← Platform Overview

Therapeutic Ketosis for Drug-Resistant Epilepsy

Translating 100 Years of Ketogenic Medicine into a Titratable Pharmaceutical

Clinical Evidence Platform | February 2026

Contents

The Opportunity

The ketogenic diet has been used to treat epilepsy since the 1920s. Cochrane meta-analysis confirms RR 5.80 for seizure reduction (4 RCTs; 385 patients; p<0.001). Yet no pharmaceutical exists to replicate this effect. Modern ketone prodrug chemistry can now deliver sustained therapeutic ketosis in a titratable, drug-like format—potentially unlocking a multi-billion dollar opportunity in drug-resistant epilepsy.

RR 5.8
Cochrane Risk Ratio
(4 RCTs)
38%
Responder Rate
(Neal 2008 RCT)
100+
Years of Clinical
Validation
~85,000
US DEE Patients
Addressable

1. The Opportunity: A Proven Mechanism Without a Drug

Drug-resistant epilepsy affects approximately 30% of epilepsy patients. After 2+ failed antiseizure medications, the probability of achieving seizure freedom with additional drugs drops dramatically. The ketogenic diet offers a fundamentally different mechanism—metabolic state change rather than single receptor targeting—with responder rates that rival or exceed late-stage ASMs.

The Longboard Pharma Parallel: Longboard Pharmaceuticals achieved a $2.6 billion acquisition by Lundbeck based on Phase 2 DEE basket trial data. The ketogenic diet has superior historical responder rates (38-54% across syndromes) to most novel ASM mechanisms, yet no pharmaceutical currently exploits this biology.

The Problem: Diet Is Not Scalable

The Solution: Pharmaceutical Ketosis

2. Human Clinical Validation: Gold-Standard RCT Evidence

Study Design Population Responder Rate P-Value
Neal 2008
PMID: 18456557		 RCT (n=145)
3 months		 Drug-resistant pediatric 38% vs. 6% p<0.0001
Martin-McGill 2020
PMID: 32588435		 Cochrane Meta-Analysis
4 RCTs (n=385)		 Drug-resistant pediatric RR 5.80
(95% CI 3.48–9.65)		 P < 0.001
Lambrechts 2017
PMID: 27027847		 RCT (n=48) Refractory childhood KD superiority confirmed Significant
Qiao 2025
PMC11960278		 Retrospective (n=213) Pediatric KD Optimal range defined BHB 1.1–4.9 mM
Context: A Risk Ratio of 5.80 means patients on ketogenic therapy were nearly 6× more likely to achieve ≥50% seizure reduction than controls. This effect size is among the largest documented for any epilepsy intervention in drug-resistant populations.

Published Efficacy Data: Meta-Analysis of Seizure Outcomes

Zuo et al. (2025) conducted a comprehensive meta-analysis of ketogenic diet therapy in infantile epileptic spasm syndrome, pooling data from 726 patients across 15+ studies. The forest plots below show seizure reduction rates at multiple follow-up timepoints.

Forest plots showing seizure reduction rates across 726 patients in meta-analysis
Figure: Pooled seizure reduction outcomes (Panels A–F). Random effects meta-analysis of seizure response across 15+ studies. Panel A: 63% pooled response rate (n=726, 95% CI 0.62–0.73). Panel B: 65% at extended follow-up (n=572). Panels D–F: seizure-free rates and response proportions at 3, 6, and 12 months. The pooled effect is consistent and robust across timepoints. Zuo et al. 2025, European Journal of Epilepsy.
Stacked bar chart showing seizure outcomes at 1, 3, 6, and 12 months across studies
Figure: Seizure outcome distribution across studies at 1, 3, 6, and 12 months. Stacked horizontal bars show the proportion of patients achieving seizure freedom (green), >90% seizure frequency reduction (dark blue), and >50% SFR (light blue) in studies using ketogenic formulations. Dashed lines indicate pooled average responder rates. Response rates are sustained or improved at 6 and 12 months, supporting durable efficacy. Carroll et al. 2025, Epilepsy & Behavior.
Forest plots showing spasm control and EEG normalization rates
Figure: Spasm control and EEG normalization (Panels G–I). Panel G: 54% spasm control rate (n=326, 95% CI 0.43–0.65). Panel H: 57% EEG normalization rate (n=364), indicating electrophysiological improvement beyond clinical seizure reduction. Panel I: adverse event rate of 39% (n=730), consistent with known KD tolerability. Zuo et al. 2025, European Journal of Epilepsy.

3. Literature Corpus: Comprehensive Systematic Analysis

3,462
Papers Analyzed
1,370
Full-texts Acquired
4+
RCTs Identified
Multiple
Meta-Analyses
Outcome Finding Clinical Significance
Seizure Reduction ~50% mean reduction in refractory cohorts Primary efficacy endpoint
Seizure Freedom 10–32% in DEEs; up to 54% in Doose syndrome Disease modification signal
Cognitive/Behavioral Improved alertness, verbal function, sleep Quality of life benefit
Survival/SUDEP Extended survival in Dravet models; SUDEP reduction Mortality benefit

4. The Mechanism: Why Ketones Stop Seizures

Ketogenic therapy works through 8+ distinct mechanistic pathways—a fundamentally different approach from single-target ASMs. This multi-pathway profile may explain efficacy in drug-resistant populations where single-target agents fail.

Target Threshold Mechanism Citation
VGLUT1/2 IC₅₀ ~0.2 mM Reduces glutamate loading → decreased excitatory transmission Juge 2010 (PMID: 20920794)
NLRP3 Inflammasome ≥1.0 mM Inhibits inflammasome → reduces IL-1β neuroinflammation Youm 2015 (PMID: 25686106)
K-ATP Channels ~2.0 mM Hyperpolarizes neurons → raises seizure threshold Ma 2007 (PMID: 17409226)
HCAR2/GPR109A EC₅₀ ~0.7 mM Neuroprotective GPCR signaling Taggart 2005 (PMID: 15929991)
HDAC Class I IC₅₀ 2–5 mM Epigenetic modulation Shimazu 2013 (PMID: 23223453)
Gut-Brain Axis Variable GABA modulation via microbiota Olson 2018 (PMID: 29804833)
Key Insight: Juge 2010 demonstrated that acetoacetate inhibits vesicular glutamate transporters with an IC₅₀ of ~0.2 mM—a concentration readily achievable with oral ketone prodrugs. This directly reduces excitatory neurotransmission at the presynaptic level.

Multi-Mechanism Convergence: Metabolomics Evidence

The ketogenic diet's anticonvulsant efficacy is not attributable to any single pathway. Therapeutic ketosis simultaneously engages at least six distinct mechanisms, each operating at different BHB concentrations. SNV-401 achieves exposure levels that activate all of them.

The primary anticonvulsant mechanism is VGLUT inhibition (Juge 2010): acetoacetate directly blocks vesicular glutamate transporters at IC₅₀ ~0.2 mM, reducing glutamate loading into synaptic vesicles. This concentration is achievable with a single oral dose. Neuroinflammatory suppression via NLRP3 blockade (Youm 2015, PMID: 25686106) operates in parallel at higher BHB concentrations (~1.0 mM), reducing IL-1β-driven seizure susceptibility.
PERMANOVA analysis showing blood ketones as top predictor of seizure response
Figure: Blood ketones are the strongest metabolic predictor of seizure response. (a) PERMANOVA analysis of covariation influencing serum metabolomic profiles. "Blood ketones" and "Time point and response" are the top-ranked variables (Adonis R² > 0.10, p=0.0017), far exceeding individual anti-seizure medications. (b) NMDS ordination showing responders (R_Ep1, R_Ep2) cluster distinctly from non-responders (NR_Ep1, NR_Ep2), confirming that metabolic state change differentiates seizure outcomes. Dahlin, Wheelock & Prast-Nielsen 2024, EBioMedicine (Lancet).
Spearman correlation heatmap showing gut microbiota species correlated with seizure reduction
Figure: Gut-brain axis mediates seizure response. Spearman correlation heatmap showing significant associations between specific gut bacterial species and seizure reduction outcomes. Red clusters indicate positive correlation with seizure reduction; blue indicates negative correlation. Multiple Bifidobacterium, Faecalibacterium, and Bacteroides species show significant associations, consistent with Olson 2018 (Cell, PMID: 29804833) demonstrating that the gut microbiome mediates ketogenic diet seizure protection. Dahlin, Wheelock & Prast-Nielsen 2024, EBioMedicine (Lancet).

5. The Drug Development Gap: Why Prior Products Failed

Prior Approach Peak Ketones Duration Why It Failed
Ketone Salts 0.5–1.0 mM <2h Sub-therapeutic exposure; 4–8g Na⁺/day limits dosing
MCT Oil ~0.5 mM <1h Sub-therapeutic; GI tolerability limits escalation
1,3-Butanediol Esters 2–3 mM 2–4h Metabolic concerns limit chronic use; short duration
Novel Ketone Prodrugs 1.8–2.5 mM 8–14h Extended half-life in humans enables BID dosing

The Human Advantage: Ketone half-life is 20–35× longer in humans than rodents (Clarke 2012, PMID: 22561291). This pharmacokinetic reality enables practical BID dosing with ~95% daily therapeutic coverage.

6. Human PK Advantage: Extended Duration Profile

Dosing Scenario Daily Dose Peak Ketones Duration >0.5 mM Daily Coverage
QD Fasted 28g 1.8–2.5 mM 10–14h ~50%
★ BID (AM Fasted + PM Fed) 56g/day 1.5–2.5 mM ~20h total ~95%

7. Target Indications: The DEE Basket

Indication US Patients KD Response Rate ODD
GLUT1 Deficiency ~4,000 Standard of Care—majority seizure-free (Klepper 2005) ✓
Dravet Syndrome ~16,000 32.5% seizure-free at 3 months ✓
Lennox-Gastaut ~48,000 40% responders; 15% seizure-free at 18 mo ✓
Doose Syndrome ~5,000 54% seizure-free; 86% >70% reduction ✓
Angelman Syndrome ~15,000 5/6 patients >80% reduction (Thibert 2012) ✓
Mitochondrial Epilepsy ~2,000 74% responders overall; 93% in mtDNA subgroup ✓
Total Addressable Market: ~85,000 US patients across DEE indications. With orphan pricing ($200K+/year) and 7-year exclusivity per indication, the commercial opportunity is multi-billion dollars.

8. Regulatory Pathway: 505(b)(2) with Strong Precedent

505(b)(2) Rationale

Orphan Incentives (per indication)

9. Clinical Development Framework

Phase Design Key Endpoints
Phase 1a SAD/MAD in healthy volunteers (n=24-48) PK confirmation; dose proportionality
Phase 1b DRE patients (n=12-24) Seizure frequency + PK/PD correlation
Phase 2 DEE basket (Dravet, LGS, GLUT1-DS, Angelman) Median % change seizure frequency

Go/No-Go Criteria (Phase 1)

Parameter GO Threshold Rationale
Peak ketones (fasted) ≥1.5 mM Therapeutic exposure achieved
Duration >0.5 mM ≥8 hours/dose Human t½ advantage confirmed
GI tolerability <20% Grade 2+ AEs Chronic use feasibility

Summary: The Evidence Speaks

This is validated biology awaiting modern drug development.

Appendix: Complete References

Landmark Clinical Trials

  1. Neal EG et al. (2008). The ketogenic diet for treatment of childhood epilepsy: RCT. Lancet Neurol. PMID: 18456557
  2. Martin-McGill KJ et al. (2020). Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev. PMID: 32588435
  3. Lambrechts DA et al. (2017). RCT of ketogenic diet in refractory childhood epilepsy. Epilepsia Open. PMID: 27027847
  4. Gilbert DL et al. (2000). Blood β-hydroxybutyrate and seizure control. J Child Neurol. PMID: 11198492
  5. Qiao X et al. (2025). Therapeutic range for pediatric KD. PMC11960278

Mechanism: Acetoacetate/VGLUT Inhibition

  1. Rho JM et al. (2002). AcAc anticonvulsant action in vivo. Epilepsia. PMID: 11952765
  2. Juge N et al. (2010). VGLUT inhibition by acetoacetate. Neuron. PMID: 20920794
  3. D'Agostino DP et al. (2013). Ketone esters increase seizure latency. Neuroscience. PMID: 23552496
  4. Veech RL et al. (2017). Ketone metabolism and NAD+. IUBMB Life. PMID: 28371201

Multi-Pathway Mechanisms

  1. Youm YH et al. (2015). BHB blocks NLRP3 inflammasome. Nat Med. PMID: 25686106
  2. Shimazu T et al. (2013). BHB as HDAC inhibitor. Science. PMID: 23223453
  3. Ma W et al. (2007). K-ATP channels in KD. PMID: 17409226
  4. Olson CA et al. (2018). Gut microbiome mediates KD anti-seizure effect. Cell. PMID: 29804833
  5. Bough KJ et al. (2006). Mitochondrial biogenesis. J Neurosci. PMID: 16807920
  6. Taggart AK et al. (2005). HCAR2/GPR109A activation by BHB. PMID: 15929991

PK & Safety

  1. Clarke K et al. (2012). Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. PMID: 22561291
  2. Stubbs BJ et al. (2017). On the metabolism of exogenous ketones in humans. Front Physiol. PMID: 29163194
  3. Soto-Mota A et al. (2019). Safety and tolerability of sustained exogenous ketosis using ketone monoester. Regul Toxicol Pharmacol. PMID: 31655093

Indication-Specific Evidence

  1. Klepper J (2005). GLUT1 deficiency syndrome. Neuropediatrics. PMID: 16217704
  2. Dravet study (2023). KD in Dravet syndrome: 32.5% seizure-free at 3 mo. PMID: 37060636
  3. Caraballo RH et al. (2014). KD in Lennox-Gastaut syndrome: 40% responder, 15% seizure-free at 18 mo. PMID: 25011392
  4. Stenger E et al. (2017). KD in Doose syndrome/MAE: 54% seizure-free, 86% responders. PMID: 28273610
  5. Thibert RL et al. (2012). Low glycemic index treatment in Angelman syndrome. PMID: 22779920
  6. Huang et al. (2022). Efficacy of ketogenic diet for mitochondrial epilepsy. Front Neurol. PMID: 35979062

Published Meta-Analyses & Metabolomics

  1. Zuo CX et al. (2025). The efficacy and safety of the ketogenic diet in infantile epileptic spasm syndrome: a meta-analysis. European Journal of Epilepsy. DOI: 10.1016/j.seizure.2025.01.022
  2. Carroll JH et al. (2025). Over twenty-five years of ketogenic diet therapy: Supporting children and adults with drug-resistant epilepsy. Epilepsy & Behavior. DOI: 10.1016/j.yebeh.2025.110268
  3. Dahlin M, Wheelock CE, Prast-Nielsen S (2024). Association between seizure reduction during ketogenic diet treatment and changes in circulatory metabolites and gut microbiota. EBioMedicine (Lancet). DOI: 10.1016/j.ebiom.2024.105436

Regulatory & Market

  1. FDA Dojolvi Approval (NDA 213687). FDA Access Data [citing 505(b)(2) pathway].
  2. Lundbeck acquires Longboard Pharmaceuticals for $2.6B. Lundbeck Newsroom 2024.

Clinical Evidence Platform | February 2026
Key Citations: Neal 2008, Martin-McGill 2020 (Cochrane), Juge 2010, Clarke 2012, D'Agostino 2013

The Ask

Orphan indication partner for DEE basket (Dravet, LGS, GLUT1-DS)

Longboard Pharmaceuticals $2.6B exit validates the metabolic epilepsy path

joel@senoviabiosciences.com