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December 22, 2020 — The FDA has approved an investigational new drug application for berubicin for the treatment of patients with glioblastoma multiforme.
The FDA has approved an investigational new drug application for berubicin for the treatment of patients with glioblastoma multiforme, according to an announcement made by CNS Pharmaceuticals, Inc.1
A trial evaluating the efficacy of the product in adults with glioblastoma who have progressed on frontline treatment will be initiated in the first quarter of 2021. The trial has undergone modifications based on communication between the regulatory agency and the pharmaceutical company. For example, now the primary end point of the trial is overall survival (OS).
“Since becoming a public company, our clear focus has been on advancing the clinical development of berubicin. We will now rapidly move to initiate our phase 2 trial of berubicin for adults with glioblastoma and expect to being enrolling patients in the first quarter of next year,” John Climaco, CEO of CNS Pharmaceuticals, stated in the press release.
“The Company will transform within the next several months as berubicin becomes the subject of up to 3 active clinical trials, which include our randomized, controlled phase 2 trial in the United States, and 2 trials planned by our sublicensee WPD in Poland,” Climaco added.
In the phase 2 trial, investigators will examine the effectiveness of berubicin vs standard-of-care lomustine in patients with glioblastoma multiforme who have progressed on initial treatment for their disease. Participants were randomized 2:1 to either the investigative arm or control arm.
Because the trial has an adaptive design, it allows for an interim analysis of the findings to illustrate differences in efficacy between the approaches; it also allows for an adjustment to the size of the study population for greatest efficacy with regard to time in development. Due to this design, the trial possesses the potential to deliver findings to the FDA that could allow for an accelerated pathway for development.
Data from the first clinical trial examining the agent demonstrated that 44% of participants achieved a clinical response; 1 of these patients experienced a durable complete response (CR).2 The agent has also been shown to improve survival in this population that is known to have a dismal median survival of just 14.6 months from the time of diagnosis.
In the phase 2 trial, investigators set out to identify the maximum-tolerate dose and dose-limiting toxicity of berubicin; they also examined pharmacokinetics, pharmacodynamics, and efficacy in those with primary brain tumors.
In the trial, a total of 35 patients with recurrent or refractory glioblastoma multiforme or other primary brain cancers were given berubicin intravenously over the course of 2 hours for 3 consecutive days every 21 days. The accelerated titration design of the trial evaluated dose escalations, with daily doses that ranged from 1.2 mg/m2 to 9.6 mg/m2.
The maximum-tolerated dose (MTD) of the agent was identified to be 7.5 mg/m2. One of 5 patients who received the agent at the MTD had a DLT. Moreover, 2 of 6 patients who received the agent at the dose of 9.6 mg/m2 reported a DLT.
The patient who experienced a durable CR proved to still be in remission over 11 years later. Additionally, 2 patients achieved partial or minor responses and 9 patients experienced stable disease. Among the 27 patients determined to be efficacy evaluable, the 12 responses translated to a 44% response rate. Moreover, pharmacokinetic data indicated that there was dose-dependent clearance, with a half-life of 32.3 hours and a large volume of distribution of 1842 L/m2. Additionally, the mean maximum plasma concentration and area under the plasma concentration-time curve seemed to proportionally increase with each escalating dose.
Additionally, the most frequent dose-limiting toxicity (DLT) was myelosuppression, particularly neutropenia. Additionally, nonhematologic adverse effects were reported, with no neurotoxicity or cardiotoxicity observed.
In June 11, 2020, the FDA granted an orphan drug designation to the anthracycline for the treatment of patients with malignant gliomas.
“We are entering an area with significant unmet medical need since the current treatment paradigm for glioblastoma remains bleak, as this aggressive and currently incurable form of brain cancer continues to claim high mortality rates,”concluded Climaco. “We have a tremendous opportunity ahead of us as we continue our mission to improve patient outcomes for glioblastoma and build on the promising results demonstrated by berubicin in its phase 1 clinical trial.”