Berbubicin

We are developing Berubicin, which is a novel therapy for the treatment of glioblastoma. Berubicin is one of the first anthracyclines (the most potent class of cancer drugs) to cross over the blood brain barrier and kill tumor cells in humans.

In the results of the first Berubicin clinical trial, 44% of the patients showed a clinical response, with one Durable Complete Response (a demonstrated lack of detectable cancer cells).

Berubicin has shown evidence of improved survival in a patient population that has currently a dismal median survival rate of only 14.6 months from its diagnosis.

Business Plan

The FDA granted Orphan Drug designation for Berubicin to the sponsor of the Phase 1 Clinical Trial, which provided seven years of marketing exclusivity. Orphan status in Europe and Japan, if granted, would provide 10 years of market exclusivity. CNS Pharmaceuticals intends to file for additional patents relating to Berubicin as well as our pipeline of other drugs.

Less than 40% of glioblastoma patients have a genetic variation (“methylated”) which makes their tumors initially more responsive to temozolomide (TMZ), the current standard of care.

However, because nearly all of these patients will quickly become resistant to TMZ, Berubicin could be prescribed after failure of first line therapy. In the remaining 60% of patients (“unmethylated”), Berubicin could be prescribed as the primary drug treatment because TMZ is ineffective in this patient population.

Furthermore, if our human trials demonstrate a significant improvement in glioblastoma patient outcomes, the FDA may grant us an accelerated review schedule under its Breakthrough Therapy Designation which may shorten the time to market dramatically.

Berubicin Phase I Clinical Trial Results

In the results of the first Berubicin clinical trial, 44% of the patients showed a clinical response, with one Durable Complete Response (a demonstrated lack of detectable cancer cells).

Phase I Trial and Pharmacokinetic Study of Berubicin (RTA 744) in Patients with Recurrent or Refractory Glioblastoma

The partial results of this study were presented both at the 2007 Annual Meeting of American Society of Clinical Oncology (ASCO) and the 2007 Annual Meeting of the Society for Neuro-Oncology (SNO), and the Annual Meeting of the European Organization for Research and Treatment of Cancer (EORTC) at Prague, Czech Republic, 2006.

ABSTRACT

Purpose

This multi-institutional phase I trial was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Berubicin, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy in patients with primary brain cancers.

Patients and Methods

Thirty-five patients with recurrent or refractory glioblastoma multiforme (GBM) or other primary brain cancers received intravenous Berubicin over 2 hours for 3 consecutive days (one course) every 21 days. Doses were escalated using an accelerated titration design and ranged from 1.2 to 9.6 mg/m2/day. Plasma levels of Berubicin and its primary metabolite, the 13-hydroxy derivative berubicinol, were measured by high-performance liquid chromatography-tandem mass spectrometry assays, and pharmacokinetic parameters were estimated and statistical tests applied, with P < 0.05 noted as indicating significance.

Results

The most common DLT was myelosuppression, specifically neutropenia. The MTD of Berubicin was determined to be 7.5 mg/m2/day. At that dose, one of five patients experienced a DLT, while two of six patients experienced a DLT at the next higher dose, 9.6 mg/m2/day. Minimal nonhematological toxicities were observed, and no neurotoxicity or cardiotoxicity was noted. One patient demonstrated a Durable Complete Response (a demonstrated lack of detectable cancer cells) and is still in remission over 11 years later, two patients had partial/minor responses, and nine patients had stable disease. For the 27 patients evaluable for efficacy, these 12 responses resulted in a 44% response rate. Pharmacokinetic studies showed dose-independent clearance, with a 32.3-hour mean half-life and a large volume of distribution of 1842 L/m2. The mean maximum plasma concentration and area under the plasma concentration-time curve appeared to increase proportionally with increasing dose.

Conclusion

Our promising tolerability and efficacy results, including one durable complete response, warrant berubicin’s continued development. The recommended initial Berubicin dose for phase II studies is 7.5 mg/m2/day over 2 hours infusion for 3 consecutive days beginning every 3 weeks.  Berubicin shows activity over a range of doses, including the durable response at 2.4mg/m2/day.

Completed Milestones:

  • Completion of Phase I clinical trial for the treatment of GBM by Reata Pharmaceuticals, Inc.
  • Received Orphan Designation from FDA for glioblastoma
  • Formation of CNS Pharmaceuticvals (2017) and initial financing (underway)
  • Licensing of Berubicin’s patent rights from Houston Pharmaceuticals to CNS Pharmaceuticals and collaborative agreement to expand IP protection (2017)
  • Entered a collaboration agreement with Reata that includes the transfer of all available data and know-how to CNS Pharmaceuticals to accelerate development of Berubicin (2017).

Future Anticipated Milestones:

  • IPO (Q4-18)
  • Commencement of Phase 2a clinical trial for the treatment of glioblastoma (2018)
  • Development of new dosage forms of Berubicin to treat additional cancers, including ovarian cancer and lymphoma.
  • Discovery of new drug candidates for other cancers
  • Development of combination therapies with Berubicin
  • Commence studies necessary to evaluate other drugs in human trials for brain cancers

More Scientific Berubicin Publications

The following is a summary of Berubicin’s data showing effectiveness in a Phase 1 Clinical Study as presented at a medical conference in Geneva:

Berubicin Shows Efficacy in Recurrent Glioblastoma Multiforme2

The novel anthracycline agent berubicin appears to have a toxicity profile consistent with that of other anthracyclines and demonstrates exceptional activity as monotherapy for recurrent glioblastoma multiforme.

These findings were presented here on October 24 at the 20th International Symposium of the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI), and the American Association for Cancer Research (AACR).

Berubicin is a 4Obenzyl anthracycline designed to circumvent P glycoprotein/MRP1mediated efflux, and has shown promise for treatment of gliomas. As such, it could extend the clinical use of the anthracyclines in the treatment of brain tumours, said investigator Timothy Madden, PharmD, Department of Experimental Therapeutics, and Director, Pharmaceutical Development Centre, University of Texas M.D. Anderson Cancer Centre, Houston, Texas.

Based on its design as a compound that can circumvent adenosine5′ triphosphatebinding cassette transporters, berubicin is not only a more potent topoisomerase 2 inhibitor than doxorubicin, but it can also cross the bloodbrain barrier (BBB), he said during the presentation of his phase 1/2 findings. Indeed, in crossing the BBB, it is sequestered preferentially in tumour tissue.

For the study, Dr. Madden and colleagues administered berubicin as a 2hour intravenous infusion on each of the first 3 days of a 21day cycle in 35 patients (arm A; 1.29.6 mg/m2) or once weekly for 4 weeks every 5 weeks in 19 patients (arm B; 7.513.3 mg/m2).

The main objectives were to determine the maximum tolerated dose, dose limiting toxicity, and qualitative and quantitative toxic effects. The secondary objectives related to the drug’s pharmacokinetics, its antitumour and clinical activity, and the relationship between its pharmacokinetics and clinical activity, with a view to further phase 2 studies.

Patients in arm A were 29 to 70 years old (male, 68.6%) and in arm B they were 26 to 69 years old (male, 57.9%). The maximum tolerated doses for these 2 treatment arms were 7.5 and 10.0 mg/m2/day, respectively. Overall, berubicin showed evidence of clinical activity, with most activity seen to date in arm A. Dr. Madden said, “The best response was a complete response, which has not happened in a phase 1 brain tumour trial in the past, or even in a phase 2.” This complete response was seen after 7 cycles in 1 patient with recurrent glioblastoma multiforme that had progressed from anaplastic astrocytoma and has been maintained for more than 18 months.

Further to this, there have been 2 partial responses and minor responses, with a number of other patients experiencing notable changes on magnetic resonance imaging after treatment in arm A.

In the safety analysis relating to all patients with grade 2 to 4 adverse events, the main blood and lymphatic system disorders in arms A and B, respectively, were: lymphopenia (38%/39%), leukopenia (24%/17%), granulocytopenia (9%/6%), neutropenia (9%/11%), anaemia (6%/6%), and thrombocytopenia (6%/11%). The only further grade 2 to 4 adverse effect seen in more than 1 patient in either arm was fatigue (12%/22%).

Dr. Madden noted, “The toxicity is similar to the available anthracyclines, with no unexpected toxicities, with the principal toxicity of manageable myelosuppression, and with no neurological toxicities.”

He added, “The next stage for this is a phase 2 trial in metastatic breast cancer, where one of the primary [metastatic] sites is the brain.”

Funding for this study was provided by Reata Pharmaceuticals.

[Presentation title: Haematological Pharmacodynamics Linked to the Pharmacokinetics of Berubicin (BRB), a BloodBrainBarrierPenetrating Anthracycline Active Against High Grade Glioma, in Phase 1/2 Clinical Trials. Abstract 600]

(2) Presented at EORTCNCIAACR By Chris Berrie, GENEVA, October 27, 2008  DocGuide.com


Acknowledgements:

Research support was provided by Reata Pharmaceutical Company, MDACC Institutional Core Grant (CA16672).

Running title:  Phase 1 trial of Berubicin in refractory brain cancer

The partial results of this study were presented both at the 2007 Annual Meeting of American Society of Clinical Oncology (ASCO) and the 2007 Annual Meeting of the Society for Neuro-Oncology (SNO), and the Annual Meeting of the European Organization for Research and Treatment of Cancer (EORTC) at Prague, Czech Republic, 2006.

Disclaimer: Dr’s Colin Meyer, Neil Thapar, Waldemar Priebe, and Timothy Madden do have equity ownership within Reata Pharmaceuticals Inc.

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