Isradipine Fails to Slow Early Parkinson Disease Progression in Phase 3 Study

Author(s):

Although animal models and early phase studies suggested some potential for the hypertension medication to slow disability progression in Parkinson disease, a phase 3 assessment showed a lack of treatment effect.

Tanya Simuni, MD, Chief of Movement Disorders in the Department of Neurology, Arthur C. Nielsen Jr. Research Professor of Parkinson's Disease and Movement Disorders, and professor of Neurology, Northwestern University Feinberg School of Medicine

Tanya Simuni, MD

Despite a display of promise in smaller, earlier phase studies, 10-mg isradipine did not appear to slow the progression of disability in patients with early-stage Parkinson disease.¹

A secondary analysis of the STEADY-PD III study to explore any potential biological and clinical correlations of disease progression in the study population is underway for the oral calcium antagonist, which approved for the treatment of hypertension under the brand name Dynacirc by Sandoz.

The research was presented at the 2019 American Academy of Neurology (AAN) Annual Meeting, in Philadelphia, Pennsylvania.

"Unfortunately, the people who were taking isradipine did not have any difference in their Parkinson symptoms over the 3 years of the study compared to the people who took a placebo," study author Tanya Simuni, MD, Chief of Movement Disorders in the Department of Neurology, Arthur C. Nielsen Jr. Research Professor of Parkinson's Disease and Movement Disorders, and professor of Neurology, Northwestern University Feinberg School of Medicine, said in a statement.²

All told, the mean ANCOVA-adjusted Unified Parkinson Disease Rating Scale (UPDRS) I-III medication on time changes for the 336-patient cohort over the 36-month treatment period were 2.99 points for the treatment group (n = 168) and 3.26 for the placebo group (n = 168). The treatment effect was 0.27 points (95% CL, —2.5 to 3.0; P = .85).

The cohort in total was a mean age of 62 years (standard deviation [SD], 9) with a mean time from Parkinson diagnosis of 0.9 years (SD, 0.7). Baseline UPDRS I-III scores were 23.1 points (SD, 8.6) and were well-balanced between placebo and isradipine groups. The study retention rate was 95%.

"Of course, this is disappointing news for everyone with Parkinson disease and their families, as well as the research community," Simuni said. "However, negative results are important because they provide a clear answer, especially for the drug that is commercially available. We will all continue to work to find a treatment that can slow down or even cure this disease."

Unfortunately, all key secondary outcomes displayed no effect of treatment with isradipine. A statistical adjustment for the usage of symptomatic therapy did not affect the comparison. Similar to previous safety signals, the most notable side effect of isradipine was edema.

Previously, the hypertension treatment had shown some potential in animal models and was found to be safe in the phase 2 STEADY-PD study in humans. STEADY-PD showed a dose-dependent tolerability of isradipine of 73% (19 of 26 patients) at the 10-mg dose, with the 5-mg dose showing tolerability of 83% (19 of 23 patients). The most common adverse events (AEs) observed in the 99-patient cohort were peripheral edema (n = 30) and dizziness (n = 24).³

In a preclinical model, isradipine reduced cytosolic Ca2+ oscillations in substantia nigra pars compacta dopaminergic neurons, without any impact on autonomous spiking or expression of Ca2+ channels. This effect was mirrored by selectively knocking down the expression of Cav1.3 channel subunits. Additionally, it lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass. The animal model investigators noted that this was a demonstration that Cav1 channels are a driver of mitochondrial oxidant stress and turnover in vivo.⁴

Investigators first showed interest in the drug when it was observed that in those taking the hypertension treatment, there was an associated lower risk of developing Parkinson disease. It is believed that the entry of calcium into dopamine neurons leads to damage in the brain. This activity is blocked by isradipine along with a number of specific channels, which was believed to possibly prevent the death of the neurons, and therefore the progression of the disease.

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REFERENCES

1. Simuni T. A phase 3 study of isradipine as a disease-modifying agent in patients with early Parkinson’s disease (STEADY-PD III): Final study results. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA.

2. Blood pressure drug shows no benefit in Parkinson's disease [press release]. Philadelphia, PA: AAN; Published May 2, 2019. eurekalert.org/pub_releases/2019-05/aaon-bpd042919.php. Accessed May 3, 2019.

3. Simuni T, Biglan K, Oakes D, et al. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson's disease (STEADY-PD). Mov Disord. 2013;28(13):1823-1831. doi: 10.1002/mds.25639.

4. Guzman JN, Ilijic E, Yang B, et al. Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J Clin Invest. 2018;128(6):2266—2280. doi: 10.1172/JCI95898.