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

Disc Medicine Receives Complete Response Letter from FDA for Bitopertin for the Treatment of EPP (GlobeNewswire) - "FDA acknowledged that AURORA and BEACON provided sufficient evidence that bitopertin significantly lowers PPIX and that there is a strong mechanistic and biological plausibility supporting the use of the PPIX biomarker in protoporphyria. FDA indicated a need to see the results of the ongoing Phase 3 APOLLO study before making a decision. Ongoing Phase 3 APOLLO study potential to serve as basis for traditional approval; topline data anticipated Q4 2026....Upon completion of APOLLO, Disc would then file a response to the CRL and expect an updated FDA decision by mid-2027."

CRL • FDA approval • P3 data: top line • Hematological Disorders

DISC-1459-301: APOLLO: A Randomized, Double-Blind, Placebo-Controlled Study of Bitopertin to Evaluate the Efficacy, Safety, and Tolerability in Participants with Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) (clinicaltrialsregister.eu) - P2/3 | N=71 | Recruiting | Sponsor: Disc Medicine Inc.

New P2/3 trial • Genetic Disorders • Metabolic Disorders

DISC-1459-501: HELIOS: Long-term study of DISC-1459 (or Bitopertin) in patients with Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP). (clinicaltrialsregister.eu) - P2/3 | N=32 | Not yet recruiting | Sponsor: Disc Medicine Inc.

New P2/3 trial • Genetic Disorders • Metabolic Disorders

DISC-1459-301: APOLLO: A Randomized, Double-Blind, Placebo-Controlled Study of Bitopertin to Evaluate the Efficacy, Safety, and Tolerability in Participants with Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) (clinicaltrialsregister.eu) - P2/3 | N=56 | Recruiting | Sponsor: Disc Medicine Inc.

New P2/3 trial • Genetic Disorders • Metabolic Disorders

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Protoporphyria and Increased Liver Stiffness and/or Liver Enzymes at Baseline (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Wake Forest University Health Sciences | N=10 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Genetic Disorders • Metabolic Disorders

In silico analysis of the multitarget potential of GlyT1 inhibitors in SLC6 transporters. (PubMed, J Biomol Struct Dyn) - "Consensus docking with DockThor, GOLD, and AutoDock Vina followed by Exponential Consensus Ranking (ECR) identified NFPS_2 as the most potent GlyT1 ligand (ECR = 1.896), forming π-π interactions with TYR99 and TRP279, while Org 24598_2 preferentially bound GlyT2, and Bitopertin showed high affinity for DAT...These results demonstrate the intrinsic multitarget behavior of GlyT1 inhibitors, highlighting conserved interaction motifs within the SLC6 family. Collectively, our findings emphasize the importance of structure-guided optimization to improve selectivity and reduce potential off-target effects while maintaining therapeutic efficacy."

Journal

An open-label phase II study of bitopertin in adults and adolescents with erythropoietic protoporphyria or X-linked protoporphyria. (PubMed, Clin Exp Dermatol) - "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 was well tolerated, and most adverse events were mild or moderate in severity."

Journal • P2 data • Genetic Disorders • Hepatology • Metabolic Disorders • Pain

New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective. (PubMed, Orphanet J Rare Dis) - No abstract available

Journal • Genetic Disorders • Metabolic Disorders • Rare Diseases

Bitopertin Shows Efficacy in Patients with Erythropoietic Protoporphyria: Results from the Randomized, Double-Blind, Placebo-Controlled AURORA Trial. (PubMed, J Am Acad Dermatol) - "Bitopertin significantly reduced protoporphyrin-IX levels, showed improved measures of sunlight tolerance, and had a favorable safety profile in patients with erythropoietic protoporphyria."

Clinical • Journal • Genetic Disorders • Hepatology • Metabolic Disorders • Pain

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