4:49 PM
Nov 09, 2017
 |  BC Innovations  |  Product R&D

Blueprint gets the GIST

How Blueprint’s BLU-285 targets mutant kinases resistant to front-line drugs

Editor's Note: This article was updated on Nov 10, 2017 at 9:16 AM PST

Blueprint is positioning its kinase inhibitor BLU-285 to take a dominant position in gastrointestinal tumors, with preclinical and Phase I data showing the compound inhibits not only mutant forms of c-Kit and PDGFRA that underlie resistance to marketed drugs, but primary mutations too. The findings, published in Science Translational Medicine last week, provide a case study for how a company can go from looking for compounds against specific mutations to producing a therapy that may be broadly useful in the first-line setting.

Third Rock Ventures founded Blueprint Medicines Corp. in 2011 to develop new types of kinase inhibitors that go beyond those on the market by addressing mutations that lead to acquired resistance. The company went public with a $146.6 million IPO in 2015 and has since raised another $373.8 million in follow-ons.

Its co-founders list several veterans of the receptor tyrosine kinase (RTK) inhibitor field, including Nicholas Lydon, Brian Druker and Charles Sawyers, who spearheaded the development of Novartis AG’s Gleevec imatinib, an inhibitor of BCR-ABL and c-Kit that was one of the first targeted therapies in cancer created by rational drug design. Druker is director of the Oregon Health & Science University (OHSU) Knight Cancer Institute, Sawyers is director of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and Lydon is co-founder and head of the consulting firm Granite Biopharma LLC.

Novartis markets Gleevec for gastrointestinal stromal tumors (GIST) and chronic myelogenous leukemia (CML).

Blueprint’s idea behind the program was to treat subpopulations of patients with resistance mutations in the activation loop within c-Kit and PDGFRA. The loop, encoded by exons 17 and 18 in the two kinases respectively, is highly conserved between the two proteins and interacts with their catalytic domains to stimulate enzymatic activity. By contrast, Gleevec competes with ATP binding in the catalytic site.

But CMO Anthony Boral told BioCentury the approach gave the company more than it bargained for, providing more extensive coverage, and possibly greater market potential than had originally been anticipated.

“BLU-285 was originally conceived as a drug for relapses targeting exon 17 mutations, but we think it covers primary and resistance mutations and could be a first-line drug,” he said.

“BLU-285 was originally conceived as a drug for relapses targeting exon 17 mutations, but we think it covers primary and resistance mutations and could be a first-line drug.”

Anthony Boral, Blueprint Medicines

GIST is often driven by primary activating mutations in c-Kit, and less frequently by mutations in PDGFRA. First-line therapy with Gleevec controls the disease for 18-24 months; however, secondary mutations commonly arise in either the ATP-binding pocket or activation loop that decrease drug binding and lead to relapse. About 5-6% of patients are treatment refractory from the outset, due to the activation loop D842V mutation in PDGFRA.

Andrew Wylie, director of oncology at Novartis Institutes for BioMedical Research (NIBR), told BioCentury he sees parallels between Blueprint’s strategy...

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