What is the Amgen Carmot collaboration regarding KRAS G12C and AMG 510?

The Amgen Carmot collaboration refers to a research partnership between Amgen and Carmot Therapeutics to discover and develop novel small molecule therapeutics, including potential treatments targeting the KRAS G12C mutation. AMG 510 (sotorasib) is a KRAS G12C inhibitor developed by Amgen, but it was not a direct result of the Carmot collaboration; Amgen and Carmot worked together on early-stage drug discovery using Carmot's Chemotype Evolution platform.

Is AMG 510 (sotorasib) part of the Amgen Carmot collaboration?

No, AMG 510 (sotorasib) was developed independently by Amgen and is not a product of the Amgen Carmot collaboration. The collaboration, announced in 2017, focused on identifying new drug candidates for various targets, including KRAS G12C, but AMG 510 originated from Amgen's own research efforts and received FDA approval in 2021 for non-small cell lung cancer.

What is the KRAS G12C mutation and how does AMG 510 target it?

The KRAS G12C mutation is a specific genetic alteration in the KRAS gene where glycine is replaced by cysteine at position 12, commonly found in certain cancers like non-small cell lung cancer. AMG 510 (sotorasib) targets this mutation by irreversibly binding to the cysteine residue, locking KRAS in an inactive state and inhibiting cancer cell growth.

Did the Amgen Carmot collaboration lead to any approved drugs for KRAS G12C?

As of now, the Amgen Carmot collaboration has not resulted in any approved drugs specifically for KRAS G12C. AMG 510 (sotorasib), the only FDA-approved KRAS G12C inhibitor from Amgen, was developed outside of this partnership. The collaboration may have advanced early-stage candidates, but none have reached clinical approval.

What is the current status of the Amgen Carmot collaboration?

The Amgen Carmot collaboration, initiated in 2017, is ongoing but specific public updates on its progress are limited. The partnership continues to focus on discovering novel small molecules using Carmot's Chemotype Evolution platform, with a potential emphasis on oncology targets including KRAS G12C, though no recent major milestones have been publicly disclosed.

Amgen Carmot Collaboration KRAS G12C AMG 510 Overview

The direct answer is that the “Amgen Carmot collaboration” refers to a research partnership formed in 2019. Through this deal, Amgen gained access to Carmot Therapeutics’ drug discovery platform to identify small-molecule inhibitors, which led to the development of the KRAS G12C inhibitor now known as AMG 510 (sotorasib). The collaboration combined Carmot’s expertise in creating novel chemical libraries with Amgen’s capabilities in oncology drug development. AMG 510 became the first KRAS G12C inhibitor approved by the FDA.

The 2019 Partnership Agreement

In 2019, Amgen and Carmot Therapeutics announced a multi-year collaboration focused on discovering small-molecule drugs against challenging targets, including KRAS G12C. The deal gave Amgen access to Carmot’s Chemotype Evolution platform, a technology that generates novel chemical matter against specific protein targets. Carmot received an upfront payment and was eligible for milestone payments and royalties on any drugs that reached the market.

Carmot’s platform works by starting with small chemical fragments and building them into larger compounds based on how they interact with the target protein. Amgen researchers used this approach to find new starting points for inhibiting KRAS G12C, a mutant form of the KRAS protein found in several cancers. The collaboration was structured to let Amgen take the lead on clinical development while Carmot continued to apply its platform to other targets in the partnership.

The KRAS G12C Target

KRAS is one of the most commonly mutated oncogenes in human cancer. The G12C mutation specifically replaces the amino acid glycine with cysteine at position 12 of the protein. This mutation is found in about 13 percent of non-small cell lung cancers, as well as in smaller percentages of colorectal and other solid tumors.

For decades, drug developers considered KRAS undruggable because the protein lacks deep binding pockets where small molecules can easily attach. The surface of the protein is relatively smooth, and it binds very tightly to its natural activator, GTP. The G12C mutation creates a small pocket near the cysteine residue that can be targeted by covalent inhibitors. These inhibitors form a permanent bond with the cysteine, locking the protein into an inactive state.

The challenge was finding a molecule that could fit into that pocket with high specificity. This is where Carmot’s platform became useful. Standard high-throughput screening had failed to produce viable leads against KRAS G12C, so a different approach was needed.

Carmot’s Chemotype Evolution Platform

Carmot Therapeutics developed the Chemotype Evolution platform as an alternative to traditional drug screening. Instead of testing millions of pre-made compounds, the platform starts with small chemical fragments that bind weakly to the target. These fragments are then linked together and elaborated in an iterative process, guided by structural data from X-ray crystallography.

The platform generates novel chemical matter that is not found in typical compound libraries. This is important for targets like KRAS G12C, where standard libraries had already been exhausted without success. Carmot’s approach produces compounds with new chemical scaffolds, which can have different properties in terms of potency, selectivity, and pharmacokinetics.

For the Amgen collaboration, Carmot applied this platform specifically to find inhibitors that could bind to the cysteine pocket of KRAS G12C. The resulting compounds were then optimized by Amgen’s medicinal chemistry team.

From Collaboration to AMG 510

The collaboration produced AMG 510, a small-molecule inhibitor that binds covalently to the cysteine residue at position 12 of mutant KRAS. The drug traps the protein in its inactive GDP-bound state, preventing it from activating downstream signaling pathways that drive cell growth.

Amgen advanced AMG 510 into clinical trials in 2018, before the collaboration was publicly disclosed. The drug showed activity in patients with KRAS G12C-mutant non-small cell lung cancer who had already received prior treatment. In a phase 1 trial, about one-third of patients had a confirmed response, and the drug was generally well tolerated.

The FDA granted AMG 510 breakthrough therapy designation in 2019 and approved it under the brand name Lumakras in May 2021. The approval was based on results from the CodeBreaK 100 trial, which showed a 36 percent objective response rate in patients with locally advanced or metastatic non-small cell lung cancer. The drug is taken orally once daily.

Role of Each Company

Amgen handled the clinical development, manufacturing, and commercialization of AMG 510. The company ran the CodeBreaK clinical program, which included trials in lung cancer, colorectal cancer, and other solid tumors. Amgen also expanded the development of sotorasib into earlier lines of therapy and combination regimens.

Carmot Therapeutics contributed the initial discovery work through its platform. The company did not participate in clinical development but received milestone payments tied to the progress of AMG 510. Carmot has since been acquired by another pharmaceutical company, but the original collaboration with Amgen had already fulfilled its primary goal of generating a clinical candidate.

The partnership structure is common in the pharmaceutical industry. A smaller biotechnology company with a specialized platform partners with a larger company that has the resources to conduct large clinical trials and manage regulatory submissions.

Impact on KRAS Drug Development

The success of AMG 510 validated the approach of targeting KRAS G12C with covalent inhibitors. Before this drug, no KRAS inhibitor had reached the market despite decades of research. The approval opened the door for other companies to develop their own KRAS G12C inhibitors, and several are now in clinical trials.

The collaboration also demonstrated the value of fragment-based drug discovery platforms for difficult targets. Carmot’s Chemotype Evolution platform had previously been used for other targets, but the KRAS G12C program was its most prominent success. The partnership showed that alternative screening methods can succeed where traditional approaches fail.

Resistance to AMG 510 remains a challenge. Tumors can develop secondary mutations in KRAS or activate bypass signaling pathways that restore cell growth. Combination therapies are being studied to address this, including combinations with immunotherapy, chemotherapy, and other targeted agents.

Key Takeaways

The Amgen-Carmot collaboration used Carmot’s Chemotype Evolution platform to discover novel small-molecule inhibitors of KRAS G12C.
AMG 510 (sotorasib) was the first drug to emerge from the partnership and became the first FDA-approved KRAS G12C inhibitor.
The collaboration combined Carmot’s fragment-based discovery technology with Amgen’s clinical development infrastructure.
The success of AMG 510 proved that KRAS could be targeted with small molecules, opening a new area of cancer drug development.
Resistance to KRAS G12C inhibitors is an ongoing challenge, and combination therapies are being studied to improve long-term outcomes.
Patients should consult their oncologist about whether KRAS G12C testing and treatment with sotorasib is appropriate for their specific cancer type.

What Is the Amgen Carmot Collaboration KRAS G12C AMG 510?