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SNV-201: Restoring Brain Energy in Neurodegeneration

First-in-Class Ketone Prodrug for Alzheimer's Disease & MCI

Clinical Evidence Platform | February 2026

Contents

The Opportunity

Alzheimer's brains are starving. Glucose uptake drops 10–25%+ before clinical symptoms—but ketone uptake remains intact. The evidence that ketones work is overwhelming: 103 preclinical studies showing cognitive improvement, multiple RCTs demonstrating dose-response, and decades of ketogenic diet data. Yet nobody has ever successfully put this biology into a drug—until now. SNV-201 delivers estimated 10–20× higher ketone exposure compared to dietary ketosis, finally achieving the sustained therapeutic levels that prior trials could only approximate.

+4.77
ADAS-Cog Improvement
(Henderson 2009)
r=0.45
Ketone-Memory
Correlation
60%
Behavioral Improvement
(103 preclinical studies)
10–20×
Higher Exposure (estimated) vs. dietary ketosis at equivalent caloric intake

1. The Opportunity: Validated Biology, Never Pharmaceuticalized

The ketogenic diet has been used therapeutically since the 1920s. For Alzheimer's disease, the rationale is even more compelling: the AD brain has a specific energy deficit that ketones can bypass. This isn't speculative—it's documented by FDG-PET imaging in thousands of patients.

The Evidence Is Overwhelming:
So Why Hasn't This Worked Yet? Prior ketogenic interventions (MCT oil, AC-1202, kMCT drinks) achieved only brief, sub-therapeutic exposure—typically 2–4 mM·h/day AUC. The ketogenic diet works but isn't scalable (median adherence <12 months). SNV-201 is the first approach capable of delivering sustained therapeutic ketosis (projected 35–50 mM·h/day; external validation pending) in a practical, titratable pharmaceutical format.

The Problem: Glucose Hypometabolism

The Solution: SNV-201 Ketone Bypass

2. The Biology: Glucose Fails, Ketones Work

The Cunnane Finding (PMID: 27458340): FDG-PET and ¹¹C-acetoacetate PET studies demonstrate that despite significant glucose hypometabolism in AD brains, ketone uptake remains essentially normal. The brain's backup fuel system is intact—it just isn't being used.

Brain Fuel Uptake: AD vs. Healthy Controls

Glucose Uptake (AD)
~75–90%
Ketone Uptake (AD)
~100%

Source: Cunnane SC et al. (2016). Regional values vary; parietal/posterior cingulate show largest glucose deficits.

3. Human Clinical Evidence: Dose-Response Is Proven

Multiple clinical studies demonstrate a consistent finding: higher ketone exposure produces greater cognitive improvement. This dose-response relationship is the foundation of the SNV-201 thesis.

Study Design Key Finding
Krikorian 2012
PMID: 21130529		 RCT (n=23), 6 weeks, MCI r=0.45 (p=0.04) ketone-memory correlation
Henderson 2009
PMID: 19664276		 RCT (n=152), 90 days, mild-mod AD +4.77 ADAS-Cog in APOE4-negative (p=0.0005)
Reger 2004
PMID: 15123336		 Crossover (n=20), acute MCT BHB correlated with recall (r=0.50, p=0.02)
Fortier 2021
PMID: 33103819		 RCT (n=83), 6 months, MCI Improved episodic memory + executive function
Bonnechère 2025
PMID: 41001501		 Meta-analysis (18 studies, n=875) SMD=0.26 (95% CI 0.11–0.40) overall effect
The Krikorian Finding: "Ketone levels were positively correlated with memory performance (r=0.45, p=0.04)." This is direct human evidence that more ketones correlate with better cognition.

4. Preclinical Validation: 103 Full-Text Studies Analyzed

Systematic review of 103 peer-reviewed studies testing ketogenic interventions in AD mouse models reveals remarkably consistent benefit across all major endpoints.

60%
Cognitive Improved
59%
Amyloid Reduced
48%
Inflammation ↓
38%
Tau Reduced
Model # Studies Key Findings
APP/PS1 26 Cognitive rescue, plaque reduction, inflammation ↓
3xTg-AD 23 Both amyloid and tau pathology improved
5xFAD 16 Synaptic function restored, LTP rescued
Tg4510 3 Tau-specific model shows ketone benefit
Functional Restoration: Approximately 40% of studies report cognitive/synaptic function restored to near wild-type levels—not just slowed decline, but actual restoration. This includes LTP, Morris water maze performance, and novel object recognition.

5. Multi-Mechanism Target Engagement

Therapeutic ketosis engages multiple neuroprotective pathways simultaneously—a fundamentally different approach from single-target drugs.

Mechanism Effect Threshold Citation
Brain Energy Rescue Alternative fuel source ≥0.5 mM Cunnane 2016
NLRP3 Inflammasome Blocks IL-1β neuroinflammation ~1.0 mM Youm 2015
LTP Restoration Rescues synaptic plasticity ~3 mM (1h) Di Lucente 2024
Microglial Modulation 63% reduction in ASC specks Observed Shippy 2020
NAD⁺ Regeneration Restores cellular redox Ratio-dependent Xin 2018
Autophagy Enhancement Protein clearance ~2.0 mM McCarty 2015
Disease-Modifying Evidence: Zhang et al. 2025 (Brain, Behavior, and Immunity) demonstrate that the ketone ester BD-AcAc2 restores cognitive function, reduces amyloid plaque burden, and normalizes neuroinflammatory gene expression in APP/PS1 mice. This is the prodrug class closest to SNV-201.
BD-AcAc2 restores cognitive and behavioral function in APP mice
Zhang et al. 2025, Fig. 1: BD-AcAc2 metabolism (A), macronutrient composition (B), and functional outcomes. APP-KE mice showed restored learning time (C), memory (D), discrimination index (E), and nest-building scores (F) to near wild-type levels. Brain Behav Immun.
BD-AcAc2 reduces hippocampal amyloid plaque burden
Zhang et al. 2025, Fig. 2: Ketone ester elevates blood BHB to ~1.5 mM (B) without altering glucose (A) or body weight (C). Immunohistochemistry (D) shows substantial reduction in hippocampal amyloid plaque number in APP-KE vs. APP mice (p<0.01). Brain Behav Immun.
Transcriptomic analysis showing IFITM3 pathway normalization
Zhang et al. 2025, Fig. 3: Volcano plots (A) show differential gene expression in APP vs. WT and APP vs. APP-KE. Venn diagram (B) identifies 28 shared upregulated and 4 shared downregulated genes. Heatmap (C) highlights IFITM3 as a central node. GO/KEGG analysis (D,E) reveals interferon response and antigen processing as primary normalized pathways. Brain Behav Immun.
IFITM3 protein normalization and hippocampal immunofluorescence
Zhang et al. 2025, Fig. 4: Western blot (A) confirms IFITM3 protein reduction in APP-KE brains. RT-qPCR (B) shows normalization of IFITM3, CCL12, LAMB2, NLRC5, NDN, and CXCL10 mRNA. Hippocampal immunofluorescence (C) shows reduced IFITM3/GFAP co-localization in APP-KE vs. APP, indicating reduced astrocyte-driven neuroinflammation. Brain Behav Immun.

6. Why Prior Products Fell Short

Prior Approach Daily AUC Why It Was Sub-Optimal
AC-1202 (Henderson trial) ~2 mM·h Brief exposure (~2h); sub-therapeutic for sustained benefit
kMCT (Fortier trial) ~4 mM·h Still only 2-3h of therapeutic levels per dose
Ketogenic Diet (sustained) ~20 mM·h Effective but impractical; adherence <12 months median
SNV-201 (BID) 35–50 mM·h 10–20× higher exposure; ~85% daily coverage

Daily Ketone Exposure Comparison (Estimated AUC)

Henderson 2009 (MCT)
~2 mM·h
Fortier 2021 (kMCT)
~4 mM·h
Ketogenic Diet
~20 mM·h
SNV-201 (BID)
35–50 mM·h

7. SNV-201 Advantage

Parameter Prior MCT Trials SNV-201 (Projected)
Peak Ketones 0.4–0.8 mM 1.5–2.5 mM
Duration >0.5 mM 1–3 hours 8–14 hours
Daily AUC 2–4 mM·h 35–50 mM·h
Daily Coverage ~15% ~85%

8. Patient Stratification: The APOE4 Opportunity

APOE4-Negative (Henderson 2009)

APOE4-Positive (Henderson 2009)

Strategic Implication: APOE4-negative subjects (~35–60% of AD population, depending on ancestry) may represent an enriched population for proof-of-concept trials. Alternatively, higher exposure with SNV-201 may overcome the APOE4 limitation.

9. Regulatory Pathway

505(b)(2) Rationale

Enrichment Strategy

10. Development Framework

Phase Design Key Endpoints
Phase 1 SAD/MAD in healthy volunteers PK confirmation; safety; tolerability
Phase 1b MCI/early AD patients ADAS-Cog signal; PK/PD correlation
Phase 2 Biomarker-enriched MCI/early AD (n=60-80) ADAS-Cog change at 24 weeks; brain imaging

Summary: The Evidence Speaks

The biology is validated. SNV-201 closes the exposure gap.

The Ask

Licensing partner for 505(b)(2) MCI program

Anti-amyloid antibodies achieve modest slowing at $26K/year. SNV-201 targets the bioenergetic root cause.

joel@senoviabiosciences.com

Appendix: Complete References

Key Human Clinical Studies

  1. Cunnane SC et al. (2016). Can ketones help rescue brain fuel supply in later life? Front Mol Neurosci. PMID: 27458340
  2. Henderson ST et al. (2009). Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease. Nutr Metab. PMID: 19664276
  3. Krikorian R et al. (2012). Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging. PMID: 21130529
  4. Fortier M et al. (2021). A ketogenic drink improves brain energy and some measures of cognition in MCI. Alzheimers Dement. PMID: 33103819
  5. Reger MA et al. (2004). Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. PMID: 15123336
  6. Clarke K et al. (2012). Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Regul Toxicol Pharmacol. PMID: 22561291
  7. Veech RL et al. (2017). Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. PMID: 28371201
  8. Youm YH et al. (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome. Nat Med. PMID: 25686106
  9. Roy M et al. (2022). A ketogenic intervention improves dorsal attention network functional connectivity in MCI. Neurobiol Aging. PMID: 35504234
  10. Ooi TC et al. (2020). Intermittent fasting enhanced the cognitive function in older adults with MCI. Nutrients. PMID: 32872655
  11. Bonnechère B et al. (2025). Effect of exogenous ketone bodies on cognition in patients with AD/MCI. medRxiv. PMID: 41001501
  12. Zhang T et al. (2025). Ketone monoester alleviates cognitive impairment via IFITM3 pathway. Brain Behav Immun. PMID: 40885497
  13. Qin Y et al. (2023). Ketogenic diet alleviates brain iron deposition via Nrf2-mediated ferroptosis pathway. Brain Res. PMID: 37164173
  14. Simpson IA et al. (1994). Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Ann Neurol. PMID: 8179300
  15. Xin L et al. (2018). Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain. Front Nutr. PMID: 30050907

Regulatory / Competitive Landscape

  1. US FDA (2024). Kisunla (donanemab-azbt) Prescribing Information.
  2. US FDA (2024). Clinical Review (Donanemab), BLA 761248.
  3. US FDA (2020). NDA 213687 Approval Letter (Dojolvi/triheptanoin) [citing 505(b)(2) pathway].

Preclinical Evidence Database: 103 Full-Text Papers

Systematic extraction from PMC full-text corpus. Outcomes: Cog+=cognitive improvement, Aβ−=amyloid reduced, Tau−=tau reduced, Infl−=inflammation reduced.

  1. Madhavan et al. (2023). bioRxiv. PMC10349929 [Cog+, Aβ−, Tau−, Infl−]
  2. Jiang et al. (2023). Neural Regen Res. PMC10358659 [Cog+, Aβ−, Tau−, Infl−]
  3. Kumar et al. (2023). Neuron. PMC10528360 [Cog+]
  4. Wang et al. (2023). Nutrients. PMC10574179 [Cog+, Aβ−, Tau−, Infl−]
  5. Wu et al. (2022). Am J Alzheimers Dis. PMC10581103 [Cog+, Aβ−, Tau−, Infl−]
  6. Di Lucente et al. (2024). Commun Biol. PMC10873348 [Cog+, Aβ−, Tau−, Infl−]
  7. Park et al. (2024). Gut Microbes. PMC10936641 [Cog+, Aβ−, Tau−, Infl−]
  8. Hansen et al. (2024). Adv Nutr. PMC10997874 [Cog+, Aβ−, Tau−, Infl−]
  9. Rutkowsky et al. (2024). Aging. PMC11042947 [Cog+, Aβ−, Tau−, Infl−]
  10. Bonzanni et al. (2024). bioRxiv. PMC11071633 [Cog+, Aβ−, Tau−, Infl−]
  11. Minhas et al. (2024). bioRxiv. PMC11230169 [Cog+, Aβ−, Tau−]
  12. Ameen et al. (2024). J Cereb Blood Flow Metab. PMC11563520 [Cog+, Aβ−, Tau−, Infl−]
  13. Di Lucente et al. (2024). FASEB BioAdv. PMC11618890 [Cog+, Aβ−, Infl−]
  14. Han et al. (2024). Aging Cell. PMC11709107 [Cog+, Aβ−, Tau−, Infl−]
  15. Pawlosky et al. (2025). J Neurochem. PMC11717676 [Cog+, Aβ−, Tau−]
  16. Madhavan et al. (2025). Cell Chem Biol. PMC11741930 [Aβ−]
  17. Bonzanni et al. (2025). iScience. PMC11754081 [Cog+, Aβ−, Tau−]
  18. Jin et al. (2023). FASEB J. PMC11892113 [Aβ−, Infl−]
  19. Chen et al. (2025). Front Nutr. PMC12171442 [Cog+, Aβ−, Tau−, Infl−]
  20. Davis et al. (2025). Am J Physiol Endocrinol. PMC12171989 [—]
  21. Garcia et al. (2025). Front Aging. PMC12339548 [Cog+, Aβ−, Infl−]
  22. Hou et al. (2025). Front Pharmacol. PMC12370757 [Cog+, Aβ−, Tau−, Infl−]
  23. Zampieri et al. (2025). Front Pharmacol. PMC12605301 [Cog+, Tau−]
  24. Jain et al. (2025). Front Aging Neurosci. PMC12672871 [Cog+, Aβ−, Tau−]
  25. M'Bra et al. (2025). Commun Biol. PMC12738548 [Cog+, Aβ−, Tau−, Infl−]
  26. Garg et al. (2025). bioRxiv. PMC12767654 [Cog+, Tau−, Infl−]
  27. M'Bra et al. (2026). Brain. PMC12782165 [Cog+, Aβ−, Tau−, Infl−]
  28. Van der Auwera et al. (2005). Nutr Metab. PMC1282589 [Cog+, Aβ−]
  29. Adibhatla et al. (2008). Subcell Biochem. PMC2293298 [Aβ−, Infl−]
  30. Yao et al. (2011). PLoS ONE. PMC3128612 [Cog+, Aβ−, Tau−, Infl−]
  31. Yao et al. (2010). Biochim Biophys Acta. PMC3200365 [—]
  32. Ding et al. (2013). PLoS ONE. PMC3608536 [Cog+, Aβ−, Tau−]
  33. Kashiwaya et al. (2012). Neurobiol Aging. PMC3619192 [Cog+, Aβ−, Tau−]
  34. Brownlow et al. (2013). PLoS ONE. PMC3771931 [Cog+, Aβ−, Tau−, Infl−]
  35. Veech et al. (2013). Ann NY Acad Sci. PMC3821009 [Cog+, Aβ−, Tau−]
  36. Ding et al. (2013). PLoS ONE. PMC3823655 [Cog+, Aβ−, Tau−, Infl−]
  37. Beckett et al. (2013). Brain Res. PMC3825515 [Cog+]
  38. Ungar et al. (2014). Brain Imaging Behav. PMC4282773 [—]
  39. Lane-Donovan et al. (2016). PLoS ONE. PMC4734705 [Cog+, Aβ−]
  40. Pawlosky et al. (2017). J Neurochem. PMC5383517 [—]
  41. Dai et al. (2017). Endocrinology. PMC5460805 [Cog+, Aβ−]
  42. Griffith et al. (2017). Int J Endocrinol. PMC5468562 [Cog+, Aβ−, Tau−, Infl−]
  43. Zhang et al. (2017). Front Mol Neurosci. PMC5712566 [Cog+, Aβ−]
  44. Zhang et al. (2018). Front Cell Neurosci. PMC5776118 [Cog+, Aβ−]
  45. Sanguinetti et al. (2018). Sci Rep. PMC5861049 [Cog+]
  46. Ma et al. (2018). Sci Rep. PMC5923270 [Cog+, Aβ−, Infl−]
  47. Wu et al. (2018). J Neurosci. PMC6067075 [—]
  48. Yin et al. (2019). Aging. PMC6660057 [Cog+, Aβ−]
  49. Cheng et al. (2020). J Neurosci. PMC6961992 [Cog+, Aβ−]
  50. Pawlosky et al. (2020). Int J Mol Sci. PMC7036949 [Cog+, Aβ−, Tau−]
  51. Krishnan et al. (2020). Nutrients. PMC7071244 [Cog+, Aβ−, Tau−, Infl−]
  52. Lilamand et al. (2020). Alzheimers Res Ther. PMC7158135 [Cog+, Aβ−, Tau−, Infl−]
  53. Jin et al. (2020). Sci Rep. PMC7366932 [Cog+, Aβ−, Infl−]
  54. Shippy et al. (2020). J Neuroinflam. PMC7507727 [Cog+, Aβ−, Tau−, Infl−]
  55. Demarest et al. (2020). Acta Neuropathol. PMC7537767 [Cog+]
  56. Liao et al. (2021). Int J Mol Sci. PMC7998170 [Cog+, Tau−, Infl−]
  57. Koppel et al. (2021). J Neurochem. PMC8222170 [Infl−]
  58. Liśkiewicz et al. (2021). Front Cell Neurosci. PMC8385303 [Cog+, Infl−]
  59. Qu et al. (2022). J Adv Res. PMC8721355 [Cog+, Aβ−, Tau−, Infl−]
  60. Xu et al. (2021). CNS Neurosci Ther. PMC8928920 [Cog+, Aβ−, Infl−]
  61. Ma et al. (2021). Lancet Public Health. PMC9047702 [Cog+]
  62. Wang et al. (2022). Front Neurosci. PMC9309893 [Cog+, Infl−]
  63. Dong et al. (2022). Comput Struct Biotechnol J. PMC9352416 [Cog+, Tau−, Infl−]
  64. Evans et al. (2022). J Neuroinflam. PMC9356477 [Cog+, Aβ−, Tau−, Infl−]
  65. Kong et al. (2022). ACS Omega. PMC9435027 [Cog+, Aβ−, Infl−]
  66. Yang et al. (2022). Front Aging Neurosci. PMC9475074 [Cog+, Aβ−, Tau−, Infl−]
  67. Pathak et al. (2022). Aging Cell. PMC9577944 [Cog+, Tau−, Infl−]
  68. Saito et al. (2022). Metabolites. PMC9693360 [Cog+, Tau−, Infl−]

Clinical Evidence Platform | February 2026
Key Citations: Cunnane 2016, Henderson 2009, Krikorian 2012, Clarke 2012, Di Lucente 2024
SNV-201: Senovia Biosciences first-in-class acetoacetate-releasing ketone prodrug