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) (C) 2015 by the American College of Cardiology Foundation.

ABSTRACTIntroduction: In this study we tested the hypothesis that tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans. Methods: Healthy men received tirasemtiv and placebo in a randomized, double‐blind, 4‐period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force–frequency relationship of tibialis anterior dorsiflexion was assessed after dosing. Results: Tirasemtiv increased force produced by the tibialis anterior in a dose‐, concentration‐, and frequency‐dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz). Conclusions: The data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input. Muscle Nerve 50: 925–931, 2014

Neuromuscular disease is often marked by insufficient neural activation of muscle activity, resulting in muscle weakness. Fady Malik and colleagues have developed an orally available small molecule that sensitizes muscles to neural activity by reducing the off rate of calcium binding to troponin C. They validate the therapeutic potential of this drug in vivo in a rat model of myasthenia gravis and show that treatment improves grip strength by 50%. Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission1. We developed a small-molecule fast-skeletal–troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal–troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal–troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.

Objective: To examine the effects of CK-2017357 in a mouse model of ALS. Background CK-2017357 is a small molecule activator of fast skeletal troponin that sensitizes the sarcomere to calcium and amplifies the muscle9s response to motor neuron input at sub-tetanic forces. Design/Methods: The potential effects of CK-2017357 were examined on muscle force, respiratory function and survival in SOD1 G93A mutant transgenic mice, a model of amyotrophic lateral sclerosis (ALS) in humans. Results: Extensor digitorum longus (EDL) muscle was stimulated via the peroneal nerve over a range of frequencies (10-200 Hz, 350 ms trains) to establish the force-frequency relationship. EDL tetanic force (26.3 ± 4.4 N/cm 2 ) was reduced by 44% ± 3.9% in 90-100 day-old SOD1 vs. WT and 66% ± 7.7% in 100-110 day-old SOD1 vs. WT, reflecting progressive loss of muscle force with disease progression. Infusion of CK-2017357 resulted in dose-dependent increases (mean ± SEM) in force at 30 Hz compared to baseline in WT (206% ± 29%), 90-100 day-old (200% ± 52%) and 100-110 day-old (153% ± 55%) SOD1 G93A mice. In female SOD1 G93A mice fed chow containing CK-2017357 (400 ppm) beginning at 11 weeks of age, animals survived to a humane endpoint longer compared to control chow-fed mice (p=0.024; hazard ratio=0.66). Body weight was similar in the two groups. There were no differences in respiratory parameters (breathing frequency, tidal volume and ventilation during hypercapnic challenge) in CK-2017357 chow-fed SOD1 G93A mice compared to WT mice. SOD1 G93A mice fed 400 ppm CK-2017357 chow exhibited a significant increase in hindlimb grip strength compared to control chow fed SOD1 G93A mice, while forelimb grip strength was not altered. Conclusions: CK-2017357 increased isometric in situ muscle force and hindlimb grip strength in SOD1 G93A mice and improved survival. These results indicate that CK-2017357 has the potential to improve muscle function in patients suffering from ALS. Supported by: Cytokinetics, Inc. Disclosure: Dr. Malik has received personal compensation for activities with Cytokinetics, Inc. Dr. Malik holds stock and/or stock options in Cytokinetics, Inc. Dr. Malik has received research support from Cytokinetics, Inc. Mr. Russell holds stock and/or stock options in Former Cytokinetics, Inc. which sponsored research in which Mr. Russell was involved as an investigator. Dr. Pannirselvam holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Pannirselvam was involved as an investigator.Dr. Pannirselvam has received research support from Cytokinetics, Inc. Dr. Hinken holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Hinken was involved as an investigator.Dr. Hinken has received research support from Cytokinetics, Inc. Dr. Thomsen holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Thomsen was involved as an investigator. Dr. Thomsen has received research support from Cytokinetics, Inc. Dr. Ardiana holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Ardiana was involved as an investigator. Dr. Ardiana has received research support from Cytokinetics, Inc. as an employee. Dr. Godinez holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Godinez was involved as an investigator. Dr. Jia holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Jia was involved as an investigator. Dr. Saikali holds stock and/or stock options in Cytokinetics, Inc. Dr. Saikali has received research support from Cytokinetics, Inc. Dr. Chen holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Chen was involved as an investigator. Dr. Chen has received research support from Cytokinetics, Inc. Dr. Morgans holds stock and/or stock options in Cytokinetics, Inc. Dr. Morgans has received research support from Cytokinetics, Inc. Dr. Jasper holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Jasper was involved as an investigator.Dr. Jasper has received research support from Cytokinetics, Inc..

This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.

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.

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.

Background: Omecamtiv mecarbil (OM), a novel selective, small molecule cardiac myosin activator that increases cardiac contractility without affecting the calcium transient in myocytes was shown to improve left ventricular (LV) systolic performance in a study of healthy men. Underlying this improvement in LV performance was a dose-dependent increase in the duration of LV contraction. We sought to quantify the effects of OM on left atrial (LA) performance. Methods: In this single center, double-blind study, 34 healthy men (age 27 ± 6.7 years) were randomized each to receive placebo and 3 different doses of OM. Baseline and 6-hour on-therapy echocardiograms with LA and LV measurements were obtained. Change from baseline was compared between placebo and maximum tolerated dose of OM (0.5 mg/kg/hr). Results: OM increased LA performance as indicated by LA reservoir function, A velocity, and A' velocity. Analogous to the increase in LV systolic ejection time (SET), OM also increased the duration of LA contraction (mitral A wave duration). No change in HR or E velocity was noted.Tabled 1Change from Baseline Echo Parameters at 6 HoursnChange from Baseline (LSM)OM (0.5 mg/kg/hr)PlaceboOM (0.5 mg/kg/hr)PlaceboDifference ± SEpLA end-diastolic volume (ml/m2)1416−4.85−5.901.05 ± 1.250.4LA end-systolic volume (ml/m2)1416−1.02−5.504.48 ± 1.530.007LA reservoir function %14168.043.904.14 ± 2.140.06MV Peak A Velocity (m/sec)16190.069−0.0210.089 ± 0.017<0.0001A' velocity, Doppler tissue imaging (cm/sec)16190.0062−0.00420.010 ± 0.0050.03LVOT VTI (cm)15193.20−0.333.53 ± 0.62<0.0001MV A wave duration (msec)161814.80−1.9416.73 ± 4.310.0002 Open table in a new tab Conclusion: This study is the initial report of improved left atrial performance with OM in healthy men. Although the effect on LA performance could be due to improved LV diastolic function, the improvement in A and A' parameters support intrinsic improvement in LA contractility. Future clinical studies will measure its effects on left atrial function in heart failure.

Tabled 1[CK-1827452] (ng/mL)1-100>100-200>200-300>300-400>400-500>500Difference of Least Squares Means ± SEMStroke Volume ≤ 50 mL at baseline (n=9 pts)SET (msec)2 ± 818 ± 7#53 ± 8&58 ± 13&69 ± 9&88 ± 8&SV (mL)∧4 ± 38 ± 3∗6 ± 316 ± 5∗14 ± 4†6 ± 3FS (%)2 ± 23 ± 12 ± 26 ± 2#4 ± 2#5 ± 2†Stroke Volume > 50 mL at baseline (n=34 pts)SET (msec)0 ± 419 ± 5†45 ± 6&57 ± 7&53 ± 8&76 ± 6&SV (mL)∧-2 ± 2-2 ± 26 ± 3#9 ± 3∗6 ± 412 ± 3&FS (%)0 ± 11 ± 13 ± 1†2 ± 11 ± 24 ± 1&∧Doppler Derived, #≤ 0.05, ∗≤ 0.01, †≤ 0.001, &≤ 0.0001 Open table in a new tab ∧Doppler Derived, #≤ 0.05, ∗≤ 0.01, †≤ 0.001, &≤ 0.0001