Making a difference for traumatic brain injury patients

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults in the developed world, each year causing approximately two million emergency room visits, 52,000 deaths annually in the U.S. alone. But standard of care is still limited to surgery and symptomatic interventions, with the only medications available to treat seizures, induce a coma to reduce the brain’s oxygen demands, and diuretics.

A new company, veriNOS pharmaceuticals GmbH, of Wurzberg, Germany hopes to change all this with a late-stage drug candidate, ronopterin. If the name of the drug sounds familiar, that’s because it was previously developed by the biotech Vasopharm, which completed the late-stage phase 3 trial in TBI in 2021. Vasopharm’s management team, led by CEO Christian Wandersee, and CMO Professor John Stover have revived research into ronopterin, incorporating veriNOS in October 2022 in order to further pursue the drug’s potential, after strong evidence that the early start of infusion is the path forward in future trials.

Wandersee commented: “Currently, there is no drug treatment available to improve neurologic outcomes for patients with acute moderate and severe TBI. In preventing and reducing the severity of secondary brain damage, ronopterin will drastically improve the standard of care for TBI. Once approved, we anticipate a rapid integration in routine treatment protocols.”

Early infusion and a planned trial

Certainly, after talks with regulators from the FDA in the US and the European Medicines Agency (EMA), veriNOS says there is a regulatory pathway in these two crucial markets: US regulators support a Phase 2b trial, while in Europe a Phase 3b trial is designed to confirm efficacy.

The Phase 2b trial discussed with the FDA has a new primary endpoint, based on a measure of brain glutamate levels already confirmed to be significantly reduced in the Phase 2a and Phase 3a trials. The extended Glasgow Outcomes Scale (eGOS) after six months, the standard scale used to measure recovery after a TBI, is the key secondary endpoint in this planned trial.

In the EU, the Phase 3b trial will evaluate eGOS after six months as the primary efficacy endpoint as in the Phase 3a trial. 

Based on the post hoc analysis of the initial Phase 2a and 3a trials, the drug infusion will start between four and 12 hours after injury, as opposed to six to 18 hours in the Phase 3 NOSTRA trial.

This followed a subgroup analysis of NOSTRA III showing an improvement versus placebo in those patients with treatment begun within 12 hours after injury - the median eGOS at three months was six in this group, versus five for those on placebo.

The treatment start within 12 hours was unfortunately relaxed for the larger study because of lengthy procedures of obtaining informed consent within the timeframe in certain countries, while the informed consent procedure for patients unable to consent was adapted, allowing earlier inclusion.

Ronopterin: decreasing extracellular brain glutamate and cell damage

Ronopterin is a selective inhibitor of inducible Nitric Oxide Synthase (iNOS) that binds to the endogenous BH4 binding site. It rapidly lowers excessive nitric oxide and radical production and decreases extracellular brain glutamate and cell damage, as well as reducing excessive inflammatory response and oedema formation.

It is the first and only iNOS inhibitor with repeated signs of neuroprotection in TBI in patients – data from two late-stage clinical trials, demonstrating reduction in glutamate levels in the brain of people with TBI. The excessive levels of glutamate present in the brain of patients with TBI results in a chemical imbalance that  causes the release of reactive oxygen species within the tissue which drives the death of neurons and other cells. This cascade of tissue damage may lead to diminished cognitive function.

Privately-owned veriNOS says all the pieces are now in place to expedite approval of ronopterin. In the US, the plan is to seek accelerated approval from the FDA with the Phase 2b trial data, allowing conditional approval until the mid-stage trial findings are confirmed. It’s a regulatory pathway used by the FDA to approve drugs for serious illnesses where there are few or no approved therapies.

European approval will follow if the Phase 3b trial produces the expected results, and the data from that trial will be used to verify data and allow permanent approval on the US market.

There’s much work to do, but Wandersee and Stover are convinced that the new plan will allow veriNOS to realise the potential of ronopterin in TBI and beyond.

The company plans to make a substantial deal with a big pharma partner after successful completion of clinical trials. It has intellectual property protection until 2042 plus orphan designation in the EU, allowing for 10 years’ market exclusivity in the EU. An application for orphan status in the US is also planned.

Beyond TBI, the company will also be looking to use ronopterin in oncology and ophthalmology. It could be used to treat brain oedema in glioblastoma, where radicals and glutamate are established as a cause of tissue damage. Using ronopterin to inhibit iNOS could also be used to treat retina damage in patients with diabetic retinopathy, with already sufficient preclinical and clinical data to start Phase 1/2 trials in these additional indications.

In oncology, ronopterin could be infused into tumour tissue and peritumoural tissue by a specially developed microdialysis catheter. Further applications could also be enabled using topical and intranasal spray.

About the author

Richard Staines, account director at Optimum Strategic Communications, made a move into PR with Optimum after more than twenty years as a journalist. He was most recently a staff writer for BioWorld, following jobs as news editor for pharmaphorum and as senior reporter for the industry newsletter APM Health Europe. With experience writing for websites, national newspapers, and magazines, Staines has always had a keen interest in health and has been writing about pharma and biotech since 2010.