Novel Agent Granted Orphan Drug Designation for T-Cell Prolymphocytic Leukemia


Investigational agent tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibiting molecule, has been granted orphan drug designation by the FDA for the treatment of patients with T-cell prolymphocytic leukemia.

Owen A. OConnor, MD, PhD

Owen A. OConnor, MD, PhD

Investigational agent tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibiting molecule, has been granted orphan drug designation by the FDA for the treatment of patients with T-cell prolymphocytic leukemia (T-PLL).1

“This orphan drug designation represents an important step…for patients suffering from T-PLL who do not currently have sufficient treatment options,” said Richard Fanelli, PhD, head of Regulatory Affairs at Imbrium Therapeutics, the manufacturer of the agent.

Orphan drug designation is granted to medicines intended for the treatment of rare diseases affecting <200,000 people in the United States. T-PLL is a rare and aggressive lymphoid malignancy that affects about 2% of patients with mature lymphocytic leukemias.

Patients with this disease often have poor prognoses attributable, in part, to their aggressive presentation and frequent misdiagnoses due to the rarity of T-PLL. Median survival for this patient population is typically around 1 year.

Tinostamustine works by improving access to the DNA strands within malignant cells, breaking them, and counteracting damage repair. Preclinical data have shown that these mechanisms may have the potential to overcome resistance toward other therapies.

Data presented at the 2014 American Society of Hematology Annual Meeting showed similar activity of tinostamustine in various in vitro models of hematologic malignancies when compared with vorinostat.2Strong antitumor activity and apoptosis were observed in both in vitro and in vivo xenograft models.

Investigators concluded that the bifunctional mechanism of tinostamustine, a fusion molecule that combines the DNA-damage effect of bendamustine with the pan-alkylating histone deacetylase inhibitor vorinostat, was active in both myeloid and lymphoid malignancies.

In March 2019, the first patient was enrolled in an expansion phase of the phase I/II clinical trial of tinostamustine in patients with relapsed or refractory hematologic malignancies following the successful completion of the dose-escalation phase (NCT02576496).3

&ldquo;Initial results in the dose-escalation phase of the study have been promising and our aim now is to establish the efficacy and safety of the treatment in cancer types for patients with very limited treatment options, either because their cancer is rare or is not responding to other treatments,&rdquo; said Owen A. O&rsquo;Connor, MD, PhD, lead study investigator and director of the Center for Lymphoid Malignancies at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center.

To be eligible for trial enrollment, patients must have had a diagnosis of a lymphoid malignancy and had no other available therapies for treatment. Patients with multiple myeloma, Hodgkin lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and T-PLL were allowed to receive tinostamustine in phase I. The dose-expansion phase will determine the overall response rate, duration or response, and safety in all 5 patient cohorts.

Preclinical experiments have also shown tinostamustine&rsquo;s activity in solid malignancies such as small cell lung cancer, soft tissue sarcoma, triple-negative breast cancer, and ovarian cancer. Clinical trials into the safety and efficacy of the agent in these malignancies are actively recruiting.


  1. >Imbrium Therapeutics Announces U.S. FDA Orphan Drug Designation for Tinostamustine for the Treatment of T-cell Prolymphocytic Leukemia [news release]. Stamford, CT: Imbrium Therapeutics; March 28, 2019. Accessed March 28, 2019.
  2. L&oacute;pez-Iglesias AA, San-Segundo L, Gonz&aacute;lez-M&eacute;ndez L, et al. The alkylating histone deacetylase inhibitor fusion molecule EDO-S101 displays full bi-functional properties in preclinical models of hematologic malignancies.Blood.2014;124(21):2100.
  3. Mundipharma EDO GmbH inititiates expansion phase of first-in-human trial to investigate use of tinostamustine in rare and difficult-to-treat blood cancers [news release]. Basel, Switzerland: Mundipharma EDO GmbH; March 5, 2019. Accessed March 28, 2019.
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