Cytokinetics (located in South San Francisco) is a late-stage biotechnology company developing first-in-class muscle activators as potential treatments for debilitating diseases in which muscle performance is compromised and/or declining. This emerging biotech company has multiple pipeline candidates with two focused on rare diseases (CK-107 and tirasemtiv), which will be the focus of this article. Cytokinetics’ corporate presentation from June 28th, provides an excellent overview of the company, and for this article, we also had the opportunity to talk with Andrew A. Wolff, MD, FACC, Chief Medical Officer of Cytokinetics since 2004 about the company’s rare disease pipeline. “Cytokinetics has two rare disease products in their pipelines (for ALS and SMA) with similar mechanism of action (MOA): Tirasemtiv and CK-107 are both fast skeletal muscle troponin activators (FSTAs), unique, first in class products that are working their way through clinical trials as potential treatments for ALS and SMA,” said Dr. Wolff.
At the Cure SMA 2017 Annual SMA Conference in Orlando on July 5th, Cytokinetics presented data relating to patient baseline characteristics and the reasons for patient screen failure, both from the first cohort of the Phase 2 clinical trial of CK-2127107 (CK-107) in spinal muscular atrophy (SMA). Cytokinetics is developing CK-107 in collaboration with Astellas Pharma as a potential treatment for people living with SMA and certain other debilitating diseases and conditions associated with skeletal muscle weakness and/or fatigue.
Cytokinetics’ lead drug candidate is tirasemtiv, a fast skeletal muscle troponin activator (FSTA). tirasemtiv is the subject of VITALITY-ALS, an international Phase 3 clinical trial in patients with Amyotrophic lateral sclerosis (ALS). tirasemtiv has been granted orphan drug designation and fast track status by the U.S. Food and Drug Administration and orphan medicinal product designation by the European Medicines Agency for the potential treatment of ALS. Cytokinetics is also partnered with Astellas for tirasemtiv.
Amyotrophic lateral sclerosis is a progressive, degenerative neuromuscular disease that affects the nerve cells in the brain and spinal cord. These motor neurons carry messages from the brain to the spinal cord and, ultimately, to the muscles that are necessary for voluntary and involuntary movement and function.
Spinal muscular atrophy is a genetic disease affecting motor neurons in the spinal cord and the control of muscle movement. It is caused by a mutation of the survival motor neuron gene 1, or SMN1, which affects nerve cells and leads to debilitating muscle function and often fatal muscle weakness. There are four primary types of SMA based on age of onset and the manifestation of the disease. Type I, also known as Werdnig-Hoffmann disease, is the most common and severe type of SMA. Type II, diagnosed in children between the ages of 6 months and 2 years, results in a delay or failure to reach motor milestones. Children with Type III, usually diagnosed before age 3 and sometimes as late as their teenage years, learn to walk but have mobility problems as they grow. This type is also called juvenile SMA or Kugelberg-Welander disease. Type IV is rare, with symptoms usually beginning after age 35. Other forms of SMA that are caused by mutations in genes other than SMN1 are spinal muscular atrophy respiratory distress (SMARD), distal SMA, and Kennedy’s disease.
Rare Disease Pipeline: Tirasemtiv and CK-107
“Tirasemtiv is the subject of a large, international Phase 3 clinical trial called VITALITY-ALS, which completed enrollment in August 2016,” said Dr. Wolff. “The trial is designed to assess its effects versus placebo on measures of respiratory function and muscle strength in people with ALS. Results from VITALITY-ALS are expected in the fourth quarter of 2017. In October 2016, an open-label extension clinical trial called VIGOR-ALS began. The trial is designed to assess the long-term safety and tolerability of tirasemtiv, in patients with ALS who have completed their participation in VITALITY-ALS.”
“CK-107 is focused on SMA and slows the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers, which sensitizes the sarcomere to calcium, leading to an increase in skeletal muscle contractility,” said Dr. Wolff. “CK-107 has been the subject of five completed Phase 1 clinical trials, which evaluated safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics.”
Dr. Wolff highlighted that tirasemtiv has been evaluated in six Phase 2 trials and three Phase 1 trials, examining its safety, tolerability, bioavailability, pharmacokinetics, and pharmacodynamics.
VITALITY-ALS is a multinational, randomized, double-blind, placebo-controlled trial that enrolled over 700 patients in 81 centers in 11 countries with possible, probable or definite ALS, diagnosed within 24 months, and with percent predicted slow vital capacity (SVC) at baseline ≥70%. SVC is a measure of the amount of air expelled from a patient’s lungs after inflation and is used to assess diaphragm strength. The primary endpoint of the trial will assess change from baseline in SVC after 24 weeks of treatment. Secondary endpoints, to be assessed at 48 weeks, include time to decline in any of the three respiratory domains of the ALSFRS-R or death; time to decline from baseline in percent predicted SVC by ≥20 percentage points or the onset of respiratory insufficiency or death; time to first occurrence of any use of assisted ventilation or death; time to decline from baseline in percent predicted SVC to ≤50% predicted or the onset of respiratory insufficiency or death; and change in the Mega-Score of muscle strength. VITALITY-ALS completed enrollment in August 2016, and results are expected in Q4 2017.
