Ep203: Sri Kosuri on Small Molecule Correctors of Disease

What It Covers

Sri Kosuri, cofounder and CEO of Octant Bio, describes how the company builds oral small molecule correctors targeting protein misfolding and mistrafficking across rare diseases, cancers, and metabolic disorders. Their lead compound OCT-980 entered phase one trials in March 2025 for rhodopsin-associated autosomal dominant retinitis pigmentosa, a progressive blindness condition affecting roughly 20,000 patients in the US and EU.

Key Questions Answered

• •Corrector drug strategy: Protein misfolding and mistrafficking underlie a large proportion of rare diseases, cancers, and metabolic disorders because the most common way mutations disrupt protein function is by preventing proper folding or cellular localization. Octant targets this mechanism with oral small molecules, similar to how Vertex's Trikafta corrects CFTR misfolding in 90% of cystic fibrosis patients, opening a replicable template across multiple disease areas.
• •Deep mutational scanning for patient stratification: Octant builds every possible single amino acid mutation of a target gene in human cells, then runs trafficking or abundance assays to map which mutations cause misfolding. Cross-referencing this map against patient genetics allows the company to predict ahead of clinical trials exactly which mutations OCT-980 will rescue, enabling precise patient selection and informing the drug's eventual label.
• •Iterative nanoscale chemistry platform: Octant synthesizes approximately 5,000 to 20,000 novel compound analogs per week, tests them in cellular assays, trains machine learning models on the results, and feeds predictions into the next synthesis cycle. Over OCT-980's hit-to-lead campaign, this process generated roughly 250,000 analogs. The p53 program has now exceeded 750,000 compounds, run by just two scientists operating on top of the automated platform.
• •Ophthalmology trial design advantage: Because retinal structure can be photographed quantitatively via OCT imaging, Octant's phase 1b multiple ascending dose study can measure rod outer segment restoration and low-light visual acuity improvements above baseline within approximately three months. Natural history data from 200 rhodopsin-ADRP patients tracked over eight years at Moorfields Eye Hospital shows only decline, making any improvement a statistically clear efficacy signal without requiring a placebo arm.
• •P53 glue corrector mechanism: Roughly half of all cancers carry p53 mutations, with the most common variants breaking DNA binding rather than destabilizing the protein. Octant is developing molecular glues that reestablish proper DNA-protein contact for multiple common p53 mutations simultaneously, activating the correct transcriptional cascade and triggering mutation-specific caspase-mediated cell death while largely sparing wild-type p53, a differentiated approach from the covalent Y220C pocket strategy used by PMV Pharma.
• •Open ADMET consortium for shared ML benchmarking: Octant co-founded Open ADMET, a consortium producing large-scale public datasets on small molecule absorption, distribution, metabolism, excretion, and toxicity properties, then running competitions among AI and ML labs to establish standardized benchmarks. The rationale mirrors how the CASP competition and Protein Data Bank enabled AlphaFold: shared ground-truth data accelerates the entire field faster than proprietary model development at individual companies.