Indian neuroscientist develops first therapy for refractory epilepsy

Decades-long research in the lab of Indian Scientist Professor Samba Reddy, who works at Texas A&M University School of Medicine, has paid off in a big way with the clinical approval of a new medicine for a previously untreatable brain disease. In March 2022, the United States Food and Drug Administration (USFDA) approved ganaxolone (Ztalmy) for the treatment of CDKL5-deficient epilepsy, a rare condition which was treatment-resistant. Ganaxolone is a synthetic version of a neurosteroid, which is a class of compounds that are synthesised in the brain and deeply influence brain functions and mood.

Reddy, an Indian citizen, is considered to be among the top two per cent of scientists worldwide and has published 225 papers, five textbooks, trained 100 students/postdocs and made 450 presentations. He has received numerous awards and honours for his contributions, including the AAPS Global Leader Award in Pharmaceuticals.

Professor Reddy’s research focusses on developing medical therapies for epilepsy, including neurosteroids. With over 20 years of research in these revolutionary compounds, Reddy is considered among the foremost experts on neurosteroids in the world. His two-decades-long work has laid a legendary foundation for neurosteroid therapies. Although neurosteroids were considered therapeutically intriguing for several years, it was not until Dr Reddy’s team discovered their mechanism of action and performed experimental trials that they took off from the bench to the clinic.

After over a decade of focussed research, Reddy and his lab uncovered that ganaxolone binds to two types of receptors in the brain: synaptic receptors, which exist on the membrane of neurons, and extrasynaptic GABA-A receptors, which reside outside the neuron. Crucially, they also found that the “calming” effect of neurosteroids is more powerful and lasts longer when they bind to the extrasynaptic receptors. Armed with this knowledge, Reddy’s team conducted pilot studies in experimental models proving that these compounds were effective in treating various forms of epilepsy. These results were ultimately used to establish clinical trials in humans, which also proved strongly successful for epilepsy.

For Professor Reddy and his team, ganaxolone becomes the second USFDA-approved therapy based on pioneering studies from their lab. In 2019, brexanolone, an injectable version of the neurosteroid allopregnanolone, became the USFDA-approved neurosteroid and made history as the first and only USFDA-approved treatment for post-partum depression.

For Reddy, the ultimate goal of his research is to directly see positive outcomes in patients. “The greatest goal in research is to provide transformational outcomes—seeing the product you helped make on shelves in the pharmacy and benefiting people,” he said. He is determined to continue his research, developing even more effective therapies and working on projects that will serve other people affected by treatment-resistant epilepsy, including brain injuries and chemical exposures in civilian and military persons.

An injectable neurosteroid therapy developed by Dr Reddy and his team has been approved for phase-III clinical trials for the treatment of status epilepticus, a condition that is often resistant to current medications. He is optimistic that his new research will lead to the development of more effective medicines with fewer side effects.