dersimelagon (MT-7117) / Mitsubishi Tanabe - LARVOL DELTA

INSPIRE: INcreased Sun Exposure Without Pain In Research Participants With EPP or XLP (clinicaltrials.gov) - P3 | N=150 | Active, not recruiting | Sponsor: Mitsubishi Tanabe Pharma America Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Metabolic Disorders • Pain

Assessment of Potential Drug-Drug Interactions for Novel Oral Melanocortin-1 Receptor Agonist Dersimelagon. (PubMed, Pharmacol Res Perspect) - P1, P2, P3 | "The impact of 300-mg dersimelagon on the pharmacokinetics (PK) of substrate drugs and the effect of co-administering verapamil on 100-mg dersimelagon PK (as substrate drug) were investigated in healthy participants in a Phase 1 study...Midazolam (CYP3A substrate), digoxin (P-gp), pravastatin (OATP), and simvastatin (CYP3A) did not show any clinically relevant DDI effects when co-administered with dersimelagon...Dersimelagon 300 mg did not elicit major DDIs involving CYP/UGT enzymes and drug transporters; however, dersimelagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvastatin, and caution should be exercised when co-administering 300-mg dersimelagon with these statin drugs. Trial Registration: ClinicalTrials.gov: NCT04793295, NCT04402489, NCT04440592, NCT02834442, NCT03520036, NCT03503266."

Clinical • Journal • CYP2C9

Discovery of MT-7117 (Dersimelagon Phosphoric Acid): A Novel, Potent, Selective, and Nonpeptidic Orally Available Melanocortin 1 Receptor Agonist. (PubMed, J Med Chem) - "Afamelanotide, an α-melanocyte-stimulating hormone (α-MSH) analogue MC1R agonist, is used clinically for treating erythropoietic protoporphyria (EPP) as a subcutaneous implant formulation. Compound 11 is currently in clinical trials for the treatment of EPP, X-linked protoporphyria (XLP), and systemic sclerosis (SSc). Proof of concept was obtained in phase 2 clinical studies on EPP and XLP."

Journal • Fibrosis • Genetic Disorders • Immunology • Metabolic Disorders • Scleroderma • Systemic Sclerosis

Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) (clinicaltrials.gov) - P3 | N=301 | Recruiting | Sponsor: Mitsubishi Tanabe Pharma America Inc. | Active, not recruiting ➔ Recruiting | N=151 ➔ 301 | Trial completion date: Jun 2025 ➔ Dec 2027 | Trial primary completion date: Jun 2025 ➔ Dec 2027

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • Genetic Disorders • Metabolic Disorders

Physiologically based pharmacokinetic modelling to predict potential drug-drug interactions of dersimelagon (MT-7117). (PubMed, Br J Clin Pharmacol) - "Overall, PBPK modelling results indicate that the simulated changes in plasma exposure of atorvastatin and rosuvastatin following coadministration with dersimelagon 100 or 200 mg are not clinically significant, but caution and appropriate clinical monitoring should be recommended."

Journal • PK/PD data • Breast Cancer • Genetic Disorders • Metabolic Disorders • Oncology • Solid Tumor

Topline results of the AURORA Trial: A phase 2, randomized, double-blind, placebo-controlled trial of bitopertin in erythropoietic protoporphyria (EADV 2024) - P2 | "Exclusion criteria included concurrent treatment with afamelanotide or dersimelagon. Bitopertin has been shown to significantly reduce PPIX levels in prior clinical and nonclinical studies of EPP. The AURORA trial evaluates whether reductions in PPIX with bitopertin can improve measures of light tolerance in adults with EPP. Topline safety and efficacy data will be presented."

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

Topline Results of the AURORA Trial: A Phase 2, Randomized, Double-blind, Placebo-controlled Trial of Bitopertin in Erythropoietic Protoporphyria (EADV 2024) - P2 | "Exclusion criteria included concurrent treatment with afamelanotide or dersimelagon. Bitopertin has been shown to significantly reduce PPIX levels in prior clinical and nonclinical studies of EPP. The AURORA trial evaluates whether reductions in PPIX with bitopertin can improve measures of light tolerance in adults with EPP. Topline safety and efficacy data will be presented."

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

TOPLINE RESULTS OF THE AURORA TRIAL: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF BITOPERTIN IN ERYTHROPOIETIC PROTOPORPHYRIA (EHA 2024) - P2 | "Exclusion criteria included alanine aminotransferase/aspartate aminotransferase values ≥2x theupper limit of normal, hemoglobin <10 g/dL, or concurrent treatment with afamelanotide or dersimelagon. Bitopertin has been shown to significantly reduce PPIX levels in prior clinical andnonclinical studies of EPP. The AURORA trial evaluates whether reductions in PPIX with bitopertin can improvemeasures of light tolerance in adults with EPP. Topline safety and efficacy data will be presented."

Clinical • P2 data • Bone Marrow Transplantation • Cholestasis • Fibrosis • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Pain • Transplantation

BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN SUBJECTS WITH ILD IN A PHASE 2 STUDY TO EVALUATE EFFICACY, SAFETY, AND TOLERABILITY OF MT-7117 IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (EULAR 2024) - P2 | "Randomized subjects (SSc-ILD+ and SSc-ILD-) were homogenous in demographics, baseline mRSS, ppFVC%, and concomitant IS. A large percentage of patients were not assessed for ILD and ILD may be missed in early dcSSc (Khanna D, Denton CP, 2021). The topline data of MT-7117 G02 will be available early 2024 and will assess the efficacy of MT-7117 to prevent disease progression in the subjects with SSc ILD+ and SSc-ILD-."

Clinical • P2 data • Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Rheumatology • Scleroderma • Systemic Sclerosis

Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dersimelagon (MT-7117), an Oral Melanocortin-1 Receptor Agonist. (PubMed, Clin Pharmacol Drug Dev) - P1 | "Maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86- and 1.87-fold higher, respectively) and severe (1.17- and 1.45-fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated."

Journal • PK/PD data • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Failure • Metabolic Disorders • Renal Disease • Scleroderma • Systemic Sclerosis

Illuminating Dersimelagon: A Novel Agent in the Treatment of Erythropoietic Protoporphyria and X-Linked Protoporphyria. (PubMed, Pharmaceuticals (Basel)) - "However, the emergence of innovative therapies, such as dersimelagon, is reshaping the therapeutic landscape for these conditions. In this review, we summarize salient features of the properties of dersimelagon, shedding light on its potential role in advancing our understanding of treatment options for EPP and XLP."

Journal • Review • Genetic Disorders • Metabolic Disorders

BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN A PHASE 2 STUDY TO EVALUATE EFFICACY, SAFETY, AND TOLERABILITY OF MT-7117 IN SUBJECTS WITH DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (SSWC 2024) - P2 | "The study included subjects with dcSSc, age >= 18 years and a disease duration <= 5 years who were on a stable standard of care treatment and receiving one stable concomitant immunosuppressant (Mycophenolate/Mycophenolic acid [MMF], Methotrexate [MTX], Hydroxychloroquine [HCQ], or Azathioprine [AZA]). There were no major imbalances in the baseline demographics or in the percentage on immunosuppressants among the three regions, although some variation in SSc autoantibody specificity were observed."

Clinical • P2 data • Fibrosis • Immunology • Inflammation • Rheumatology • Scleroderma • Systemic Sclerosis

Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) (clinicaltrials.gov) - P3 | N=151 | Active, not recruiting | Sponsor: Mitsubishi Tanabe Pharma America Inc. | Trial completion date: Dec 2024 ➔ Jun 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Genetic Disorders • Metabolic Disorders

Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Diffuse Cutaneous Systemic Sclerosis (clinicaltrials.gov) - P2 | N=76 | Completed | Sponsor: Mitsubishi Tanabe Pharma America Inc. | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

INSPIRE: INcreased Sun Exposure Without Pain In Research Subjects With EPP (clinicaltrials.gov) - P3 | N=150 | Recruiting | Sponsor: Mitsubishi Tanabe Pharma America Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Trial completion date • Trial primary completion date • Genetic Disorders • Metabolic Disorders • Pain

INSPIRE: INcreased Sun Exposure Without Pain In Research Subjects With EPP (clinicaltrials.gov) - P3 | N=150 | Not yet recruiting | Sponsor: Mitsubishi Tanabe Pharma America Inc.

New P3 trial • Genetic Disorders • Metabolic Disorders • Pain

Current trials in erythropoietic protoporphyria: are placebo controls ethical? (PubMed, Orphanet J Rare Dis) - "However, given the availability of an already approved treatment option for EPP the use of a placebo arm is questionable from an ethics point of view. We analyze the issue and suggest that a noninferiority active-control trial without placebo is an ethically and scientifically more valid design to test the efficacy of dersimelagon as well as other EPP treatments."

Journal • Genetic Disorders • Metabolic Disorders

Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) (clinicaltrials.gov) - P3 | N=151 | Active, not recruiting | Sponsor: Mitsubishi Tanabe Pharma America Inc. | Trial completion date: Sep 2023 ➔ Dec 2024 | Trial primary completion date: Sep 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Genetic Disorders • Metabolic Disorders

Dersimelagon in Erythropoietic Protoporphyrias. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Genetic Disorders • Metabolic Disorders

Dersimelagon in Erythropoietic Protoporphyrias. (PubMed, N Engl J Med) - No abstract available

Journal • Genetic Disorders • Metabolic Disorders

Dersimelagon in Erythropoietic Protoporphyrias. (PubMed, N Engl J Med) - No abstract available

Journal • Genetic Disorders • Metabolic Disorders

STUDY DESIGN OF THE AURORA TRIAL: A PHASE 2, RANDOMIZED, DOUBLE- BLIND, PLACEBO-CONTROLLED TRIAL OF BITOPERTIN IN ERYTHROPOIETIC PROTOPORPHYRIA (EHA 2023) - P2 | "Exclusion criteria include AST/ALT values ≥2x the upper limit of normal, hemoglobin <10 g/dL, or concurrent treatment with afamelanotide or dersimelagon. The AURORA study is designed to evaluate bitopertin as a potential disease-modifying treatment and will test the hypothesis that bitopertin can reduce PPIX and improve light tolerance in adults with EPP. Clinical trial"

Clinical • P2 data • Bone Marrow Transplantation • Cholestasis • Fibrosis • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Pain • Transplantation

INITIAL DATA FROM THE BEACON TRIAL: A PHASE 2, RANDOMIZED, OPEN-LABEL TRIAL OF BITOPERTIN IN ERYTHROPOIETIC PROTOPORPHYRIA (EHA 2023) - "Exclusion criteria include aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥2x upper limit of normal and hemoglobin <10 g/dL, as well as concurrent treatment with afamelanotide or dersimelagon. Interim safety and efficacy data supporting the hypothesis that GlyT1 inhibition with bitopertin has the potential to be disease-modifying for EPP will be presented. Clinical trial"

Clinical • P2 data • Bone Marrow Transplantation • Cholestasis • Fibrosis • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Pain • Transplantation

BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN A PHASE 2 STUDY TO EVALUATE EFFICACY, SAFETY, AND TOLERABILITY OF MT-7117 IN SUBJECTS WITH DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (EULAR 2023) - P2 | "The study included subjects who have been diagnosed with dcSSc ≥ 18 years of age and a disease duration ≤ 5 years who are on a stable standard of care treatment, receiving one stable concomitant immunosuppressant (Mycophenolate/Mycophenolic acid [MMF], Methotrexate [MTX], Hydroxychloroquine [HCQ], or Azathioprine [AZA]). Subjects in NA were more likely to be on MMF. *US and Canada † UK, Germany, Spain, Italy, and Belgium ‡ Includes MMF, MTX, HCQ, and AZA Conclusion There were no major differences in the baseline demographics such as disease duration, sex and age, and no major differences in disease severity as well as the percentage of use of immunosuppressants among the regions although some variation in SSc autoantibody specificity were observed."

Clinical • P2 data • Fibrosis • Immunology • Inflammation • Rheumatology • Scleroderma • Systemic Sclerosis

"Dersimelagon in Erythropoietic Protoporphyrias | NEJM https://t.co/rNVZWYW6ir" (@MerciePatrick)

Genetic Disorders • Metabolic Disorders