Currently available medications do not offer safe and effective relief for the often debilitating symptoms experienced by many of the estimated 10 million Americans with essential tremor (ET). Researchers at Brigham and Women’s Hospital are working to develop novel therapies for these patients by applying innovative drug design concepts to validated disease targets.
The sole FDA-approved drug for ET is the β-adrenergic antagonist propranolol, an unselective beta-blocker that only reduces tremor amplitude by up to 50% and does not reduce frequency. Furthermore, propranolol produces clinical benefits in just 40% of patients. Worse yet, many patients discontinue treatment due to fatigue, bradycardia, and other side effects.
Meanwhile, although 74% of ET patients respond well to ethanol, daily use of this therapeutic option is not a viable solution.
Kevin Hodgetts, PhD, director of the Brigham’s Laboratory for Drug Discovery in Neuroscience (LDDN), is leading efforts to develop a therapeutic compound to safely treat ET patients who are treatment-resistant to propranolol and who respond to ethanol. He and his team calculate that the compound will provide symptom relief in over 3 million new ET patients. Furthermore, their preliminary results predict that combining their compound and propranolol will significantly enhance the anti-tremor effects, expanding the potential market.
Collaborating With a World-leading ET Expert
Dr. Hodgetts is a medicinal chemist who previously worked in the pharmaceutical industry, focusing on drug discovery. He joined the LDDN, which seeks to transform discoveries in the basic biology of disease into opportunities for drug discovery, in 2012.
Earlier this year, Harvard Medical School named Dr. Hodgetts a recipient of a Blavatnik Therapeutics Challenge Award, which included the two-year, $1 million grant that is funding his current research aimed at finding a therapeutic compound for ET. Elan Louis, MD, chair of the Department of Neurology at UT Southwestern Medical Center and one of the world’s leading ET authorities, is an expert advisor for this research.
Using GABAA PAMs as a Starting Point in Drug Discovery
The LDDN is taking an innovative approach to drug discovery for ET. The team began by identifying compounds—gamma-aminobutyric acid type A (GABAA) positive allosteric modulators (PAMs)—that achieved clinical efficacy in ET but had intolerable on-target adverse effects. (GABA acting via GABAA receptors is the brain’s major inhibitory neurotransmitter system and regulates excessive brain excitability, which is associated with ET.) Importantly, the team also determined these compounds’ toxicity source: excessive potentiation.
“Current drugs stimulate the target too much,” Dr. Hodgetts explains. “For ET, compounds don’t need as much activity to be efficacious. We’re using assays to predict which compounds have the activity we want without the excessive side effects. In other words, we’re trying to dial down compound activity to what we think will be therapeutic, yet safe.”
Using GABAA PAMs as a starting point, Dr. Hodgetts and his colleagues are applying medicinal chemistry to make new molecules that are slightly different and then test them for changes in activity and off-target safety effects.
“It’s an iterative process, and we try to improve the molecule stage by stage,” Dr. Hodgetts says. “If we think we have an exciting molecule, we send it to one company to do the pharmacokinetics and see how much of it gets into the blood and the brain. And when we find a compound that has the activity and safety we require, we send it to another company for a mouse model of essential tremor.”
One point of focus for the LDDN is harmane, a GABAA negative allosteric modulator (NAM) that Dr. Louis has shown is increased in ET patients. “We’ve modeled some of our compounds around harmane to mimic its structure,” Dr. Hodgetts says. “And we’ve found that by doing medicinal chemistry on that structure, we can reverse the activity of harmane, which can cause tremors. So that’s part of the target of our compounds—to block the actions of harmane.”
Drug Shows Encouraging Efficacy and Safety Results
Preliminary studies of one prospective drug using in vivo models demonstrated that it delivered on-target efficacy with reduced adverse effects. In addition, the results predicted:
- A combination of the drug and propranolol would substantially enhance anti-tremor effects
- The efficacious dose of propranolol may be significantly reduced in this combination
“Therefore, we believe that those currently taking propranolol may experience significant benefits from a low-dose combination of a GABAA PAM and propranolol and suffer fewer side effects,” Dr. Hodgetts wrote in an application for the Blavatnik Award.
The LDDN continues to make and test compounds to pinpoint the optimal one for development. The planned development path includes an initial assessment of the clinical efficacy of the drug as a monotherapy, followed by a combination trial. Through the Harvard Business School’s Nucleate program, an MBA student has been paired with a research scientist in the lab to explore the possibility of starting a company or finding investors to fund clinical trials.
“ET is not as well-known as Parkinson’s disease, and it’s not as debilitating—though it can be as it progresses,” Dr. Hodgetts says. “Since many ET patients are embarrassed to have ‘the shakes,’ they tend to stay inside and withdraw from society. So we believe our drug could have quite an impact.”