A Small Change in Gene Expression May Lead to a Big Change in MDS Treatment

Posted By Michael Kelly, M.D., M.P.H., M.S., Senior Medical Director

April 9, 2021

By Michael Kelly, M.D., M.P.H., M.S., Senior Medical Director

Myelodysplastic syndrome. A complex name for a complex disease. Although a relatively rare type of blood cancer, MDS carries with it a tremendous burden for patients and few treatment options that can effectively stop the disease. We, at Syros, based on our insights into the genomic drivers of MDS, are working on a new therapy that could have a profound impact on the way MDS is treated in the future.

A disease with many faces and challenges

MDS can take many forms. The underlying causes of disease can vary in different patients, but MDS develops when blood-forming cells in the bone marrow become abnormal, resulting in low blood cell counts. Some patients can live for years without experiencing serious symptoms. But, for patients with what’s known as higher-risk MDS – about half of all MDS patients – the picture is bleaker. Debilitating fatigue due to severe anemia. More illnesses due to increased risk of infections. Easy bruising or bleeding in response to injury. Once diagnosed, some patients use blood transfusions to address these symptoms, but the effects are often temporary, leaving patients dependent on frequent transfusions to maintain a meaningful quality of life.

What’s more, people with HR-MDS often respond poorly or are not candidates for the various treatment options available today. And one in three will progress to acute myeloid leukemia (AML), which is a closely related but far more deadly cancer.

In part because HR-MDS is a complex disease, it can be challenging for physicians to find the “just right” treatment approach for each patient and, in the past, tough for drug developers to come up with new medicines. The existing standard of care – hypomethylating agents, or HMAs – provide limited benefit for HR-MDS and, aside from HMAs, no new therapies have been approved in over a decade.

Recent changes signal new hope

More recently, the picture for HR-MDS has started to change. Many new therapies for AML have been introduced in the last several years and those successes are starting to spill over into MDS. Since 2019, at least seven mid- or late-stage clinical trials have started testing new potential medicines for HR-MDS, including our recently initiated Phase 3 trial of SY-1425. SY-1425 is a targeted investigational therapy that we are developing in a subset of newly diagnosed HR-MDS patients who have overexpression of the RARA gene. Approximately 30% of people with HR-MDS are RARA-positive, and SY-1425 represents the first targeted approach in clinical development for this patient population.   

We believe that SY-1425, when combined with azacitidine, has the potential to provide high rates of complete remissions for the thousands of people living with RARA-positive HR-MDS. 

What does RARA have to do with it?

Thanks to a growing understanding of the disease biology, we now know that there are dozens of drivers of MDS. In some people, the main driver may be an abnormal gene; in others, it may be the abnormal expression of an otherwise normal gene, which results in too much or too little of an important protein. When we can identify the underlying disease driver that is causing MDS in specific subsets of patients, we can develop a medicine to target it. That’s what we’ve done with SY-1425. 

And we have reason to believe that this approach will work. In an earlier study in relapsed or refractory RARA-positive HR-MDS patients, SY-1425 when used alone showed improved blood counts and reduced bone marrow blasts, including a marrow complete response in one patient. We have also seen high rates of complete responses when SY-1425 is combined with azacitidine in patients with low-blast count AML, a condition close to HR-MDS on the disease continuum. Lastly, studies have shown that SY-1425 is well-tolerated and doesn’t exacerbate the blood-related complications that can be typical of treatment with azacitidine, such as anemia and neutropenia.

Testing a targeted approach

SY-1425 is currently the only investigational therapy in clinical development for RARA-positive patients. The Phase 3 trial will compare the complete remission rate between patients who receive SY-1425 plus azacitidine and patients who receive placebo plus azacitidine, approximately 190 RARA-positive newly diagnosed HR-MDS patients in all. We are enormously grateful to the patients who decided to join this trial and the families, nurses and physicians who support them. We couldn’t do this without them. More information about the trial is available on using the study identifier NCT04797780. 

By employing this targeted approach – identifying RARA-positive patients and using a treatment that is designed to target a driver of their MDS – we aim to improve outcomes for a subset of people with HR-MDS who have been waiting far too long for better options and brighter futures.