Becoming A Backbone Therapy: Lessons Learned With Actuate Therapeutics

A conversation with Actuate Therapeutics CEO Dan Schmitt

Being the backbone of anything — a work project, a friend group, even a family unit — carries a lot of responsibility and importance. The same is true for pharmaceutical drugs, wherein therapies with a backbone designation balance efficacy and toxicity in a way that supports other treatments.

But it’s not terribly easy or quick to achieve. Just ask Dan Schmitt, CEO at Actuate Therapeutics.

In this Q&A, Schmitt delves into why the company’s elraglusib program has a safety profile, mechanism of action, and breadth of combination data that make it a compelling candidate.

Schmitt also addresses how current and planned trials are structured to confirm that potential, and what the team has learned from advancing multiple clinical studies in parallel across adult and pediatric oncology settings.

Clinical Leader: Elraglusib is noted as a possible backbone therapy. What is a backbone therapy, and what makes elraglusib a suitable candidate?

Dan Schmitt: A backbone therapy is one that has shown the ability to be combined with other treatments for a particular indication in a manner that enhances or improves the anti-tumor effects of the other treatments. Backbone therapies in general have some mechanism of action that contributes to the antitumor activity of whatever it is combined with. A key feature of a backbone therapy is that it is relatively well tolerated as a single agent and that it does not significantly alter the risk-benefit profile of whatever it is combined with by enhancing or contributing toxicity. In addition, a backbone therapy should be amenable to combination with existing approved or standard of care treatments but also provide a basis for considering combinations with new experimental therapies that are also in development in a particular indication.

Elraglusib checks all these boxes. It’s relatively well tolerated with a benign safety profile as a single agent. It inhibits DDR and NF-kB-mediated gene expression, which mediate drug resistance, enhancing the antitumor effects of many different chemotherapeutic agents in both chemosensitive and chemo-refractory or resistant patients. Clinical data that has explored a wide variety of elraglusib-chemotherapy combinations suggests that the addition of elraglusib does not significantly alter the risk-benefit profile of the chemotherapy partner and that no new safety signals are observed with the combination. And, Based on its mechanisms of action, elraglusib may be amenable to combination with a wide variety of signaling inhibitors and genomic drugs such as inhibitors of RAS, MEK, HER2, RAF, CDKs, EGFR, and others.

How does your trial design reflect your ambitions for elraglusib to become a backbone therapy?

To establish elraglusib as a potential backbone therapy, we need to explore multiple drug combinations. Our initial focus will be on metastatic pancreatic cancer (mPDAC) and Ewing sarcoma, while also considering future indications under evaluation for elraglusib tablets, the oral formulation. While we currently refer to elraglusib as a possible backbone therapy in mPDAC, future studies will explore elraglusib as a backbone therapy in combination with other therapeutic agents in indications beyond mPDAC.

Thus, our trial strategy (this goes beyond the design of one study) takes this into consideration. For example, the 1801 trial initially explored the combination of elraglusib with eight different chemotherapies and demonstrated good tolerability when combined with all eight chemotherapy regimens with initial evidence of antitumor activity with several chemotherapy agents in several different indications, including metastatic melanoma (as a single agent), non-small cell lung cancer, colorectal cancer, CNS malignancies, and others. This study was reported in Carneiro et al. Clin Cancer Res. 2024; 30:522-531.

The company also ran a trial in pediatric cancers (the 1902 study) combining elraglusib with several different chemotherapy regimens, and the results of that study will be reported in early 2026. We previously described positive antitumor data, including CRs in refractory/resistant patients with Ewing sarcoma, when elraglusib was combined with cyclophosphamide/topotecan, with a manageable safety profile and no new significant safety signals reported in the combination. We have further pursued additional combinations through investigator-initiated trials (IITs) in mPDAC, including combinations with FOLFIRINOX (also first line standard of care in mPDAC) and the combination of an anti-PD-1 plus FOLFIRINOX. The company is open to exploring additional drug combinations to position elraglusib as a backbone therapy with chemotherapy in mPDAC and pediatric cancers. This may include additional IITs or collaborations with sponsors interested in combining elraglusib with agents such as RAS, MEK, or checkpoint inhibitors for mPDAC, as well as therapies used in pediatric malignancies.

Once we initiate the Phase 1 study with elraglusib tablets and identify an RP2D, a similar strategy of exploring additional combinations with different therapeutic agents and in different indications through IITs and collaborations will also be explored. All of our studies, including Phase 1 studies, are designed to assess both safety and initial evidence of anti-tumor activity, which allows us to check the aforementioned boxes. 

How do you communicate with and convince regulators that elraglusib should become an anchor in the pancreatic cancer standard of care?

Considering elraglusib as a backbone therapy is really an application of how elraglusib will be used and further tested, potentially even if it receives its first approval. Currently, there is no way to get approval for elraglusib in combination with Drug X and then have it also be approved in combination with Drugs Y and Z, unless you also develop clinical data that supports its use in combination with Drugs Y and Z. The same applies for an indication. Good examples are androgen deprivation for prostate cancer, immune modulators in myeloma, and EGFR mutation-targeted drugs in lung cancer, but each combination or indication needed to be tested explicitly in a clinical study and shown to work and have an acceptable safety profile, leading to the eventual consideration of these agents as backbone therapies. However, if a drug like elraglusib is designated or described as a potential backbone therapy by scientific and clinical investigators, it informs how people think about testing it, which drug combinations they might consider, and which indications they will pursue. It further opens up exploration of hypotheses around mechanisms that might not be considered unless one was considering elraglusib as a backbone therapy.

What are the options for elraglusib and your trials if it does not present data that support it as a backbone therapy?

From a development path perspective, thinking about elraglusib as a backbone therapy creates synergies in development.

For example, positive data with chemotherapy combinations suggest clinical indications to pursue. For example, positive data with the combination of elraglusib/carboplatin in 1801 Part 2 suggest elraglusib could be a backbone for indications treated with carboplatin regimens, e.g., NSCLC, gynecologic malignancies, esophageal cancer, etc. Data from several patients with these cancer types enrolled in 1801 support this (Carneiro et al., 2024).

Elraglusib is currently being studied in three separate trials. Tell us about each of them and how running them concurrently is beneficial.

There is only one trial that is recruiting patients right now: NCT06896188 9-ING-41 (elraglusib) combined with retifanlimab, plus modified FOLFIRINOX. Previous studies of elraglusib plus GnP in mPDAC (1801 Part 3B), elraglusib plus FOLFIRINOX/losartan in mPDAC (NCT05077800), and the Phase 1 portion of NCT04239092 9-ING-41 (elraglusib) in pediatric patients with refractory malignancies (Phase 2 portion terminated; Phase 1 completed) are no longer accruing patients.  

In our case, because the studies were exploratory and open label, there was benefit in seeing safety data/tolerability and early hints of antitumor activity (e.g., disease control) that provided early and real-time validation for the program across multiple populations (e.g., adults with mPDAC, pediatric patients with various malignancies) and also within the same cancer type (e.g., mPDAC). This allowed us to build and attract interest from treating oncologists, potential investigators, patients, patient advocacy groups, and consortia interested in working with or being treated with elraglusib as well as investors interested in supporting our mission.

What are the challenges of running the trials concurrently?

Bandwidth is always a challenge for any small company. We have had many investigators, consortia, and possible collaborators reach out to us and propose IITs, collaborations in cancers that we were interested in but did not have the internal ability to explore, and ask about participation in future clinical studies. We have a strong internal team that must multitask to manage all these different potential interactions. This requires the team to prioritize both human and financial resources and balance advancing the state of knowledge of elraglusib activity with the core activities needed to drive our programs to registration. Driving development on the back of multiple trials through a pandemic, changes in research funding, and fluctuating biotech markets have presented challenges to development, financing, and continuing to maintain momentum across all biotech, including Actuate.. .

We also have regulatory reporting obligations for each program and establishing and maintaining a productive working relationship with regulators is a high priority that can be challenging in an ever-evolving regulatory landscape. Further, the company has requirements for non-clinical studies and CMC that need to be aligned with the progress across multiple clinical trials to ensure that the company is on track to reach its ultimate goal: drug registration.

Solid project management is important when you have multiple concurrent trials, and since we have team members assigned across multiple programs, prioritizing their time commitments to support these projects is critical to our success. Finally, making sure that we communicate results and plans in a balanced, rigorous, and transparent way to clinicians, regulators, and investors is essential to the integrity of the science and the company.

What lessons have you learned thus far with the elraglusib trials? And how might others learn from your experience?

Drugs with new or multiple mechanisms of action can be challenging to develop. The sooner you can determine a clinical hypothesis or hypotheses to test and implement that in a study, the faster you will attract interest from leaders in the field. This translates to patient interest and ultimately helps accrue your trial.

Optimize trial design to answer the question germane to your drug, and if possible,  how best to fit your drug into existing clinical paradigms for accelerating potential adoption.

Design your studies to address survival benefits as soon as possible, even if it is in an exploratory way.

People want to not only live longer but also to live well during their treatment. Keep the patient experience in view as you design your trials and make sure you address how it affects patients’ daily living if your drug works for them. There have been many anecdotal comments from investigators on how patients just feel better during and after elraglusib treatment, and we will include measures to more fully capture and quantify these effects in future trials .

Integrate and communicate with the community in your cancer of interest, both on the investigator and clinician side as well as on the patient side. These are the people you are trying to help, so you want to gather their input and insights as soon as possible.

About The Expert:

Dan Schmitt is president and chief executive officer of Actuate Therapeutics and has more than 30 years of leadership experience across operations, product development, and business development in the pharmaceutical and biotechnology industries. He has held senior executive roles at both large pharma and emerging biotech companies, including Fujisawa, Searle/Pharmacia, and Ilex Oncology. Over his career, Schmitt has led the development and launch of multiple pharmaceutical products and executed numerous high-value licensing, acquisition, and development transactions totaling nearly $1 billion in up-front and potential milestone payments. He holds an M.B.A. and a B.S. in chemistry from West Virginia University and has held research affiliations with the National Foundation for Cancer Research and the University of North Carolina School of Medicine. Schmitt has also served as an Entrepreneur-in-Residence at Northwestern University and as an external consultant to leading academic institutions.