Introduction to Tolero Pharmaceuticals Inc.
Tolero Pharmaceuticals (Tolero) recently announced more data for their ongoing Phase 2 trial evaluating Alvocidib for MCL-1 Dependent Relapsed or Refractory AML
Tolero, a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases presented new data from its ongoing Phase 2 Zella 201 trial evaluating the efficacy and safety of Alvocidib, a potent CDK9 inhibitor, in combination with cytarabine and mitoxantrone in patients with MCL-1 dependent relapsed or refractory (R/R) acute myeloid leukemia (AML). The results were presented recently at the 60th Annual Meeting of the American Society of Hematology in San Diego, California. The CDK9 inhibitor is a protein in constant development in cancer therapy.
AML is a relatively rare cancer that starts in the bone marrow and often quickly moves into the blood as well. It can also spread to other parts of the body including the lymph nodes, liver, spleen, central nervous system, and testicles. Most often AML develops from cells that would turn into white blood cells (often other than lymphocytes) however at times it develops in other types of blood-forming cells. Based on American Cancer Society estimates, about 60,000 new cases of leukemia (all varieties) and 24,000 deaths from leukemia occur annually. Nearly 20,000 new cases of AML will occur—mostly in adults. Approximately 10,600 will die annually. Earlier in the year, investment website SeekingAlpha produced an article covering AML from the investors’ perspective and included recent AML approvals including:
- Enasidenib (Idhifa, approved 2017); developed by Agios Pharmaceuticals (AGIO)
- Gemtuzumab ozogamicin (Mylotarg, approved 2017); developed by Pfizer (PFE)
- Midostaurin (Rydapt, approved 2017); developed by Novartis (NVS)
- CPX-351 (Vvxeos, approved 2017); developed by Jazz Pharmaceuticals (JAZZ)
Tolero’s Alvocidib represents a competitive new entrant on the market should it be approved.
Toledo Pharma’s Zella 201 Trial
Tolero’s Zella 201 is a biomarker-guided Phase II study of Alvocidib followed by cytarabine and mitoxantrone in MCL-1 dependent relapsed/refractory AML. Tolero’s updated Stage 1 findings on their Phase II trial reveal that Alvocidib combined with cytarabine (chemo medication) and mitoxantrone displayed promising clinical activity in patients with MCL-1 dependent R/R AML. Induced myeloid leukemia cell differentiation protein MCL-1 is a protein that in humans is encoded by the MCL 1 gene.
Thus far Tolero has evaluated 23 patients with the following metrics; complete remission (57%, n =13) complete remission with incomplete recover (n =3), meeting the predefined criteria to move to Stage 2 of the study. The company reported that the study found an overall response rate of 61% (n=14) and patients experienced a median overall survival of 11.2 months. They report that the adverse events that did occur were “consistent with those noted in previous alvocidib studies and included diarrhea, tumor lysis syndrome, elevated ALT and AST levels, sepsis, and hypoxia. Early deaths were observed among patients, however, the commercial sponsor reports that they were due to sepsis (n =4) and mitral valve rupture (n =1). They report that these deaths were not considered as related to Alvocidib.
As Joshua F. Zeidner, MD, lead investigator and assistant professor at Lineberger Comprehensive Cancer Center at University of North Carolina, Chappell Hill noted “patients with relapsed and/or refractory AML have a dismal prognosis with a lack of effective available therapies and represent a high unmet need.” Dr. Zeidner continued “the response rates and clinical activity observed in the Zella 201 study are encouraging and support further evaluation of Alvocidib in combination with Cytarabine and Mitoxantrone in patients with relapsed or refractory MCL-1-dependent AML.”
Overall Tolero’s progress looks promising for its Zella 2011 trial, and this leads to the broader question as to the health of Tolero as a commercial sponsor.
What is the history of Alvocidib?
Originated by Sanofi and developed by both Tolero and the National Cancer Institute, it has not yet been approved by regulatory authorities (e.g. FDA). Sumitomo targeted a New Drug Application (NDA) for fiscal 2018 earliest. Also known as Flavopiridol, it is a flavonoid alkaloid CDK9 kinase inhibitor under development for AML. It has also been studied for treatment of arthritis and atherosclerotic plaque formation. The compound is a semisynthetic derivative of rohitukine which was initially extracted from Aphanamixis polystachya and later from Dysoxylum binectariferum. Alvocidib is licensed from Sanofi for exclusive worldwide rights for development and commercialization. As part of the original licensing deal, Tolero (Sumitomo) must make payments to Sanofi on the successful achievement of milestones related to the commercialization and pay tiered royalties on sales of Alvocidib.
Who is Tolero Pharmaceuticals?
Tolero was founded by David Bearss in 2011 in Lehi, Utah. Bearss started Tolero to focus on several new oncology and supportive care products and advance them from preclinical through clinical trials. Bearss has built the most successful biopharmaceutical venture in Utah. A native of Washington, Bearss grew up in Utah and graduated from Brigham Young University with a Biology degree. Bearss has had an exceptionally successful career as covered in a 2018 Lehi Free Press article. Bearss was an Associate Professor at Brigham Young University, a Co-director of the Center for Investigational Therapeutics at the well-known Huntsman Cancer Institute, and an Associate Professor in the Department of Oncological Sciences at the University of Utah. He has published more than 80 manuscripts and book chapters and secured over 25 patents issued or pending, according to his LinkedIn profile.
His goal from the start was to alleviate human suffering through the discovery and development of innovative therapeutics to treat and cure life-threatening diseases. Tolero raised nearly $30 million prior to its acquisition. In 2017 Japanese-based Sumitomo Dainippon Pharmaceutical corporation (Sumitomo) completed its acquisition of Tolero for nearly $800 million. It included an upfront payment of $200 million as well as milestone payments of up to $580 million. Dainippon acquired Tolero due to its excellent drug discovery capabilities for kinase inhibitors and other drug targets and for its’ drug targets and compounds in development including CDK9 inhibitor Alvocidib. The transaction was reported in formal presentations and memorialized in January 2017. Again, as part of the acquisition, Sumitomo acquired several compounds including Alvocidib (CDK9) which is under clinical development for the treatment of hematologic malignancies, and has strengthened its development pipeline in oncology, a strategic focus area. Its products include the following:
[table id=12 /]
|Dev Name||Generic Name||Mechanism of Action||Target Indication||Dev Stage|
|Phase 2 completed
|TP-0903||TBD||AXL receptor tyrosine kinase inhibitor||Solid tumors
Alvocidib is the front runner for FDA approval for Tolero (Sumitomo). The entrepreneurs and investors behind Tolero are to be commended. Drug development is a high-risk, high reward affair. Tolero had raised capital toward the end of 2016, it apparently need some bridge financing prior to the acquisition and arranged for a loan from Sumitomo for up to $6 million. Bearss was able to not only navigate multiple financings while developing innovative new treatment platforms, but also maintain a viable operation to keep the venture moving from 2011 to the acquisition in early 2017. As reported during the transaction, the following major shareholders included founder David Bearss (founder) at 22.1%; Orelot LLC at 15.2% and Alger Health Sciences Fund 8.8%. Given Mr. Bearss only started the venture in 2011 TrialSite News would classify him as highly impressive actor in the drug development space.
Tolero is a clinical-stage biopharmaceutical company dedicated to improving and extending patients battling hematological and oncological diseases. The Utah-based venture, now an indirect wholly-owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., has developed a diverse pipeline targeting important biological drivers of blood disorders to treat leukemia, anemia, and solid tumors as well as targets of drug resistance and transcriptional control. Based on TrialSite News research efforts, we conclude that Tolero made a necessary and savvy business move with the Sumitomo transaction. They now have a mid-sized but well-capitalized corporate parent with $4.1 billion in revenue, $1.25 billion cash position, and a market capitalization of nearly $15 billion. Thousands of patients struggling with dangerous forms of AML will hopefully have more powerful treatment options in the near future. Should the regulatory authority issue approvals, and ensuring sales follow thereafter, the principal Tolero investors may also experience a tremendous financial windfall.
Mr. O’Connor has spent nearly 20 years providing technology and services to the clinical trials and health technology industry. An entrepreneur, he has been instrumental in building a few different ventures focusing on FDA 21 Part 11 enterprise document management, technology-enabled patient recruitment services, clinical document and safety data exchange, as well as population health and community care coordination for at-risk populations. Mr. O’Connor has built a comprehensive research site data base and intelligent clinical research site news curation engine with TrialSite News. He earned his combined MA and JD from the University of California (Los Angeles and Hastings College of the Law).