Breaking New Ground in 2025 with 8 First-in-Class Drugs Close to FDA Approval – Part I

In 2024, the FDA approved a range of innovative therapies, including gene and cell therapies, targeted biologics, and novel small molecules. Notable approvals included Orchard Therapeutics’ Lenmeldy (atidarsagene autotemcel), the first gene therapy for metachromatic leukodystrophy and Aztrazeneca’s Voydeya (danicopan), a complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria, amongst some. Many of these approvals addressed high-unmet-need conditions, such as Alzheimer’s disease, rare genetic disorders, and advanced cancers. As the pharmaceutical industry advances, 2025 will bring another wave of first-in-class drugs that introduce entirely new mechanisms of action. These potential approvals aim to further reshape treatment landscapes. Here are 4 groundbreaking drugs on track for FDA approval in 2025.

Donidalorsen Targets Prekallikrein Production to Provide Long-Lasting Protection Against HAE

Ionis Pharmaceuticals is developing donidalorsen as a potential treatment for hereditary angioedema (HAE), a rare genetic disorder characterized by unpredictable episodes of severe swelling in different parts of the body. These episodes can cause significant pain and, in some cases, become life-threatening if they obstruct the airways. Existing treatments, such as C1 esterase inhibitors and kallikrein inhibitors, help manage symptoms but often require frequent administration through intravenous or subcutaneous injections.  

Donidalorsen takes a different approach by targeting the genetic production of prekallikrein (PKK), a protein involved in the inflammatory process that triggers HAE attacks. As an antisense oligonucleotide, it works by degrading the messenger RNA (mRNA) responsible for PKK production in liver cells, leading to lower PKK levels and a reduced frequency of attacks. This mechanism may offer more sustained protection with less frequent dosing compared to current therapies. Clinical studies have shown that donidalorsen provides consistent and long-lasting benefits over a two-year treatment period.

RGX-121 Delivers Gene Therapy to Treat Hunter Syndrome with Sustained Results

RGX-121, developed by REGENXBIO, is a one-time gene therapy designed to treat Hunter syndrome (MPS 2) by delivering a functional copy of the iduronate-2-sulfatase (I2S) gene directly to the central nervous system (CNS). Using an adeno-associated virus (AAV9) vector, the therapy enables CNS cells to produce the missing enzyme, helping to break down accumulated glycosaminoglycans (GAGs) that contribute to disease progression. 

In the ongoing CAMPSIITE trial, patients receiving RGX-121 have shown an 85% median reduction in cerebrospinal fluid (CSF) levels of heparan sulfate (HS) D2S6, a key biomarker of brain disease activity. Patients have sustained these improvements for up to two years. Following a pre-Biologics License Application (BLA) meeting with the FDA, RGX-121 is moving toward potential approval in 2025, which would make it the first gene therapy for Hunter syndrome.

A deficiency of the I2S enzyme causes Hunter syndrome, a rare genetic disorder that is essential for breaking down GAGs, complex sugar molecules involved in connective tissue maintenance. Without sufficient I2S, GAGs build up in cells, leading to progressive damage that affects multiple organs and the CNS. This accumulation results in severe symptoms, including developmental delays, organ enlargement, skeletal abnormalities, and neurological decline. Current treatments, such as intravenous enzyme replacement therapy (ERT), can help manage symptoms but are unable to effectively address neurological complications due to their inability to cross the blood-brain barrier. 

Fitusiran Reduces Antithrombin to Improve Blood Clotting in Hemophilia A and B

Fitusiran, developed by Sanofi, is a first-in-class therapeutic candidate for treating hemophilia A and B, a rare genetic bleeding disorder characterized by improper blood clotting. Hemophilia occurs due to a deficiency or dysfunction of specific clotting factors, which impairs the body’s ability to stop bleeding, even from minor injuries. Fitusiran is a small interfering RNA (siRNA) therapy that targets antithrombin, a protein that inhibits blood clotting. By reducing antithrombin levels, fitusiran aims to enhance thrombin generation and restore balance to the blood clotting process.

Traditional hemophilia treatments involve frequent intravenous infusions of clotting factor concentrates, which can be burdensome, especially for patients who develop inhibitors that make factor replacement less effective. In contrast, fitusiran administers subcutaneously and works independently of factors, making it suitable for patients with or without inhibitors. Phase 3 clinical trials have shown that fitusiran significantly reduces annualized bleeding rates compared to on-demand treatment. Notably, 66% of participants with inhibitors experienced no bleeding episodes during the nine-month treatment period.

Ivonescimab Combines PD-1 and VEGF Targeting to Treat Non-Small Cell Lung Cancer

Ivonescimab, developed by Akeso Biopharma, is a promising candidate for the treatment of non-small cell lung cancer (NSCLC) and may be extended to other cancer types. This humanized bispecific antibody targets two key pathways involved in cancer progression. 

First, it binds to programmed cell death protein 1 (PD-1), a checkpoint protein on immune cells that, when engaged by PD-L1, suppresses immune responses and allows cancer cells to evade detection. By blocking the PD-1/PD-L1 interaction, ivonescimab enhances the body’s immune system’s ability to target tumor cells. Second, ivonescimab targets vascular endothelial growth factor (VEGF), which promotes angiogenesis, the formation of new blood vessels that supply tumors with the nutrients needed for growth. By inhibiting VEGF, ivonescimab starves tumors of their blood supply.

This dual-target approach combines immune checkpoint inhibition and anti-angiogenesis, potentially offering a more effective treatment compared to traditional therapies that target only one pathway. In clinical trials, ivonescimab has shown promising anti-tumor activity with a manageable safety profile in patients with advanced solid tumors.

Related posts:

Spotlight: Roche’s SMA Drug, Risdiplam Makes Strong Case for Regulatory Approval Ionis’ Once-Monthly Treatment for Rare Hereditary Disease Achieves Trial Endpoints AbbVie’s JAK1 Inhibitor Aces Ulcerative Colitis Trial, Prospers Amid Tough Regulatory Climate Sanofi and Sobi Receive Breakthrough Therapy Designation for Hemophilia A Drug

Author

Denisse Sandoval