UK Charity Starts Early-Stage Clinical Studies Of Lilly's Cdc7 Inhibitor
Executive Summary
The drug development arm of the UK charity, Cancer Research UK, has started early clinical development of potentially a new type of anticancer, a Cdc7 inhibitor, discovered by Eli Lilly, in an effort that could boost traction in this new area of research.
The Centre for Drug Development of the UK’s leading cancer charity, Cancer Research UK, announced Aug. 23 it will start testing a novel type of anticancer from Eli Lilly & Co.under its partnership scheme that aims to make sure promising compounds don't fall through the cracks of industry's development processes.
It will evaluate the tolerability of Eli Lilly’s LY3143921 in a Phase I study of oral doses given daily for 21 days, and repeated up to 12 times. It will also establish the recommended dose in patients with various cancers including advanced bowel, lung ovarian, urothelial, pancreatic, breast, head and neck, and oesophageal cancer.
The Centre’s mission is to find new ways to treat cancer, and the charity sponsors and funds the early clinical development of compounds that it believes are of interest because of their mode of action, although the originating company retains all underlying rights to their programs. The compounds usually come from companies that are not prioritizing their development, and Lilly does seem to have a full plate when it comes to potential novel anticancers.
As well as waiting US approval for the cyclin-dependent kinase (CDK) 4/6 inhibitor, abemaciclib, in two breast cancer indications, Lilly also outlined a revamped oncology R&D strategy a month ago, which included an ERK1/2 inhibitor that is in Phase I, a CHK1 inhibitor, prexasertib, under evaluation for ovarian cancer, and a TIM-3 checkpoint inhibitor monoclonal antibody (see sidebar).
Under Cancer Research UK’s clinical development partnership scheme, companies can decide after the completion of the charity’s clinical studies if they want to develop the product or to allow the charity to search for another development partner, whilst retaining a share in any future revenues.
Cdc7 inhibitors
The cell division cycle 7 (Cdc7) protein is a serine-threonine kinase that is required to start DNA replication in cells, and its inhibition in healthy cells usually leads to the cells staying in a viable state. However, cancer cells appear more sensitive to Cdc7 inhibitors and proceed to apoptosis (cell death). Moreover, tumor cells with defective p53 genes appear to be more susceptible to Cdc7 inhibitors, including patients with metastatic bowel cancer, squamous non-small cell lung cancer and high-grade serous ovarian cancer.
The industry has Takeda Pharmaceutical Co. Ltd.’s TAK-931 as an example of another Cdc7 inhibitor in early clinical studies. Sierra Oncology Inc. has a compound, SRA141/AS-141 in preclinical studies. (Also see "ProNAI Defects From Oligos to DDR As Sierra Oncology" - Scrip, 31 Jan, 2017.)
Companies such as Roche, AbbVie Inc. and Amgen Inc. have had research programs in the area, but have not reported any progress. Informa Pharma’s Pharmaprojects reports the industry's Cdc7 inhibitor pipeline as follows:
Selected CDc7 Inhibitors In Development
Source: Informa Pharma’s Pharmaprojects.
Company | Compound | Stage of Development |
Takeda Pharmaceutical Co. Ltd. | TAK-931 | Phase I |
Eli Lilly & Co./Cancer Research UK | LY3143921 | Phase I |
Eli Lilly & Co. | LY3177833 | preclinical |
SBI Biotech Co. Ltd./Sierra Oncology Inc./Carna Biosciences Inc. | AS-141/SRA141 | preclinical |
LBS-007 | preclinical | |
XL-413 | discontinued | |
NMS-1116354 | discontinued | |
Nerviano Medical Sciences SRL | RXDX-103 | no development reported |
Roche | Cdc7 inhibitors | no development reported |
Amgen Inc. | Cdc7 inhibitors | no development reported |
AbbVie Inc. | Cdc7 inhibitors | no development reported |
The charity’s Drug Development Centre has been involved in the development of a number of marketed agents, including the PARP inhibitor rucaparib (Clovis Oncology Inc.’s Rubraca), the prostate cancer therapy abiraterone ([Janssen Biotech NV]’s Zytiga) and the brain cancer therapy temozolomide (Merck & Co. Inc.’s Temodar). Currently it has more than 30 potential new agents in preclinical, Phase I and early Phase II studies, in collaboration with companies that include AstraZeneca PLC, Amgen, Bicycle Therapeutics Ltd. and Merck Serono SA.