The long journey of a small molecule of hope

A groundbreaking clinical trial for the drug KME-0584 could begin in early 2025, offering new hope for people with relapsed AML and high-risk MDS. Achieving this rare milestone reflects the long-term investment in basic research and years of teamwork by many people at Cincinnati Children’s, NCATS and the start-up company Kurome Therapeutics.

For people who have yet to find a successful treatment for their advanced acute myeloid leukemia (AML), participating in a new clinical trial of the investigational drug KME-0584 could be the start of a life-changing journey.

If all goes well, these trips could begin for up to 100 patients within a few months.

For Daniel Starczynowski, PhD, cancer biologist and director of the new Advanced Leukemia Therapies and Research Center at Cincinnati Children’s, reaching this moment reflects 19 years of scientific work largely behind the scenes. Not just his own, but the collective efforts of a small army of co-inventors, research collaborators, institutional leaders, philanthropists, investors and drug development experts.

“This is one of the few therapeutics ever developed at Cincinnati Children’s, from initial concept to a clinical candidate with a submitted IND (Investigational New Drug Application) open to begin clinical trials,” says Starczynowski. “I think this helps create a plan for how drug research can be done in a place like this. It is an encouraging message for leadership that their investments are making progress, and for the scientific community that the observations they make and the discoveries they publish can sometimes actually find their way into the clinic.”

What is KME-0584?

That’s startup Kurome Therapeutics’ research name for a small molecule that inhibits the function of not just one, but two critical proteins associated with relapsed or refractory AML and an associated condition called high-risk myelodysplastic syndrome (HR ), related to -MDS).

After years of study, Starczynowski and colleagues determined that inhibiting both IRAK1 and IRAK4 kinases is necessary for controlling this rare but often fatal form of leukemia.

According to the National Institutes of Health, more than 20,000 people in the United States are diagnosed with AML and another 20,000 to 30,000 are diagnosed with MDS each year. Most cases occur in older adults. However, AML also affects approximately 600 children in the United States each year, making it the second most common blood cancer in children after acute lymphoblastic leukemia (ALL).

The disease occurs when the bone marrow produces too many abnormal immature cells called myeloid blasts. These cells do not mature into normal white blood cells. Because they accumulate in the bone marrow and blood, they prevent the formation of other healthy blood cells. This can lead to life-threatening conditions such as anemia, excessive bleeding and bruising, and difficult-to-control infections.

There are already various treatment options for AML. However, about 25% of patients do not achieve remission, and about half of those who do achieve remission experience a relapse. There are very few treatment options available for HR-MDS.

These are the difficult cases that the inventors of KME-0584 want to solve.

The scientific journey began two decades ago

The first clues leading to the new possible treatment emerged in late 2009, when Starczynowski published his results in Natural medicine.

For the past five years, Canadian-born Starczynowski has been a postdoctoral researcher at the University of British Columbia in Vancouver. There he led work characterizing the function of a microRNA called miR-146a. This appeared to play a large role in a gene signaling pathway linked to bone marrow disorders that can lead to AML. The main targets of miR-146 were the genes TRAF6 and IRAK1, which normally regulate inflammatory signaling. However, when miR-146 is deleted in MDS and AML, TRAF6 and IRAK1 signaling are activated and contribute to the development of MDS and AML.

Starczynowski joined Cincinnati Children’s in 2010. He was recruited here by a cancer research team that included Yi Zheng, PhD; John Perentesis, MD; Stella Davies, MBBS, PhD; Jose Cancelas, MD, PhD; H. Leighton Grimes, PhD; and James Mulloy, PhD.

“I was impressed by the world-renowned expertise in experimental hematology and leukemia that they had at the Institute of Cancer and Blood Diseases. It was an ideal fit for the type of work I wanted to do as a basic cancer biologist,” says Starczynowski. “This was the ideal supportive and collaborative environment for me to launch my career.”

Over the years, Starczynowski has authored or co-authored more than 100 research papers. He also became a naturalized US citizen in May 2022.

Much of his work at Cincinnati Children’s delved deeper into the role of aberrant inflammatory signaling and, in particular, the dual functions of the kinases IRAK1 and IRAK4 in MDS and AML.

“These two kinases are essentially partners in crime,” says Starczynowski. “We had both been involved in these diseases individually, but the idea was always that if you targeted one, it would effectively block signaling affecting the other. In recent studies, we found that inhibition of both factors is required to disrupt the critical signaling pathway in AML. In fact, we recently published that functional compensation occurs when either is blocked alone. This has never been appreciated in the past.”

The NCATS library launches a drug development chase

As the role of IRAK1 and IRAK4 became clearer, Starczynowski began collaborating with Craig Thomas, PhD, a leading chemistry and drug development expert at the National Center for Advancing Translational Sciences (NCATS).

Founded in 2011, NCATS is a branch of the NIH that receives federal funding to help researchers accelerate the translation of laboratory discoveries into new treatments. Thomas and Starczynowski combed through the NCATS library of small molecule data and found a potential “hit.”

“As soon as they found a hit, we validated the molecule in our laboratory,” says Starczynowski. “Then they performed further chemical optimization of the molecule and we achieved an optimized hit.”

Thomas and his team are considered co-inventors of the drug, now called KME-0584.

Only 1,600 steps left

For many scientific advances, reporting an optimized “hit” can be the end result of the work.

After years of experimentation, the lab team confirms a connection between one or more genes and the way their signals cause normal body function to go awry and cause disease. Some research teams are going a step further into the translation process and reporting that an existing drug, or perhaps an entirely new compound, is known to specifically affect this novel genetic signaling process.

Whether this hopeful-sounding compound can be used as a real drug that is safe and effective in humans is largely left to others – especially big pharmaceutical companies – to figure out.

Enter Kurome Therapeutics.

A challenge that has long complicated drug development for rare and orphan diseases is that large, for-profit companies may not see enough market potential in an interesting idea to justify further investment. This reality has led nonprofit and government research institutions around the world to do more of the preclinical preparatory work themselves.

This is the path that Starczynowski’s potential AML treatment approach had to follow.

In 2020, CincyTech, a seed investment and startup organization, announced the formation of Kurome Therapeutics as a preclinical-stage drug development company. Kurome licensed the technology from Cincinnati Children’s and appointed Jan Rosenbaum, PhD, as president and chief executive officer and Starczynowski as chairman of the company’s scientific advisory board.

In 2021, the company announced raising $15 million in a “Series A” early-stage funding round. These resources helped Kurome take this first small molecule “hit” much further.

“We generated more than 1,600 new derivatives to arrive at our clinical candidate,” says Starczynowski. “Once we found that first optimized hit, it was a big step to get to the actual clinical candidate. The people at Kurome have done a tremendous amount of medicinal chemistry, validation and optimization and as a result we have a real drug with exquisite properties at our fingertips.”

The research team synthesized molecule by molecule, conducted a series of graded tests to learn more about their basic properties, and then selected promising versions for even further analysis.

“The FDA expects to know how the compound circulates through the body, how it is processed, how it binds to our targets and for how long,” says Starczynowski. “We need to know a tremendous amount of information about how the drug will work and what its potential toxicities are.”

Obtaining an IND requires conducting all of these tests—without fanfare, long after the key discoveries have been published in respected medical journals—he says.

A grand slam in a never-ending game

If publishing in a top journal feels like a home run for science, advancing that discovery by obtaining an IND is more of a grand slam.

But the game is far from over. The first doses of the clinical trial have yet to be administered. The results for these patients remain to be seen. Whether this and possibly further clinical trials will result in an FDA-approved drug to combat MDS and AML will be several years away. For a small biotech company like Kurome, collaborating with larger companies or pursuing acquisition opportunities can be crucial to getting to clinical trials.

“I think everyone realizes that this whole effort can happen in the blink of an eye at any time. “Still, this is a really important milestone for Cincinnati Children’s,” says Starczynowski. “There aren’t many examples in the history of Cincinnati Children’s where we developed a new drug from the beginning. This could be one of those successes. We certainly hope it will be.”