Microbiome-Targeted Agent PLL001 Passes Safety Check in Phase 1/2 Trial of ALS

In a recent company update, PLL Therapeutics announced positive safety data from a phase 1/2 trial (NCT06513546) testing PLL001, a microbiome-targeted, gut-brain axis therapeutic, in patients with early-stage amyotrophic lateral sclerosis (ALS). All told, the therapy met its primary safety objective and will now proceed to part 2 of the study, where investigators will assess efficacy and next steps.¹

Part 1 of the study was a randomized, double-blind, single-ascending dose evaluation involving 12 patients with ALS across 3 dose-level cohorts, with 4 subjects per cohort. Within each cohort, participants were randomly assigned 3:1 to receive a single subcutaneous dose of PLL001 or placebo, with placebo safety data pooled across groups.

According to PLL, the agent showed a favorable and tolerably safety profile, with no serious adverse events (SAEs) reported in the phase 1 portion. Led by Susan Mathers, MD, of Monash University in Australia, the early findings also revealed no treatment-emergent adverse events that led to study discontinuation for the participants involved.

“We are very encouraged by the phase I results in the 12 patients with ALS, which validate the safety profile of PLL001,” Jean-Pascal Zambaux, co-founder and chief executive officer at PLL, said in a statement.¹ “This is a critical step forward in our mission to restore the intestinal epithelium barrier, thereby treating the root cause of ALS – a disease linked to the dysbiosis of the gut. Our teams in Australia, New Zealand and France are diligently advancing this program into phase II.”

Phase 2 of the study, expected to start in Q2 of this year, will include a 6-month treatment period pinning PLL001 against placebo, followed by an additional 6-month open-label extension. Part 2 will randomized 141 participants to receive 1 of 2 dose levels of PLL001 or placebo, with 40 subjects per group and additional enrollment to account for dropouts.

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In part 2, an initial safety cohort of 21 participants (7 per group) will undergo 14 days of once-daily dosing, after which safety data will be reviewed by the Safety Review Committee before full enrollment proceeds. Participants receiving riluzole may continue therapy and will be stratified at randomization to ensure balanced distribution across treatment arms. Randomization will also be stratified using the TRICALS risk profile calculator to maintain comparable ALS disease characteristics among groups.²

To date, there are no approved therapeutics for ALS that work to restore the gut. Some in the field believe this type of approach could have meaningful biologic and potentially clinical implications, although research in this area is still evolving. In recent years, emerging data has suggested that ALS is not purely a motor neuron disease confined to the central nervous system, having other effects on systemic inflammation, metabolic dysfunction, microbiome dysbiosis, and increased intestinal permeability.

PLL-001 is designed to halt systemic and neural inflammation and restore gut health. PLL001 comprises four active drug substances, the SCFAs acetate, butyrate, lactate and propionate, each conjugated to a poly-L-lysine (PLys) carrier to improve cellular uptake. Short chain fatty acids (SCFAs) play a key role in the maintenance of gut health. They also act as signaling molecules, through free fatty acid receptors (FFARs), to suppress innate and adaptive immune responses and broadly influence gut physiology. Their effects are not limited to the gut. Bacteroides and Firmicutes bacterial species are the microbiome’s main sources of SCFAs. Declines in their activity can lead to a reduction in SCFA availability and an increase in gut permeability, immune activation, and chronic systemic and CNS inflammation, as antigens and toxins normally held within the gut lumen spill out into the circulation and cross the blood-brain barrier. PLL001 alleviates this shortage directly.

REFERENCES
1. PLL Therapeutics reports positive safety and tolerability results from phase I/II trial in ALS (Amyotrophic Lateral Sclerosis). News release. February 18, 2026. Accessed February 23, 2026. https://firstwordpharma.com/story/7107390
2. A Study to Evaluate the Safety, Efficacy, and Pharmacodynamics of PLL001 in ALS Patients. Clinicaltrials.gov. Updated July 23, 2025. Accessed February 23, 2026. https://clinicaltrials.gov/study/NCT06513546
3. The PLL Therapeutics approach: PLL-001 therapy. PLL Therapeutics. Accessed February 23, 2026. https://www.pll-therapeutics.com/clinical-trials/