Orphan-drug designation will be granted by the FDA Office of Orphan Drug Products Development to novel drugs or biologics that may treat a condition affecting less than 200,000 persons in the US or occurs in more than 200,000 persons and for which there is no reasonable expectation that the cost of development and distribution of the drug will be recovered. ALS is a progressive, neurodegenerative disease that afflicts 20,000 to 30,000 people in the US.
The designation offers a number of potential incentives, which may include a seven-year period of US marketing exclusivity from the date of marketing authorization, funding for clinical studies, study design assistance, waiver of FDA user fees, and tax credits for clinical research.
Cytokinetics has plans to commence a Phase II Evidence of Effect clinical trial for CK-2017357 in ALS patients in the first half of 2010.
Andrew Wolff, senior vice president and chief medical officer of Cytokinetics, said: “We are pleased that the FDA has granted orphan drug status to CK-2017357 for the potential treatment of ALS. This designation indicates their recognition that this novel drug candidate may address significant unmet medical needs in patients suffering from this grievous and uniformly fatal disease.
“With the planned initiation of our Phase II Evidence of Effect trial in patients with ALS, we look forward to continuing to work closely with regulators, as well as with our clinical investigators and key opinion leaders in the field of ALS, to advance this promising drug candidate through clinical development.”
Cytokinetics recently revealed the data from two Phase I clinical trials evaluating CK-2017357. The first trial is a two-part, single-dose, Phase I clinical trial of CK-2017357. Part A of this trial is designed to evaluate the safety, tolerability and pharmacokinetic profile of increasing single doses of this drug candidate in healthy volunteers and to determine its maximum-tolerated dose and plasma concentration.
Till date, single doses up to 2000mg have been administered without intolerable adverse events being observed. Part B of this trial was designed to assess the pharmacodynamic effects of CK-2017357 on skeletal muscle function after single oral doses of 250, 500 and 1000 mg, and to assess the relationship of the effects observed to the associated plasma concentrations of CK-2017357, also in healthy volunteers.
In Part B, CK-2017357 produced concentration-dependent, statistically significant increases versus placebo in the force developed by the tibialis anterior, the muscle evaluated in Part B of this trial. CK-2017357 was well-tolerated and no serious adverse events were reported.
The second trial was a multiple-dose, Phase I clinical trial of CK-2017357 designed to investigate the safety, tolerability and pharmacokinetic profile of CK-2017357 after multiple oral doses to steady state in healthy male volunteers. The trial assessed doses that produced plasma concentrations in the range associated with pharmacodynamic activity in Part B of the single-dose Phase I study. At steady state, both the maximum plasma concentration and the area under the CK-2017357 plasma concentration versus time curve from before dosing until 24 hours after dosing were generally dose-proportional.
In general, systemic exposure to CK-2017357 in this trial was high and inter-subject variability was low. In addition, these multiple-dose regimens of CK-2017357 were well-tolerated, and no serious adverse events were reported. The company believes that these results, in combination with the single-dose Phase I clinical trial data, support movement into planned Phase II Evidence of Effect clinical trials in patients with neuromuscular diseases and other conditions that may limit mobility, specifically amyotrophic lateral sclerosis (ALS) and claudication.
CK-2017357 selectively activates the fast skeletal troponin complex by increasing its sensitivity to calcium, leading to an increase in skeletal muscle force. This mechanism of action has demonstrated encouraging pharmacological activity in preclinical models that may relate to the potential treatment of diseases associated with aging, muscle wasting or neuromuscular dysfunction.
Skeletal muscle contractility is driven by the sarcomere, the fundamental unit of skeletal muscle contraction. It is a highly ordered cytoskeletal structure composed of skeletal muscle myosin, the cytoskeletal motor that is directly responsible for converting chemical energy into mechanical force, actin, and a set of regulatory proteins, troponins and tropomyosin, which make the actin-myosin interaction dependent on changes in intracellular calcium levels.
Cytokinetics’ skeletal muscle contractility program is focused to the discovery and development of small molecule skeletal sarcomere activators.