Cytokinetics R&D Day Spotlights Muscle Programs Beyond Heart Failure Drug

Cytokinetics skeletal troponin activator CK-‘357 generates buzz on the Street, even before proof-of-concept data is in.

Cytokinetics made headlines with its heart failure drug in May after Amgen elected in to its option on worldwide rights (except in Japan), but its pipeline - presented at an R&D day in September - holds other assets that could be strong candidates from the young company. In particular, Cytokinetics' early stage skeletal muscle candidate garnered excitement from Wall Street for its wider breadth of uses.

The firm presented an array of possibilities for the fast skeletal troponin activator, CK-2017357, noting the mechanism's effects on amplifying motor neuron input, increasing muscle power and slowing muscle fatigue.

In terms of pharmaceutical markets, Cytokinetics listed cachexia syndromes like COPD and chronic kidney disease; age-related deficits like frailty; rehabilitation-related deficits including stroke rehab and post-op recovery; neuromuscular disorders, such as ALS and myasthenia gravis; as well as other disease targets, including chronic fatigue, metabolic syndrome and obesity.

But the drug maker and analysts seem to be rather enthusiastic in predicting the potential of CK-2017357, without yet having data from proof-of-concept studies to validate its safety and efficacy.

The only evidence thus far of the promise held by the skeletal tropinin activator mechanism of action is preclinical. The drug is currently in a Phase I dose escalation study looking at pharmacokinetics and safety in healthy male volunteers. The next step will be to assess its pharmacodynamic effect.

Still, Cytokinetics thinks that the broad potential of CK-'357 could help it move through clinical trials "more rapidly" than the company's Phase II heart failure drug omecamtiv mecarbil (formerly CK-'452), chief executive Robert Blum said in an interview. "The candidate could, we think, address not necessarily a larger market opportunity [than the heart failure drug omecamtiv], but certainly more indications." He added that this is because there are more types of conditions tied to skeletal muscle weakness and dysfunction compared to heart failure.

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Optimistic Outlook On The Street

Following the R&D day, analysts were optimistic about both CK-'357 and omecamtiv. Though omecamtiv arguably has drawn the most attention to date, presentations during the R&D overview seem to have piqued attention regarding '357.

"We believe '357 has the potential to demonstrate a significant, clinically meaningful impact on many disease states, albeit not as a disease-modifying agent," Lazard Capital Market analysts said in a Sept. 18 note. They also expect Cytokinetics to partner the drug after proof-of-concept studies.

In reiterating a "buy" rating after the company's R&D day, Needham analysts note: "We are impressed with the skeletal muscle activator program in particular, given the potential for a rapid development course in orphan diseases, as well as the novel nature of this therapeutic approach."

Planned Trial Strategy Would Provide PoC For Range Of Activity

Cytokinetics says skeletal troponin activators amplify motor neuron input by augmenting force development in response to nerve stimulation, and can also overcome a neuromuscular blockade. Additionally, these activators can increase muscle power (measured by force times velocity) and slow muscle fatigue. In preclinical studies, Cytokinetics found that troponin activators slowed the development of muscle fatigue in a model of peripheral vascular disease.

It is because of the varied pathways that the drug has so many potential uses. After the Phase I program works out the PK/PD in healthy volunteers, Cytokinetics intends to start a range of Phase II studies to gather evidence of effect in diseased or compromised patients.

At the R&D overview, the firm outlined a set of planned Phase II studies in different disease settings, each involving a different aspect of the skeletal muscle activator areas of effect - amplifying motor neuron input, increasing muscle power and slowing muscle fatigue. Those should then translate into proof of concept in related disease areas, from age-related deficits to peripheral vascular disease.

One planned evidence-of-effect Phase II study, for example, is amyotrophic lateral sclerosis, a disease characterized by muscle weakness and fatigue. Cytokinetics sketched out a study in patients in earlier stages of ALS, to capture patients before their rapid downward course to evaluate '357's potential sparing of remaining muscle capacity. The firm is considering a crossover trial with one or two single active doses versus placebo, with a preliminary estimate of 20-42 patients.

A second planned evidence-of-effect Phase II study is in myasthenia gravis. The chronic, debilitating disease is characterized by a defect in the transmission of nerve impulses to skeletal muscles and is hallmarked by muscle weakness, the firm explained. The Phase II study would target patients with mild to moderate disease with generalized symptoms, before initiation of standard immunosuppressive therapy. Like ALS, it would entail a crossover study of the acute effect of a single active dose, with enrollment of 20-34 patients.

The last evidence-of-effect area identified by Cytokinetics was frailty and disuse, where the firm thinks a skeletal muscle activator (with appropriate nutrition and resistance training) could improve functional performance and/or hasten recovery. There, company officials outlined a general Phase II crossover study of about 34 patients, targeting elderly patients with baseline functional impairment, where researchers could assess improvement in endpoints like short performance physical battery score, walk tests or muscle strength assessments.

The sole proof-of-concept trial previewed by Cytokinetics was in claudication, an effect of peripheral arterial disease that involves cramping pains in the legs due to obstruction of the arteries to the leg during exercise. It can lead to impaired muscle metabolism over time. "A skeletal muscle activator potentially could reduce fatigue and improve the duration of symptom-free exercise therapy, thereby potentially enabling more exercise," the firm's material explains.

The PoC clinical trial would follow patients with moderate disease of longer duration, patients whose symptom-limited walking distance is more impaired and who likely will have more impaired muscle metabolism due to chronic effects of PAD, Cytokinetics said. The firm is considering use of maximum treadmill walking distance as a primary endpoint - which it notes has been accepted by FDA as an endpoint - as well as other quality of life measures. The trial would run for three months of treatment duration, and enroll approximately 50 patients per group; that would yield an 80 percent power to detect an increase of 85 meters versus placebo in change from baseline walking distance.

Standard and Poor's analysts said they "are encouraged" by plans to test CK-'357 in small efficacy studies across broad uses before moving to larger proof-of-concept trials.

Cytokinetics hopes to begin some of these trials next year, starting with ALS as one of the first.

Initial Round Of Studies Offer Strategic Benefits

The firm's selected areas for its initial studies of '357 offer some additional benefits - Cytokinetics' targets are orphan conditions like ALS and myasthenia gravis where there are multiple paths to identify clinical benefit.

ALS, a progressive, fatal neurodegenerative disease, is one indication that may lead FDA to grant an accelerated regulatory approval for the drug, since patients have little to no other means of increasing muscle force and strength now, Blum said. There are about 5,000 to 8,000 new cases in the U.S. per year and nearly 120,000 globally, mainly affecting people between the ages of 40 years and 70 years.

The current Phase I study for '357 in ALS has two objectives. The first is to evaluate dose escalation in a randomized, double-blind placebo-controlled group, with secondary endpoints being safety and tolerability as well as pharmacokinetics. The second objective is to establish a PK/PD relationship of skeletal muscle activation.

For ALS, Cytokinetics intends to study patients in earlier stages of the disease, shortly after being diagnosed in order to capture these patients before they hit a rapid downward course to best evaluate potential sparing of remaining muscle capacity.

The primary endpoint of the study being considered is ALS Functional Rating Scale-Revised by FDA, which is a 48-point scale that measures patient function. Other potential endpoints include forced vital capacity, muscle strength assessments, such as leg press or stair climb, the Appel ALS functional scale - a means of predicting survival time in patients - and quality of life.

In examining several endpoints, Cytokinetics is likely aiming see the drug demonstrate an effect in multiple ways.

Myasthenia gravis offers a similar opportunity. In that orphan condition, Cytokinetics could use the Quantitative Myasthenia Gravis Score as the primary endpoint, an index based on qualitative testing of several sentinel muscle groups and accepted by FDA. Cytokinetics also is considering several secondary endpoints for this use, including MG muscular score, manual muscle testing, MGFA classification, MG-ADL scale and quality of life.

"Though some indications will be evaluated in a small population, which may have orphan designations, others will be evaluated in larger, heterogeneous populations and would require larger clinical trials," Blum said. "Now we're looking at how to develop this compound and how to partner," he added.

Muscle Biology: The Complete Package

Cytokinetics also is working on a smooth muscle contractility program, which could lead to drugs for pulmonary hypertension, bronco relaxants and vasodilators, Blum said.

Plans for Phase I testing in this program are expected to begin in 2010 in chronic diseases, such as hypertension and asthma. This fits in with the company's strategy to evaluate several types of muscle function at once, such as cardiac myosin activators, like omecamtiv, and skeletal muscle activators.

"We are uniquely focused to muscle biology, and with that we can efficiently combine capital with technical advancements and produce a portfolio of novel mechanisms of action," Blum added.

Needham analysts expect that the smooth muscle program will allow for a "rapid" proof-of-concept study, but that further development will likely require Cytokinetics to seek a larger biotech or pharma partner. Still, the company is in a stable financial position following Amgen's decision to opt in to worldwide rights to omecamtiv and take over all develop costs for the drug. The May transaction also sparked a license payment of $50 million (Also see "Amgen Elects Option On Cardiac Drug, Improving Cytokinetics' Strong Cash Position" - Pink Sheet, 26 May, 2009.).

Cytokinetics Inches Closer To Filing Omecamtiv

Phase IIa studies for omecamtiv, the drug maker's most advanced candidate in development, support advancements into Phase IIb studies, company execs said. The data from earlier studies demonstrated clinically meaningful increases in cardiac systolic function.

Cytokinetics is hoping to seek indications for use in reduction in death or hospital readmission and improvement in symptoms and functional status when it comes time to file with FDA. Omecamtiv is being evaluated in both oral and I.V. uses.

The heart failure drug was the primary asset in scoring an earlier 2006 deal between Amgen and Cytokinetics for cardiac contraction therapies, which brought the smaller San Francisco, Calif.-based company $75 million upfront. According to the earlier agreement, in opting to take worldwide rights to omecamtiv, Amgen also will provide pre-commercialization and commercialization milestones of up to $600 million, plus royalties that increase based on net sales ([See Deal]).

-Carlene Olsen ([email protected])