Ten promising first-in-class drugs on track for FDA approval in 2025

First-in-class drugs are therapies that utilize novel mechanisms of action, offering new approaches to challenging diseases. In 2024, the U.S. Food and Drug Administration (FDA) approved 50 new molecular entities, with 24 designated as first-in-class – will 2025 do better?

For instance, cobenfy is the first new schizophrenia drug approved in nearly three decades. Developed by Karuna Therapeutics and later acquired by Bristol Myers Squibb, it targets the cholinergic system through muscarinic receptors, differing from traditional dopamine-based treatments. 

Another example is rezdiffra, the first-ever therapy approved for metabolic-associated steatohepatitis (MASH), a chronic liver disease. Looking ahead, 2025 is poised to be an exciting year for drug approvals, with several first-in-class therapies on the horizon.

But what does the upcoming hold for us in terms of FDA approvals? Let’s take a closer look at ten first-in-class drugs set to be approved in 2025.

Donidalorsen 

• Developer: Ionis Pharmaceuticals
• Indication: Hereditary angioedema (HAE)
• Technology: Antisense oligonucleotide

Donidalorsen is developed by Ionis Pharmaceuticals for HAE. HAE is a rare genetic disorder that causes recurrent episodes of severe swelling (angioedema) in various parts of the body. These episodes can be unpredictable, painful, and sometimes life-threatening if they affect the airways.

Donidalorsen is an antisense oligonucleotide designed to reduce the production of prekallikrein (PKK), a protein involved in the activation of inflammatory mediators that lead to HAE attacks. By specifically targeting and degrading the messenger RNA (mRNA) responsible for PKK production in liver cells (hepatocytes), donidalorsen decreases PKK levels, thereby reducing the frequency and severity of HAE attacks.

Current treatments for HAE include C1 esterase inhibitors, kallikrein inhibitors, and bradykinin receptor antagonists, which are administered either intravenously or subcutaneously and may require frequent dosing. 

Donidalorsen offers a novel approach by targeting the genetic production of PKK, potentially providing more sustained protection against HAE attacks with less frequent dosing. This mechanism differs from existing therapies that primarily focus on inhibiting proteins already present in the bloodstream. Additionally, donidalorsen’s targeted action may result in fewer side effects and improved patient adherence compared to current treatment options.

In clinical studies, donidalorsen demonstrated consistent and sustained protection from HAE attacks over a two-year treatment period. 

Fitusiran

• Developer: Sanofi
• Indication: Hemophilia A and B
• Technology: siRNA

Developed by Sanofi, fitusiran is a first-in-class candidate for hemophilia A and B. Hemophilia is a rare genetic bleeding disorder in which the blood doesn’t clot properly, leading to excessive bleeding even from minor injuries. The condition is caused by a deficiency or dysfunction of specific clotting factors.

Fitusiran is a small interfering RNA (siRNA) therapeutic designed to reduce the production of antithrombin, a protein that inhibits blood clotting. By lowering antithrombin levels, fitusiran aims to enhance thrombin generation, rebalancing hemostasis and preventing bleeding episodes in individuals with hemophilia.

Traditional hemophilia treatments involve regular intravenous infusions of clotting factor concentrates to replace the missing or deficient clotting factors. These treatments can be burdensome due to the frequency of administration and the development of inhibitors that render factor replacement less effective. Fitusiran is subcutaneously administered and factor-independent, making it suitable for patients with or without inhibitors. 

In phase 3 clinical trials, fitusiran prophylaxis demonstrated significant reductions in annualized bleeding rates compared to on-demand treatment. For instance, the study reported that 66% of participants with inhibitors experienced no bleeding episodes during the nine-month treatment period.

Ivonescimab

• Developer: Akeso Biopharma, with global licensing (excluding China) to Summit Therapeutics
• Indication: Oncology
• Technology: Bispecific antibody

This candidate developed by Akeso Biopharma is indicated for non-small cell lung cancer (NSCLC) but could be extended to other types of cancer. Ivonescimab is a humanized bispecific antibody that simultaneously targets two pathways in cancer progression:

• Programmed cell death protein 1 (PD-1): PD-1 is a checkpoint protein on immune cells that, when engaged by its ligand PD-L1, inhibits the immune response, allowing cancer cells to evade detection. Ivonescimab binds to PD-1, preventing its interaction with PD-L1, to improve the body’s immune response against tumor cells.
• Vascular endothelial growth factor (VEGF): VEGF promotes the formation of new blood vessels (angiogenesis) that supply nutrients to tumors, facilitating their growth. By binding to VEGF, ivonescimab inhibits this process, starving the tumor of its blood supply.

The dual mechanism of PD-1 and VEGF simultaneously enhances anti-tumor immunity and inhibits tumor angiogenesis. Traditional cancer therapies often target a single pathway, which can limit their effectiveness due to the complex nature of tumor biology. This integrated approach has the potential to produce more robust anti-tumor effects compared to therapies that inhibit only PD-1 or VEGF individually.

In clinical studies, ivonescimab has demonstrated promising anti-tumor activity with a manageable safety profile in patients with advanced solid tumors. 

Mirdametinib

• Developer: SpringWorks Therapeutics
• Indication: Neurofibromatosis type 1-associated plexiform neurofibromas
• Technology: Selective inhibitor

SpringWorks Therapeutics is developing a candidate for neurofibromatosis type 1-associated plexiform neurofibromas. Neurofibromatosis type 1 (NF1) is a genetic disorder that affects the growth and development of nerve tissues. It is caused by mutations in the NF1 gene, which encodes a protein called neurofibromin. Neurofibromin acts as a tumor suppressor by regulating cell growth, but mutations in the NF1 gene result in uncontrolled cell proliferation.

Plexiform neurofibromas (PNs) are a specific type of tumor that occurs in people with NF1. They develop along peripheral nerves and are composed of a complex network of abnormal nerve tissue and connective tissue. Although they are non-cancerous, they can grow extensively and cause significant complications.

Mirdametinib is a selective inhibitor of MEK1 and MEK2, which are key components of the MAPK/ERK signaling pathway. This pathway is often overactive in various tumors, including those associated with NF1. By inhibiting MEK1/2, mirdametinib reduces the phosphorylation and activation of downstream proteins ERK1 and ERK2, leading to decreased tumor cell proliferation and survival. The pivotal phase 2b trial demonstrated significant tumor reduction, with a manageable safety profile. 

Currently, there are limited treatment options for NF1-associated plexiform neurofibromas, especially for adults. Mirdametinib’s oral administration and ability to penetrate the central nervous system make it a convenient option for patients who lack options.

Plozasiran

• Developer: Arrowhead Pharmaceuticals
• Indication: Severe hypertriglyceridemia (SHTG) and familial chylomicronemia syndrome (FCS)
• Technology: RNAi

Arrowhead’s first-in-class drug candidate is being developed for both SHTG and FCS and could also reach the market in 2025. SHTG is a condition characterized by extremely high levels of triglycerides in the blood. Triglycerides are a type of fat lipid stored in the body for energy, but excessively high levels can cause serious health complications.

FCS is a rare genetic disorder that causes severe elevations in triglycerides due to the accumulation of chylomicrons, which are lipoprotein particles responsible for transporting triglycerides in the blood.

Plozasiran, previously known as ARO-APOC3, is an RNA interference (RNAi) therapeutic reducing the production of apolipoprotein C-III (APOC3). APOC3 is a key regulator of triglyceride metabolism – elevated levels are associated with increased triglycerides and a higher risk of pancreatitis and cardiovascular diseases. 

By specifically silencing the mRNA transcripts of the APOC3 gene in liver cells, plozasiran decreases the synthesis of APOC3, leading to reduced triglyceride-rich lipoproteins in the bloodstream.

Current treatment options for severe hypertriglyceridemia and FCS are limited, often involving dietary restrictions and lipid-lowering medications that may not adequately control triglyceride levels. 

In clinical studies, plozasiran demonstrated substantial efficacy in lowering triglyceride levels. For instance, in patients with severe hypertriglyceridemia, plozasiran treatment resulted in triglyceride levels falling below the 500 mg/dL threshold associated with acute pancreatitis risk in most participants. Additionally, improvements were observed in other triglyceride-related lipoprotein parameters. 

RGX-121

• Developer: REGENXBIO
• Indication: Mucopolysaccharidosis type 2 (MPS 2) – Hunter syndrome
• Technology: Gene therapy

MPS 2, commonly known as Hunter syndrome, is a rare recessive genetic disorder caused by a deficiency of the enzyme iduronate-2-sulfatase (I2S). This enzyme is responsible for breaking down glycosaminoglycans (GAGs), complex sugar molecules involved in building connective tissues. 

Without sufficient I2S, GAGs accumulate in cells throughout the body, leading to progressive damage that affects multiple organs and the central nervous system (CNS). This accumulation results in a range of symptoms, such as developmental delays, organ enlargement, skeletal abnormalities, and neurological decline. 

Current treatments, like intravenous enzyme replacement therapy (ERT), have limited ability to cross the blood-brain barrier, making them less effective in addressing the neurological aspects of the disease.

RGX-121 is a one-time gene therapy delivering the gene encoding the I2S enzyme directly to the CNS using an adeno-associated virus (AAV9) vector. By introducing a functional copy of the I2S gene into CNS cells, RGX-121 aims to restore the production of the I2S enzyme, enabling the breakdown of accumulated GAGs and potentially halting or reversing the progression of neurological symptoms. This targeted delivery is intended to provide a permanent source of the enzyme within the CNS, overcoming the limitations of current ERTs.

In the ongoing CAMPSIITE trial, RGX-121 has demonstrated promising results. Notably, patients receiving RGX-121 at the pivotal dose level exhibited an 85% median reduction in cerebrospinal fluid (CSF) levels of heparan sulfate (HS) D2S6 – a key biomarker of brain disease activity – approaching normal levels and sustained for up to two years. 

REGENXBIO completed a pre-Biologics License Application (BLA) meeting with the FDA, supporting an accelerated approval pathway for RGX-121. This could indicate a potential FDA approval in 2025 for the first-in-class drug, which would make it the first gene therapy approved for the treatment of MPS 2.

Suzetrigine

• Developer: Vertex Pharmaceuticals
• Indication: Moderate-to-severe acute pain and peripheral neuropathic pain
• Technology: Non-opioid analgesic

Suzetrigine, formerly known as VX-548, is an oral analgesic that selectively inhibits the voltage-gated sodium channel NaV1.8. NaV1.8 is predominantly expressed in peripheral pain-sensing neurons and plays a crucial role in transmitting pain signals. By targeting NaV1.8, suzetrigine modulates pain transmission without affecting other sodium channels, potentially reducing the risk of side effects associated with less selective analgesics.

Pain management strategies often rely on opioids, which carry risks of addiction and other adverse effects. If approved in 2025, Vertex’s first-in-class drug candidate could offer a non-opioid alternative to pain management.

Suzetrigine has demonstrated efficacy in treating moderate-to-severe acute pain. In phase 3 clinical trials, it met primary endpoints, showing significant pain reduction compared to placebo in patients undergoing surgical procedures. 

However, the results were mixed for neuropathic pain as suzetrigine did not demonstrate a significant difference from the placebo in pain reduction. 

Telisotuzumab vedotin

• Developer: AbbVie
• Indication: Non-small cell lung cancer (NSCLC) with c-met protein overexpression
• Technology: Antibody-drug conjugate

Telisotuzumab vedotin, also known as Teliso-V, is an antibody-drug conjugate (ADC) targeting cancers that overexpress the c-Met protein. c-Met is a receptor tyrosine kinase involved in cellular processes such as growth, survival, and metastasis. Overexpression of c-Met is associated with tumor progression and poor prognosis in various cancers including NSCLC.

The ADC comprises two main components:

• Monoclonal antibody (telisotuzumab): This antibody specifically binds to the c-Met protein on the surface of cancer cells.
• Cytotoxic agent (monomethyl auristatin E – MMAE): Once the antibody binds to c-Met, the ADC is internalized by the cancer cell. Inside the cell, MMAE is released, leading to cell cycle arrest and programmed cell death.

Currently, there are no approved cancer therapies specifically targeting c-Met overexpression in NSCLC. Telisotuzumab vedotin, by delivering a cytotoxic agent directly to c-Met–expressing tumor cells, could improve efficacy while minimizing damage to normal tissues. 

In September 2024, AbbVie submitted a BLA to the FDA for the first-in-class drug, telisotuzumab vedotin, in previously treated NSCLC, potentialy reaching the market in 2025. 

UGN-102

• Developer: UroGen Pharma
• Indication: Low-grade intermediate-risk non–muscle-invasive bladder cancer (LG-IR-NMIBC)
• Technology: hydrogel-based formulation

UGN-102 combines mitomycin, a chemotherapeutic agent, with UroGen’s proprietary reverse thermal gel technology. This formulation is administered directly into the bladder as a liquid at lower temperatures. Upon reaching body temperature within the bladder, it transforms into a gel, allowing for prolonged contact between mitomycin and the bladder lining. This extended exposure enhances the drug’s ability to ablate cancerous cells effectively.

The current standard treatment for LG-IR-NMIBC involves transurethral resection of bladder tumor (TURBT), a surgical procedure to remove tumors. However, TURBT is associated with risks such as bleeding, infection, and a high recurrence rate. UGN-102 offers a non-surgical alternative that can be administered in an outpatient setting, potentially reducing the need for repetitive surgeries.

In phase 3, UGN-102 demonstrated a complete response rate of 79.6% at three months following the first use. Among those who achieved complete response, 82.3% maintained their response at 12 months, indicating durable efficacy.

Additionally, the trial showed that UGN-102, with or without TURBT, led to a 55% reduction in the risk of recurrence, progression, or death compared to TURBT alone. If approved in 2025, this first-in-class drug candidate would be the first FDA-approved non-surgical treatment for LG-IR-NMIBC.

UX111

• Developer: Ultragenyx Pharmaceuticals
• Indication: Sanfilippo syndrome type A 
• Technology: Gene therapy

Sanfilippo Syndrome type A, also known as mucopolysaccharidosis type 3A (MPS 3A), is a rare genetic disorder similar to Hunter syndrome caused by a deficiency in the enzyme heparan N-sulfatase. This enzyme deficiency leads to the accumulation of heparan sulfate in the body’s cells. 

The buildup primarily affects the CNS, resulting in progressive neurodegeneration. Children with MPS 3A typically experience developmental delays, behavioral issues, sleep disturbances, and a decline in cognitive and motor functions. Currently, there are no approved treatments that address the underlying cause of this disorder.

UX111 is a gene therapy that delivers a functional copy of the SGSH gene, which encodes the heparan N-sulfatase enzyme, directly to the CNS. Utilizing an AAV vector, the therapy is administered through a single intravenous infusion. Once delivered, the functional gene enables the production of the deficient enzyme, facilitating the breakdown of accumulated heparan sulfate.

In clinical studies, UX111 showed a reduction in cerebrospinal fluid heparan sulfate levels, a biomarker indicative of disease activity. Additionally, preliminary data suggest potential stabilization or improvement in neurocognitive function among treated patients. 

Ultragenyx Pharmaceuticals plans to seek accelerated approval for UX111. The FDA has agreed to consider cerebrospinal fluid heparan sulfate as a surrogate endpoint for evaluating the therapy’s efficacy. Ultragenyx aims to submit its BLA in early 2025, with the potential for UX111 to become the first approved treatment for Sanfilippo syndrome type A.

The FDA in 2025, a well-oiled machine

According to Citeline’s Biomedtracker’s projections, the FDA should deliver close to 70 approvals and label expansion in 2025. Among these 70 potential candidates, oncology is as usual the most represented disease area. 

Additionally, in 2019, the FDA indicated that it anticipated approving 10 to 20 cell and gene therapy products annually by 2025. So, if oncology is the number one disease area for FDA approvals, cell and gene therapy definitely lead the way in terms of technology. This year will be the occasion to confront the FDA’s prediction of a cell and gene therapies approval boom to reality. 

Obesity is another important topic that has been trending in the last couple of years and will still be in 2025. If we had written this article a couple of months back, Novo’s obesity drug CagriSema would have been a serious candidate for the list. However, the clinical trial results disappointed and even caused a $125 billion drop in the company’s market value. 

While it is still an honorable mention, it seems 2025 will be more about new trials rather than approval for CagriSema. Perhaps 2026 will be its year.

As 2025 unfolds, the industry will watch closely to see if these first-in-class drug candidates meet their potential. For patients living with rare diseases like MPS 2 or facing aggressive cancers like NSCLC, these first-in-class therapies offer hope for better outcomes and, in some cases, the first viable treatment options.