Zuranolone (ZURZUVAE™) is an oral positive allosteric modulator of CNS GABA signaling developed by Sage Therapeutics, in collaboration with Biogen, which was approved in August 2023 by the FDA for the treatment of postpartum depression (PPD). In 2019 Sage had received approval for brexanolone (ZULRESSO™), an IV formulation of the endogenous GABA PAM neurosteroid hormone for PPD, but an oral drug is expected to greatly increase access to treatment. Zuranolone was also investigated for major depressive disorder, although the FDA declined to extend approval for this indication.

Vertex’s VX-548 is a potential first-in-class, exquisitely selective, oral NaV1.8 inhibitor that recently captured headlines for its positive Ph. III data. With the ongoing opioid epidemic throughout the US, there is an urgent unmet medical need for non-addictive pain medications as alternatives to opioids. They plan to file an NDA by mid-2024 for the treatment of moderate-to-severe acute pain. This case study highlights what’s publicly known about Vertex’s journey in pain leading up to the Ph. III readout for VX-548, and why this is such a watershed moment for pain management.

Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2. This Featured Case Study reviews how it was discovered, how it works, and why it matters.

Compound 8 is a dual 5-HT2A and 5-HT2C receptor inverse agonist developed to address the limitations of pimavanserin.

Genentech announced that fenebrutinib (GDC-0853), a non-covalent BTK inhibitor entering Ph. III, showed significant human CNS exposure and reduced new brain lesions in Ph. II for relapsing multiple sclerosis. Fenebrutinib is the only reversible BTK inhibitor in Ph. III for MS, and has the opportunity to differentiate on safety relative to covalent inhibitors. This case study highlights notable challenges overcome in the discovery of fenebrutinib including surprising metabolism, animal-specific on-target toxicity, and more.