Closely-held NeuroproteXeon has received agreement on a special protocol assessment from the FDA for a Phase 3 trial of its inhaled pharmaceutical grade product, XENEX, a xenon gas formulation, as a neuroprotecter against brain cell death following acute neurologic injury, such as cardiac arrest.
“We’re hoping to start the trial in the U.S., Canada and Europe in the second quarter next year and complete it in 15 months,” CEO, Bill Burns, says in an interview with BioTuesdays.com.
There is no approved neuroprotective pharmacotherapy after cardiac arrest and only about 10% of patients survive to discharge from hospital, with 75% of deaths due to brain damage. The current standard of care, known as targeted temperature management (TTM), or therapeutic hypothermia (TH), improves survival only modestly.
According to Mr. Burns, xenon gas has been used in the medical community for diagnostic and treatment purposes, including as an anesthetic, for more than 60 years. “A landmark discovery was made in 1998 that xenon is a potent N-Methyl-D-aspartic acid (NMDA) antagonist with neuroprotective properties,” he adds.
NeuroproteXeon’s intellectual property is comprised of a suite of patents around the method of use and delivery of XENEX, the longest of which extends until 2029.
In addition, XENEX has received orphan drug status in the U.S. and Europe, granting market exclusivity of seven years and 10 years, respectively, not including a potential pediatric extension. XENEX also meets FDA criteria for an expedited review.
Mr. Burns explains that among other things, XENEX’s anti-NMDA properties prevent excessive entry of calcium into cells, a precursor to early cell death following several forms of acute neurological injury. XENEX’s mechanism of action also reduces expression of genes associated with programmed cell death, or apoptosis, and increases anti-apoptotic proteins after neuronal injury. And it is synergistic with TTM cooling.
In an unusual departure, the Journal of the American Medical Association in March published results of NeuroproteXeon’s Phase 2 trial, “given the interest and importance in finding therapies for hypoxic ischemic brain injury,” said editor-in-chief, Dr. Howard Bauchner.
The Phase 2 study, which compared the efficacy of XENEX combined with standard of care (SOC), including TTM, versus SOC-alone over 24 hours, reached its primary endpoint by reducing brain damage based on neuroimaging. Specifically, there was 41.7% less damage to white matter in the brain, which was the leading predictive value of mortality at six months.
While the Phase 2 study was not statistically powered to show a difference in the secondary endpoint of survival, the six-month mortality rate in the XENEX group was 27.3%, compared with 34.5% in the control group. The Phase 2 study included patients with up to a 45-minute delay in return to spontaneous circulation (ROSC).
According to a post-hoc analysis of patient with a ROSC of 30 minutes, the Phase 2 study demonstrated a 14% improvement in absolute survival among XENEX patients, which is a major enhancement, Mr. Burns contends, and an 11% improvement in functional outcome, both compared with standard of care. Improvements in functional outcome could result in being able to return to work. Both FDA and EMA have agreed that a ROSC of 30 minutes is the appropriate inclusion criteria.
Mr. Burns says NeuroproteXeon hopes to close a $40-million Series B financing* in the current quarter, with the first tranche earmarked for a Phase 3 trial and development of a hospital commercial program. The second tranche of the financing would be used to finish the trial, file an NDA, and develop a prototype device suitable for ambulances.
The ventilator and monitoring components that make up the XENEX Phase 3 clinical trial device are FDA cleared and the company plans to begin designing a commercial delivery device in January, he adds.
NeuroproteXeon hopes to enroll more than 1,400 patients, who have a sustainable pulse for more than 30 minutes after cardiac arrest, in its Phase 3 trial at 33 sites in the U.S., Canada and Europe. Patient follow-up will be conducted after 30 days in the U.S. and Canada, and after 90 days in Europe.
The study is designed to compare the efficacy of XENEX plus SOC versus SOC-alone. The primary endpoint is good functional outcome, with mortality as a secondary endpoint.
Mr. Burns says NeuroproteXeon plans to release an interim analysis of about 700 patients in the first quarter of 2018, with the trial scheduled to conclude in the third quarter of that year. If successful, NeuroproteXeon plans to file an NDA before the end of 2018.
Cardiac arrest represents a $5-billion global market across trauma centers and hospital intensive care units.
In the U.S., some 570,000 people a year suffer cardiac arrest, leading to a sudden loss of heart function and brain damage, of which 137,000 regain a sustainable pulse and are eligible for TTM. Two-thirds of cardiac arrests occur outside of hospital.
If the Phase 3 trial is successful, NeuroproteXeon expects to sell a 24-hour administration of XENEX to hospitals at a price of $12,000 per procedure, which Mr. Burns says is below an analogous inhalation therapy from Mallinckrodt for neonatal oxygenation. “Their product is for improved oxygenation, while ours would be for improved function and survival.”
NeuroproteXeon’s marketing strategy is based on device loan or lease agreements to minimize capital spending by hospitals in return for contracts to purchase XENEX.
The company previously signed a 12-year exclusive contract, renewable for a further 10-plus years, with Praxair, which is one of only two international suppliers of cGMP pharmaceutical grade xenon gas.
In addition to its lead cardiac arrest program, NeuroproteXeon is in preclinical development to adapt xenon gas to treat anesthesia induced developmental neurotoxicity.
Mr. Burns explains that if children under the age of three are subjected to prolonged or multiple bouts of anesthesia, an average of 10% of these children can develop cognitive impairment. “Early work in lower animals has shown that xenon is neuroprotective,” he suggests, adding that the FDA is funding a xenon program in non-human primates in anesthesia induced developmental neurotoxicity.
The company patent portfolio also extends to cover the use of xenon gas for the treatment of stroke and traumatic brain injury.
“Our value proposition is that XENEX protects against brain cell death, helps hospitals avoid CAPEX and benefits managed care and reimbursement because 75% of survivors return to the work force,” Mr. Burns contends.
* Editor's Note: This article does not constitute an offer to sell or the solicitation of an offer to buy any securities of NeuroproteXeon, and shall not constitute an offer, solicitation or sale of any security in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdictioniton.