Guggenheim 3rd Annual Healthcare Innovation Conference - SEPTERNA INC

Financial Performance:

• Reported over $565 million in cash and marketable securities as of the end of Q3.
• Current cash runway extends through at least mid-2029, covering the entire development pipeline.
• Financial figures exclude potential milestone payments from the existing collaboration with Novo.

Guidance and Future Outlook:

• Anticipates Phase 1 data readouts for SEP479 (hyperparathyroidism) and SEP631 (mast cell indications) in Q1 of next year.
• Aims to initiate Phase 1 clinical trials for the new Graves' disease candidate, SEP204, in Q1 of next year.
• Plans to proceed directly to Phase 2 studies in patients for SEP479 in the second half of the year, contingent on completing chronic toxicology studies.
• Long-term goal includes developing oral, once-daily replacements for peptide-based hormone therapies (PTH, incretins) and blocking antibodies.

Business Segments and Product Lines:

• SEP479: A long-acting small molecule agonist targeting the parathyroid hormone (PTH) receptor for hyperparathyroidism; preclinical data in monkeys showed a 50% reduction in endogenous PTH and increased serum calcium with a 3–4 day half-life.
• SEP204: A new small molecule negative allosteric modulator of the TSH receptor for Graves' disease and thyroid eye disease; demonstrates high selectivity (>1000-fold) over reproductive receptors (FSHR, LHR) and normalized thyroid hormone levels in rat models with Graves-derived antibodies.
• SEP631: A small molecule negative allosteric modulator of the MRG-PRAX2 receptor currently between Phase 1 and 2, evaluating mast cell indications.
• Osteoporosis Program: An early-stage discovery program utilizing a short-acting PTH receptor agonist approach to address unmet needs for oral anabolic agents.
• Novo Collaboration: An off-target agreement involving five targets with four concurrent programs advancing well.

Market and Competitive Landscape:

• Identifies significant unmet need for oral small molecule alternatives to injectable peptide therapies (e.g., Urovipath) in hyperparathyroidism and osteoporosis.
• Targets the "moderate" patient population in hyperparathyroidism currently managed only with calcium/vitamin D, aiming to expand the treatable pool beyond severe cases requiring daily injections.
• Highlights the opportunity to address both Graves' disease and thyroid eye disease (TED) simultaneously via TSHR modulation, a dual benefit not fully addressed by current standard-of-care antithyroid drugs or specific TED therapies like teprotumumab.
• Notes the historical difficulty of targeting GPCR peptide receptors and allosteric sites with small molecules, positioning their platform as a differentiator.

Risks and Challenges:

• Potential variability in dosing requirements for individual patients in hyperparathyroidism, necessitating a titration protocol and potentially multiple pill strengths.
• Historical challenges in achieving appropriate human dose projections for TSHR modulators, requiring extensive medicinal chemistry optimization to ensure once-daily oral efficacy.
• Safety risks associated with chronic therapy, requiring robust chronic toxicology studies before advancing to Phase 2.

Management Commentary and Tone:

• Management expressed high confidence and excitement regarding the platform's ability to solve historically difficult GPCR drug discovery challenges.
• Tone was capital-efficient and strategic, emphasizing the ability to build a substantial pipeline from scratch and the long-term value of oral hormone replacement therapies.
• Emphasized the biological validation of targets and the expectation to derive significant learning signals from Phase 1 trials.

Analyst Questions and Answers:

• Q: Importance of K170 in TSHR data? A: K170 is a blocking TSH autoantibody serving as a positive control that reduced proptosis in early trials; SEP204 achieved similar or superior efficacy in high-dose groups.
• Q: Rationale for osteoporosis focus? A: Leverages existing PTH expertise; addresses a massive unmet need for oral anabolic agents, supported by new clinical trial endpoint standards (SABR Initiative).
• Q: Expected Phase 1 biomarkers for SEP479? A: Targeting ~50% reduction in endogenous PTH and ~0.3–0.5 mg/dL increase in serum calcium in healthy volunteers.
• Q: Dosing flexibility and pill size? A: Anticipates a reasonable once-a-day pill size, though multiple dose strengths may be required similar to Urovipath; a quantitative systems pharmacology model is being built to optimize dosing.
• Q: Path to Phase 2 for SEP479? A: Plans to skip Phase 1b in patients and move directly to Phase 2 following Q1 Phase 1 readout and completion of chronic safety studies to facilitate potential long-term open-label extensions.

Other Key Points:

• SEP479 demonstrated consistent 3–4 day half-life across all tested cohorts in the SAD portion of the ongoing Phase 1 trial.
• The company developed an in-house mouse model of Graves' disease to demonstrate the reversal of proptosis (bulging eyes) and thyroid histology changes with SEP204.
• Management highlighted the long-term nature of hormone replacement therapies (40+ years), reinforcing the value proposition of oral administration over daily injections.