BI 425809 Glycine Drug Improves Schizophrenia Cognition

observational-study PMID: 33610228

BI 425809 Glycine Drug Improves Schizophrenia Cognition

Quick Summary: A new drug called BI 425809 blocks the glycine transporter to boost brain glycine levels, aiming to help thinking skills in people with schizophrenia. In a 12-week study, doses of 10 mg and 25 mg taken daily improved cognition more than a placebo, with no major safety issues. This could offer hope for better daily functioning, but more research is needed.

What the Research Found

This study tested BI 425809, a drug that stops the glycine transporter from removing glycine—a natural brain chemical that supports learning and memory—from the brain. Schizophrenia often causes thinking problems like trouble focusing or remembering, which make life harder. The drug was added to regular schizophrenia meds to see if it could fix these issues.

Key results showed real improvements in thinking skills after 12 weeks:
- People on 10 mg daily saw about 2 points better on a standard thinking test (called MCCB) compared to placebo.
- The 25 mg dose improved scores by about 1.7 points over placebo.
- Five different math models confirmed the drug works better at higher doses, with effect sizes of 0.30 to 0.34—meaning a small but noticeable boost in cognition.
- Side effects were similar to placebo, happening in 41-59% of people on the drug versus 44% on placebo, with no serious problems linked to the doses.

In simple terms, this glycine-based drug helped sharpen mental skills without adding big risks, especially at mid-to-high doses.

Study Details

Who was studied: 509 outpatients aged 18-50 with stable schizophrenia, already on standard antipsychotic meds. They were from 81 centers in 11 countries, and the study ran from 2018 to 2019.
How long: 12 weeks of daily treatment, with thinking tests at the start, week 6, and week 12. About 87% finished the full study.
What they took: Oral pill once a day as an add-on: 2 mg, 5 mg, 10 mg, or 25 mg of BI 425809, or a matching placebo. Doses were randomly assigned blindly so no one knew who got what.

The trial was double-blind and placebo-controlled, meaning it was fair and unbiased.

What This Means for You

If you or a loved one has schizophrenia, cognitive struggles can make jobs, relationships, and daily tasks tough. This research points to BI 425809 as a potential add-on treatment that could improve focus, memory, and problem-solving—helping you live more independently. The 10 mg and 25 mg doses showed the best results, but it's not available yet; phase 3 trials are next to confirm if it's ready for doctors to prescribe.

Important note: This drug targets glycine in a specific way, unlike over-the-counter glycine supplements. Don't start supplements based on this—talk to your doctor. It highlights glycine's role in brain health, but real benefits here come from this prescription option, not diet tweaks.

Study Limitations

Every study has limits, so here's what to keep in mind:
- Early stage: This is phase 2 research with 509 people; larger phase 3 trials are needed to prove it works long-term.
- Short time frame: Only 12 weeks, so we don't know about effects or safety over months or years.
- Specific group: Focused on stable outpatients, not those in crisis or with severe, hard-to-treat schizophrenia—results may not apply to everyone.
- Drug vs. supplements: BI 425809 is a targeted inhibitor, not the same as eating glycine-rich foods or taking pills. This doesn't prove supplements help cognition in schizophrenia.
- Funding bias: Made by Boehringer Ingelheim, the drug company, which might influence results slightly.

Overall, these findings are promising but not a guarantee—wait for more studies before getting excited. Check ClinicalTrials.gov (NCT02832037) for updates.

Key Findings

The study found that BI 425809, a glycine transporter-1 inhibitor, significantly improved cognitive function in schizophrenia patients at 10 mg and 25 mg doses. Five of six dose-response models showed statistically significant cognitive benefits over placebo, with the highest efficacy observed at 10 mg (standardized effect size 0.34) and 25 mg (effect size 0.30). Adverse event rates were comparable across treatment and placebo groups, suggesting a favorable safety profile.

Study Design

This was a phase 2, double-blind, randomized, placebo-controlled trial conducted across 81 centers in 11 countries. A total of 509 outpatients aged 18–50 years with schizophrenia on stable antipsychotic therapy were enrolled. Participants were assigned (1:1:1:1:2 ratio) to receive BI 425809 (2, 5, 10, or 25 mg once daily) or placebo for 12 weeks. Cognitive outcomes were assessed using the MATRICS Consensus Cognitive Battery (MCCB), with efficacy and safety analyses conducted at weeks 6 and 12.

Dosage & Administration

BI 425809 was administered orally once daily at doses of 2 mg, 5 mg, 10 mg, or 25 mg as an add-on to stable antipsychotic treatment. Placebo was used as the control. Dose allocation was block-randomized via interactive response technology, ensuring blinding of patients, investigators, and trial personnel.

Results & Efficacy

Cognitive Improvement: At week 12, the 10 mg and 25 mg doses showed significant improvements in MCCB composite T-scores versus placebo:
10 mg: adjusted mean difference 1.98 (95% CI 0.43–3.53; p=0.015)
25 mg: adjusted mean difference 1.73 (95% CI 0.18–3.28; p=0.032)
Dose-Response Models: Five models (linear, linear in log, Emax, sigmoid Emax, logistic) confirmed a non-flat dose-response relationship (p=0.015–0.0038).
Safety: Adverse events were reported in 41–59% of BI 425809 groups vs. 44% in placebo, with no dose-dependent increase in side effects.

Limitations

Phase 2 Design: Results require confirmation in larger phase 3 trials.
Population Specificity: Participants were outpatients with stable schizophrenia, limiting generalizability to acute or treatment-resistant cases.
Short Duration: 12 weeks may be insufficient to assess long-term efficacy and safety.
Funding Source: Industry sponsorship (Boehringer Ingelheim) introduces potential bias.
Mechanism vs. Glycine Supplementation: BI 425809 modulates glycine transporters, not directly equivalent to glycine supplementation.

Clinical Relevance

This study suggests that targeting glycine transporter-1 may be a viable strategy to address cognitive deficits in schizophrenia, a major unmet clinical need. However, BI 425809 is a pharmacological drug, not a dietary glycine supplement. The findings do not support the use of glycine supplements for cognitive improvement in schizophrenia but highlight a potential future therapeutic avenue. Clinicians should await phase 3 trials before considering this mechanism for treatment. For supplement users, these results are not directly applicable, as glycine’s role in cognition remains unclear compared to this novel inhibitor.

Note: The study was registered as NCT02832037 and published in The Lancet Psychiatry (2021).