Safety of the antimyostatin monoclonal antibody LY2495655 in healthy subjects and patients with advanced cancer.

Abstract

2516 Background: Skeletal muscle wasting (cachexia) is a prevalent and not readily managed condition in advanced cancer patients. LY2495655 is a humanized monoclonal antibody to myostatin, which has demonstrated positive effects on cachexia measures in animal models. We present phase I trial data on use of LY2495655 in healthy volunteers (Study 1) and interim data from an ongoing phase I study in patients with advanced cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, blinded, single-dose, parallel, dose-escalation study evaluating the safety and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics (PKs) of LY2495655 in patients with advanced cancer not receiving chemotherapy. Dose cohorts (2 mg-700 mg, ≥3 patients per cohort) were to be treated until the maximum tolerated dose (MTD) was met, or the highest dose (700 mg) cohort was completed. Final locked data from Study 1 and interim data from the dose escalation phase of Study 2 were used in the analyses. Results: In Study 1, 64 healthy volunteers were enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had received treatment with LY2495655 at the time of the analysis. In both studies, all doses of LY2495655 were well tolerated (no DLTs were observed and MTD was not reached), and nonlinear PKs were observed (most evident in lower dose levels). In Study 1, thigh muscle volume generally increased with LY2495655. In Study 2, increased muscle volume was observed only at 21-mg and 70-mg doses. Consistent increases in hand grip strength and improvements in functional tests were observed at doses ≥21 mg. Conclusions: There were no unusual safety concerns in healthy subjects or cancer patients. PK results were consistent between the 2 studies. Increases in muscle volume were observed in both studies, with concomitant improvement in functional measures. However, there is no clear trend in dose-dependent efficacy, possibly due to extremely small sample sizes and patient heterogeneity. Enrollment in Study 2 continues with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic cancer patients.

Muscle wasting and survival following pre-operative chemoradiotherapy for locally advanced rectal carcinoma

“…Over the past decade our understanding of muscle wasting in cancer has greatly increased [30,31], and has led to the initiation of clinical trials investigating interventional strategies aimed at halting or reversing cancer related muscle wasting. [32][33][34][35] Whether these treatment regimens are efficacious remains to be answered, but if so the interval between chemoradiotherapy and surgery might offer a perfect window of opportunity to improve the overall condition of LARC patients.…”

Sarcopenia impairs survival in patients with potentially curable hepatocellular carcinoma

“…The underlying mechanism of muscle wasting in cancer has been thoroughly investigated in recent years and led to successful inhibition of muscle wasting in experimental models, e.g., by using myostatin inhibitors. A phase II clinical trial on LY2495655, a humanized monoclonal antibody to myostation, is currently investigating its effect on overall survival in advanced or metastatic pancreatic cancer patients. This is just one of many current clinical trials investigating the inhibition of muscle wasting in cancer patients.…”

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

“…Thus, Mstn inhibitors have been considered promising tools for the treatment of cachexia. In 2012, two Phase I clinical trials under the same study evaluated the safety and tolerability of the humanized monoclonal antibody to myostatin LY2495655 in healthy subjects and patients with advanced cancer (175). According to the results obtained, the efficacy of LY2495655 was well demonstrated in the case of healthy volunteers, in which it caused an increase in thigh muscle volume.…”

“…According to the results obtained, the efficacy of LY2495655 was well demonstrated in the case of healthy volunteers, in which it caused an increase in thigh muscle volume. Increases in muscle volume were observed also in patients with advanced cancer, though only when the drug was administrated at relatively low doses (21 and 70-mg) without unusual safety concerns (175). In 2018, a Phase II trial was performed on a group of inoperable patients or with metastatic pancreatic cancer, who suffered from cachexia.…”