Big Pharmas busy reaching out for KRAS targeted therapy

Considered impossible technology for 40 years, but recently showed plausible clinical findings

Amgen and Mirati leading the R&D race, Novartis, Sanofi, Merck and Bayer starts preclinical

Global pharmaceutical giants are eager to develop targeted therapy for ‘Kirsten rat sarcoma viral oncogene homolog (KRAS)’ mutation, initially considered as an impenetrable technology for last four decades.

 

Apparently, KRAS mutation is found in about one out of four cancer types.

 

Specifically, the mutation is frequently found in cancer types with bad prognosis like lung cancer, colon cancer and pancreatic cancer.

 

Pioneered by Amgen, small and big companies like Novartis, Sanofi, Bayer, Boehringer Ingelheim, Merck and Mirati Therapeutics are fiercely competing against each other to dominate the blue ocean.

 

◆Why did MSD bet USD 2.5 billion on candidate medicine in preclinical trial phase?

 

On Jan.

 

13 (local time), MSD exclusively licensed-in an anticancer candidate medicine targeting KRAS from Japanese-based Otsuka Pharmaceutical’s subsidiaries, Taiho and Astex.

 

MSD has agreed to pay maximum 2.5 billion dollars (approximately 2.75 trillion won) including an upfront payment of 50 million dollars (approximately 55 billion won).

 

To win the competition against Revolution Medicines, Boehringer Ingelheim decided to put forth a colossal bet.

 

The reason behind MSD’s massive payment for a candidate medicine at a preclinical trial level coincides with the recent global pharmaceutical industry trend.

 

Lately, the global pharmaceutical industry is hectic with KRAS targeted therapy R&D.

 

Although the technology was thought to be impossible to crack for last 40 years, KRAS targeted therapy nabbed the Big Pharmas’ attention after Amgen showed the possibility in the commercialization in 2019.

 

◆40 years of going nowhere, KRAS targeted therapy results in a first clinical findings in 2019 KRAS is one of factors that cause cancer.

 

KRAS activates transmission of signals from the cell surface receptor to the nucleus.

 

It is at the same level as anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), which already have developed targeted therapy for.

 

It is actually the first cancer-causing gene the human race has discovered.

 

But since the first discovery in 1982, the relevant treatment development was sluggish for four decades.

 

Compared to other cancer-forming genes, KRAS has more frequent mutations and transforms the protein structure into a wide array of variations.

 

And it has been hindering the targeted therapy development until lately.

 

The frequency is apparently high for the KRAS mutation causing a number of lethal cancers like lung cancer, colon cancer and pancreatic cancer.

 

And vast amount of researches were done to study the gene, but all of them failed at the end.

 

In 2013, however, a group of researchers at University of California found a groundbreaking discovery of ‘binding pockets.’ Since then it was picked up as a candidate medicine and its first clinical findings were announced in 2019 after completing the preclinical phase.

 

◆Amgen takes the lead in R&D, sotorasib initiates Phase III clinical trial

First, it was Amgen who presented the clinical results.

 

AMG-510, also known as sotorasib, is evaluated as a frontier among the KRAS targeted therapy candidates.

 

The Phase I clinical trial kicked off from August 2018.

 

The result of the trial was unveiled at the 2019 International Association for the Study of Lung Cancer (IASLC).

 

Cancer patients with non-small cancer lung cancer (NSCLC), colon cancer or pancreatic cancer showing KRAS mutation participated in the clinical trial.

 

Five out of ten NSCLCL patients in the study had the KRAS mutation.

 

A Phase II clinical trial, unveiled at the European Society for Medical Oncology conference last year, also demonstrated positive results.

 

After using sotorasib in 53 patients with NSCLC, their progression-free survival (PFS) marked 6.3 months while the response rate reached 32.2 percent.

 

Amgen is still currently conducting the Phase III trial that compares the drug against cell-killing chemotherapy docetaxel.

 

In late last year, the U.S.

 

Food and Drug Administration (FDA) designated the investigational drug as a Breakthrough Therapy.

 

Besides the AMG-510 single therapy, the company is also running a clinical trial on a combination therapy with other various anticancer treatments.

 

The drug is likely to get approval within this year at earliest.

 

◆Mirati, Sanofi, Novartis, Boehringer, Moderna and Bayer all on board Mirati Therapeutics is following Amgen closely.

 

The company kicked off the clinical trial in January 2019, and now MRTX849 is in process of running a Phase 1/2 study.

 

The Phase II interim analysis was disclosed late last year.

 

The objective response rate (ORR) in 51 patients with NSCLC marked 45 percent.

 

The company aims for the FDA approval in the latter half of the year.

 

Moreover, Sanofi and Revolution Medicine are collaborating together on developing RMC-4630 since June 2019.

 

In a partnership with Araxes Pharma, Johnson and Johnson started a clinical study on ARS-3248 from July 2019.

 

Eli Lilly initiated the clinical trial on LY3499446 in November 2019.

 

Last year, Mirati and Novartis started working on another candidate medicine TNO155, and its Phase 1/2 clinical trial began from last April.

 

Navire Pharma and Erasca respectively started Phase I trial on BBP-398 in last August and Phase I trial on ERAS-601 in last December.

 

Even more companies like Boehringer Ingelheim, Bayer, Moderna, Merck and Jacobio Pharmaceuticals are now into seeking KRAS targeted therapy with preclinical trial ongoing.

 

In South Korea, Orum Therapeutics is reportedly exploring KRAS related R&D