LHP588 · program
LHP588 for Alzheimer's disease
LHP588 (formerly COR588), an oral brain-penetrant lysine-gingipain (Kgp) inhibitor, for P. gingivalis-positive mild-to-moderate Alzheimer's disease. This is a precision-medicine program: rather than treating all Alzheimer's patients, it enrolls only the biomarker-defined subgroup with a positive salivary PCR test for P. gingivalis, the subgroup in which the first-generation molecule atuzaginstat (COR388) showed 57% slowing of ADAS-Cog11 decline (p=0.02) in the GAIN Phase 2/3 trial despite that trial missing its overall co-primary endpoints. The compound completed a first-in-human Phase 1 SAD/MAD study in Australia (NCT04920903, 64 healthy adults, sponsored by Cortexyme under the name COR588) with no serious adverse events across 25-200 mg, an 11-to-12-hour half-life supporting once-daily dosing, and confirmed high CNS penetration after 10 days. FDA issued a 'Study May Proceed' letter clearing the IND on 2023-11-16 after reviewing safety, chronic toxicology, manufacturing, the Phase 1 human data and the Phase 2 protocol. The Phase 2 SPRING trial (Stopping PRogression of P. gINGivalis-positive Alzheimer's disease with gingipain INhibition; NCT06847321, LHP588-201) began on 2025-02-17 at Northwest Clinical Research Center in Bellevue, Washington and is expanding across the United States: 300 patients with mild-to-moderate Alzheimer's disease (MMSE 12-24), a positive P. gingivalis saliva rinse and plasma p-tau217 above a cutoff, randomized 1:1:1 to LHP588 25 mg, LHP588 50 mg or placebo once daily for 48 weeks, with cognitive (ADAS-Cog11), functional and global endpoints (CDR-SB, ADCS-ADL, MMSE) and biomarkers including P. gingivalis load, whole-brain atrophy and plasma p-tau217. The trial is funded by a $49.2M National Institute on Aging grant (R01AG088524, awarded 2025-08-22) and supported by a $12M Series A closed 2026-04-23. ClinicalTrials.gov estimates primary completion in January 2029; Lighthouse has issued no topline guidance. No FDA designation (fast track, breakthrough, orphan or RMAT) has been announced for LHP588, and no dose-arm changes, protocol discontinuations or safety holds are publicly disclosed as of the registry's 2026-07-14 update.
Development timeline
- UpcomingClinicalTrials.gov estimated primary completion of the Phase 2 SPRING trial (NCT06847321) of LHP588 25 mg and 50 mg vs placebo in P. gingivalis-positive mild-to-moderate Alzheimer's disease: January 2029 (estimated study completion 2029-03-15).
- Phase 2 advance: the SPRING trial (NCT06847321, LHP588-201) actual start date per ClinicalTrials.gov, announced by Lighthouse on 2025-02-26. The step before this — FDA's 'Study May Proceed' letter clearing the LHP588 IND on 2023-11-16 — is not represented as its own timeline row because the closed event vocabulary has no code for an IND clearance (see _comment, vocabulary gap `ind_cleared`); it is recorded in the program description.↗
- metCortexyme reported successful completion of the Phase 1 single- and multiple-ascending-dose study of COR588 (now LHP588): well tolerated from 25 mg to 200 mg with no serious adverse events, an 11-to-12-hour half-life supporting once-daily dosing, dose-proportional PK exceeding the exposure targeted for efficacy, and high CNS penetration confirmed after 10 days of dosing.↗
- Phase 1 SAD/MAD completed (actual primary completion and study completion 2022-04-30 per ClinicalTrials.gov). Cortexyme announced SAD results on 2022-03-08 and the successful completion of the full study on 2022-07-27: well tolerated from 25 mg to 200 mg with no serious adverse events and no clinically significant vital-sign, laboratory, telemetry or ECG findings; dose-proportional PK with an 11-to-12-hour half-life consistent with once-daily dosing; high CNS penetration confirmed after 10 days of once-daily dosing in the MAD portion (50, 100, 200 mg).↗
- First-in-human Phase 1 randomized, double-blind, placebo-controlled single- and multiple-ascending-dose study of COR588 began at Nucleus Network in Melbourne, Australia, sponsored by Cortexyme, Inc. (64 healthy adult subjects, NCT04920903). COR588 was the compound later renamed LHP588 — Cortexyme became Quince Therapeutics on 2022-08-01 and sold the asset to Lighthouse Pharmaceuticals on 2023-01-27.
Readouts
- January 2029AnticipatedRegistry resultsNCT06847321
ClinicalTrials.gov estimated primary completion of the Phase 2 SPRING trial (NCT06847321) of LHP588 25 mg and 50 mg vs placebo in P. gingivalis-positive mild-to-moderate Alzheimer's disease: January 2029 (estimated study completion 2029-03-15).
- 2022-07-27ReportedTopline datametNCT04920903
Cortexyme reported successful completion of the Phase 1 single- and multiple-ascending-dose study of COR588 (now LHP588): well tolerated from 25 mg to 200 mg with no serious adverse events, an 11-to-12-hour half-life supporting once-daily dosing, dose-proportional PK exceeding the exposure targeted for efficacy, and high CNS penetration confirmed after 10 days of dosing. ↗
Clinical trials in Alzheimer's disease
NCT06847321LHP588-201Phase 2Recruitingn=300
A Randomized, Double-Blind, Placebo-Controlled Study of LHP588 in Subjects With P. Gingivalis-Positive Alzheimer's Disease (SPRING)
NCT04920903COR588Phase 1Completedn=64
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, First-in-Human, Single- and Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Oral COR588 in Healthy Adult Subjects
metsecondaryPharmacokinetics — AUC, Cmax, Tmax, half-life, and central nervous system penetration — Half-life 11-12 hours; dose-proportional exposure
COR588 showed an 11-to-12-hour half-life consistent with once-daily dosing and a dose-proportional pharmacokinetic profile that achieved and exceeded the exposure targeted for therapeutic efficacy. High central nervous system penetration was confirmed after 10 days of administration in the multiple-ascending-dose portion — the basis for the once-daily oral regimen carried into Phase 2 and, per Lighthouse, for plasma levels sufficient to engage the target. Absolute bioavailability and Tmax were not reported.
metprimarySafety and tolerability — incidence and severity of treatment-emergent adverse events, chemistry, hematology, urinalysis, vital signs, telemetry and ECG
COR588 (later LHP588) was well tolerated across all cohorts from 25 mg to 200 mg in the single-ascending-dose portion (32 healthy adults, four cohorts) and from 50 mg to 200 mg once daily for 10 days in the multiple-ascending-dose portion, with no serious adverse events. No clinically significant findings were observed on vital signs, laboratory values, telemetry or ECGs, and no clinical chemistry or hematology safety concerns were seen at any dose. Lighthouse later characterised the same study as showing no dose-limiting and no dose-related adverse effects.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| LHP588 oral capsule (25 mg / 50 mg once daily) Phase 2 SPRING (NCT06847321): 25 mg (one 25 mg capsule) or 50 mg (two 25 mg capsules) orally once daily in the fasted state — at least one hour before or two hours after a meal, at approximately the same time each day — for 48 weeks, with a 2-week up-titration for the high-dose arm. Phase 1 (NCT04920903, run as COR588): single ascending doses of 25 mg to 200 mg across four cohorts in 32 healthy adults; multiple ascending doses of 50, 100 and 200 mg once daily for 10 days. | Oral | Once daily | — |
Mechanism of action
Orally available, brain-penetrant small-molecule inhibitor of lysine-gingipain (Kgp), a cysteine protease secreted by Porphyromonas gingivalis and its principal virulence factor. Kgp is a bacterial enzyme, not a human receptor, so the mechanism is anti-virulence rather than neurotransmitter pharmacology: inhibiting Kgp is described as blocking gingipain toxicity in infected tissue while also reducing P. gingivalis viability and bacterial load. The disease hypothesis, originating in Cortexyme's work on gingipains detected in Alzheimer's brain, is that chronic P. gingivalis infection drives neuroinflammation, amyloid-beta accumulation and tau pathology, and that a subgroup of Alzheimer's patients identifiable by a salivary P. gingivalis test can be treated by suppressing that infection. Clinical proof-of-concept for the mechanism (not for this molecule) comes from the Phase 2/3 GAIN trial of the first-generation Kgp inhibitor atuzaginstat (COR388), where the prespecified P. gingivalis-saliva-positive subgroup showed 57% slowing of decline on ADAS-Cog11 at the high dose (p=0.02) despite the overall trial missing its co-primary endpoints. LHP588 was optimized for selectivity and metabolism relative to atuzaginstat, giving a once-daily oral profile; the Phase 1 study confirmed high CNS penetration after 10 days of dosing and plasma exposures the company states are sufficient for target engagement. No enzyme-inhibition constant (Ki or IC50) against Kgp has been published for LHP588/COR588, and no data on selectivity against arginine-gingipains (Rgp) or human cathepsins is publicly available.
| Target | Action | Affinity |
|---|---|---|
| Lysine-gingipain (Kgp)primary | Inhibitor | —ⓘ |
← Full LHP588 compound page (identity, identifiers, all indications)
Sources
- Cortexyme Successfully Completes Phase 1 Single and Multiple Ascending Dose Clinical Trial of COR588 (2022-07-27, wire copy) — MAD 50-200 mg once daily for 10 days, no serious adverse events, high CNS penetration confirmed — Cortexyme, Inc. (via BioSpace)
- Lighthouse Pharmaceuticals Initiates Phase 2 SPRING Trial of LHP588 in P. gingivalis-positive Alzheimer's Disease (2025-02-26) — note: served under a page title belonging to the 2023-11-16 IND release — Lighthouse Pharmaceuticals, Inc.
- Lighthouse Pharmaceuticals Receives $49.2 Million Grant from NIA to Advance Phase 2 Study of LHP588 for P. gingivalis-positive Alzheimer's Disease (2025-08-22) — Lighthouse Pharmaceuticals, Inc.
- NCT04920903 — A Phase 1, Randomized, Double-Blind, Placebo-Controlled, First-in-Human, Single- and Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Oral COR588 in Healthy Adult Subjects (sponsor: Cortexyme Inc.) — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT06847321 (LHP588-201, SPRING) — A Randomized, Double-Blind, Placebo-Controlled Study of LHP588 in Subjects With P. Gingivalis-Positive Alzheimer's Disease — ClinicalTrials.gov (U.S. National Library of Medicine)