Dosing started in Phase 1 study of globin-switching therapy CLY-124
Novel SCD treatment aims to switch back on fetal hemoglobin production
The first healthy volunteer has been dosed in a Phase 1 clinical study of CLY-124 — a novel oral small molecule that Cellarity is developing to treat sickle cell disease — following clearance of the company’s investigational new drug application by the U.S. Food and Drug Administration.
“Initiation of our first-in-human clinical study for CLY-124 represents the delivery of our first clinical asset from our platform with the potential for transformative improvement in care for individuals suffering from sickle cell disease,” Cameron Trenor, MD, Cellarity’s chief medical officer, said in a company press release.
The global trial will evaluate the safety and tolerability of the experimental therapy, first in healthy volunteers and then in people with sickle cell disease. According to Cellarity, the results “will offer important insights” into how the treatment candidate works in people.
The use of CLY-124 represents a new strategy for switching back on the production of fetal hemoglobin (HbF), the protein in red blood cells produced before birth to carry oxygen through the body. Normally, around the time of birth, the body naturally switches from making HbF to producing adult hemoglobin, known as HbA.
SCD is caused by a mutation in the gene responsible for producing HbA, which leads to the production of hemoglobin S (HbS), an abnormal form of the protein. HbS tends to clump together into rigid strands, which distort red blood cells into a sickle shape. These misshapen cells are less flexible and can block blood flow in small vessels, leading to symptoms such as pain, fatigue, and anemia, or low numbers of red blood cells.
CLY-123 discovered using artificial-intelligence-driven platform
CLY-124 is designed to switch back on the production of HbF through a so-called globin-switching mechanism, which could prevent HbS from clumping and compensate for the lack of a working adult hemoglobin. This is expected to help ease the symptoms of sickle cell disease.
“The novel mechanism of CLY-124, which naturally increases fetal hemoglobin through globin-switching, could address pain, anemia, and other symptoms to improve organ function and quality of life,” Trenor said.
The small molecule was discovered using Cellarity’s artificial intelligence-driven platform, which allowed researchers to study how red blood cells develop. To do so, the scientists looked at changes in gene activity, called transcription, to find new biological signals — known as regulators — that control the production of HbF.
Instead of targeting DNA or inhibiting proteins, called transcription factors, that control globin gene activity, CLY-124 blocks a chemical change — known as a post-translational modification — in a protein complex that would normally switch off the production of HbF. Blocking that modification switches it back on.
Ted Myles, Cellarity’s CEO, said the company’s “unique approach to drug discovery is producing therapies that have the potential to shift the treatment paradigm for a range of complex diseases with persistent unmet need,” such as SCD.
“CLY-124 is the first validation of our powerful proprietary discovery platform that has allowed us to see biological pathways and create medicines that conventional discovery efforts could not have achieved,” Myles said.
In lab studies using human cells, CLY-124 increased the levels of HbF to more than 20% without causing cell death, known as cytotoxicity. This suggests that CLY-124 could be both effective and safe, with the added benefit of being taken by mouth.
Our strong body of preclinical evidence suggests CLY-124 may offer best-in-class fetal hemoglobin production without the cytotoxicity associated with conventional therapies, and importantly, could be accessible to all patients through a once-daily oral pill.
The Phase 1 clinical study is also testing the therapy’s pharmacokinetics, or how it moves into, through, and out of the body. Following that, patients with a diagnosis of sickle cell disease will be enrolled. Researchers will also test how well CLY-124 switches on the production of HbF.
“As we begin our first clinical study, we look forward to collaborating with scientific and clinical partners as well as the [sickle cell disease] community of families, caregivers and advocates as we aim to elevate the standard of care for people living with this disease,” Myles said.
According to Trenor, the therapy has the potential to be a game-changer for patients.
“Our strong body of preclinical evidence suggests CLY-124 may offer best-in-class fetal hemoglobin production without the cytotoxicity associated with conventional therapies, and importantly, could be accessible to all patients through a once-daily oral pill,” Trenor said.
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