Ms Antisense Drug Shows Early Promise, But Long-Term Benefit Remains Unknown

ARTICLE IN BRIEF

A new study suggests another way to target VLA-4 as a strategy for relapsing MS: use antisense oligonucleotides to prevent the key cell adhesion molecule from being produced in the first place.

SEATTLE-Inhibiting migration of lymphocytes into the CNS is a potent strategy against multiple sclerosis (MS), as shown by the effectiveness of the monoclonal antibody natalizumab. That treatment blocks Very Late Antigen 4 (VLA-4), a key cell adhesion molecule, which allows lymphocytes to adhere to vessel walls.

A new study described here at the AAN annual meeting suggests another way to target VLA-4: use antisense oligonucleotides to prevent VLA-4 from being produced in the first place. Preliminary results indicate it effectively reduces lesions, although the trial was too short to permit conclusions about more clinically relevant outcomes.

Antisense molecules are short nucleotide sequences that match a target sequence of messenger RNA. The antisense molecule binds to the mRNA in the nucleus, preventing translation and thereby blocking protein synthesis.

STUDY PROTOCOLS

In the current study, an antisense molecule, called ATL1102, was designed to bind to mRNA encoding a subunit of the VLA-4 protein, according to lead study author Volker Limmroth, MD, PhD, chairman of the department of neurology at Cologne City Hospitals in Cologne, Germany.

Seventy-seven patients with relapsing-remitting MS were given ATL1102 or placebo by subcutaneous injection twice weekly for eight weeks. Two-thirds of the patients were women, with a mean age in the late 30s. They were evaluated by MRI at baseline and then every four weeks for 16 weeks.

The cumulative number of new active lesions at week 12 was 6.2 for patients receiving placebo, and 3.0 for patients receiving antisense therapy, a difference of 54 percent (p = 0.01). The number of gadolinium-enhancing lesions differed by 67 percent (p = 0.002). There were no significant changes in the Expanded Disability Status Scale or in relapse rates, but treatment and follow-up were too short to derive definite conclusions about the effect on these measures, Dr. Limmroth said.

Adverse events severe enough to cause termination of treatment occurred in one patient on placebo, and three taking ATL1102. For those on active treatment, all three had thrombocytopenia, which was reversed by stopping the treatment. The cause of this effect is unknown, Dr. Limmroth said.

Natalizumab therapy can result in progressive multifocal leukoencephalopathy, due to reactivation of the JC virus. There were no signs of JC virus in the bloodstream due to ATL1102 treatment. Monitoring the CSF would have been more definitive, said Dr. Limmroth, but would have been unethical for this short-term, proof-of-concept trial. All patients discontinued treatment at the end of the trial.

Whether antisense reduction of VLA-4 production is a better strategy than blockade of the same target with a monoclonal antibody remains to be seen. Dr. Limmroth noted that there are animal data suggesting that preventing expression of the receptor from the beginning, so that no receptor reaches the cell surface, may be more effective than blocking the receptor once it is in place. Furthermore, he said: Antisense drugs are oligonucleotides, not proteins. Monoclonal antibodies are proteins and may cause neutralizing antibodies; this cannot happen with antisense oligonucleotides.

EXCITING, SHORT-TERM OUTCOME

It is always exciting when there is a new treatment for multiple sclerosis, according to Gary Birnbaum, MD, director of the MS Treatment and Research Center at the Minneapolis Clinic of Neurology in Golden Valley, MN. However, the study used a fairly short-term outcome, and there are data indicating that you can eliminate contrast-enhancing lesions and not affect disease progression and relapse rate. Whether this will translate into long term benefit remains to be seen.

Dr. Birnbaum also cautioned, The more aggressive you are in altering the immune system, the more likely you are to have side effects. The long-term consequences have always been an issue, given that patients will be receiving treatment for many years. Current treatments do a pretty good job, he said. Newer medications really have to do better to justify using them.