it's relatively old news but the agreement with Pfizer on early trials combining CB839 with palbociclib and separately, talazoparib are really good news for CALA and investors. The fact that Pfizer is even talking with CALA is huge. I'm much less enthusiastic about talazoparib, the PARP inhibitor acquired in the Medivation BO, relative to palbociclib, a CDK inhibitor.
Cyclin dependent kinases (CDKs) have been potential therapeutic targets since the late 1990s when the molecular machinery of DNA replication was originally being figured out. CDKs are key regulators of DNA replication - a required process that occurs before a cell can divide and produce two new cells. Cytotoxic chemotherapeutics traditionally targeted cells actively replicating DNA. These therapies had been the SOC for decades - everything from radiation, DNA alkylating compounds, topoisomerase inhibitors to microtubule binders (taxanes). Then along came Gleevec which targeted the protein product resulting from a specific genetic lesion - the Philadelphia Chromosome. The protein product of the Philadelphia Chromosome happened to be a kinase - actually a fusion protein of two proteins (BCR-ABL) resulting in a constitutively activated kinase. but I digress... The fact is, Gleevec was phenomenally successful in extending lives while simultaneously improving patient's QoL. The age of kinase-targeted oncology therapeutics was here.
The crazy thing about CDKs, from my point of view, was the lack of effort by BigPharm or biotechs to develop CDK inhibitors. Sanofi had an entire group - they were named "CDK inhibitor group" - 40-50 people - devoted to studying CDK therapies. They existed for over 7yrs without ever moving a compound from discovery into clinical development! I'm sure other BigPharms had similar programs. Not sure, but I think Pfizer's palbociclib was developed in-house. Palbociclib inhibits two CDKs, CDK4 and 6 and is already generating $4B in revenue for Pfizer treating metastatic breast cancer - see Forbes link below.
Also, palbociclib's MoA should synergize with CB839 from a metabolic point of view. DNA replication is an energy-intensive exercise and rate of cellular replication (and thus, tumor growth) is entirely dependent on nutrient availability. Inhibiting glutaminase reduces the availability of nitrogen containing building blocks to synthesize nucleic acids and amino acids - both required at high levels during DNA replication.....