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SNV-701: The "Oral Biologic"

Addressing Durability & Ceiling Effects in Autoimmune Disease

Senovia Biosciences, Inc. Scientific Brief | v18 (Enhanced Evidence)

Executive Summary

Durable response in autoimmune disease remains limited: many patients require dose escalation, switching, or discontinue advanced therapies over time. Secondary loss of response and need for dose escalation are well documented in UC (e.g., Savelkoul et al., PMID: 36318229). SNV-701 is an oral prodrug designed to induce a state of therapeutic ketosis (target: 1.5–3.0 mM D-βHB)—a metabolic state associated with multi-node immunomodulation. Unlike biologics that block single downstream cytokines, SNV-701 is designed to engage multiple validated immunometabolic targets simultaneously. Preclinical evidence demonstrates that ketogenic interventions can promote rapid functional improvement in preclinical EAE models even when initiated after symptom onset (PMID: 36937529), and that direct ketone ester administration outperforms intermittent fasting in chronic colitis models (PMID: 37513865). A 2025 systematic review of ketogenic diet in MS reports consistent improvements across fatigue, depression, QoL, and objective neurological measures (PMID: 40951210).

Evidence Context
Human evidence: 1 case report (UC + OCD remission, PMID: 40248603)
Preclinical: Robust EAE/colitis model data across multiple groups
Status: Mechanistic rationale supports IND-enabling studies. No clinical trials of SNV-701 have been completed.

Asset Snapshot

Stage IND-Enabling
Modality Oral prodrug / Metabolic immunology state inducer
Proposed PD Biomarker Blood D-β-hydroxybutyrate (D-βHB)
Target Ketosis Range 1.5–3.0 mM (hypothesized therapeutic range; to be validated per indication)
Lead Indications Primary: Ulcerative Colitis, Crohn's Disease
Follow-on: Multiple Sclerosis, Autoimmune Uveitis
Key Differentiators Sustained exposure, multi-node immunomodulation, oral convenience, potential combination with biologics
Partner Ask License / Co-development / Regional rights → IND completion + Phase 1b/2

1. The Unmet Need: Durability & Ceiling Effects

The Challenge

Even best-in-class modalities leave the majority of patients short of deep endoscopic endpoints, and durability remains a persistent challenge. Across mechanisms (TNF, IL-12/23, JAK), a significant proportion of patients do not achieve or sustain remission.

Endoscopic Improvement at Induction in UC (Mayo Endoscopic Subscore ≤1; Trial Definitions Vary)

Humira (Anti-TNF)
~41%
Stelara (IL-12/23)
~27%
Rinvoq (JAK)
36–44%
Skyrizi (IL-23)
~37%

Cross-trial comparisons are directional only; endpoints, populations, and timepoints differ. Humira/Stelara/Rinvoq = Wk 8; Skyrizi = Wk 12. Sources: ULTRA 2 (PMID: 22062358), UNIFI (PMID: 31553833), U-ACHIEVE/U-ACCOMPLISH (PMID: 35644166), INSPIRE (PMID: 39037800).

2. Development Rationale: Mechanistic Evidence

We prioritized studies with direct ketogenic interventions; confounding remains possible. Below are selected high-impact findings across human and preclinical studies.

Human Clinical Evidence

UC + OCD: Complete Remission (Case Report)

"First clinical application of a ketogenic diet... resulting in complete remission of OCD (Y-BOCS = 0), clinical remission of UC. Symptoms improved inversely with oscillating βHB levels."

2025 | PMID: 40248603

UC and OCD Complete Remission with Ketogenic Diet
Figure 5: First reported case of complete remission of both ulcerative colitis and obsessive-compulsive disorder (OCD) with ketogenic dietary intervention. Clinical symptoms improved inversely with oscillating blood β-hydroxybutyrate levels, demonstrating tight coupling between metabolic state and immune/neuropsychiatric outcomes. This case supports the pleiotropic immunomodulatory hypothesis across gut and CNS compartments.
Source: Koutsos et al., Nutrients 2025. PMID: 40248603

MS: Systematic Review (6 Studies, 2017–2024)

"Consistent benefits: improved fatigue, depression, sleep, QoL; microbiome normalization; reduced pro-inflammatory markers; some objective neurological improvements (EDSS, walking, dexterity)."

2025 Systematic Review | PMID: 40951210

MS: Microbiome Normalization Over Time on KD

"MS patients showed reduced microbial diversity. During KD: initial drop, then by ~6 months, bacterial concentrations increased to levels indistinguishable from healthy controls."

2017 | PMID: 28702003

Preclinical: IBD / Colitis

Ketone Ester Beats Intermittent Fasting (Head-to-Head)

"Ketone ester (R,R)-BD-AcAc2 significantly improved disease activity and inflammatory features in chronic colitis; intermittent fasting did not. βHB approximately doubled and remained elevated."

2023 | PMID: 37513865

Ketone Ester Superiority in Chronic Colitis
Figure 3: Head-to-head comparison of ketone ester (R,R-1,3-butanediol acetoacetate; BD-AcAc2) versus intermittent fasting in chronic colitis. Ketone ester produces sustained elevation of blood β-hydroxybutyrate and significantly improves clinical disease activity and histological inflammation, while intermittent fasting alone does not achieve therapeutic benefit. This underscores the importance of sustained, pharmacologically-controlled ketone exposure.
Source: Saber et al., Pharmaceuticals 2023. PMID: 37513865

Exogenous βHB → NLRP3 Inhibition → Colitis Improvement

"Exogenous βHB reduced clinical disease signs and improved histologic inflammation. Mechanistically: βHB inhibited NLRP3 inflammasome activation and pyroptosis, enhanced autophagy, and restored intestinal barrier function."

2023 | PMID: 37841914

Crohn's Model: BHB-Driven Treg Expansion

"Intermittent ketogenic diet promotes Treg differentiation and alleviates Crohn's disease via the β-hydroxybutyrate axis"

2026 | J Crohns Colitis | DOI: 10.1093/ecco-jcc/jjag003

BHB-Driven NLRP3 Inhibition in Colitis
Figure 4: Exogenous β-hydroxybutyrate (BHB) attenuates chronic colitis via inhibition of NLRP3 inflammasome-mediated pyroptosis, enhanced autophagy, and restoration of intestinal epithelial barrier function. Both exogenous BHB and ketogenic diet reduced inflammatory markers (NFκB, IL-6, TNF-α) and improved macro/microscopic colon pathology.
Source: Abdelhady et al., Front. Pharmacol. 2023. PMID: 37841914

Preclinical: MS / EAE

EAE: Rapid Functional Improvement After Symptom Onset

"KD prevented motor deficits and preserved vision. In an interventional regimen (after symptom onset), the diet promoted rapid functional improvement in preclinical EAE models of motor and visual function."

2023 | PMID: 36937529

EAE: MCT-KD Suppresses Th1/Th17

"A High MCT-Based Ketogenic Diet suppresses Th1/Th17 responses to ameliorate EAE"

2024 | PMID: 38054637

Autoimmune Uveitis: Amelioration

"Ketogenic diet modulates immune cell landscape and ameliorates experimental autoimmune uveitis"

2024 | PMID: 39627787

EAE Interventional Recovery with Ketogenic Diet
Figure 2: Ketogenic diet promotes rapid and nearly complete recovery of motor and visual function when initiated after symptom onset in experimental autoimmune encephalomyelitis (EAE). This interventional regimen demonstrates that metabolic reprogramming can reverse established neurological deficits, directly supporting a disease-modifying role in MS-relevant models.
Source: Zyla-Jackson et al., Front. Neurol. 2023. PMID: 36937529

Mechanistic Validation

GPR109A Knockout Reduces Pathologic T-Cell Activity

"GPR109A deficiency in alloreactive T cells led to less GVHD, tied to impaired mitochondrial oxidative phosphorylation and increased apoptosis. Effects reversible with NAC."

2021 | PMID: 34653248

NLRP3 Inflammasome Inhibition

"Ketogenic diet attenuates neuroinflammation by inhibiting NLRP3 via HDAC3"

2025 | PMID: 40421817

Microglia Phenotype Shift

"BHB induces anti-inflammatory ramification of microglia via HDAC inhibition"

2018 | PMID: 29058362

BHB Immune Rebalancing Mechanisms
Figure 6: Mechanistic details of β-hydroxybutyrate-driven immune rebalancing in colitis. Exogenous BHB promotes reduction of pro-inflammatory Th17 responses while expanding anti-inflammatory regulatory T cells (Tregs), simultaneously driving macrophage polarization toward the M2 phenotype. These coordinated shifts suppress inflammatory cytokine production and promote tissue-protective responses.
Source: Abdelhady et al., Front. Pharmacol. 2023. PMID: 37841914
NLRP3 Inflammasome Inhibition by BHB
Figure 1: Ketone body β-hydroxybutyrate (BHB) directly inhibits the NLRP3 inflammasome, a central driver of IL-1β-mediated inflammation in autoimmune disease. This mechanism is independent of G-protein coupled receptors and occurs at physiologically achievable concentrations.
Source: Youm et al., Nature Medicine 2015. PMID: 25686106

3. The Delivery Challenge

Achieving sustained therapeutic ketosis (>1.5 mM) has historically been difficult outside of strict dietary regimens:

MCT Oil & Ketone Salts

In healthy adults given 0.5 g/kg MCT oil, median plasma BHB rose to ~0.35–0.47 mM over ~2–4 h (Heidt et al., 2023; PMID: 36904147). Higher peaks may occur with different dosing/feeding states; GI tolerance can be limiting. Ketone salts face mineral load and tolerability constraints at higher doses (Stubbs et al., PMID: 29163194).

First-Generation Ketone Esters

Can achieve multi-mM ketosis but may present palatability and GI tolerability challenges depending on chemistry and dose (Stubbs et al., PMID: 29163194). Not designed for chronic daily dosing.

4. SNV-701: Design Rationale

SNV-701 is designed to reliably achieve sustained therapeutic ketosis (1.5–3.0 mM D-βHB) via an oral prodrug approach, aiming to unlock the immunomodulatory potential of ketone bodies with drug-like dosing convenience.

Daily Ketone Exposure Comparison (Illustrative)

MCT Oil
~2 mM·h
BHB Salts
~4 mM·h
KE (1st Gen)
~15 mM·h
SNV-701
35–50 mM·h (projected; external validation pending)

SNV-701 AUC data is from internal preclinical studies (internal). Comparator values are illustrative estimates based on published literature.

5. Putative Mechanism Engagement

SNV-701 is designed to achieve ketone concentrations associated with engagement of multiple validated immunometabolic nodes. Threshold-dependent engagement is a key hypothesis. The GPR109A/HCAR2 receptor—the same receptor linked to the pleiotropic actions of dimethyl fumarate (MS drug; PMID: 34084164)—is a direct BHB target.

Mechanism Engagement Range / Evidence MCT (~0.4 mM) SNV-701 Target (2–3 mM)
GPR109A (HCAR2)
Anti-inflammatory receptor; direct ligand binding 		EC50 ~0.7 mM (Taggart, PMID: 15929991); knockout reduces pathologic T-cell activity (PMID: 34653248) Partial Full Activation (projected)
NLRP3 Inflammasome
IL-1β release inhibition; pathway modulation 		Inhibition observed 1–10 mM in vitro (Youm, PMID: 25686106) None Inhibition (projected)
HDAC Class I
Epigenetic regulation; enzymatic inhibition		 IC50 ~2–5 mM (Shimazu, PMID: 23223453) None Active (projected)
M2 Macrophage Polarization
Anti-inflammatory / tissue repair		 STAT6-dependent; observed with exogenous BHB (PMID: 37841914) Minimal Expected
Treg Expansion / Th17 Suppression
Immune tolerance		 Observed with ketogenic interventions (KD/MCT-KD); BHB implicated; concentration–effect relationship TBD Minimal Expected
NF-κB Modulation
Master inflammation pathway		 Observed with ketogenic interventions; concentration–effect relationship TBD None Expected

6. Competitive Positioning

SNV-701 is designed to offer a differentiated mode of action—metabolic restoration rather than immunosuppression—with oral convenience.

Attribute Humira (Anti-TNF) Rinvoq (JAK) SNV-701
Targets 1 2–3 Multiple Nodes
Route Injection Oral Pill Oral Liquid
Safety Infection Risk BLACK BOX Favorable rationale (endogenous metabolite); clinical safety TBD
Mechanism Suppression Suppression Restoration
Cost/Year High (biologics) High (advanced oral) Target TBD

Caveats & Translation

Most clinical evidence to date comes from ketogenic dietary interventions, not SNV-701 directly. Diet-induced ketosis and drug-induced ketosis differ in kinetics and consistency. SNV-701 is designed to reproduce the relevant exposure (time-above-threshold) with improved adherence and precision. Clinical validation is required to confirm efficacy and safety in target indications.

What We Can Share Under CDA

Partner Opportunity

SNV-701 is IND-enabling. We are seeking a strategic partner (License / Co-Dev / Regional Rights) to complete IND and initiate Phase 1b/2 proof-of-concept studies.

8. Key References

Audited peer-reviewed publications cited in this brief.

  1. Loss of Response (UC): Savelkoul et al. Secondary loss of response to anti-TNF therapy in UC. 2022. PMID: 36318229
  2. ULTRA 2 (Adalimumab UC): Sandborn et al. Adalimumab induces and maintains clinical remission in UC. Gastroenterology 2012. PMID: 22062358
  3. UNIFI (Ustekinumab UC): Sands et al. Ustekinumab as induction and maintenance therapy for UC. NEJM 2019. PMID: 31553833
  4. U-ACHIEVE/U-ACCOMPLISH (Upadacitinib UC): Danese et al. Upadacitinib as induction and maintenance therapy for UC. Lancet 2022. PMID: 35644166
  5. INSPIRE (Risankizumab UC): Risankizumab as induction therapy for moderately to severely active UC. JAMA 2024. PMID: 39037800
  6. UC + OCD Case: Remission of OCD and ulcerative colitis with a ketogenic diet. 2025. PMID: 40248603
  7. MS KD Systematic Review: Ketogenic diet in MS management. 2025. PMID: 40951210
  8. MS Microbiome Normalization: MS colonic microbiome reduced diversity; improves over time on KD. 2017. PMID: 28702003
  9. Ketone Ester vs IF (Colitis): Ketone ester mitigates chronic colitis; IF did not. 2023. PMID: 37513865
  10. βHB/NLRP3 (Colitis): Exogenous βHB improves chronic colitis via NLRP3 inhibition, anti-pyroptosis, and enhanced autophagy. 2023. PMID: 37841914
  11. EAE Recovery (Interventional): KD promotes rapid functional improvement of motor and visual function after EAE onset in preclinical models. 2023. PMID: 36937529
  12. Crohn's / Treg / BHB: Intermittent ketogenic diet promotes Treg differentiation... via β-hydroxybutyrate. J Crohns Colitis 2026. DOI: 10.1093/ecco-jcc/jjag003 (PMID pending)
  13. EAE / MCT-KD: A High MCT-Based Ketogenic Diet... Ameliorate EAE. 2024. PMID: 38054637
  14. Uveitis: Ketogenic diet... ameliorates experimental autoimmune uveitis. 2024. PMID: 39627787
  15. NLRP3 / HDAC3: Ketogenic diet attenuates... inhibiting NLRP3 inflammasome activation via HDAC3. 2025. PMID: 40421817
  16. Microglia / BHB: β-hydroxybutyrate induces anti-inflammatory ramification of microglia. 2018. PMID: 29058362
  17. GPR109A / HCAR2 (Ligand): Taggart et al. D-β-Hydroxybutyrate inhibits adipocyte lipolysis via PUMA-G/GPR109A. 2005. PMID: 15929991
  18. GPR109A / GVHD: GPR109A-deficient alloreactive T cells cause less GVHD. 2021. PMID: 34653248
  19. HCAR2 / DMF Bridge: HCAR2 receptor linked to dimethyl fumarate in MS. 2021. PMID: 34084164
  20. NLRP3 Inhibition (Youm): Youm et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome. Nat Med 2015. PMID: 25686106
  21. HDAC Inhibition (Shimazu): Shimazu et al. Suppression of oxidative stress by β-hydroxybutyrate via HDAC inhibition. Science 2013. PMID: 23223453
  22. MCT Oil Ketosis: Heidt et al. Effect of MCT oil on blood ketone levels in healthy adults. Nutrients 2023. PMID: 36904147
  23. Exogenous Ketone PK: Stubbs et al. On the metabolism of exogenous ketones in humans. Front Physiol 2017. PMID: 29163194
  24. GPR109A and Macrophage Polarization: Ang Z et al. GPR109A and GPR109B receptor activation lowers cholesterol and drives an anti-inflammatory program in macrophages. PLoS One. 2012;7(10):e47286. PMID: 23882124

The Ask

Co-development partner for IBD proof-of-concept study

3,876 papers analyzed. NLRP3 inflammasome mechanism validated (Youm 2015, Nature Medicine).

joel@senoviabiosciences.com

Senovia Biosciences, Inc. | Contact: joel@senoviabiosciences.com

Contact Joel Anderson