There is solid scientific rational and preclinical data supporting a clinical trial of isradipine CR as a potential disease modifying agent in early PD. Human pharmacokinetic data demonstrate that it is feasible to achieve the serum concentrations in humans that were neuroprotective in preclinical models with the FDA approved dosage range. Pilot data demonstrate acceptable tolerability of isradipine CR in the PD population. Tolerability is inversely proportional to the dosage dependent. Considering that tolerability of isradipine CR is inversely proportional to the dosage exposure, it is essential to proceed with the dose selection tolerability study in preparation for the future efficacy trials.
The tolerability, defined as the ability to complete the study, of three dosages of isradipine CR relative to placebo in subjects with early Parkinson's disease will be examined first. The dosage that is tolerable and demonstrates preliminary efficacy will be evaluated further in the future pivotal efficacy studies.
PD is the second most common neurodegenerative disease that affects 1% of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta. Recent data demonstrated that the selective vulnerability of these neurons may be due to the reliance of these and other neurons susceptible to PD pathology, on L-type Cav1.3 Ca2+ channels and, more importantly for PD, that blocking these channels with israpadine, a dihydropyridine Ca2+ channel antagonist, protects these neurons in in vitro and in vivo models of parkinsonism. Recent epidemiological data also points to a reduced risk of PD with chronic use of dihydropyridines. Isradipine is an approved agent for the treatment of hypertension. Phase II clinical studies found that isradipine is safe and tolerable at the daily dose of 10 mg or below in participants with early PD. Isradipine penetrates the blood brain barrier and 10 mg daily dose is expected to achieve serum concentrations within the range found to be neuroprotective in animal models of PD.
Based on these results, STEADY-PD3 was conducted as a randomized Phase 3, 2-arm, double-blind, parallel group trial with subjects randomized to Isradipine immediate release 5 mg or matching placebo twice daily for 36 months. The primary efficacy measure was the change in the total UPDRS score in the active treatment arm versus placebo between the baseline and 36 months. If patients needed to start symptomatic therapy, they continued on their randomized treatment assignment in conjunction with the symptomatic therapy and primary outcome was assessed in the medications ON state. The primary analysis was based on the intent-to-treat principle and included all subjects who had 36 month data. The study had 95 % retention rate.
The study was negative for the primary outcome, showing no difference in PD symptoms over the 3 years of the study between the active and placebo arms.