Migraine drug could prove effective against nerve agents

30th April 2018 (Last Updated April 30th, 2018 14:10)

Drug development company Proniras has entered a contract with the US Biomedical Advanced Research and Development Authority (BARDA) to explore Eli Lilly’s investigational migraine drug tezampanel as a potential treatment for nerve agent-induced seizures.

Migraine drug could prove effective against nerve agents
Migraine drug tezampanel to be examined as a potential treatment for nerve agent-induced seizures. Credit: US Food and Drug Administration

Drug development company Proniras has entered a contract with the US Biomedical Advanced Research and Development Authority (BARDA) to explore Eli Lilly’s investigational migraine drug tezampanel as a potential treatment for nerve agent-induced seizures.

The contract with BARDA is to last five years, and is worth up to $89.5 million. Under its terms, Proniras will be responsible for the preclinical studies, clinical development and manufacture of tezampanel, while BARDA will finance the research. Payments are connected to milestones attained during studies, manufacturing and clinical development under the FDA’s Animal Rule, allowing Proniras to submit efficacy data from animal instead of human models.

“As recent events have clearly demonstrated, the need for medical countermeasures that can effectively treat nerve agent exposure is sadly more than theoretical,” Proniras co-founder Christopher Toombs said.

“Tezampanel holds great potential as a solution to this serious challenge, having shown favourable safety and pharmacokinetic profiles in clinical trials for acute migraine and demonstrating efficacy in preclinical models of nerve agent-induced seizures.”

Proniras was launched by Accelerator Life Science Partners in 2016 with the purpose of developing tezampanel for a variety of seizure disorders. The global rights to the migraine drug were licensed from Eli Lilly, which is assisting in financing the research alongside the funding arms of Johnson & Johnson and WuXi AppTec. Proniras has announced its plans for a secondary financing round, though the amount of venture capital raised will not be disclosed.

Tezampanel (LY-293558) is a small molecule compound which has previously shown efficacy in clinical trials as a treatment for acute migraine and other neurological conditions. It works by inhibiting glutamate signalling through the GluK1 receptor subunit. Its potential use in seizure treatment was identified through the discovery that seizure activity is heightened by an increased glutamate signalling.

Benzodiazepines are currently used for the treatment of nerve agent-induced seizures. However, data has shown that over time seizures can become refractory to these drugs, often causing more severe episodes following only a brief period of suppression. Benzodiazepines act as sedatives, slowing down bodily functions and stimulating the brain chemical gamma amino butyric acid (GABBA) which reduces functions such as breathing.

Recent studies have shown tezampanel to halt seizures in rat models exposed to the nerve agent soman. Its direct inhibition of glutamate signalling has been identified as an indication of its superiority to benzodiazepines.

Proniras has disclosed plans to initiate human safety trials of tezampanel and apply for its Orphan Drug Designation by 2020, with approval anticipated by 2022.

The main nerve agents are sarin, soman, tabun and VX. All are man-made, organophosphorus compounds manufactured for the purpose of chemical warfare. They work through inhibiting cholinesterase enzymes in plasma, erythrocytes and cholinergic nerve endings in tissues. Typical symptoms include nausea and vomiting, drooling, abdominal pain, involuntary urination, muscle spasms and seizures.

Current treatments include the antidotes atropine and pralidoxime chloride (2-PAM chloride). However, the efficacy of 2-PAM chloride is known to diminish as time elapses due to the strengthening of the bond between the enzyme and nerve agent, an effect seen most commonly in soman.

The recent poisoning of former Russian spy Sergei Skripal and his daughter Yulia in Salisbury, UK saw the use of a strain of nerve agents developed by the Soviet Union in the 1970s and 80s. One of the chemicals, known as A-230, is reportedly five to eight times more lethal than VX, which can cause death within minutes.