27 Feb 2012

By amplifying muscle responses to nerve inputs, researchers have developed a drug with the potential to boost muscle strength in people with amyotrophic lateral sclerosis. Cytokinetics, Inc., of South San Francisco, California, detailed the molecule’s mechanism in the February 19 Nature Medicine online. The compound CK-2017357 (“CK-357” for short) sensitizes muscle cells to the calcium that activates contraction, making them flex even if the incoming signals from neurons are weak. Cytokinetics is already testing the drug in Phase 2 trials for ALS as well as myasthenia gravis, a weakening disorder caused by autoimmunity to the muscle receptor for the neurotransmitter acetylcholine.

“If you can make the muscles a little bit stronger, it would make a big difference for people with ALS,” said Robert Miller, director of the Forbes Norris MDA/ALS Research Center at the California Pacific Medical Center in San Francisco. The drug boosts strength by 15-25 percent in healthy people, noted Miller, who has participated in trials with Cytokinetics. For a person with ALS, that kind of increase could mean the ability to get around as well as to eat, bathe, and dress independently, he said.

Cytokinetics has not published its trial data yet, but has reported on Phase 2 results at the 21st International Symposium on ALS and Motor Neuron Diseases held in Orlando, Florida, in December 2010, and the 63rd Annual Meeting of the American Academy of Neurology in Honolulu in April 2011. Lead investigator Jeremy Shefner of the State University of New York (SUNY) Upstate Medical University in Syracuse presented trial data from 67 people who received single-dose treatments, spaced at least six days apart, of a high dose, low dose, and placebo, and then were tested six hours later. Both the people with ALS and their physicians, blinded to the treatment, more likely reported improvement in subjects' muscle strength after they took the active drug. In hand-grip tests, people on the medication were slower to fatigue, and in breathing tests, they could inhale and exhale a greater volume of air during one minute than they could before the treatment. The main side effect was dizziness.

Shefner reported on another trial at the 22nd International Symposium on ALS/MND held in Sydney, Australia, in November 2011. In the first part of that study, the researchers provided the drug once a day over a two-week period to 24 people with ALS. CK-357 was well tolerated, and the dizziness tended to wear off during the trial period. While the study was underpowered to detect clinical benefits, some people seemed to improve in their ability to perform daily functions and in their breathing ability. Now, Cytokinetics is in the second phase of that trial, testing CK-357’s effects when given concurrently with the ALS drug riluzole in another 24 people. In another experiment, the researchers are trying escalating doses in a different set of two dozen volunteers. Armed with data from these studies, Shefner hopes to begin a Phase 2b trial for efficacy later this year, he told ARF.

In the Nature Medicine paper, senior author Fady Malik of Cytokinetics and first author Alan Russell, who has since moved to GlaxoSmithKline in Durham, North Carolina, offer the first published report of how CK-357 does what it does. They identified the drug in a screen for medication that would increase the contraction of the sarcomere, the muscle’s actin- and myosin-containing structure that shortens in response to neural input. In a resting muscle, the troponin protein complex sits between the actin and myosin, blocking contraction. Calcium binding to troponin causes it to move out of the way.

In the paper, Malik and colleagues showed that CK-357 binds to troponin and makes it more likely to hang on to calcium, freeing up actin and myosin for contraction. “For every dollop of calcium you toss in there, you get a stronger or more forceful contraction,” said Miller, who is not an author on the study. This understanding of the mechanism should allow the researchers to better refine muscle activators like CK-357, he said.

In rats, CK-357 caused a stronger muscle contraction in response to nerve stimulation than in untreated animals. Importantly, mainly the fast-twitch muscles were sensitized by CK-357; slow-twitch fibers were affected to a lesser extent, and cardiac muscle not at all. Altering heart muscle physiology could raise the heart rate, an unwanted side effect, Malik said. Fast-twitch muscles are used for actions like running up the stairs or rising from a chair, while slow-twitch fibers are for endurance activities like standing upright. Thus, CK-357 could give a person “greater power to initiate muscle movements,” Malik suggested.

The team tested the treatment in a rat model for myasthenia gravis. With increasing doses of CK-357, the mice hung on to a bar more tightly, and they also maintained muscle force for longer than control animals. The group has also found that CK-357 similarly sensitizes muscles to nerve input in ALS model mice overexpressing human mutant superoxide dismutase 1, Malik said, but has not yet published those results.

“I would think it would improve motor function and quality of life,” commented Michael Miller of the University of Alabama at Birmingham, who was not involved in the study. The drug might also slow ALS disease progression, he speculated, although he said he would remain skeptical until the data are in. Robert Miller agreed it is too soon to know about progression, but noted that the diaphragm, which leads to death if it fails, or reliance on a ventilator, does contain fast-twitch muscles. “If the very few nerve contacts that you have [in the diaphragm] are functioning more efficiently, could you prolong life? That is certainly possible,” Shefner said.

For CK-357 to work, the muscles must still receive some whisper of input from motor neurons. “When all the nerves are gone, there is obviously nothing we can do,” Malik said. But axons retract slowly, Malik said, so for most of the disease course, some nerve input should be available. Robert Miller added that, even as some nerve-muscle connections wither, other nerves reinnervate the junction.

The muscle-focused treatment might help neurons, too, Michael Miller speculated, since there is evidence that properly contracting muscles send neurotrophic factors back to the neurons (Schinder and Poo, 2000). Muscle is an attractive target for treatments, Michael Miller noted, because it is a large, easy-to-reach tissue and there is no blood-brain barrier to cross. In the Cytokinetics trials, CK-357 is given orally. The company is also considering the medicine’s potential in muscular dystrophy or sarcopenia, the muscle loss that accompanies natural aging.—Amber Dance

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References

Paper Citations

1. Schinder AF, Poo M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 2000 Dec;23(12):639-45. PubMed.

External Citations

1. trial data
2. first part of that study
3. another experiment

Further Reading

Papers

1. Palma E, Inghilleri M, Conti L, Deflorio C, Frasca V, Manteca A, Pichiorri F, Roseti C, Torchia G, Limatola C, Grassi F, Miledi R. Physiological characterization of human muscle acetylcholine receptors from ALS patients. Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20184-8. PubMed.
2. Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, Moore DH, Schoenfeld D, Mather JL, Archibald D, Sullivan M, Amburgey C, Moritz J, Gribkoff VK. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med. 2011 Dec;17(12):1652-6. PubMed.
3. Canzi L, Castellaneta V, Navone S, Nava S, Dossena M, Zucca I, Mennini T, Bigini P, Parati EA. Human Skeletal Muscle Stem Cells' Anti-inflammatory Activity Ameliorate Clinical Outcome in Amyotrophic Lateral Sclerosis Model. Mol Med. 2011 Nov 4; PubMed.
4. Onesto E, Rusmini P, Crippa V, Ferri N, Zito A, Galbiati M, Poletti A. Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis. J Neurochem. 2011 Jul;118(2):266-80. PubMed.
5. Staunton L, Jockusch H, Ohlendieck K. Proteomic analysis of muscle affected by motor neuron degeneration: the wobbler mouse model of amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2011 Mar 25;406(4):595-600. PubMed.
6. Dadon-Nachum M, Melamed E, Offen D. The "dying-back" phenomenon of motor neurons in ALS. J Mol Neurosci. 2011 Mar;43(3):470-7. PubMed.

News

1. NEALS: In ALS Trials, One Design Does Not Fit All 27 Oct 2011
2. Clinical Trials for ALS: Taking Stock of 2009, Looking to 2010 15 Jan 2010
3. Muscle MicroRNA Repairs Nerve-Muscle Connection in ALS Model 11 Dec 2009
4. More Mitochondrial Mayhem in ALS Motor Neurons, Muscles? 20 Jan 2012
5. ALS Muscle Matters: Biopsy and Frog Egg Models Probe Pathology 12 Dec 2011
6. Motors and Muscles—Pacing ALS Progression 17 May 2009