Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. Results: The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. Conclusions: The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

Somatic Gene Therapy Research in Pediatric Populations: Ethical Issues and Guidance for Operationalizing Early Phase Trials.

Currently, pediatric research involving investigational gene therapies (GT, used without intending to imply a therapeutic effect) targets a broad range of indications (including rare and ultra-rare diseases) that vary in severity and availability of approved disease-modifying therapies. Because of this diversity of circumstances, there is no one-size-fits-all list of ethical concerns relevant to all uses of investigational GTs in children. Here, we review the main ethical issues, specifically those surrounding the current state of knowledge about GT product-related immunogenicity, toxicity, duration, irreversibility, informed consent/assent, trial design (including the question of who 'goes first'), participant and caregiver burdens, and equity in diagnosis and access to research opportunities. Ethical issues that can be anticipated to arise in pediatric GT clinical trials, e.g., the uncertainty and risk of this research, the resultant preclusion of GT trial participants from other research, the length of follow-up monitoring, and the urgency often felt by caregivers dealing with dire, rapidly progressive conditions, should be proactively identified, addressed in accordance with existing best practices, and transparently discussed among all stakeholders.

The novel kinesin spindle protein (KSP) inhibitor SB-743921 exhibits marked activity in in vivo and in vitro models of aggressive large B-cell lymphoma.

The kinesin spindle protein (KSP) is a mitotic protein essential for cell cycle control and motility. SB-743921 (hereafter SB-921) is an inhibitor that selectively targets the ATP-binding domain of the KSP. The preclinical activity of SB-921 was evaluated in models of diffuse large B-cell lymphoma (DLBCL). The cytotoxicity of SB-921 was evaluated in a series of germinal center (GC-DLBCL) and post-germinal center (ABC-DLBCL) DLBCL cell lines and a murine lymphoma xenograft model. GC-DLBCL lines generally demonstrated greater sensitivity to SB-921. IC50 values ranged between 1 nM and 900 nM for GC-DLBCL compared to 1 nM to 10 µM for ABC lines. SB-921 demonstrated marked activity in a xenograft model of Ly-1 (GC-DLBCL). While SB-921 was relatively more active in GC derived cell lines, ABC-derived lines still underwent apoptosis at higher concentrations. These results demonstrate that SB-921 inhibits proliferation and induces apoptosis in both GC-DLBCL and ABC-DLBCL.

The addition of granulocyte-colony stimulating factor shifts the dose limiting toxicity and markedly increases the maximum tolerated dose and activity of the kinesin spindle protein inhibitor SB-743921 in patients with relapsed or refractory lymphoma: results of an international, multicenter phase I/II study.

This was a phase I study of SB-743921 (SB-921) in patients with relapsed/refractory lymphoma. Previous studies established that neutropenia was the only dose limiting toxicity (DLT). The primary objective was to determine the DLT, maximum tolerated dose (MTD) and efficacy of SB-921 with and without granulocyte-colony stimulating factor (G-CSF). Sixty-eight patients were enrolled, 42 without G-CSF, 26 with G-CSF. In the cohort without G-CSF, SB-921 doses ranged from 2 to 7 mg/m(2), with 6 mg/m(2) being the MTD. In the cohort with G-CSF support, doses of 6-10 mg/m(2) were administered, with 9 mg/m(2) being the MTD, representing a 50% increase in dose density. Fifty-six patients were evaluable for efficacy. Four of 55 patients experienced a partial response (three in Hodgkin lymphoma and one in non-Hodgkin lymphoma, all at doses ≥ 6 mg/m(2)); 19 patients experienced stable disease, 33 patients developed progression of disease. G-CSF shifted the DLT from neutropenia to thrombocytopenia, allowing for a 50% increase in dose density. Responses were seen at higher doses with G-CSF support.

Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.

OBJECTIVES: The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. BACKGROUND: Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. METHODS: In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). RESULTS: The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. CONCLUSIONS: Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565).

Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide.

Calcitonin gene-related peptide (CGRP) is a well-validated target for migraine therapy and a known potent systemic vasodilator. LBR-101 is a monoclonal antibody against CGRP in clinical development for the preventive treatment of episodic and chronic migraine. Understanding the hemodynamic and cardiovascular consequences of chronic CGRP inhibition is therefore warranted. Given the conservation in CGRP sequence between monkeys and humans, addressing this question in monkeys is ideal as it allows dosing at super-therapeutic levels. To this end, two independent studies were conducted in monkeys: a single dedicated cardiovascular safety study and a repeat-dose, chronic study, both with electrocardiogram and hemodynamic assessments. LBR-101 was very well tolerated in both studies, with no clinically significant changes noted in any hemodynamic parameter, nor any relevant changes noted in any ECG parameter. In cynomolgus monkeys, cardiovascular and hemodynamic parameters do not appear to be affected by long-term inhibition of CGRP with LBR-101.

Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP.

BACKGROUND: The vascular effects of acute calcitonin gene-related peptide (CGRP) inhibition are well described, but the effects of sustained inhibition warrant further exploration in humans. OBJECTIVES: The objective of this article is to assess the effects of sustained CGRP inhibition on blood pressure, heart rate, and ECGs in healthy women ≥ 40 years of age. METHODS: In this double-blind, placebo-controlled study, 31 women (mean age = 56) were randomized to receive placebo or an anti-CGRP monoclonal antibody at doses up to 2000 mg. Participants were confined for seven days and followed for 168 days. Cardiac telemetry was conducted for eight hours after infusion completion. Hemodynamic assessments and ECGs were conducted six times during Day 1 and periodically for three months. RESULTS: No clinically relevant changes in systolic or diastolic blood pressure, heart rate, or ECG parameters (RR, PR, QRS, or QTcF) were observed when comparing baseline vs. post-dose time-points or in-between groups. No significant changes were seen for adjusted QTcF (baseline subtracted and placebo and baseline subtracted). No significant differences or relevant abnormalities were seen when comparing parameters obtained at Tmax vs. any other time-point. CONCLUSION: Sustained CGRP inhibition was not associated with hemodynamic or ECG changes in a population at an increased age risk for cardiovascular events.

Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: Results of the Phase 1 program.

BACKGROUND: LBR-101 is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide. OBJECTIVE: The objective of this article is to characterize the safety and tolerability of LBR-101 when administered intravenously to healthy volunteers, by presenting the pooled results of the Phase 1 program. METHODS: LBR-101 was administered to 94 subjects, while 45 received placebo. Doses ranged from 0.2 mg to 2000 mg given once (Day 1), as a single IV infusion, or up to 300 mg given twice (Day 1 and Day 14). RESULTS: Subjects receiving placebo reported an average of 1.3 treatment-emerging adverse events vs 1.4 per subject among those receiving any dose of LBR-101, and 1.6 in those receiving 1000 mg or higher. Treatment-related adverse events occurred in 21.2% of subjects receiving LBR-101, compared to 17.7% in those receiving placebo. LBR-101 was not associated with any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The only serious adverse event consisted of "thoracic aortic aneurysm" in a participant later found to have an unreported history of Ehlers-Danlos syndrome. CONCLUSION: Single IV doses of LBR-101 ranging from 0.2 mg up to 2000 mg and multiple IV doses up to 300 mg were well tolerated. Overt safety concerns have not emerged. A maximally tolerated dose has not been identified.

Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer.

The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during cycle 1. A total of 16 patients were treated at three dose levels: 10 mg/m (n=3), 12 mg/m (n=6), and 14 mg/m (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor, human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The maximum tolerated dose was 12 mg/m and dose-limiting toxicity was grade 3 increased aspartate aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%; 38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization (partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this schedule in patients with previously untreated advanced breast cancer.

Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study.

BACKGROUND: Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. METHODS: In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. FINDINGS: The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. INTERPRETATION: These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. FUNDING: Cytokinetics Inc.