domagrozumab (PF-06252616) / Pfizer - LARVOL DELTA

A Generic Detection Method for the Doping Control Analysis of Fc-Fusion Proteins and Monoclonal Antibodies in Equine Plasma. (PubMed, Drug Test Anal) - "This study is aimed at developing a generic detection method for doping control analysis of nine targeted proteins, each containing the Fc domain of human IgG or IgG from other species in equine plasma, namely, three recombinant Fc-fusion proteins (sotatercept, follistatin-Fc (FST-Fc), and erythropoietin-Fc (EPO-Fc)) and six mAbs (bimagrumab, domagrozumab, garetosmab, landogrozumab, bedinvetmab (Librela), and frunevetmab (Solensia)). The results have demonstrated the method's applicability to equine doping control. This generic method involving affinity purification by Protein A has provided a pragmatic and effective approach to cope with the doping control of novel Fc domain-containing proteins."

Journal • ACVR2A

Relationship Between Quantitative Magnetic Resonance Imaging Measures and Functional Changes in Patients With Duchenne Muscular Dystrophy. (PubMed, Muscle Nerve) - P2 | "These findings support the use of MRI biomarkers as potential surrogate endpoints in clinical trials of patients with DMD."

Journal • MRI • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Simultaneous detection of myostatin-targeting monoclonal antibodies in dried blood spots and plasma using liquid chromatography-tandem mass spectrometry with field asymmetric ion mobility spectrometry. (PubMed, J Pharm Biomed Anal) - "In this study, we aimed to develop and validate a multitarget method to detect the prohibited transforming growth factor-β superfamily-targeting monoclonal antibodies, such as landogrozumab, domagrozumab, and the activin receptor type IIB-targeting antibody, bimagrumab, in human plasma and dried blood spot (DBS) samples using liquid chromatography-tandem mass spectrometry. Recovery was 31.6-49.8 % for DBS and 51.4-85.3 % for plasma, with no significant matrix effect. This study provides an effective method for doping analysis and novel protein detection."

Journal

Two year muscle MRI observations from a phase 1b trial of fordadistrogene movaparvovec (PF‐06939926) for Duchenne muscular dystrophy (DMD) (ESGCT 2023) - P1b, P2 | "An external reference (ER) cohort was derived from DMD participants (n = 48) with ≥1 yr of randomized domagrozumab treatment (active→placebo, placebo→active, or active→active) from trial NCT02310763 and met eligibility criteria for this trial. Thigh MRI findings are further supported by evaluating upper limb MRI measure. After dosing with FM, quantitative muscle MRI measurements show favorable changes up to 2-yrs that correlate with functional outcomes."

P1 data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Two-Year Clinical Outcomes with Fordadistrogene Movaparvovec for Duchenne Muscular Dystrophy (DMD) and Contextualization with External Controls (ASGCT 2023) - P1b | "A second external control group with similar baseline characteristics was constructed using 2-year data from patients with at least 1 year of treatment randomized to active→placebo, placebo→active, or active→active in a null phase 3 domagrozumab trial. At 2 years, fordadistrogene movaparvovec was associated with clinically meaningful preservation of motor function in subjects with DMD when compared with selected external controls with similar pre treatment characteristics. As this was a comparison with nonrandomized groups or pooled clinical trial data there is the potential for confounding bias. Continued assessment of fordadistrogene movaparvovec is warranted in randomized, placebo-controlled trials."

Clinical • Clinical data • Late-breaking abstract • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Dual-energy X-ray absorptiometry measures of lean body mass as a biomarker for progression in boys with Duchenne muscular dystrophy. (PubMed, Sci Rep) - P2 | "This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD...DXA-derived percent lean mass at Week 49 also correlated with 4SC and North Star Ambulatory Assessment at Week 97. These data indicate that whole-body DXA measures can be used as biomarkers for treatment effects and disease progression in patients with DMD, and warrant further investigation.Trial registration: ClinicalTrials.gov, NCT02310763; registered 8 December 2014."

Biomarker • Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Population PK and PD Analysis of Domagrozumab in Pediatric Patients with Duchenne Muscular Dystrophy. (PubMed, Clin Pharmacol Ther) - P1, P2 | "This study provides insights into the regulation of myostatin in healthy adults and pediatric patients with DMD. Clinicaltrials.gov identifiers: NCT01616277 and NCT02310763."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Pediatrics

Novel approaches to analysis of the North Star Ambulatory Assessment (NSAA) in Duchenne muscular dystrophy (DMD): Observations from a phase 2 trial. (PubMed, PLoS One) - P2 | "These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as "not obtainable" for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test."

Journal • P2 data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Influence of myostatin inhibitor on smooth muscle cells regeneration (EAU 2022) - "Our study demonstrates for the first time that myostatin is expressed in bladder SMCs. In addition, Domagrozumab and Suramin improve bladder SMCs proliferation and increase in the expression of late contractile proteins. This study indicates that both myostatin inhibitors may have a tissue engineering therapeutic potential for patients with incontinence and other smooth muscle disorders."

Erectile Dysfunction • Urinary Incontinence • Urology • MYH11 • SMTN

Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab. (PubMed, J Neurol) - P2 | "Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014."

Biomarker • Clinical • Journal • MRI • P2 data • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Safety and disease monitoring biomarkers in Duchenne muscular dystrophy: results from a Phase II trial. (PubMed, Biomark Med) - P2 | "Patients & Data were collected during a Phase II trial of domagrozumab... Results support the use of GLDH as a specific biomarker for liver injury in patients with Duchenne muscular dystrophy. Clinical trial registration: ClinicalTrials.gov, NCT02310763."

Biomarker • Clinical • Journal • P2 data • Duchenne Muscular Dystrophy • Genetic Disorders • Hepatology • Liver Failure • Muscular Dystrophy • TNNI3

Quantitative muscle MRI biomarkers in Duchenne muscular dystrophy: cross-sectional correlations with age and functional tests. (PubMed, Biomark Med) - P2 | "Aim: Using baseline data from a clinical trial of domagrozumab in Duchenne muscular dystrophy, we evaluated the correlation between functional measures and quantitative MRI assessments of thigh muscle... The moderate correlation between functional tests, age and baseline MRI measures supports MRI as a biomarker in Duchenne muscular dystrophy clinical trials. Trial registration: ClinicalTrials.gov, NCT02310763; registered 4 November 2014."

Biomarker • Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • MRI

A phase 1b/2a, open-label, multiple ascending dose trial of domagrozumab in FKRP limb-girdle muscular dystrophy. (PubMed, Muscle Nerve) - "We conclude that although domagrozumab was safe in patients in LGMD2I, there was no clear evidence supporting its efficacy in improving muscle strength or function."

Clinical • Journal • P1/2 data • Muscular Dystrophy • MRI

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy. (PubMed, Neuromuscul Disord) - P2 | "Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619."

Clinical • Journal • P2 data • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Pfizer terminates domagrozumab (PF-06252616) clinical studies for the treatment of Duchenne muscular dystrophy (Pfizer Press Release) - "Pfizer...announced today that it is terminating two ongoing clinical studies evaluating domagrozumab (PF-06252616) for the treatment of Duchenne muscular dystrophy (DMD): a Phase 2 safety and efficacy study (B5161002) and an open-label extension study (B5161004). The Phase 2 study (B5161002), did not meet its primary efficacy endpoint...The studies were not terminated for safety reasons. Pfizer will continue to review the data to better understand any insights they may provide, and will share results with the scientific and patient community."

Trial termination • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

An Open-label Extension Study To Evaluate Safety Of PF-06252616 In Boys With Duchenne Muscular Dystrophy (clinicaltrials.gov) - P2; N=105; Not yet recruiting; Sponsor: Pfizer

New P2 trial • Biosimilar • Gene Therapies

Detection of the myostatin-neutralizing antibody Domagrozumab in serum by means of Western blotting and LC-HRMS. (PubMed, Drug Test Anal) - "Following optimization, both assays were comprehensively characterized. They can readily be modified to include further protein drugs and will expand the range of available tests for emerging myostatin inhibitors."

Journal

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease. (PubMed, J Clin Pharmacol) - "Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD."

Clinical • Journal • PK/PD data

Pfizer pipeline (Pfizer Press Release)

Discontinuation

Comparing Model Performance in Characterizing the PK/PD of the Anti-Myostatin Antibody Domagrozumab. (PubMed, Clin Transl Sci) - "Whereas the MM-BK model was identified as optimal in fitting the data, with all parameters estimated with high precision, the QSS model also converged but was not able to capture the nonlinear decline. Although the least mechanistic model, MM-IDR had the lowest OFV, the MM-BK model was further developed as it provided a reasonable fit and allowed simulations regarding GDF-8 target coverage for Phase 2 dose selection with sufficient certainty to allow for testing of the underlying mechanistic assumptions."

Journal • PK/PD data

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Domagrozumab (PF-06252616), an Antimyostatin Monoclonal Antibody, in Healthy Subjects. (PubMed, Clin Pharmacol Drug Dev) - "Target engagement was observed with an increase in extent of myostatin modulation, plateauing at the 20 mg/kg IV dose. Downstream pharmacology following myostatin binding by domagrozumab was only observed in the 10 mg/kg single IV cohort (increase in whole-body lean mass of 5.38% using dual-energy x-ray absorptiometry) and the 10 mg/kg repeat-dose cohort (muscle volume increase of 4.49% using magnetic resonance imaging)."

Journal

A Trial of PF-06252616 in Ambulatory Participants With LGMD2I (clinicaltrials.gov) - P1b/2; N=19; Completed; Sponsor: Kathryn Wagner; Active, not recruiting ➔ Completed; Trial primary completion date: Aug 2018 ➔ Jan 2019

Clinical • Trial completion • Trial primary completion date

A Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Duchenne Muscular Dystrophy (clinicaltrials.gov) - P2; N=121; Terminated; Sponsor: Pfizer; Completed ➔ Terminated; Termination Date 30AUG2018: Reason for termination: Lack of Efficacy

Clinical • Trial termination

An Open-label Extension Study To Evaluate Safety Of PF-06252616 In Boys With Duchenne Muscular Dystrophy (clinicaltrials.gov) - P2; N=59; Terminated; Sponsor: Pfizer; N=105 ➔ 59; Completed ➔ Terminated; Termination Date: 30Aug2018; Reason for termination: Lack of Efficacy

Clinical • Enrollment change • Trial termination