As developers work on cracking KRAS, Germany's Boehringer has quietly begun testing its pan-KRAS drug in humans
For decades, scientists scratched their heads about KRAS, the notorious cancer-causing protein. Its smooth terrain long eluded manipulation, largely due to the absence of a distinct pocket for a drug to latch on to. However, the process of trial and error finally yielded progress — triggering a flock of companies, including Amgen, J&J, Merck, and AstraZeneca, to engineer compounds designed to annex the oft’ mutated oncogene. And now, it looks like Germany’s Boehringer Ingelheim has officially entered the fold.
The first KRAS pocket established by Amgen $AMGN for attack is G12C, although smaller rival Mirati $MRTX is at the large drugmaker’s heels. The KRAS G12C mutation is found in roughly 14% of non-small cell lung cancer (NSCLC) patients and 5% of colorectal cancer patients, who are largely presented with a poor prognosis and tend to be resistant to standard therapies.
On Tuesday, Evercore ISI’s Umer Raffat pointed out that Boehringer now has a clinical-stage KRAS inhibitor in its arsenal. And unlike Amgen and Mirati, the German drugmaker’s approach is a pan-KRAS inhibitor that hits SOS1 as well as G12C. SOS1 is a protein that turns KRAS from an “off” to “on” state.
Amgen’s keenly watched AMGN510 made a splash at the ASCO conference this year after a small, early study showed five out of 10 patients suffering from advanced, drug-resistant NSCLC saw a partial response to the experimental treatment, including one who went on to achieve a complete response after the data cutoff point. Last month, those data were updated at the World Conference on Lung Cancer. Researchers tracked a 54% partial tumor response, and observed tumors shrinking in seven of 13 NSCLC patients.
Analysts have been intoxicated with the potential of the compound for this category of heavily treated patients with few options at their disposal — and have already forecast the drug will generate billions in peak sales, should it secure approval.
But over the weekend at the ESMO meeting in Barcelona, enthusiasm for the drug outside of lung cancer dampened, after Amgen unveiled data from the tranche of colorectal cancer patients. Researchers reported a single partial response among 12 colorectal cancer patients.
Meanwhile, Mirati’s Phase I/II data emanating from its experimental drug, MRTX849, for advanced solid tumors that harbor KRAS G12C mutations are expected in the fourth quarter. The little biotech has tied up with Novartis — and the two are looking at combining the G12C drug with a therapy that targets SHP2, which functions as a key regulator of cell cycle control.
Revolution Medicines has the same potential combo in-house. Other KRAS contenders include Moderna $MRNA and Merck’s $MRK mRNA-5671; J&J’s $JNJ collaboration with Wellspring on ARS-3248, a G12C targeted small molecule; and AZD4785, licensed by AstraZeneca $AZN from Ionis — although the compound has been discontinued after a poor showing in clinical trials.
In August, Boehringer tied up with MD Anderson investigators in Houston to create a joint “virtual research and development center” looking at two popular prospects: KRAS inhibition and a TRAILR2 agonistic antibody for apoptosis.
As an oncogene, KRAS has the potential to render normal cells cancerous. Akin to HRAS and NRAS, it belongs to the RAS family of oncogenes and plays a key role in cell division, cell differentiation, and apoptosis.