News

The Journey to “Druggable”

By Matthew Marx, Ph.D.
Senior Vice President, Drug Discovery at Mirati Therapeutics

The field of KRAS research is at an undeniably exciting crossroads. Medicines on the market have proved the “undruggable” could be drugged. Combination trials are on the move, searching out regimens that effectively fight against acquired resistance. A wave of new options is on the horizon that will expand treatments over the next few years.

As the first and only chemist on Mirati’s drug discovery team in 2015, I’ve reflected on the once in a lifetime opportunity to be on a team of inventors who developed a medicine that made history for patients, academia and the biopharma industry. These recollections are shared with hope that understanding the exploratory thinking, deliberate risks and essential collaboration between partners will energize others to undertake similarly groundbreaking endeavors. To borrow from Carl Sagan, one must know the past to understand the present.

Early Days
Mirati was a young company in 2014, barely two years old when our Chief Scientific Officer James Christensen launched the KRAS program. Dr. Christensen, who had long been captivated by the challenge of bringing forward potential therapies for cancer patients with KRAS mutations, recognized with the publication of University of California researchers’ early work that the combination of medical need and technical opportunity were coming to a head. Energized by the opportunity to be an early contributor to the field, Christensen and the few scientists on Mirati’s discovery team began early efforts on our KRAS project. With pharmacology and translational biology teams in place, I joined the effort as the first in-house chemist several months later.

By April of 2015, Mirati’s discovery efforts were well underway. Understanding the concept of the switch-II binding pocket and other factors that drove in vitro activity were foundational to our discovery efforts. Yet, there were still many questions left to be answered in our search to create the best drug candidate with appropriate pharmacokinetic properties and the best chances of success in clinical studies. This process of learning was exciting!

One of the biggest challenges was the need to identify a compound with acceptable predicted human pharmacokinetics (PK) and with this process also came one of the team’s greatest learnings. By late 2016, we found compounds with good mouse bioavailability and knew that significant tumor regressions resulted. But, it took another year to find the desired cross-species exposure and projected human PK. The team introduced an unusual technical feature: using a fluoro-acrylamide as an electrophile to make a covalent bond with Cys-12. The discovery story of adagrasib was later published in the Journal of Medicinal Chemistry.

Although the field of covalent inhibition is quite mature, to the best of our knowledge, this chemical feature had never been used in a clinical-stage molecule, which opened questions around the compound’s future safety and efficacy. Our preclinical data provided positive indicators, so we took the calculated risk of employing this modification in our compounds. While slightly reducing the potency of the molecule, this modification yielded significant metabolic stabilization resulting in acceptable pharmacokinetics across species and, eventually, in humans.

Fast Forward
Adagrasib entered the clinic in January 2019 and relatively early in Phase 1 did we begin to see promising results. The first patient was dosed shortly after the holidays and as the study continued it was clear some patients were responding. At the time, Mirati employees only numbered around 50 so we had the opportunity to share some results with the entire staff. This was an exciting moment! Results were shared externally in the fall of 2019 at the EORTC-NCI-AACR Symposium. In a pivotal, public moment for Mirati, James Christensen presented the full scope and depth of the preclinical efficacy data across tumor types. His presentation was followed by Pasi Jänne, M.D. who presented the interim Phase 1 data that showed adagrasib’s efficacy and safety in patients and the potential to advance the drug into a Phase 2 registrational study. As the presentation concluded, soft whispers of excitement rippled through the audience. The energy was electric! Filled with purpose, I couldn’t wait to get back home to do more.

At this point, Mirati’s Drug Discovery division and capabilities had grown significantly allowing us to dedicate time to both the burgeoning KRAS program while expanding our attention to other potential targets. We have an exceptionally talented team of medicinal chemists, protein chemists, computational chemists and crystallographers, bolstered by collaborations around the globe. WuXi AppTec has been one of our longest standing partners with whom we work closely across the chemistry, DMPK, toxicology, cancer biology and structural biology teams. Close personal relationships have formed over the years and our partnership in 2023 is stronger than ever. Gaining these additional areas of resource and expertise were instrumental in the current breadth of Mirati’s pipeline.

Looking Ahead
I’m thrilled to say there are more exciting opportunities on the near-term horizon for Mirati and our clinical collaborators. Our pipeline has grown to include the first, oral KRASG12D inhibitor, MRTX1133, and is the first orally-delivered G12D inhibitor to enter Phase 1 clinical trials. The molecule’s discovery story is unique. We were able to achieve complete target inhibition of G12D activity, selectivity against wild-type KRAS, and broad inhibition of tumor growth in preclinical models in the absence of a covalent protein interaction, as utilized by adagrasib. Additionally, MRTX0902 is a SOS1 inhibitor in Phase 1 and has shown to be an effective combination therapy with adagrasib in preclinical studies.

Equally exciting, our team has created a new approach to PRMT5 inhibition which there is reason to believe will be well differentiated from previous efforts in the industry. We chose to target PRMT5 specifically in cancer cells with an accumulation of the molecule MTA, which results from a deletion in the gene, MTAP. This approach is being evaluated in MRTX1719, a PRMT5/MTA complex inhibitor with a Phase 1 study underway. If successful, we will have created a potential precision medicine for the ~10% of all human cancers harboring an MTAP deletion while simultaneously avoiding the systemic toxicities of early agents.

Each of these agents targets a potential patient population significantly larger than that of adagrasib. All of these molecules are in dose-escalation studies in patients right now, and we look forward to presenting additional clinical data in the second half of 2023.

In Reflection
Looking back at the course of my career and my involvement with the adagrasib discovery and development project, I’m encouraged in two ways. At the start of my career, some chemists and patent lawyers thought the industry faced a crisis and that in a matter of years the industry would run out of chemical matter to work on, as a result of aggressive patenting strategies used at the time. I’m happy to report that this is not the case, and it likely never will be (I certainly hope I’m right!). The innovation of medicinal chemists to find creative, new molecules never ceases to amaze me, and of course advances in synthetic chemistry continue to open new doors. I tell my Mirati coworkers, “Every single molecule that is invented for our programs has likely never been conceived or prepared before, in all of history. The process of creation, preparation and evaluation of each and every one of these molecules is exciting to me – one of them may very well be the treatment for someone’s cancer.” And in the case of adagrasib, that hope came true.

Secondly, the centers of drug discovery innovation have significantly shifted since I entered this business 25 years ago after my post-doctorate. Back then, almost all drug discovery work was led by large pharma, with very little work done by collaborative partners or biotechs. Today, there is so much investment across a wide platform of chemical technologies – RNA-binding molecules, molecular glues that degrade, glues that activate, modalities such as cryo-EM, encoded libraries, AI and machine learning – the pace of investment and innovation is really exciting. Plus, the barriers to information sharing, global communication and collaboration are so low that interacting with experts of any field and in any location is very easy. Our close partnership with WuXi AppTec is evidence of this new way of working and share equally in the success of our pipeline. Global collaboration will unlock and accelerate future achievements in oncology research. I wish I were a young scientist again!

The past 8 years at Mirati have been some of the most exciting in my professional career and I’m thankful for all the team members, collaborators and supporters who made it possible. The WuXi AppTec team has been a constant, productive and effective partner and we deeply appreciate their support on this journey as we work to create new and meaningful treatments for people living with cancer.