Rtid-03. Design and Initiation of Pivotal Studies for Berubicin, a Novel, Potent Topoisomerase Ii Poison for the Treatment of Recurrent Glioblastoma Multiforme (Gbm)

Abstract

Berubicin (WP744) is a doxorubicin analog that crosses the blood-brain barrier (BBB), shows significant CNS uptake, and induces more DNA damage but lower lethality than doxorubicin at equivalent doses. Berubicin also prolongs the survival time of intracranial orthotopic glioma models in mice compared to temozolomide, currently the standard of care in GBM. A Phase 1 study at MD Anderson in patients with recurrent glioma treated with escalating doses of Berubicin administered qdx3 repeated q21 days showed that it was well tolerated, with myelosuppression (neutropenia and thrombocytopenia) as the dose-limiting toxicity. Of 25 patients evaluable for efficacy, there was 1 complete response (13+ years), 1 partial response, and 10 patients with stable disease for a clinical benefit rate of 48%. To assure a rapid and economically practicable development program, two companies have collaborated to conduct trials in the US and EU, leading to a potentially more rapid approval of Berubicin for treating GBM in patients with limited options. CNS Pharmaceuticals, Inc. has initiated a randomized, controlled clinical trial of Berubicin vs. lomustine in adults with recurrent GBM. WPD Pharmaceuticals has sub-licensed Berubicin to study recurrent GBM in adults in an open-label trial. This is a unique collaboration in which the same overall design, eligibility criteria, procedures, and database for patients receiving Berubicin are used by both companies, ensuring that there will be a more robust and substantial data set for evaluation of activity and safety. The primary endpoint of the CNS study, to be conducted in the US and Europe, is overall survival (OS). The WPD study conducted in the EU has a primary endpoint of overall response rate (ORR). The data from these two trials are expected to provide sufficient information to support a potential registration program in both the US and EU for the treatment of patients with glioblastoma.

Recurrent Glioblastoma: Ongoing Clinical Challenges and Future Prospects

“… 61 In a Phase I trial in recurrent GB, 12 of the 35 patients (48%) attained longer PFS. 62 In 2020, the US FDA granted Orphan Drug Designation to berubicin for the treatment of recurrent GB and granted it Fast Track Designation in 2021. An ongoing phase II trial (ClinicalTrials.gov NCT04762069) is comparing berubicin versus lomustine in recurrent GB.…”

Looking for the Holy Grail—Drug Candidates for Glioblastoma Multiforme Chemotherapy

“…Among the tested drug candidates for GBM therapy, a new molecule targeting DNA replication is Berubicin (NCT04915404, NCT04762069). Berubicin is a doxorubicin analog that, contrary to currently used anthracyclines, crosses the BBB and can reach brain tissue [81]. Similar to other anthracyclines, the primary mechanism of action of Berubicin involves the drug's ability to intercalate within DNA base pairs, causing the breakage of DNA strands and inhibition of nucleic acids' synthesis.…”

“…Berubicin inhibits the enzyme topoisomerase II (TopoII), causing DNA damage and apoptosis induction [82]. Berubicin demonstrated significantly more cytotoxic activity in an orthotopic GBM murine model than TMZ [81]. Berubicin has already been tested in a phase 1 clinical trial at the MD Anderson Cancer Institute in patients with recurrent glioma [83].…”

Interactions of a Novel Anthracycline with Oligonucleotide DNA and Cyclodextrins in an Aqueous Environment

“…Berubicin is a chemotherapy medication that has primarily been developed for the treatment of glioblastoma, the most aggressive and treatment-resistant type of brain cancer. − This drug belongs to the family of anthracyclines ,, and is able to cross the blood–brain barrier and reach brain tumors effectively. , Anthracyclines aim mainly at inducing DNA damage in the targeted tumor cells by interfering with the action of topoisomerase II, a nuclear enzyme that fixes topological problems in DNA caused mainly by the processes of replication and transcription. ,− Intercalation into DNA is numbered among the mechanisms of action of anthracyclines due to the existence of an aglycone planar structure that is capable of intercalating between the strands of DNA. , Aglycone is a system of four rings with one of them being a saturated and substituted ring to which a side chain and one or more sugar residues are covalently attached (see Figure a); , it is noted that the characteristic reddish color of anthracyclines is owed to this system of rings. , Berubicin is an O-benzylated derivative of doxorubicin, one of the prototype molecules of the anthracycline class; the difference between them lies only in the sugar moiety. The advantage of berubicin in relation to other anthracyclines is its ability to circumvent the multidrug resistance mechanisms, − in contrast with the other anthracyclines. , This makes it more effective at inducing DNA damage, while at the same time being less lethal, compared to the parental drug, doxorubicin . In addition to the advantages, substituting berubicin for doxorubicin makes the drug more hydrophobic which may be undesired in certain cases.…”

“…Berubicin is a chemotherapy medication that has primarily been developed for the treatment of glioblastoma, the most aggressive and treatment-resistant type of brain cancer. 1 − 4 This drug belongs to the family of anthracyclines 1 , 2 , 5 and is able to cross the blood–brain barrier and reach brain tumors effectively. 1 , 6 Anthracyclines aim mainly at inducing DNA damage in the targeted tumor cells by interfering with the action of topoisomerase II, a nuclear enzyme that fixes topological problems in DNA caused mainly by the processes of replication and transcription.…”