Drugs targeting the GLP-1 receptor and PD-1/PD-L1 pathway are money spinners for companies like Eli Lilly, Novo Nordisk and Merck and Co., so it’s no surprise that drug developers continue to chase these targets in the clinic.
But drugs aimed at novel targets are also winning approvals and could blaze new therapeutic trails on the market.
In September, the FDA greenlit Scholar Rock’s myostatin inhibitor Isembyld. It’s the first therapy to target muscle loss in spinal muscular atrophy, a rare, progressive neuromuscular disease. And Scholar Rock isn’t alone. Roche/Genentech and iBio are also pursuing myostatin inhibition, including in spinal muscular atrophy and obesity.
Ionis scored a novel target win in September with Zanvastro, a drug that became the first disease-modifying treatment for Alexander disease when it received FDA approval. Zanvastro targets glial fibrillary acidic protein messenger RNA.
And in August, the FDA approved Takeda Pharmaceuticals’ Mimrylo, a first-in-class hepcidin mimetic for erythrocytosis in adults with the blood cancer polycythemia vera.
Here are three more emerging drug targets with promising clinical activity.
The target: Cadherin-17 for solid tumors
High CDH17 expression is associated with metastatic tumor progression, especially in gastrointestinal tumors. Several candidates targeting that overexpression with antibody-drug conjugates have already progressed into the clinic.
Mabwell is among the companies developing a CDH17-targeting ADC. The company dosed its first U.S. patient in January in a trial evaluating its candidate, 7MW4911, for colorectal cancer and other advanced gastrointestinal tumors.
Another frontrunner, Sotio Biotech, is developing the ADC SOT109 for colorectal cancer. The company dosed its first patient in a phase 1/2 trial in September. The drug received an FDA fast track designation and has best-in-class potential, the company said.
Other avenues have yielded less success, though. In August, Chimeric Therapeutics ceased trial enrollment for a CDH17-targeting CAR-T cell therapy because of dose-limiting toxicities. Boehringer Ingelheim also quietly removed a bispecific antibody from its oncology pipeline after trials showed limited clinical activity.
The target: DNA polymerase theta for cancers with DNA repair defects
Several aggressive cancers, including one with the BRCA gene mutation, rely on the DNA repair enzyme Polθ to repair themselves. Inhibiting it could selectively kill tumor cells without harming healthy cells.
Companies are tackling Polθ inhibition in the clinic in two ways: Some are targeting the enzyme’s helicase domain, while others are going after the polymerase domain.
One heavy hitter in this domain is GSK. The drugmaker is testing GSK4524101 as both a monotherapy and combined with its oral small molecule PARP inhibitor, Zejula, in advanced solid tumors. AstraZeneca, SynRx Therapeutics and Moma Therapeutics also have clinical candidates with this approach in development.
On the polymerase domain side is Artios Pharma, which is pursuing the target with ART6043 for advanced germline BRCA-mutated, HER2-negative breast cancer. That candidate is in phase 2 trials and has FDA fast track designation.
The target: Tumor necrosis factor-like ligand 1A for immune-mediated inflammatory diseases
With dealmaking by companies like Roche and Merck and a significant phase 3 win, TL1A is the most familiar — and competitive — target on our list.
The initial clinical focus is inflammatory bowel diseases like ulcerative colitis and Crohn’s disease. There, anti-TL1As set themselves apart by potentially treating both inflammation and fibrosis. Unlike biologics like Humira and Entyvio, which only target the immune system and don’t directly stop fibrosis, TL1A also activates fibroblasts. TL1A holds pipeline-in-a-pill potential for other inflammatory diseases, too.
Merck leads the anti-TL1A development pack with the monoclonal antibody tulisokibart, inherited from its $10.8 billion Prometheus Biosciences acquisition in 2023. The company notched a phase 3 victory when tulisokibart showed clinical remission at 12 weeks in patients with moderately to severely active ulcerative colitis. Merck is pursuing other indications for tulisokibart, too, including the skin condition hidradenitis suppurativa where it also recently reported positive clinical results. But it struck out in testing tulisokibart for systemic sclerosis-associated interstitial lung disease.
Roche is hot on Merck’s heels with its monoclonal antibody afimkibart, which the company added to its roster after acquiring Televant Holding from Roivant for $7.1 billion in 2023. The company is conducting phase 3 trials in both ulcerative colitis and Crohn’s disease. While Merck is further ahead clinically, analysts say afimkibart’s subcutaneous delivery could trump tulisokibart’s IV delivery.
Teva and Sanofi are also in the anti-TL1A race. Their human monoclonal antibody duvakitug also scored in a phase 2b win earlier this year in patients with ulcerative colitis and Crohn’s disease.
