OT-82, a preclinical stage drug candidate developed at Roswell Park Comprehensive Cancer Center (RPCCC) Buffalo, shows promise as a treatment to fight high-risk leukemia. Licensed for R&D and commercialization to OncoTartis, a biotech venture organized by RPCCC’s professor Andrei Gudkov, they announced positive preclinical research evidence generated by a collaboration with Australia’s Children’s Cancer Institute with the announcement of published results in journal Leukemia. OT-82 is now in a Phase I clinical trial. The IP has the attention of a Russian Billionaire and the largest Russian pharmaceutical company—both representing the first major venture investment in the sponsor.
A Potentially Powerful New Weapon Against Blood Cancers?
A significant proportion of blood cancers in both adults and children remain resistant to current treatments and are often deadly. Someone dies from some form of blood cancer in the United States every 9 minutes according to the Leukemia & Lymphoma Society.
The Investigational Drug: OT-82
OT-82, a NAMPT (NicotinAMide Phosphoribosyl Transferase) inhibitor, was originally developed at Buffalo, New York’s Roswell Park Comprehensive Cancer Center (RPCCC). Led by RPCCC’s Andrei Gudkov and colleagues, they report that although the team compounds that led to OT-82 were found via phenotypical cell-based screening of chemical libraries, the mechanism of action was elucidated and confirmed through a combination of shRNA screening and affinity chromatography approach. NAMPT catalyzes the conversion of nicotinamide to nicotinamide mononucleotide (NMN), a precursor of NAD. That determines its key role in bioenergetics of the cell and in the activity of NAD-dependent proteins such as sirtuins, PARPS, etc. as described in the OncoTartis website.
Due to a higher demand for NAD+ and ATP, many tumor cells are very sensitive to NAMPT inhibition. Out of all malignancies, leukemia cells are the most dependent on the activity of metabolic pathways utilizing NAD+, as evidenced by Ying-Hua Wang in journal Cell.
Key actor in the discovery of OT-82, professor Andrei Gudkov of RPCCC and Chief Scientific Officer of OncoTartis, noted, “The main principle of the research strategy that led us to OT-82 was the identification of a pharmacological agent specifically toxic for malignant cells of blood origin. We were surprised when the compound that came out of an unbiased search appeared to be a NAMPT inhibitor, an enzyme that has been considered as a target for cancer treatment but whose association with malignancies of blood origin was unknown. We are especially excited about the potential use of OT-82 for treatment of refractory childhood malignancies, an opportunity revealed in the joint studies with our Australian partners.”
The Current Clinical Trial
The current Phase I clinical trial tests OT-82, an investigational drug in two (2) stages including 1) determine the safety and tolerability and the maximum dose (MTD) or the maximum dose of OT-82 administered orally to participants and 2) determine the preliminary efficacy of the investigational drug in relapsed or refractory lymphoma at the MTD or the maximum tested dose. In both stages, the sponsor OncoTartis and the investigative site will evaluate the pharmacokinetics (absorption, distribution, metabolism, elimination) of the drug. It is hoped that participants with relapsed or refractory lymphoma treated with OT-82 in this study will experience slower tumor growth or reduction of tumor size.
The study commenced this past summer and ends in June 2021. The sponsors have targeted 50 patients for evaluation at three participating investigational sites including 1) City of Hope National Medical Center, Duarte, CA (principal investigator Jasmine M. Zain, MD); 2) University Hospitals Seidman Cancer Center, Cleveland, OH (principal investigator Paolo Caimi, MD); and 3) Thomas Jefferson University Hospital, Philadelphia, PA (principal investigator Neil Palmisiano, MD).
The Preclinical Research: Children’s Cancer Institute Key Contributor
OncoTartis and Children’s Cancer Institute jointly announced the publication of two research manuscripts in journal Leukemia centering on OT-82. An international collaborative occurring in both Buffalo, NY and Sydney, Australia, point to new treatment opportunity for patients with currently incurable blood cancers.
The first preclinical published study describes the discovery, mechanism of action, toxicological profile, and preclinical efficacy of the investigational drug for the treatment of refractory leukemias and lymphomas. It takes advantage of the discovery of extremely high dependence of malignancies originating from the hematopoietic system of elevated levels of nicotinamide dinucleotide (NAD), an essential component of multiple metabolic and stress response mechanisms of the cell as reported recently in the sponsor’s press release.
The second study describes the results of the collaboration with the Children’s Cancer Institute (Sydney, Australia). A world leader in establishing a large collection of refractory children’s leukemias grown in laboratory mice for new drug testing, the Children’s Cancer Institute’s investments ongoing make it the widely accepted most clinically relevant models of childhood leukemia anywhere in the world. The preclinical investigators utilized this collection in Australia to compare the efficacy of OT-82 with current treatments for childhood leukemia. OT-82 demonstrated remarkable efficacy when used alone and was even more effective when used in combination with conventional treatments, thereby indicating promise for children with high-risk blood cancers, reported the team in a press release.
The Sponsor: Has the Attention of Russian Billionaire
OncoTartis was founded by RPCCC’s professor in 2011 based on intellectual property in preclinical research from Professor Andrei Gudkov’s laboratory at RPCCC, Buffalo, NY. They are developing a novel category of anti-cancer drugs directed against tissue-specific targets for a subset of cancers (breast, prostate, ovarian, melanoma and hematological malignancies). The leading product, OT-82, is a NAMPT inhibitor and is in a Phase I/2a study initiated in 2019.
The venture raised $6 million in 2017 from Norma Investments which represents Russian billionaire Roman Abramovich and Pharmstandard International S.A., a venture arm of the largest Russian pharmaceutical company, based in Luxembourg.
In preclinical research, OncoTartis has leveraged RPCC’s Mikhail V. Chernov, Marina P Antoch and Jean Veith as well as the collaboration with the prominent Children’s Cancer Institute including Shiloh Middlemiss, Klaartje Somers, Richard B. Lock, Murray D. Norri, and other team members.
Principal investigators for the current Phase I clinical trial includes:
Jasmine M. Zain, MD, City of Hope National Medical Center
Paolo Caimi, MD, University Hospitals Seidman Cancer Center
Neil Palmisiano, MD Thomas Jefferson University Hospital
Children’s Cancer Institute
Children’s Cancer Institute was founded by two fathers of children with cancer in 1976 and is the only independent medical research institute in Australia wholly dedicated to research into the causes, prevention, and cure of childhood cancer. Today they employ over 300 researchers, operational staff, and students.
Roswell Park Comprehensive Cancer Center (RPCC)
RPCCC was founded in 1898 and organized as a New York State public-benefit corporation located in Buffalo, is a leading cancer research and treatment center. It is the first dedicated medical facility for cancer treatment and research in the United States. It conducts clinical research on cancer (e.g., it is a research site with 133 beds) and develops new drugs (sponsor).
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