Emerging epilepsy treatment landscape: KOLs see substantial unmet need and constructive potential for novel epilepsy therapies

Overview

This KOL call update examines treatment gaps and emerging therapies in focal epilepsy and developmental and epileptic encephalopathies. Physicians described strong unmet need and constructive interest in several novel mechanisms, but repeatedly tied real-world uptake to efficacy confirmation, tolerability, psychiatric adverse events, reimbursement, and access.

Core views

The KOL discussion began with the persistent treatment gap in focal epilepsy. The physicians said only approximately 25–30% of patients achieve seizure freedom despite many available therapies, and roughly one-third remain refractory after multiple treatments. This backdrop supports interest in differentiated mechanisms, but the KOLs stressed that real-world tolerability and neuropsychiatric adverse events will ultimately shape use among refractory patients. For Rapport Therapeutics' RAP-219, a TARPy8-selective AMPA receptor negative allosteric modulator, the physicians were encouraged by its novel selectivity profile and early clinical efficacy. They nevertheless noted historical caution with AMPA-targeted agents such as Fycompa because of anger, irritability, aggression, and agitation. One KOL suggested that selective cerebellar targeting, potentially sparing cortical and limbic structures, could reduce those risks. The central remaining requirement is validation in a larger randomized Phase 3 focal-onset-seizure study. The KOLs also expect possible translation from focal-onset seizures to primary generalized tonic-clonic seizures, with Phase 3 initiation expected in 1H27. Ahead of October Phase 2 bipolar-mania data, safety and tolerability are an investor focus, although the physicians saw limited direct read-through to focal-onset seizures because the underlying conditions differ. The physicians were positive on Xenon's Kv7/M-channel approach for refractory focal epilepsy. They described the mechanism as potentially preferentially suppressing pathological neuronal firing rather than being ubiquitously expressed across the brain, and noted that the approximately 50% seizure reduction and dose-response profile for XENE compared well with existing antiseizure-medication studies. One doctor initially envisioned azetukalner mainly in the third-line-and-beyond setting, with monitoring for psychiatric or behavioral effects, while another indicated that more than 30% of his practice is highly refractory. The KOLs expected meaningful initial interest: one anticipated use in about half of refractory patients during the first year, while another expected interest from one-half to two-thirds of patients. They also viewed BHVN's mechanistically similar program favorably, while retaining neuropsychiatric tolerability as a key adoption determinant. In DEEs, the KOLs characterized JAZZ's Epidiolex as a meaningful treatment contributor. One physician estimated that one-third to one-half of patients have benefited through seizure reduction, tolerability, and potential mood or behavioral calming effects, particularly after other medicines have failed. They expect a solid oral capsule to improve convenience and adoption for adults who struggle with the volume or taste of the current sesame-oil, strawberry-flavored oral liquid; one KOL expected the capsule to become the preferred formulation. For Praxis' relutrigine, the physicians were encouraged by the persistent sodium-channel inhibitor's mechanism and the EMBOLD data in SCN2A- and SCN8A-DEEs. They saw the state-dependent mechanism as potentially advantageous from a sodium-channel-toxicity perspective and believed efficacy could extend to broader DEE populations in the ongoing Phase 3 EMERALD study. Adoption, however, depends on preserving a favorable tolerability profile in the larger study. The KOLs indicated that a more modest placebo-adjusted seizure reduction than in EMBOLD could still be acceptable if tolerability remains favorable, given that many DEE patients exhaust current options. For Stoke's zorevunersen, KOLs were broadly enthusiastic about antisense oligonucleotide therapies that address underlying genetic biology rather than solely suppress seizures. In Dravet syndrome, they saw potential value beyond seizure reduction through disease modification and possible improvements in developmental, cognitive, behavioral, and functional outcomes. They considered intrathecal administration acceptable given disease severity and unmet need, although they would favor alternative routes for future therapies. The report also provides company-specific valuation frameworks. JAZZ's $337 12-month target is based entirely on DCF using a 9% WACC and 1% terminal growth rate, with 2026–2028 non-GAAP EPS estimates of $23.71, $25.12, and $25.67. PRAX's $575 target blends a $554 DCF value at 70% weight with a $625 theoretical M&A value at 30% weight. RAPP's $62 target blends a $54 DCF value at 70% weight with an $81 theoretical M&A value at 30% weight. STOK's $44 target weights DCF at 85% and theoretical M&A value at 15%, while XENE's $75 target similarly weights DCF at 85% and theoretical M&A value at 15%.

Analysis framework

Goldman Sachs hosted two physician KOLs and used their clinical-practice perspectives to assess unmet need, mechanism differentiation, potential treatment positioning, and adoption constraints across focal epilepsy and DEEs. The report then links those views to company-specific clinical milestones and valuation frameworks, including DCF and, for selected companies, theoretical M&A values.

Methodology notes

• Industry AnalysisSupply-demand framework

  Assessment of unmet patient need, refractory populations, available treatment limitations, and the potential uptake of new therapies.

  The report uses physician observations on seizure freedom, treatment failure, and patient demand to explain why novel epilepsy mechanisms may find clinical adoption if their efficacy and tolerability hold up.

• Valuation methodsDCF (Discounted Cash Flow)

  Discounted cash flow valuation using stated WACC and terminal-growth assumptions.

  Goldman Sachs derives intrinsic values for JAZZ, PRAX, RAPP, STOK, and XENE from DCF assumptions, then uses those values alone or in blends with theoretical M&A values to set targets.

• Event-Driven and Behavioral Finance

  Theoretical M&A valuation and M&A ranking.

  For PRAX, RAPP, STOK, and XENE, the report incorporates a weighted theoretical acquisition value based on forecast sales multiples and the firm's M&A ranking framework.

Asset mapping & comparison

Structured mapping from thesis to named assets (strengths, weaknesses, peers, risks).

• Jazz Pharmaceuticals (JAZZ)

  Covered company with Epidiolex exposure in DEEs.

  Strengths

  KOLs view Epidiolex as a meaningful contributor; a capsule formulation could improve convenience and adoption.

  Weaknesses

  Current oral liquid volume and taste can be difficult for some patients.

  Comparison

  The capsule is expected to offer convenience relative to the existing oral liquid formulation.

  Risks

  Sales could be affected by supply constraints, reimbursement or market-access challenges, adverse events, regulatory setbacks, or competition after patent and exclusivity expiration.

• Praxis Precision Medicines Inc. (PRAX)

  Covered company developing relutrigine for DEEs.

  Strengths

  KOLs were constructive on relutrigine's state-dependent mechanism, emerging profile, and potential translation into broader DEEs.

  Weaknesses

  EMERALD must confirm efficacy and tolerability in a larger study.

  Comparison

  A more modest placebo-adjusted seizure reduction than EMBOLD could remain acceptable if favorable tolerability is maintained.

  Risks

  Regulatory, commercial, and clinical risks include an unfavorable Phase 3 EMERALD outcome or EMBRAVE3 failure.

• Rapport Therapeutics (RAPP)

  Covered company developing RAP-219 for focal epilepsy.

  Strengths

  KOLs expressed optimism about TARPy8 selectivity and early efficacy, with potential to reduce neuropsychiatric risk through selective targeting.

  Weaknesses

  The early profile requires confirmation in a larger randomized Phase 3 study.

  Comparison

  Historical AMPA therapies such as Fycompa provide both an efficacy precedent and a psychiatric-adverse-event caution.

  Risks

  Failure to replicate results in Phase 3 focal-onset-seizure or Phase 2 bipolar-disorder studies, slower adoption, reimbursement failure, regulatory, competitive, IP, and financing risk.

• Stoke Therapeutics Inc. (STOK)

  Covered company developing zorevunersen for Dravet syndrome.

  Strengths

  KOLs were enthusiastic about disease-modifying genetic therapy that could improve outcomes beyond seizure frequency.

  Weaknesses

  Treatment requires intrathecal administration, although physicians considered this acceptable for severe disease.

  Comparison

  The approach seeks to address underlying biology rather than simply suppress seizures.

  Risks

  Clinical failure in Phase 3 EMPEROR, payer resistance to pricing or disease-modification claims, and a smaller or harder-to-reach patient population.

• Xenon Pharmaceuticals Inc. (XENE)

  Covered company developing azetukalner for focal epilepsy.

  Strengths

  KOLs favor the Kv7/M-channel mechanism, approximately 50% seizure reduction, dose response, and substantial interest among refractory patients.

  Weaknesses

  Psychiatric and behavioral tolerability will need monitoring, particularly in real-world use.

  Comparison

  KOLs saw the profile as favorable versus historical GABAergic or AMPA-based approaches and mechanistically similar to BHVN's program.

  Risks

  Efficacy and safety from X-TOLE2 may not translate to X-ACKT, X-NOVA2, or later studies; commercialization may require partners in certain markets.

Key data

• Focal-epilepsy seizure freedom~25–30%KOL estimate of patients achieving seizure freedom despite numerous approved therapies.
• Refractory focal-epilepsy population~one-thirdKOL estimate of patients remaining refractory despite multiple therapies.
• XENE seizure reduction~50%Reported seizure reduction and dose response compared favorably with existing ASM studies.
• Epidiolex patient benefitone-third to one-halfOne KOL's estimate of patients benefiting through seizure reduction and tolerability.
• JAZZ 2026/2027/2028 non-GAAP EPS$23.71 / $25.12 / $25.67Goldman Sachs estimates.
• RAPP Phase 3 PGTCS initiation1H27Expected initiation timing cited by the KOLs.

Impact & implications

The report argues that the size of the refractory population creates room for novel epilepsy treatments, but clinical differentiation alone is insufficient. Adoption will depend on whether larger studies confirm efficacy and preserve favorable safety profiles, especially regarding psychiatric effects, as well as on formulation convenience, reimbursement, and patient access.

Risks

• For emerging focal-epilepsy therapies, psychiatric and behavioral adverse events could limit real-world uptake.
• RAP-219 requires validation in a larger randomized Phase 3 study.
• Relutrigine adoption depends on a favorable efficacy-tolerability balance in the Phase 3 EMERALD study.
• Zorevunersen faces Phase 3 efficacy, payer-access, pricing, and patient-identification risks.
• XENE faces clinical-translation and global-commercialization execution risks.

What to watch

• RAP-219 Phase 2 bipolar-mania data in October, particularly safety and tolerability observations.
• RAP-219 randomized Phase 3 focal-onset-seizure validation and planned 1H27 Phase 3 initiation in primary generalized tonic-clonic seizures.
• Initial real-world azetukalner experiences, including psychiatric or behavioral effects and use in refractory patients.
• PRAX Phase 3 EMERALD data, especially relutrigine tolerability and translation into broader DEEs.
• STOK Phase 3 EMPEROR results and payer reception to disease-modification claims.