Emil Kuriakose has more than a decade of biopharmaceutical industry experience, leading clinical development strategy and execution of therapeutics across multiple indications.
Credit: Terns Pharmaceuticals.
Chronic myeloid leukemia (CML) treatment has undergone a remarkable transformation over the past two decades.
Once a uniformly fatal disease, CML is now a manageable chronic condition for many patients, thanks to the development of targeted therapies. Advances in understanding the molecular drivers of the disease, particularly the role of the BCR-ABL (breakpoint cluster region-Abelson) fusion protein, have paved the way for several therapies that can control the disease long-term.
Despite these successes, many patients still experience resistance or intolerance to existing treatments. Innovations in drug design, including the development of allosteric BCR-ABL inhibitors, are providing new opportunities to address these unmet needs.
DDN spoke with Emil Kuriakose, Chief Medical Officer at Terns Pharmaceuticals, to discuss the promise of next-generation allosteric therapies, and what emerging clinical data suggest about the future of care for patients living with this chronic condition.
Why does an unmet need remain in CML, even with several effective treatments available?
CML is a cancer of the blood cells that originates in the bone marrow. It is driven by an abnormal genetic rearrangement called the Philadelphia chromosome, which produces the disease-causing protein BCR-ABL. BCR-ABL is a kinase, which functions like a switch to activate multiple proteins and signaling pathways in bone marrow cells, causing their uncontrolled proliferation.
CML is treated with drugs called tyrosine kinase inhibitors (TKIs), which work by blocking BCR-ABL and effectively turning it off. The introduction of TKIs has transformed CML from a universally fatal disease into a chronic malignancy that typically requires life-long therapy.
While there are several approved TKIs, close to 50 percent of patients are unable to stay on their TKI due to disease resistance or intolerable side effects.
- Emil Kuriakose, Chief Medical Officer at Terns Pharmaceuticals
While there are several approved TKIs, close to 50 percent of patients are unable to stay on their TKI due to disease resistance or intolerable side effects. Additionally, only 15–20 percent of patients achieve sufficiently deep and prolonged responses to be considered cancer-free and cured, and able to discontinue therapy. Therefore, there is still a significant need for improved BCR-ABL-targeting TKIs that achieve rapid deep responses with better safety, tolerability, and convenience that would allow more patients to remain on therapy long enough to achieve a true cure for their disease.
What are the biggest challenges patients face when staying on long-term therapy?
Ongoing treatment over many years can become a significant burden for patients. Long-term use of approved first-, second-, and third-generation TKIs is often accompanied by multiple adverse events from off-target effects, including pleural effusion (a collection of fluid around your lungs) and potentially life-threatening cardiovascular complications.
Acquired disease resistance also remains a recurring issue for many CML patients, with chronic use of these active-site TKIs often leading to the emergence of mutations in BCR-ABL that prevent the drugs from working. In addition, some TKIs have strict fasting requirements and cannot be taken with food, which can disrupt daily routines and negatively impact patients’ quality of life.
How do newer approaches like allosteric inhibitors differ from traditional TKIs?
Traditional active-site TKIs are designed to bind to the ATP-binding site of the BCR-ABL fusion protein. Because all kinases, including BCR-ABL, have very similar active sites, these drugs can also block the active sites of several normal kinases. This low selectivity can lead to off-target inhibition of healthy kinases, such as wild-type ABL1 and ABL2, which have been linked to cardiovascular and other toxicities.
Allosteric BCR-ABL inhibitors work differently. They bind to a unique region of the protein called the ABL myristoyl pocket. When an allosteric inhibitor binds to this pocket, it induces a structural change that turns the protein into its inactive form, shutting down kinase activity without blocking the active site.
Because normal kinases do not have a myristoyl pocket, allosteric inhibitors can selectively target the disease-causing BCR-ABL protein. This higher selectivity allows for stronger inhibition of BCR-ABL while reducing off-target effects and associated toxicities compared with traditional active-site TKIs.
What potential benefits could allosteric inhibitors bring to patients’ day-to-day lives?
The approval of asciminib, the first allosteric BCR-ABL TKI, marks a new class of medicines and a major advance in CML treatment, offering significant improvements in efficacy and safety compared to first- and second-generation active-site TKIs. Allosteric TKIs such as TERN-701 represent the next generation of CML medicines, with superior therapeutic potential versus active-site TKIs.
What promising trends are you seeing in recent clinical studies of allosteric BCR-ABL inhibitors?
Although asciminib represents the best available CML therapy today, as a first-in-class allosteric inhibitor there are still opportunities to improve efficacy, safety, and convenience. TERN-701, an investigational therapy, is part of the next generation of allosteric TKIs currently in clinical development. It is a proprietary, oral, potent small molecule allosteric BCR-ABL TKI that has been granted Orphan Drug Designation by the FDA for the treatment of CML.
Early data from the Phase 1 CARDINAL clinical trial evaluating TERN-701 showed compelling molecular responses in heavily pre-treated CML patients with high baseline BCR-ABL transcript levels, including those previously treated with asciminib, starting at the lowest doses. We saw an encouraging early safety profile, with no dose-limiting toxicities observed during dose escalation. Additionally, data showed that TERN-701 can be taken with or without food, a key differentiator from asciminib, which needs to be taken on an empty stomach with a 3-hour fasting window around each dose.
What do recent clinical results tell us about the safety and tolerability of next-generation therapies?
Early results from the Phase 1 CARDINAL trial of TERN-701 showed an encouraging safety profile, with no dose-limiting toxicities at any dose. There were also no clinically meaningful changes in liver and pancreatic enzymes, blood pressure, electrocardiogram, or other vitals in treated study participants. The trend towards improved safety relative to asciminib in dose escalation supports a potential wider therapeutic index, which would enable administration of higher doses that achieve maximal target coverage and potentially improved efficacy.
Could newer therapies eventually make treatment-free remission a reality for more patients?
Each year, nearly 10,000 patients in the US are diagnosed with CML and will often face challenges in achieving long-term disease control due to drug resistance or intolerance with currently approved active-site or allosteric TKIs. Today, only a small number of patients achieve and maintain the deep molecular response necessary to safely stop therapy and achieve what is known as treatment-free remission.
Our goal is for TERN-701 to deliver improved efficacy, safety, and convenience, with early data supporting a differentiated, potentially best-in-class profile that could help more patients achieve treatment-free remission.
How do you see the treatment landscape for CML evolving in the next 5–10 years?
CML prevalence in the US is expected to triple by 2040, making innovative treatments and improved quality of life critical priorities.
– Emil Kuriakose, Chief Medical Officer at Terns Pharmaceuticals
CML prevalence in the US is expected to triple by 2040. As most patients may now live with CML for several decades and have a normal lifespan, advancing innovative treatment options and improving quality of life are critical areas of need.
Based on their improved efficacy and safety profile, we foresee allosteric TKIs being used early on in the treatment course, as is already evident with the rapid uptake of asciminib in the frontline setting. Next-generation allosteric TKIs, such as TERN-701, have the potential to further improve efficacy, safety and convenience compared to currently available therapies. This could help patients achieve deeper and more sustained responses with better tolerability, which we hope will improve clinical outcomes and quality of life and take us a step closer towards truly curing CML.
This interview has been condensed and edited for clarity.
