bitopertin (RG1678) / Roche, Disc Medicine - LARVOL DELTA

Results from the first clinical trial of the selective GlyT1 inhibitor bitopertin for steroid-refractory Diamond-Blackfan Anemia (NCT05828108) (ASH 2025) - P1/2 | "Bitopertin is safe and well-tolerated in steroid-refractory DBA. Bioavailability,pharmacokinetics and effects upon hemoglobin are consistent with prior experience in patients initiallytreated with bitopertin in large clinical trials for schizophrenia. Although bitopertin did not yieldtransfusion-independence in these patients, the baseline iron overload, marrow hypocellularity and priorfailure of steroids reflect a cohort with long-standing disease and minimal erythropoietic marrow reserve.Ongoing work with model systems underscores the importance of this reserve while continuing tosuggest efficacy in DBA, especially in steroid-dependent patients (i.e., responsive to medical intervention).Future studies may consider bitopertin as a steroid-sparing agent for steroid-responsive DBA patients.Funding: This study was supported by the NHLBI Division of Intramural Research and a CooperativeResearch and Development Agreement (CRADA) with Disc Medicine, Inc."

Clinical • Anemia • CNS Disorders • Genetic Disorders • Hematological Disorders • Schizophrenia • RPL11 • RPL5 • RPS26

Interim Results from the HELIOS Study: An Open-Label, Long-Term Extension Study of Bitopertin in Erythropoietic Protoporphyria (ISDS 2025) - P2, P2/3 | "By reducing PPIX levels, bitopertin targets the underlying pathophysiology of EPP/XLP. Interim data from HELIOS, including participants treated for >2 years, demonstrate sustained reductions in PPIX and support a favorable longer-term safety profile of bitopertin in adult and adolescent patients with EPP/XLP."

Clinical • Genetic Disorders • Hepatology • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease

In Silico Post-screening of Anti-polymerization Agents to Treat Sickle Cell Disease. (PubMed, bioRxiv) - "We first demonstrate the effectiveness of our integrated platform by showcasing the therapeutic efficacy of two FDA-approved drugs, Hydroxyurea (HU) and voxelotor. Next, we evaluate the therapeutic efficacy of two potential anti-sickling agents under clinical trial, namely Bitopertin and osivelotor...We further quantify the relationship between drug dosage and the duration of noncompliance that leads to loss of therapeutic efficacy for voxelotor and osivelotor, providing guidance for optimizing dosage strategies to reduce the risk associated with noncompliance. In summary, our in silico platform serves as a valuable tool for post-screening analysis of potential anti-sickling agents by considering their PK and anti-sickling efficacy under patient-specific hemoglobin level and organ-specific oxygen level, thereby gaining insights into their potential therapeutic efficacy alone or in combination before clinical trials."

Journal • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

Results from the AURORA Study: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Bitopertin in Erythropoietic Protoporphyria (ISDS 2025) - P2 | "Bitopertin targets the underlying pathophysiology of EPP with reductions in PPIX linked to improved clinical outcomes. Bitopertin treatment resulted in improvements in sunlight tolerance and was well tolerated, consistent with the favorable safety profile observed in prior studies involving >4000 non-EPP participants."

Clinical • P2 data • Genetic Disorders • Hepatology • Metabolic Disorders • Pancreatitis

Impact of bupivacaine and bitopertin on neuroinflammatory responses in bv2 microglial cells (Neuroscience 2025) - "Additionally, there were no marked differences between bupivacaine, bitopertin, or combination of them on GlyT1 expression levels in the LPS-treated BV2 cells.Our initial results suggest that bupivacaine and bitopertin synergistically inhibits the inflammatory responses in activated microglia. Combination of these drugs holds promise as a potential therapeutic strategy to improve efficacy and reduce neuroinflammation."

Late-breaking abstract • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Psychiatry • IL6 • TNFA

Degeneration of Dopamine Neurons Reduces Function of Striatal Glycine Receptors (Neuroscience 2025) - "Recent studies have shown that the development of dyskinesia and episodic psychosis events can be treated using glycine transporter type 1(GlyT1) inhibitors such as bitopertin...Additionally, GlyR-evoked currents decreased at 7, 14, and 21 days following 6-OHDA treatment. These data suggest a specific role of striatal GlyRs in mediating synaptic plasticity and dopaminergic tone, which could be involved in the progression of PD."

CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

Application of a Validated Method for Quantifying Circulating Protoporphyrin IX to the Beacon Trial of Bitopertin in Erythropoietic Protoporphyria (ASH 2023) - P2 | "Fully-validated LC-MS/MS assays to quantify metal-free PPIX and Zn-PPIX in plasma and whole blood were used to analyze clinical samples from the BEACON study evaluating bitopertin in EPP. PPIX values were consistent with previously reported values for patients with EPP. The methods also provided improved accuracy and specificity for metal-free vs."

Genetic Disorders • Hematological Disorders • Metabolic Disorders • Pruritus

Interim Analyses from the Beacon Trial: A Phase 2, Randomized, Open-Label Trial of Bitopertin in Erythropoietic Protoporphyria (ASH 2023) - P2 | "By reducing whole-blood PPIX levels, bitopertin targets the underlying pathophysiology of EPP, resulting in consistent improvements in multiple measures of light tolerance and quality of life. Bitopertin has been well tolerated to date with no changes in hemoglobin, and its safety profile in EPP is consistent with prior studies that enrolled more than 4000 participants. Updated results will be presented at the meeting."

Clinical • P2 data • Bone Marrow Transplantation • Genetic Disorders • Hepatology • Metabolic Disorders • Transplantation

Preclinical Studies of the GlyT1 Inhibitor Bitopertin in Diamond-Blackfan Anemia (ASH 2023) - P1/2 | "The improved in vitro erythroid differentiation of DBA patient marrow and RPS19-deficient CD34+ cells and the improved anemia of RPL11 haploinsufficient mice suggest that bitopertin might mitigate anemia in DBA patients. These encouraging preclinical data supported the initiation of a Phase 1/2 clinical trial (NCT05828108: Young et al, abstract this meeting)."

Preclinical • Anemia • CNS Disorders • Genetic Disorders • Hematological Disorders • Psychiatry • Schizophrenia • CD34 • HPX • RPL11 • TFRC

A Phase I/II, Intra-Patient Dose-Escalation Study of Bitopertin, a Selective Inhibitor of GlyT1 and Heme Synthesis, for Steroid-Refractory Diamond-Blackfan Anemia (ASH 2023) - P1/2 | "Status: This study has been granted an FDA IND (165778) and is open for enrollment. It is monitored under the NIH Institutional Review Board (001528-H) and is registered with the U.S. National Library of Medicine (NCT05828108)."

Clinical • P1/2 data • Anemia • Aplastic Anemia • Genetic Disorders • Hematological Disorders • Infectious Disease • Metabolic Disorders

Inhibition of Glycine Transporter 1 Reduces Phototoxicity in a Mouse Model of Erythropoietic Protoporphyria (EPP) (ASH 2024) - "The GlyT1 inhibitor bitopertin has been shown to decrease whole-blood PPIX levels in patients with EPP in Phase 2 clinical studies (Dickey, 2024; Ross, 2024) and in animal models (Wu, 2022)...Collectively, this study demonstrated that oral GlyT1 inhibitor administration decreased PPIX levels in RBCs, resulting in diminished phototoxicity upon light exposure in the EPP mouse model. Overall, these data support the rationale for treating patients with EPP with GlyT1 inhibitors."

Preclinical • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders

Results from the Beacon Trial: A Phase 2, Randomized, Open-Label Study of Bitopertin in Erythropoietic Protoporphyria (ASH 2024) - P2 | "Bitopertin has been well tolerated to date with no changes in hemoglobin, and its safety profile in EPP is consistent with prior studies that enrolled more than 4000 participants. Additional analyses will be presented at the meeting."

Clinical • P2 data • Bone Marrow Transplantation • Genetic Disorders • Hepatology • Metabolic Disorders

Results from the Aurora Study: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Bitopertin in Erythropoietic Protoporphyria (ASH 2024) - P2 | "Its safety profile in EPP is consistent with prior studies of bitopertin that enrolled more than 4000 participants in other non-EPP indications. Additional analyses will be presented at the meeting."

Clinical • P2 data • Genetic Disorders • Hepatology • Metabolic Disorders • Pancreatitis

Dose-time-concentration prediction method based on GRU-TCN with temporal-channel attention. (PubMed, Comput Methods Biomech Biomed Engin) - "Experiments on Buyang Huanwu Decoction (normal/inflammatory) and simulations (RG1678, RIF) show GT-TCA reduces MAE by 22.7% and improves R2 by 4% versus baselines (p < 0.05). Ablation confirms attention lowers MAE and RMSE by 6% and 5%. The model demonstrates robustness and provides more precise quantitative evidence to support precision dosing."

Journal

Bitopertin: GlyT1 Inhibitor (Heme Synthesis Modulator) (GlobeNewswire) - "Accelerating activities to support a potential US approval and launch in late 2025 or early 2026."

FDA approval • Launch US • Hematological Disorders

Targeting NMDA receptor hypofunction in schizophrenia: promise and pitfalls of glutamatergic modulation (ECNP 2025) - "Additionally, glycine transporter-1 (GlyT1) inhibitors such as bitopertin have been developed to elevate synaptic glycine concentrations, thereby boosting NMDA receptor-mediated neurotransmission...Future research should prioritise stratified approaches, identifying patient subgroups most likely to respond, optimising dosing strategies, and combining pharmacotherapy with cognitive or psychosocial interventions. Such personalised treatment paradigms may ultimately be essential in harnessing the potential of NMDA receptor-based therapies for this highly heterogeneous disorder."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

A role for Glycine Transporter-2 inhibitors in regulating accumbal dopamine levels and voluntary alcohol intake in rats (ECNP 2025) - " Effects on nAc DA and glycine levels, alcohol intake and the alcohol deprivation effect (ADE) were examined in male Wistar rats following systemic treatment with full or partial GlyT2-inhibitors (Org-25543, Opiranserin and N-arachidonyl-glycine(NAGly)) or a combination of GlyT1 (Bitopertin) and full or partial GlyT2-inhibitors (Org-25543, NAGly), using in vivo microdialysis and a free-choice alcohol consumption model (NAGly only) with repeated cycles of alcohol deprivation. The reduction in alcohol intake following treatment with a partial GlyT2-inhibitor (NAGly, Opiranserin) could be explained by its tendency to slightly elevate basal nAc DA levels, in line with the previously established and more pronounced effects of GlyT1-inhibition. The present findings do not unequivocally support an accumbal, intrasynaptic GlyR-mediated mechanism responsible for alterations in DA output and/or alcohol intake following GlyT2-blockade since at least extracellular glycine levels..."

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders

Disc Medicine Announces Receipt of FDA Commissioner’s National Priority Voucher (CNPV) for Bitopertin in Erythropoietic Protoporphyria (EPP) (GlobeNewswire) - "Disc is seeking accelerated approval of bitopertin for patients aged 12 years and older with EPP. The CNPV program is designed to reduce the drug application review process to 1-2 months."

FDA event • Hematological Disorders

Glutamate modulation by evenamide produces statistically significant and clinically relevant improvement in patients with treatment-resistant schizophrenia (ECNP 2025) - "Recent examples include pimavanserin, which did not provide evidence of significant benefit as adjunctive therapy in inadequate responders [1] and Lu-AF35700 which failed to produce significant improvement as monotherapy in TRS [2]. Glycine re-uptake inhibition with bitopertin did not produce significant benefits in patients with inadequately controlled positive symptoms [3]. New results with KarXT indicate no significant benefit compared to placebo when used as add-on to second-generation antipsychotics (SGA) in inadequate responders despite having demonstrated improvement in acutely psychotic patients as monotherapy [4]...Results from the more recent, phase 3, double-blind, placebo-controlled, 4-week, add-on study demonstrated statistically significant and clinically important improvements in 291 patients with inadequate response to SGA including clozapine. Positive findings from these two studies, which will need to be confirmed in a larger phase 3 trial in patients..."

Clinical • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

Effect of Bitopertin on the Liver and on Levels of Protoporphyrin IX in Bile, Blood, Liver, and Stool in Patients With Erythropoietic Protoporphyria/X-linked Protoporphyria and Increased Liver Stiffness and/or Liver Enzymes at Baseline (clinicaltrials.gov) - P1 | N=10 | Not yet recruiting | Sponsor: Wake Forest University Health Sciences | Initiation date: Sep 2025 ➔ Jan 2026

Trial initiation date • Genetic Disorders • Metabolic Disorders

Disc Medicine Announces Submission of New Drug Application (NDA) to US FDA for Accelerated Approval of Bitopertin for Patients with Erythropoietic Protoporphyria (EPP) (GlobeNewswire) - "The NDA submission is supported by the results of the Phase 2 BEACON and AURORA studies in EPP, as well as prior data generated by Roche, including a safety database of over 4,000 clinical trial participants."

FDA filing • Hematological Disorders

Results from the HELIOS Study: A Phase 2, Open-label, Long-term Extension Study of Bitopertin in Erythropoietic Protoporphyria (EADV 2025) - P2, P2/3 | "By reducing PPIX levels, bitopertin targets the underlying pathophysiology of EPP and XLP. Initial data from HELIOS include results from participants who have received bitopertin for over 2 years and support a favorable long-term safety profile with bitopertin in adult and adolescent patients with EPP or XLP."

Clinical • P2 data • Bone Marrow Transplantation • Genetic Disorders • Hepatology • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease

Study of the Selective GlyT1 Inhibitor Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia (clinicaltrials.gov) - P1/2 | N=15 | Completed | Sponsor: National Heart, Lung, and Blood Institute (NHLBI) | Recruiting ➔ Completed | N=30 ➔ 15 | Trial completion date: Nov 2029 ➔ Aug 2025 | Trial primary completion date: May 2029 ➔ Aug 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Anemia • Genetic Disorders • Hematological Disorders

Blocking extracellular glycine uptake mediated by GlyT1 mitigates protoporphyria. (PubMed, J Clin Invest) - "report that inhibition of the glycine plasma membrane transporter GLYT1 using bitopertin decreased PPIX accumulation and ameliorated liver disease using human in vitro and mouse in vivo models. Their findings support the ongoing development of bitopertin to treat protoporphyria, while concurrently pointing to underexplored roles of glycine in erythroid cells."

Journal • Genetic Disorders • Hepatology • Liver Failure • Metabolic Disorders • Pain

Effect of Bitopertin on the Liver and on Levels of Protoporphyrin IX in Bile, Blood, Liver, and Stool in Patients With Erythropoietic Protoporphyria/X-linked Protoporphyria and Increased Liver Stiffness and/or Liver Enzymes at Baseline (clinicaltrials.gov) - P1 | N=10 | Not yet recruiting | Sponsor: Wake Forest University Health Sciences

New P1 trial • Genetic Disorders • Metabolic Disorders