Trial investigators getting excited about their own results is hardly a revelation, but in the case of mid-stage studies of Cytokinetics’ (CYTK) ALS drug CK-357 (CK-2017357) there was a genuine buzz over the observations.
The phase IIa study was not large, but nevertheless experts on the panel at the 21st International Symposium on ALS/MND for the first time saw encouraging improvements in muscle strength and function in ALS patients. Long-term effects are yet to be established and the drug has a long way to go, but Cytokinetics has cash to see it through next year and is swiftly moving to a proof-of-concept study with further functional outcomes.
CK-357, an activator of skeletal troponin, a protein complex involved in muscle contraction, is designed to raise the quality of life of ALS patients by improving submaximal musculoskeletal functioning – that is, everyday muscle movements that normally do not require huge exertions of energy.
By contrast, the only approved drug for ALS, riluzole, is designed to prolong survival, not suppress symptoms (Therapeutic focus – ALS field entering pivotal stage, August 2, 2010).
For patients of this incurable and progressively debilitating disease, the ability to perform tasks as simple as feeding oneself is arguably the most important factor to their wellbeing, and of those caring for them.
Phase I data reported earlier this year showed CK-357 increased muscle contraction in healthy subjects.
Results from the phase IIa 67-patient trial, which studied single doses of the drug, showed that 29 of 65 patients taking the higher 500 mg dose felt better six hours after treatment, compared with 18 out of 63 on placebo – deemed statistically significant. Further outcomes were being observed, including ALS Functional Assessment, grip strength and submaximal grip strength, shoulder extension fatigue and sniff inspiratory pressure, although none were specified as a single primary achievement measure. The drug increased grip strength and endurance, and inspiratory pressure in a dose-dependent manner.
Information is however limited on endurance of action and repeated dosing. Indeed investigators pointed out they are unsure what effect improving muscle function has on maintaining the nerves that supply that muscle.
Cytokinetics management recognised the single-dose trial design was limited, and longer-term, multiple-dose, proof-of-concept trials generating ALS Functional Scale data is warranted.
The safety profile was promising with no drug-related drop-outs. Only 12% of neurologic side effects were moderate in nature, mainly related to dizziness but with no increase in actual falls. The remaining 88% of adverse events were mild, although longer studies will show if this effect accentuates and attenuates with chronic use.
Importantly, said panellist expert Professor Robert Miller, is that these improvements are more encouraging than any he has seen from thousands of ALS patients he has treated.
“The idea that we could improve strength and function is quite honestly mindblowing,” said Prof Miller. “I realise we don’t have enough evidence to fully say, but these data to me suggest that it is possible. What our patients want to continue to do is be able to bathe themselves, dress themselves and feed themselves. These are submaximal activities, which are critically important.”
Starting next year is a three-month, proof-of-concept study with further functional outcomes, including respiratory effect, to provide guidance for phase III design.
"Evidence of effect"
That Cytokinetics’ share price fell 22% on Monday with the trial announcement perhaps paints a misleading picture. Some investors could have been disappointed by the lack of any update from the company on partnering plans, indicating the company may have to take on the risk of lengthy and expensive pivotal trials.
However, when Cytokinetics announced last week that “evidence of effect” data would be presented at the conference, the share price gained 34%, to $2.93. The sudden share price surge last week means profit-taking is likely to be a factor in the sell-off yesterday, while the stock is still trading above last week’s levels, currently at $2.30.
Speaking to EP Vantage, Gregory Wade of Wedbush Securities thought it very possible the drop was the result of simple profit-taking.
“We thought the data was positive,” he continues, saying that these results would put the company in good stead for a partnership, which Wedbush anticipates could happen before proof-of-concept is established, possibly even before the end of the year.
If these initial signs are upheld in the long term, CK-357 could represent an highly important inhibitor of the symptoms of disease progression. The conference panel mused that its mechanism of action could be applicable to all manner of disease patients experiencing muscle-wasting and fatigue. Another phase IIa “evidence of effect” trial is ongoing in patients with claudication (limping) associated with peripheral artery disease.
Cytokinetics will have to raise funds next year if it intends to advance the drug much further alone. If further good data are released later next year, partnering options should be greatly enhanced. A partner before the new year, though, would be music to investors ears.
Disclosure: No positions