The final FDA approval of 2025 went to Vanda’s NK1R antagonist tradipitant (Nereus®) for the treatment of motion-induced nausea and vomiting. While the value of NK1R antagonists as antiemetics is well established, tradipitant is the first new drug to be approved for motion sickness in over 40 years. This approval marks a major win for Vanda, but it is the recent positive Ph. 2 data for tradipitant in mitigating GLP-1R agonist-induced nausea and vomiting that may hint at the true potential of this molecule.

Aceclidine (Vizz®) is a predominantly pupil-selective muscarinic agonist approved in 2025 as an ophthalmic solution for presbyopia, an age-related loss of near vision. It induces miosis primarily via the iris sphincter with minimal ciliary muscle stimulation, positioning it as a pupil-forward approach to improving near vision via a pinhole depth-of-focus effect. Approval was supported by the Ph. 3 CLARITY program, in which once-daily aceclidine produced clinically meaningful gains in near vision without sacrificing distance visual acuity.

As part of our Flash Talk webinar series, we present a follow-up article for Nicholas Hertz’s Flash Talk, “Safer CNS Drugs with BrainOnly™ Pharmacology.” You can also check out the recording of the talk on our Drug Hunter YouTube channel. In this follow-up article, we discuss the development of Montara Therapeutics’ BrainOnly™ platform for CNS-relevant diseases.

The rise of GLP-1R agonists and the recent approval of semaglutide for MASH have reignited interest in drug targets for severe liver diseases. MASH remains one of the most unforgiving indications in the clinic; multiple mechanisms with promising preclinical biology—including FGF21, DGAT2, HSD17B13, PPAR agonism, among others—have led to disappointing clinical outcomes. Against this background, an important question must be asked: beyond metabolic modulation, which targets can address the underlying drivers of disease, and what has held progress back?

Ganaplacide is a novel oral antimalarial, which appears to disrupt the Plasmodium parasite’s secretory/trafficking pathway, that is being developed in combination with lumefantrine (GanLum) for uncomplicated P. falciparum malaria. The compound shows multi-stage antiparasitic activity and a mechanism differentiated from legacy antimalarial classes. In the Ph. 3 KALUMA trial, GanLum met its primary endpoint of non-inferiority to Coartem® (artemether–lumefantrine). If approved, GanLum would add a mechanistically distinct regimen as resistance continues to pressure established therapies.

GCase, a lysosomal β-glucosidase encoded by GBA1, is a key genetic risk node in Parkinson’s and Gaucher’s diseases, linking defects in lipid metabolism to neurodegeneration. Initial approaches utilizing active‑site pharmacological chaperones were limited by on‑target lysosomal inhibition, prompting a shift toward non‑inhibitory allosteric modulators. Emerging CNS‑penetrant allosteric activators, including pariceract (BIA 28‑6156), GT‑02287, and VQ‑101, are currently in clinical development for GBA1‑associated and idiopathic Parkinson’s disease and will test this enzyme activation approach.

Sunvozertinib (Zegfrovy), Dizal Pharmaceutical’s covalent EGFR inhibitor with some selectivity for ex20ins mutations, gained FDA approval for the treatment of nSCLC after progression on platinum-based chemotherapy. Ex20ins mutations comprise a particularly challenging subset of EGFR-driven cancers, with the first three generations of EGFR inhibitors displaying insufficient efficacy in the clinic. While several companies are advancing their own EGFR ex20ins inhibitors into Ph. 2 and 3 trials, Sunvozertinib is currently the only FDA-approved small molecule to treat EGFR ex20ins-driven nSCLC.

Vimseltinib is an oral CSF1R inhibitor for adults with symptomatic TGCT (tenosynovial giant cell tumor). CSF1R, a type III receptor tyrosine kinase activated by CSF1 and IL-34, regulates the survival, proliferation, and differentiation of myeloid-lineage cells. TGCT is a rare synovial tumor driven by CSF1 gene rearrangements that cause CSF1 overexpression, promoting macrophage-rich lesions that can cause morbidity. While pexidartinib validated CSF1R inhibition clinically, its broad kinase activity and hepatotoxicity underscore the need for selective agents—setting the stage for vimseltinib.

Among the plethora of emerging targets being pursued using targeted protein degradation, the transcription factors WIZ (widely interspaced zinc finger) and ZBTB7A (zinc finger and BTB domain containing 7A) have recently caught our attention as promising targets for a disease-modifying approach for SCD (sickle cell disease) and β-thalassemia. Check out our coverage of the competitive landscape to see why industry activity may have picked up in this space.

Test your knowledge with a short quiz covering drug discovery concepts from Module 1.

Neurodegenerative disorders are complex diseases whose often heterogeneous biology has hampered translation from preclinical promise to clinical benefit. Drug repurposing has emerged as a potentially pragmatic shortcut, allowing earlier entry into mid- to late-stage trials. In this review, we highlight four repurposing tools that drug hunters can utilize across repurposing campaigns, in the context of four small molecules originally approved for other indications that are now being clinically tested for use in neurodegenerative diseases.

Bezuclastinib is a selective, oral KIT(D816V) inhibitor with NDAs in progress for SM (systemic mastocytosis) and GIST (gastrointestinal stromal tumors). The Ph. 2 SUMMIT trial met all primary and secondary endpoints, with improvement in patient-reported total symptom scores as well as biomarkers of mast cell burden. With positive clinical results in non-advanced SM, advanced SM, and GIST, bezuclastinib is emerging as a promising therapy for KIT-driven diseases.

Kygevvi (doxecitine + doxribtimine) is a first-in-class oral nucleoside therapy for the ultra-rare mitochondrial disorder TK2 deficiency. When TK2 can’t phosphorylate deoxycytidine and deoxythymidine, mitochondrial dNTP pools collapse, mtDNA maintenance falters, and progressive myopathy—often with respiratory failure—follows. Kygevvi aims to bypass that bottleneck by supplying pyrimidine nucleosides to feed salvage pathways and restore mtDNA-relevant nucleotide balance. The program emerged from academic work and later advanced through Modis → Zogenix → UCB, earning multiple FDA designations.

ENPP1, a negative regulator of the cGAS-STING pathway and promoter of adenosine-rich TME, is rapidly gaining attention in the patent literature. The ability of ENPP1 to indirectly modulate this pathway — as well as its aberrant expression in numerous cancers — has brought significant interest from the immuno-oncology field. This patent target review will delve into the cGAS-STING pathway’s role in cancer, the therapeutics hypotheses driving activity around ENPP1, and some of the ENPP1 inhibitor scaffolds emerging in the patent literature.

As the understanding of oral bioavailability in the bRo5 (beyond rule of 5) physicochemical property landscape matures, the unshackling of Drug Hunters from traditional design constraints (and the accompanying exploration of non-traditional chemical space) has yielded a rapid evolution of therapeutic MoAs. Despite an abundance of dimeric and dual-engaging xenobiotics and secondary metabolites throughout the natural world – alluding to their significance in regulating biological processes – the adoption of this strategy to drugs has been limited until recently.