One step at a time

HELSINKI, Finland—Drawing a bit closer toward finding a potential cure for Parkinson’s disease (PD) is Herantis Pharma Plc, which recently announced first-in-human, top-line results from a Phase 1/2 clinical trial examining its proprietary novel drug candidate CDNF (cerebral dopamine neurotrophic factor) in 17 patients with PD.

As a novel neuroprotective and neurorestorative factor, CDNF acts on several mechanisms relevant to Parkinson’s disease, and has been shown to protect neurons from degeneration and to restore the function of already degenerating neurons in preclinical studies.

“This first set of top-line data provides a solid basis for the next part of the study and confirms the positive safety and tolerability profile of CDNF,” says Pekka Simula, CEO of Herantis. “Building on the established safety profile and encouraging observations, we have initiated the planning for a Phase 2 study with a longer treatment period that will assess the efficacy of CDNF in earlier-stage, well-characterized Parkinson’s patients.”

CDNF has been safe in preclinical studies and in the completed parts of the ongoing Phase 1/2 clinical study thus far, according to the company. And in disease models, CDNF has protected and regenerated dopamine-generating cells in the midbrain, suggesting potential for disease modification of PD.

“We extend our thanks to the clinical study sites and the patients who contributed to the advancement of this very important and challenging trial,” Simula adds.

The first part of the study, in which patients with advanced-stage PD received repeated CDNF dosing for six months, resulted in promising signals in some patients. This includes dopamine transporter PET imaging, an indirect measure of the dopaminergic function. Herantis expects to announce the next set of results, including details on the exploratory endpoints, in Q3 2020.

These patients first received a surgically implanted dose delivery system provided by Renishaw plc, and then repeated and increased CDNF or placebo dosing for six months.

All patients who completed the first part of the trial volunteered to participate in the extension study, in which every patient—including those previously randomly assigned to the placebo group—will receive one of the two dose levels of CDNF on a monthly basis.

“We have emphasized that while we were positively surprised to see a signal of efficacy already after six months of CDNF dosing, we are still eagerly waiting for the 12-month data including more information on both primary and secondary endpoints,” Simula tells DDNews. “The experts certainly share this view, and while considered good news, the interim results should also be considered an ‘evolving story.’

“So, we are obviously very excited to see an increased DAT-PET signal even in some of these late stage Parkinson’s patients, who had already lost most of their dopaminergic neurons when CDNF treatment was started.”

Dopamine transporter, or DAT, is a presynaptic membrane protein that provides a biomarker for following the dysfunction and restoration of dopaminergic terminals in nigrostriatal pathway, Simula explains. Thus, DAT-PET imaging provides a surrogate for the progression of Parkinson’s disease, which includes an expected annual decline of 6 to 13 percent.

“Encouraged by the good safety of CDNF and promising signals of efficacy already after six months of treatment, we are currently planning a Phase 2 study to start patient recruitment in 2021,” he says. “Our goal is to recruit earlier stage patients since CDNF is expected to be of greatest benefit to patients with more dopaminergic neurons remaining.”

If CDNF “could truly stop disease progression, it would be of significant societal value,” Simula states. “Almost a decade ago, it was estimated that such Parkinson’s therapy would save the U.S. society almost ($500,000) per patient. Of course, the current formulation, infused directly in the brain, limits the applicability in PD patients, but we hope to overcome that with our next-generation, non-invasive xCDNF.”

The primary endpoints of the study not only evaluated the safety and tolerability of CDNF, but the drug delivery device and accuracy of surgical placement of the device in the study patients. Secondary and exploratory endpoints include initial signs of efficacy of CDNF treatment, e.g. Unified Parkinson’s Disease Rating Scale, motor score evaluation, patient diary, dopamine transporter PET imaging, and the levels of different forms of alpha synuclein in serum and CSF.

PD is a slowly progressing, incurable neurodegenerative disease caused by the loss of dopaminergic neurons in the midbrain. Common first symptoms of the disease include tremors, rigidity and slowness of movement. While the motor symptoms can be treated with medication, the progression of the disease cannot be prevented.

The benefits of medication may be lost with disease progression, or their side effects can become unmanageable. The disease is also associated with non-motor symptoms such as sleep problems, depression and anxiety, which are not alleviated by current Parkinson’s drugs. It is estimated that 7 million to 10 million people worldwide suffer from Parkinson’s disease.