Research Breakthroughs Result in Potential New Parkinson’s Drug

The federal Food and Drug Administration is contemplating approving a brand new Parkinson’s drug that would supply sufferers a “second honeymoon” by way of controlling their motor signs.

AbbVie Pharmaceuticals has submitted a New Drug Application (NDA) to the federal Food and Drug Administration for the primary novel drug therapy for Parkinson’s illness in additional than half a century. The drug tavapadon selectively prompts a mind goal known as the D1 dopamine receptor. Its potential as a brand new therapy for Parkinson’s illness and different problems was pioneered by University of Virginia School of Medicine Professor of Pharmacology and Neuroscience Richard B. Mailman, PhD.

About Parkinson’s Disease

More than 11 million individuals world wide live with Parkinson’s, and the situation is the quickest rising age-related neurological illness. Parkinson’s causes tremor – uncontrollable shaking – in addition to stiffness, slowness and problem transferring. It will increase the chance of falls and might include signs similar to fatigue, insomnia, reminiscence loss and impaired means to pay attention. The main pathological change in Parkinson’s is the gradual dying of nerve cells that make and use dopamine for operate. Despite many years of analysis, no manner has been discovered to cease this degeneration.

Current Therapy for Parkinson’s

The main breakthrough in remedy occurred a half-century in the past when the drug levodopa was found. Levodopa is named “dopamine replacement” as a result of it’s transformed into dopamine by the dopamine nerve cells that stay alive. It made a dramatic distinction in each high quality of life and lifespan of Parkinson’s sufferers and has been the gold commonplace therapy ever since. Unfortunately, levodopa requires some remaining dopamine nerve cells to work. Because these cells maintain dying throughout the development of Parkinson’s, levodopa finally loses its effectiveness, or it causes insupportable unwanted side effects similar to extreme actions (known as dyskinesias) and psychological confusion and hallucinations.

In idea, scientists can use medicine that mimic dopamine within the mind by activating proteins known as dopamine receptors. These medicine are known as “dopamine agonists” and plenty of have been authorised for human use. None of them, nevertheless, is as efficient as levodopa, and so they have many unwanted side effects that restrict their use.

In 1984, Mailman did experiments that made him notice all the present “dopamine agonists” focused a particular subset of receptors known as “D2-like.” His experiments prompt that the opposite kind of dopamine receptor (“D1-like”) was really chargeable for most of levodopa’s useful results. He additionally suspected focusing on D1-like receptors wouldn’t have lots of the unwanted side effects of the authorised “dopamine agonist” medicine.

He fashioned a crew to find a brand new drug that might get into the mind and bind solely to the D1 dopamine receptor. Over a few years, his crew was profitable and confirmed that the experimental drug was as efficient as levodopa in animal fashions of Parkinson’s illness and in individuals. His findings have been confirmed by different scientists and by scientific analysis from a significant pharmaceutical firm, all of whom discovered {that a} D1 agonist (in contrast to the authorised dopamine agonists) works in addition to levodopa in individuals with Parkinson’s illness.

Challenges in Translating Research

In late Nineteen Nineties, the joy of this new discovery was hindered by the truth that all of those the first-generation medicine have been solely injectable. When administered incorrectly (e.g., injected by vein), they brought on unacceptable drops in blood stress. During this time, a brand new addition to the analysis crew, Xuemei Huang, MD, PhD, was coaching as a motion dysfunction specialist and scientific researcher. Working at Emory University with Jose Juncos and the late Mahon Delong, MD, she designed a scientific examine that confirmed that D1 agonists might be administered in a manner that prevented the blood stress issues. This discovering indicated that an oral drug of this sort might be used for remedy. Huang is now Nina and Ken Botsford Bicentennial Professor and Chair of UVA’s Department of Neurology and has continued her analysis in these areas.

Medicinal Chemistry Advances Open the Door

While persevering with his primary lab analysis, Mailman continued to attempt to persuade pharmaceutical corporations, massive and small, on the significance of this method to Parkinson’s sufferers. He continued regardless of the general feeling the trade that the Parkinson’s market was “too small” to be value an funding.

The breakthrough got here in 2007 when he was invited to go to Pfizer to debate the scientific potential of D1 agonists. Although Mailman didn’t notice it on the time, this go to satisfied a Pfizer crew led by Dr. David Gray of each the medical and enterprise affect of discovering a D1 agonist and the significance to have a capsule relatively than as an injection.

Gray later famous he too had confronted skepticism about this concept, however his revolutionary medicinal chemistry was the essential step in direction of getting a drug into the clinic. In 2017, Pfizer publicly introduced that its D1 agonist program for Parkinson’s at a world congress. At that assembly, Mailman launched Huang to Pfizer to debate thrilling laboratory knowledge suggesting novel therapy of superior (late-stage) Parkinson’s, for which there isn’t a medical possibility. Pfizer agreed to assist with a scientific trial that Huang and her crew later executed efficiently.
In 2018, Pfizer transferred the D1 agonist drug program to Cerevel Therapeutics, a brand new firm that led the ultimate scientific trials. Cerevel was acquired by AbbVie in 2024.

FDA Application

AbbVie’s announcement on Sept. 26 of a New Drug Application for tavapadon is the final step earlier than the drug may turn into out there to basic affected person use. Tavapadon is designed to extend the period of time when Parkinson’s sufferers have management of their signs and requires them to solely take drugs as soon as per day. Clinical trials present that it might be used alone or along side levodopa.

Effect on Quality of Life

Levodopa has been the usual for sufferers with Parkinson’s illness, providing a “honeymoon” interval that no different drug has matched. In scientific follow, levodopa requires a number of doses daily at extra frequent intervals, whereas tavapadon would require just one dose per day. It additionally could present sufferers with extra superior Parkinson’s a “second honeymoon” by way of wonderful management of their motor signs. Finally, Mailman’s crew has proven {that a} drug like tavapadon could present spectacular advantages within the very late levels of PD when sufferers are confined to wheelchair or mattress care. An preliminary small scientific trial led by Huang within the first-ever examine of this stage of the illness yielded optimistic outcomes.

“Dr. Mailman’s decades-long journey to make lab ideas work in the clinic is a wonderful story about the importance of scientific research and dedication to an idea even when it was not generally accepted,” Huang mentioned. “When my movement-disorder colleagues and patients asked when tavapadon will be available, I have a warm feeling inside when I say ‘soon.’”

Mailman added, “This announcement from AbbVie culminates an idea that has taken 40 years to bring to fruition. I was very pleased to be recruited to UVA to continue this exciting research. UVA has outstanding scientific collaborators, and the Manning Institute’s mission to accelerate the development of new treatments and cures for the most challenging diseases was a major attraction for me.”

“I look forward to sharing my knowledge and seeing the impact of this new category of drug to transform how we treat Parkinson’s patients. We also are researching how it may impact other disorders where D1 receptors may play a critical role, such as cognition, ADHD and autism,” he mentioned. “I was excited to be recruited to UVA because of colleagues like Kevin Pelphry, Jeff Elias, Binit Shah, Anita Clayton, Nikolay Dokholyan and others with complementary expertise.”

Mark T. Esser, PhD, chief scientific officer and head of UVA’s Paul and Diane Manning Institute of Biotechnology, added: “It has been a pleasure to meet and start working with Drs. Mailman, Huang and their team since I arrived. Their story underscores the importance of teamwork and perseverance as the journey to success is never a straight line and often long. The Manning Institute will bring together the critical ingredients of persistence, passion and people with the right skills to work together under ‘one roof’ to transform science into medicines.”

About the Clinical Trials

Tavapadon has been examined in two Phase 3 scientific trials, TEMPO-1 and TEMPO-2, that enrolled individuals who had been identified with Parkinson’s for lower than three years. A 3rd Phase 3 trial, TEMPO-3, seemed on the drug’s results in sufferers taking levodopa however nonetheless experiencing issues with motor management.

The TEMPO-1 and -2 trials discovered that sufferers who acquired tavapadon (versus a placebo) confirmed a statistically vital enchancment of their motion issues, whereas TEMPO-3 confirmed that combining tavapadon and levodopa elevated the period of time every day when trial contributors have been freed from dyskinesia or involuntary actions.

In addition to the outcomes from the finished trials, AbbVie mentioned it has additionally submitted to the FDA early outcomes from the continuing TEMPO-4 examine that’s inspecting the long-term security and efficacy of tavapadon by 58 weeks of therapy.

The commonest adversarial reactions to tavapadon have been nausea, headache and dizziness, whereas the most typical adversarial reactions amongst these taking each tavapadon and levodopa have been nausea and dyskinesia.

While Mailman and Huang are inventors on patents associated to D1 agonists, neither could have any monetary acquire from the advertising and marketing of tavapadon whether it is authorised by the FDA.

To sustain with the newest medical analysis information from UVA, subscribe to the Making of Medicine weblog.