First Patient Enrolled in Investigator-Initiated Study of Tinostamustine in Glioblastoma

STAMFORD, Conn.--(BUSINESS WIRE)--Purdue Pharma L.P. today announced that the first patient has been enrolled in a Phase 1 investigator-initiated clinical trial of tinostamustine, an investigational treatment, in patients with newly-diagnosed unmethylated O⁶-Methylguanine-DNA-methyltransferase (MGMT) glioblastoma multiforme (unmethylated nGBM),¹ the most common and aggressive type of primary malignant brain tumor.² Now open at The University of Texas MD Anderson Cancer Center, the open-label, non-randomized trial will investigate the safety profile, maximum tolerated dose (MTD), and efficacy of tinostamustine.

Glioblastoma is an incurable cancer with a very poor prognosis.² Median overall survival is only 15 months and survival rates have shown no notable improvement in the past 30 years.^3,4 The current standard of care for the disease includes surgery and postoperative radiation therapy with concurrent and adjuvant chemotherapy using temozolomide.^5-7 Prognosis is significantly worse for patients with the unmethylated MGMT form of glioblastoma because that tumor type is less likely to respond to currently available treaments.⁸ Under current standard of care, the two-year overall survival rate was 46 percent in patients with MGMT-methylated nGBM versus 14 percent in patients with unmethylated nGBM.⁸

“We are excited to see tinostamustine advance into a Phase 1 study in patients with unmethylated glioblastoma multiforme, an extremely aggressive and fatal form of brain tumor,” said John Renger, PhD, vice president, Head of Research & Development and Regulatory Affairs, Purdue Pharma. “The limited brain penetration of some medications across the blood-brain barrier contributes to the poor prognosis of this disease, however, preclinical data suggest tinostamustine may have the potential to cross the blood-brain barrier to deliver therapeutic central nervous system concentrations.”

The dual-acting therapy candidate tinostamustine, previously known as EDO-S101, is a novel and potentially first-in-class alkylating deacetylase inhibitor (AK-DACi) therapy. Clinical research is underway to evaluate its ability to improve access to and break the DNA strands within cancer cells, and counteract the cancer cells’ attempts to repair the DNA damage.^9-12

The potential utility of tinostamustine in the treatment of glioblastoma is supported by various pre-clinical data, and the molecule has shown anti-tumor activity in multiple in-vitro models of glioblastoma. In a pharmacokinetic analysis of tinostamustine administered to murine models by IV bolus and continuous IV infusion (CIVI), tinostamustine crossed the blood-brain barrier with central nervous system (CNS) penetration of 16.5 percent and 13.8 percent for IV bolus and CIVI administrations, respectively.¹³ CNS penetration with adequate therapeutic CNS concentration is essential for the treatment of brain tumors.

Tinostamustine is an investigational treatment and it is not approved for use in glioblastoma patients. Tinostamustine is also in development for a range of rare or difficult-to-treat blood cancers and advanced solid tumors. The completion of the first-in-human Phase 1 dose escalation study of tinostamustine in patients with relapsed or refractory (difficult-to-treat) hematological malignancies for which there are no available therapies was announced recently, and a Phase 1/2 study in advanced solid tumors was initiated in 2017. Tinostamustine is being developed in the US by Mundipharma EDO on behalf of Purdue Pharma.

To find out more about the study, visit clinicaltrials.gov.

This release discusses an investigational new drug under development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such investigational drug will successfully complete clinical development or receive regulatory approval.

About Purdue Pharma

Purdue Pharma L.P. develops and provides prescription medicines that meet the evolving needs of healthcare professionals, patients, and caregivers. We were founded by physicians and we are currently led by a physician. Beyond our efforts to provide quality medications, Purdue is committed to supporting national, regional and local collaborations to drive innovations in patient care. Privately held, Purdue is pursuing a pipeline of new medications and technologies through internal research & development and strategic industry partnerships. For more information, please visit www.purduepharma.com.

References

1. MD Anderson Cancer Center. EDO-S101 for MGMT unmethylated glioblastoma (nGBM) (NCI-2018-00872). Available from https://clinicaltrials.gov/ct2/show/NCT03452930. NLM identifier: NCT03452930.
2. American Brain Tumor Association. Glioblastoma. 2016. Retrieved from https://www.abta.org/tumor_types/glioblastoma-gbm/.
3. Koshy M, et al. Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neurooncol. 2012;107(1):207–12.
4. Tamimi AF, Juweid M. Epidemiology and Outcome of Glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 8.
5. Stupp R, et al. Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep. 2005;5(3):198–206.
6. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.
7. Stupp R, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66.
8. Hegi ME, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.
9. López-Iglesias AA, et al. The alkylating histone deacetylase inhibitor fusion molecule EDO-S101 displays full bi-functional properties in preclinical models of hematological malignancies. Blood. 2014;124(21):2100.
10. López-Iglesias AA, et al. Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair. J Hematol Oncol. 2017:20;10(1):127.
11. De Filippi R, et al. The first-in-class alkylating histone-deacetylase inhibitor (HDACi) fusion molecule EDO-S101 exerts potent preclinical activity against tumor cells of Hodgkin Lymphoma (HL) including bendamustine-resistant clones. Blood. 2015;126:2481.
12. Yan S, et al. Synergistic inhibition of tumor growth and overcoming chemo-resistance by simultaneously targeting key components in DNA damage/repair, epigenetic, and putative cancer stem cell signaling pathways using novel dual-functional DNA-alkylating/HDAC inhibitor and tumor suppressor gene nanoparticles in lung cancer. Cancer Res. 2012;72(1):2741.
13. Qui Y, Li Z, Copeland A, Mehrling T, Tun HW. Combined alkylation and histone deacetylase inhibition with EDO-S101 has significant therapeutic activity against brain tumors in preclinical models. Oncotarget. 2018;9(46):28155–28164.