**Background:** Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with limited treatment options; only riluzole and edaravone are FDA-approved, each providing only modest survival benefit. Given the complex pathophysiology, combination therapies targeting multiple mechanisms may be more effective. This case report explores the use of artificial intelligence phenotypic response surface (AI-PRS) technology to personalize drug-dose combinations for a patient with advanced ALS.
**Methods:** A 75-year-old East Asian male with ALS (diagnosed 2018, ALSFRS-R score 14 at admission, on ventilator via tracheostomy) was enrolled. Next-generation sequencing (whole-genome sequencing) identified variants in ALS-associated genes (e.g., FUS rs1052352, C9orf72 rs10122902, SETX, SIGMAR1, VAPB, ZNF512B rs2275294). The AI-PRS platform, which requires only (N^2+3N+2)/2 tests to identify optimal drug-dose combinations, was used to design a 4-drug regimen: ibudilast, riluzole, tamoxifen, and ropinirole. The trial proceeded through multiple phases: initial 4-drug combination (March 3–May 21, 2021) with four dose adjustments; then a 3-drug combination (ibudilast, riluzole, ropinirole; July 3–13, 2021); and finally a 2-drug combination (ibudilast, riluzole; July 28–September 28, 2021) with dose escalation. Outcomes included muscle strength (isometric handheld dynamometer, grooved pegboard test, hand grip test) and plasma biomarkers (NfL, TDP-43, CK). Adverse events were monitored.
**Key Results:** The initial 4-drug combination (20 mg/d ibudilast, 25 mg/d riluzole, 20 mg/d tamoxifen, 0.75 mg/d ropinirole) showed improvement in neck flexion/extension, elbow flexion/extension, and decreased NfL, CK, and TDP-43. A second dose (40 mg/d ibudilast, 50 mg/d riluzole, 10 mg/d tamoxifen, 0.75 mg/d ropinirole) continued improvement but hypotension occurred. Subsequent doses led to variable responses; deep vein thrombosis (DVT) was diagnosed and treated with rivaroxaban. Tamoxifen was removed due to DVT concerns. The 3-drug combination (ibudilast, riluzole, ropinirole) resulted in decreased motor function and transient vision loss, leading to ropinirole removal. The 2-drug combination of 20 mg/d ibudilast and 25 mg/d riluzole (July 28–August 18, 2021) improved left-hand pegboard test and grip strength. Doubling doses to 40 mg/d ibudilast and 50 mg/d riluzole (August 28–September 26, 2021) showed noticeable improvement in all three tests without hypotension. However, increasing ibudilast to 60 mg/d (with riluzole 50 mg/d) caused severe visual complaints, headache, nausea, elevated heartbeat, and decreased muscle strength, leading to trial halt. Hypotension was later attributed to the ophthalmic drug brinzolamide/brimonidine tartrate (Simbrinza) and resolved upon discontinuation. Vision impairment was attributed to cataracts, common in ALS patients.
**Clinical Implications:** This case demonstrates the feasibility of using AI-PRS to personalize drug-dose combinations for ALS, with the 2-drug combination of ibudilast and riluzole showing the most consistent benefit. The findings align with prior literature suggesting that ibudilast plus riluzole may improve ALS progression compared to single drugs. However, adverse events (hypotension, DVT, vision impairment) highlight the need for careful monitoring and individualized adjustments. The study is limited by its single-patient design, lack of control, and confounding from comorbidities and concomitant medications. Larger clinical trials are warranted to validate AI-PRS-guided personalized therapy in ALS.