Dosing Begins in Phase 1 Trial of AP-472, for Dyskinesia With Levodopa

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by Patricia Inácio, PhD |

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A Phase 1 trial of AP-472, Appello Pharmaceutical‘s lead investigational therapy to ease levodopa-induced dyskinesia in Parkinson’s disease, has started dosing healthy adults.

The study will randomly assign young, middle-aged, and elderly adults to escalating doses of AP-472 or a placebo. It aims to evaluate the therapy’s safety, tolerability, and pharmacokinetics, which refers to the movement of a medicine into, through, and out of the body.

Results will help to inform the best doses for further testing in clinical studies in Parkinson’s patients, the company said in a press release.

Enrollment for this Phase 1 trial is currently open to healthy adults at Worldwide Clinical Trials in San Antonio, Texas. More information is available here.

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“Moving forward with the clinical trial is the next critical step in advancing AP-472 to help people with Parkinson’s disease,” said Brian Laden, PhD, president and CEO of Appello.

AP-472 was originally developed at Vanderbilt University’s Warren Center for Neuroscience Drug Discovery (WCNDD), and supported by funds from groups that included the National Institutes of Health and The Michael J. Fox Foundation.

“It has taken nearly 20 years of work to achieve this moment,” Laden said.

Parkinson’s is characterized by the loss of nerve cells that produce the neurotransmitter dopamine (a chemical messenger) in the substantia nigra, a region of the brain that regulates muscle movement and coordination.

As the disease progresses, the drop in dopamine levels affects other neurotransmitters, including glutamate, the major excitatory neurotransmitter in the central nervous system (brain and spinal cord).

AP-472 is a highly selective, small molecule, positive allosteric modulator (PAM) designed to increase the binding of glutamate to a receptor in nerve cells called metabotropic glutamate receptor subtype 4 (mGluR4).

The brain has several mGlus receptors, which are critical in maintaining the normal function of the glutamatergic system. Targeting this specific mGlu receptor is thought to be key to modulating its activity in a controlled manner.

Contrary to approaches that target the main active site common to all receptors, PAMs binds to a secondary and separate site on the receptor, which allows for specific targeting and, possibly, better modulatory control at disease mediating receptors, decreasing the risk of off-target activity side effects.

Therapies that work to restore glutamate levels are likely to help lessen Parkinson’s symptoms, including the motor complications that arise after long-term use of dopamine replacement therapies, such as levodopa. Also known as L-DOPA — a precursor to dopamine — levopoda over time can lead to uncontrollable movements, a condition called levodopa-induced dyskinesia or LID.

“Patients need a drug that works in a fundamentally different way from dopamine replacement therapy. That is what AP-472 does,” said Robert Elfont, chief medical officer at Appello.

Testing of AP-472 in preclinical models of Parkinson’s disease showed that the therapy reached the brain and helped to ease animals’ motor symptoms, including rigidity and immobility. Its benefits were greater when administered in conjunction with levodopa.

“Parkinson’s disease patients have a tremendous need for new drugs to improve their symptoms at the point when levodopa-based drugs are no longer effective on their own,” said Rajesh Pahwa, MD, director of the Parkinson’s Disease and Movement Disorder Center, University of Kansas Medical Center.

According to Appello, AP-472 is intended to work with levodopa, this way increasing “on” periods — the time during the day that people have their symptoms controlled without dyskinesia.

“It is exciting to see a highly specific and potent mGlu4 PAM tested in the clinic. This class of drugs has great potential to significantly improve the lives of Parkinson’s disease patients,” said David Standaert, MD, PhD, a neurologist with the University of Alabama at Birmingham.

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