’s ensifentrine  

Indication: Chronic obstructive pulmonary disease 
PDUFA date: June 26, 2024 

Verona's ensifentrine is an investigational drug designed as a first-in-class therapy, which targets chronic obstructive pulmonary disease (COPD) by offering both bronchodilator and anti-inflammatory activities. This dual-action mechanism comes from its ability to inhibit two key enzymes involved in airway muscle contraction and inflammation. This results in the widening of the airways and a reduction in inflammation, offering a novel approach to COPD treatment. 

Clinical trials, particularly the phase 3 ENHANCE-1 and ENHANCE-2 studies, have demonstrated ensifentrine's potential to significantly improve lung function and to reduce the rate of moderate to severe COPD exacerbations over a 24-week period. Notably, the ENHANCE trials have revealed meaningful improvements in patients' daily symptoms and quality of life measures, underscoring ensifentrine's promise as a valuable addition to existing COPD treatment options. 

If approved, ensifentrine could become the first novel mechanism for the maintenance treatment of COPD in over a decade, marking a significant milestone in the management of the disease and offering new hope to patients with moderate and severe COPD. 

7. Rocket Pharmaceuticals’ Kresaldi  

Indication: Leukocyte adhesion deficiency
PDUFA date: June 30, 2024  

Kresaldi (marnetegragene autotemcel) is an investigational autologous gene therapy developed by Rocket Pharmaceuticals intended for the treatment of severe leukocyte adhesion deficiency-I (LAD-I), a rare pediatric disease caused by mutations in the ITGB2 gene, resulting in impaired immune system function. The therapy aims to provide a functional copy of the ITGB2 gene, facilitating leukocyte adhesion and combating infections.

The NJ-based biotech is hopeful that the therapy has the potential to change the treatment paradigm for patients living with severe LAD-I — one of the most aggressive and highly fatal immunodeficiencies ever characterized. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2 and survival beyond the age of 5 is uncommon.

Back in 2022, Rocket revealed promising phase 2 trial results: 3-24 months after Kresladi (then RP-L201) infusion, all nine trial patients sustained stable CD18 expression with no therapy-related serious adverse events. Furthermore, among all participants, the overall survival at one year was 100% — and patients are reporting a statistically significant reduction in all hospitalizations.

In February, the FDA extended the priority review period for the therapy by three months, pushing it from March to June. The agency said it wanted to allow additional time to review clarifying chemistry, manufacturing and controls information submitted by Rocket in response to the FDA's information requests. 

8. Gilead's seladelpar 

Indication: Primary biliary cholangitis 
PDUFA date: August 14, 2024

Seladelpar is an oral, selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, shown to regulate critical metabolic and liver disease pathways. Gilead picked up the blockbuster hopeful in its recently announced $4.3 billion acquisition of CymaBay Therapeutics.

Seladelpar is intended for the treatment of primary biliary cholangitis (PBC) including pruritus (itching). PBC is a rare, chronic, cholestatic liver disease, mainly affecting women, that impairs liver function and quality of life. 

The critical phase 3 RESPONSE trial demonstrated seladelpar's effectiveness, where it significantly outperformed a placebo in achieving primary composite endpoints related to biochemical responses and the normalization of alkaline phosphatase levels at 12 months. Additionally, seladelpar showed a statistically significant improvement in reducing pruritus at six months, with sustained effects through 12 months among patients experiencing moderate-to-severe pruritus. 

If approved, seladelpar has the potential to generate sales of $1.9 billion by 2029, according to LSEG data.

9. Karuna Therapeutics’ KarXT 

Indication: Schizophrenia
PDUFA date: September 26, 2024 

KarXT is a potentially revolutionary schizophrenia treatment, marking the first major pharmacological innovation in the field in decades. The orally administered drug uniquely targets M1/M4 muscarinic receptors, diverging from traditional treatments by avoiding dopamine and serotonin pathways. This dual-action strategy seeks to exploit xanomeline's benefits while mitigating side effects with trospium, potentially introducing a unique treatment option for severe mental health conditions. 

Marked as a groundbreaking therapy, KarXT distinguishes itself with a novel action mechanism that could significantly impact mental health care upon regulatory approval. This approach represents a potential shift in treating mental illnesses, offering hope for improved outcomes for patients with limited options. 

Bristol Myers Squibb acquired Karuna Therapeutics for $14 billion in December 2023, securing the promising KarXT. 

10. BridgeBio Pharma’s acoramidis  

Indication: Transthyretin-mediated amyloid cardiomyopathy
PDUFA date: November 29, 2024 

Acoramidis, a highly potent oral small molecule, is being developed as a potential treatment for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). ATTR-CM is a progressive and potentially fatal disease caused by the accumulation of misfolded transthyretin protein in the heart tissue, leading to amyloid deposits. These deposits cause thickening and stiffening of the heart walls, impairing the heart's ability to pump blood efficiently, which can result in heart failure and other cardiovascular complications. 

Acoramidis aims to slow or stop the progression of ATTR-CM by emulating the protective T119M mutation, which stabilizes TTR tetramers. 

In mid-2023, BridgeBio shared initial positive findings from the ATTRibute-CM study, with comprehensive results unveiled at the European Society of Cardiology Congress in August 2023. Key findings included an 81% survival rate with acoramidis treatment compared to 74% with placebo, aligning closely with the expected life expectancy in the absence of ATTR-CM (85%).  

11. AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan  

Indication: Triple-negative breast cancer 
PDUFA date: Fourth quarter of 2024 

Datopotamab deruxtecan (Dato-DXd), a collaborative effort by AstraZeneca and Daiichi Sankyo, is an antibody-drug conjugate (ADC) aimed at TROP2. It features a humanized anti-TROP2 IgG1 monoclonal antibody, tethered via a cleavable tetrapeptide linker to a payload that inhibits topoisomerase I, derived from camptothecin.  

In findings disclosed at the European Society for Medical Oncology (ESMO) Congress in October 2023, Dato-DXd demonstrated a significant improvement in reducing the risk of progression or death in advanced non-small cell lung cancer (NSCLC) and inoperable or metastatic hormone receptor (HR)-positive, HER2-low, or HER2-negative breast cancer across two phase 3 studies.