01/01/2025
The Year in Review: 5 Small-Molecule Drugs Approved by the FDA in 2024
Since January 2024, 46 novel drugs have been approved by the U.S. Food and Drug Administration (FDA), with roughly half of these being small molecules. These innovations represent life-saving progress in the treatment of a wide range of human diseases, including many cancers and several diseases previously lacking pharmaceutical treatment options. Each newly approved drug stands as the culmination of years – or even decades – of arduous scientific research. From initial hit identification, optimization, and characterization through pre-clinical and clinical evaluation, the collaborative efforts of many dedicated scientists are required to take these therapeutics from bench to bedside. As the year comes to a close, we’re highlighting five small molecules approved by the FDA in 2024, giving you a peek at how these innovative drugs were discovered and developed, as well as what might be on the horizon for the years to come.
Rezdiffra (resmetirom) | Madrigal Pharmaceuticals
In March 2024, the FDA approved Rezdiffra (resmetirom) for the treatment of non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring, providing the first direct treatment option for NASH patients with significant liver fibrosis. Resmetirom is a liver-targeted small-molecule agonist of THR-β, a thyroid hormone receptor. Treatment with resmetirom has been shown to improve a number of liver biomarkers, and ongoing clinical trials seek to establish its efficacy against non-alcoholic fatty liver disease (NAFLD) and well-compensated NASH cirrhosis. The drug, first reported in 2014 under the name MGL-3916, came out of attempts to optimize a pyridazinone series for THR-β selectivity and was subsequently shown to decrease LDL cholesterol and triglycerides in patients with dyslipedemia. Resmetirom is thought to act by inhibiting the STAT3 and NF-κB signaling pathways, ultimately altering the expression of genes involved in metabolism, cholesterol synthesis, and fatty acid biosynthesis. Additional small-molecule compounds targeting THR-β continue to be investigated for their efficacy in treating NASH, as well as other conditions associated with hepatic steatosis.
Duvyzat (givinostat) | Italfarmaco S.p.A.
March 2024 also saw the FDA approval of Duvyzat (givinostat), the first non-steroidal drug for the treatment of Duchenne muscular dystrophy (DMD). Givinostat treatment was shown to delay the progression of muscle weakness in ambulant DMD patients, possibly by downregulating fibroadipogenic processes. This orally active small molecule is a histone deacetylase (HDAC) inhibitor that was first published in 2005 under the name ITF2357. HDACs regulate gene expression by modulating chromatin structure, and their inhibition has broad anti-inflammatory and anti-tumor effects. Ongoing clinical trials are investigating the efficacy of givinostat in treating polycythemia vera (NCT06093672), while additional therapeutic applications continue to be explored. For example, givinostat treatment has been shown to interact synergistically with other anti-cancer therapeutics, to ameliorate immune dysregulation during severe COVID-19 infection, and even to exert neuroprotective effects that promote recovery following traumatic brain injury and neonatal hypoxia-ischemia. This diverse array of potential indications continues to motivate the development of both broad-spectrum and homolog-specific HDAC inhibitors, as well as novel approaches for the delivery and targeting of these powerful therapeutics.
XOLREMDI (mavorixafor) | X4 Pharmaceuticals
At the end of April, mavorixafor became the first drug to be approved by the FDA for the treatment of WHIM syndrome, an inherited immunodeficiency named for several of its key symptoms (Warts, Hypogammaglobulinemia, recurrent bacterial Infections and Myelokathexis). WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that prevent it from being efficiently internalized, hyperactivating chemokine signaling. While researchers continue to clarify the molecular mechanisms underlying this pathology, several specific impairments to hematopoiesis and immune function have been reported. WHIM mutations are known to impede the trafficking of neutrophils and other leukocytesfrom the bone marrow to the blood, and they have been shown to disrupt T-cell priming by destabilizing interactions between T-cells and antigen-presenting cells. As a CXCR4 antagonist, mavorixafor alleviates overactive signaling to restore immune homeostasis. Clinical trials demonstrated that mavorixafor treatment promotes neutrophil egress to increase white blood counts in WHIM syndrome patients, with infection frequency, severity, and duration concomitantly reduced. Mavorixafor has also shown potential as a treatment for melanoma and other cancers, while findings that CXCR4 is dysregulated across many neurodegenerative diseases have sparked ongoing efforts to develop mavorixafor-based inhibitors for the treatment of Alzheimer’s and Parkinson’s diseases.
Ohtuvayre (ensifentrine) | Verona Pharma
Ohtuvayre (ensifentrine) was approved by the FDA in June 2024 for the treatment of chronic obstructive pulmonary disease (COPD). This small-molecule drug exerts both bronchoprotective and anti-inflammatory effects to improve forced expiratory volume in 1 second (FEV1) and alleviate other symptoms of COPD. Ensifentrine was initially reported in 2006 as RPL554, a long-lasting trequinsin-like inhibitor of two phosphodiesterases (PDE3 and PDE4). These enzymes, which regulate cAMP/cGMP signaling in a range of cell types, have been targeted individually by a number of existing FDA-approved therapeutics (including the PDE3 inhibitors amrinone and milrinone and the PDE4 inhibitors rolipram and apremilast). However, simultaneous inhibition of both enzymes has remained an attractive therapeutic objective due to purported synergistic effects, particularly with respect to respiratory function. Indeed, ensifentrine treatment was shown to relax bronchial cells following histamine-induced contraction, as well as to improve mucociliary clearance and mucus hydration. Recent research indicates that ensifentrine can effectively reduce MRSA-induced lung inflammation, suggesting that the drug may become indicated for an expanded range of lung-related diseases in the years to come.
Revuforj (revumenib) | Syndax Pharmaceuticals
In November, the small-molecule inhibitor Revuforj (revumenib) was approved by the FDA for the treatment of relapsed and refractory acute leukemias in adult and pediatric patients harboring a KMT2A translocation. KMT2A is a histone-specific lysine methyltransferase that modulates chromatin conformation to regulate a variety of gene expression programs. While KMT2A rearrangement has been implicated in leukemogenesis since the gene’s discovery in the early 1990s, more recent molecular research has clarified its mechanistic underpinnings: translocation leads to the production of aberrant KMT2A fusion proteins that drive inappropriate transcriptional activity, particularly disrupting HoxA expression and downstream hematopoietic development. Importantly, KMT2A can only bind and activate Hox promoters in concert with a coactivator, menin, spurring efforts to identify drugs capable of disrupting the interaction of these two partners. One such initiative led to the discovery of revumenib, a compound shown to abrogate KMT2A-menin interactions and reduce oncogenic gene expression. In clinical trials, revumenib treatment was shown to increase remission rates in patients with KMT2A-rearranged acute leukemia. Recent evidence suggests that combination treatment with revumenib and tamibarotene may have synergistic effects, while alternative menin inhibitors continue to be explored and developed.
These five small-molecule drugs represent only a fraction of the innovative therapeutics that demonstrated clinical efficacy in 2024. To explore further, check out the full roster of drugs approved by the FDA over the past year. Or click here to connect with one of our expert scientists and explore how Momentum’s suite of analytic services can advance your drug discovery and development research in 2025 and beyond.
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