ATL1102 is a therapeutic candidate for relapsing forms of multiple sclerosis (MS) being developed by Antisense Therapeutics. ATL1102 is a second-generation antisense inhibitor of CD49d, a subunit of the VLA-4 (Very Late Antigen-4) receptor found on the surface of lymphocytes (a type of white blood cell).
Antisense drugs (therapies containing the non-coding strand of messenger RNA, or mRNA, a molecule central to translating DNA into protein) have been used over the years to treat such diseases as cancer, amyotrophic lateral sclerosis (ALS), diabetes, and those with an inflammatory component like asthma and arthritis.
How ATL1102 works
Antisense drugs block the production of the target protein. ATL1102 is designed to reduce levels of CD49d.
By blocking CD49d production, ATL1102 is thought to reduce the VLA-4 receptor on the surface of lymphocytes (white blood cells involved in the immune response). VLA-4 normally allows lymphocytes to move from the blood vessels into a tissue, which can lead to inflammation, such as the central nervous system (CNS) in MS. By preventing the lymphocytes from entering the CNS, inflammation could be reduced and this could reduce disease progression. VLA-4 is a clinically validated target for MS treatments, and antisense inhibition of the receptor has demonstrated effectiveness in published preclinical studies in animal models of the disease.
Interestingly, in a Phase 2a clinical study in MS patients, treatment led to “an observed reduction in B cell numbers,” Antisense reported in 2016, and the company is now petitioning for future studies that would involve people with progressive forms of this disease (secondary progressive MS).
History of ATL1102 research
Preclinical studies in monkeys with MS showed positive treatment results at ATL1102 doses ranging from 1.5 to 3 mg/kg over six months. Likewise, Phase 1 clinical trials successfully tested the drug’s safety and tolerability in healthy volunteers.
A randomized Phase 2a trial was conducted in 77 patients with relapsing MS (RMS) in Australia, with treated patients given 200 mg ATL1102 by subcutaneous injection three times in the first week, then twice weekly for the next seven weeks, and others given placebo. The trial met its primary endpoint, demonstrating a significant reduction in disease progression (54.4 percent) in treated patients compared to placebo after two months of treatment. Results were reported in the journal Neurology in November 2014, and the researchers concluded that the trial provides “evidence for the first time that antisense oligonucleotides may be used as a therapeutic approach in neuroimmunologic disorders such as MS.”
Next steps For ATL1102
According to a February 2017 update from Antisense, an application for a Phase 2b study in 195 MS patients is on track for submission to the U.S. Food and Drug Administration (FDA) by April, where it will then be reviewed.
A smaller study of ATL1102 in secondary-progressive MS (SPMS) patients is also proposed that will take place in Germany, with Volker Limmroth, a neurologist at Cologne City Hospital, as a principal investigator. This study will evaluate the efficacy, safety, and mechanism of action of ATL1102, 200 mg once weekly for 24 weeks, in 16 SPMS patients.
Successful trial data could lead to an early access program begin established for MS patients who don’t respond to or cannot tolerate existing therapies.
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