None listed
Conditions
Brief summary
Background: Antisense oligonucleotides (ASOs) are an innovative new class of drugs that inhibit the expression of proteins by sequence-specific binding to the protein’s mRNA. ATL1102 is a 2nd generation antisense inhibitor of CD49d, a subunit of Very Late Antigen 4 (VLA-4) which plays a key role in cell adhesion to vessel walls. VLA-4 blockade, as shown by monoclonal antibodies such as natalizumab, prevents activated lymphocytes from migrating into the CNS and significantly reduces disease activity in MS. Objective: To evaluate VLA-4 Antisense (ATL1102) in the treatment of RR-MS Methods: Randomized, double-blind, placebo-controlled multicenter Phase-IIa trial. 77 patients with RR-MS were treated for 8 weeks with either 200mg of ATL1102 or placebo subcutaneously twice weekly and evaluated for 16 weeks. MRI scans were performed at screening, and then monthly over 16 weeks. Primary efficacy variable: cumulative number of new active lesions (CNNAL; new gadolinium-enhancing T1 lesions (T1-Gd), new or enlarging T2 lesions) on MRIs taken at weeks 4, 8 and 12. Secondary efficacy variable: cumulative volume of T1-Gd lesions (CVT1L) on MRIs taken at weeks 4, 8 and 12. Results: ITT population: 74 patients with a valid baseline MRI and at least one post-baseline MRI scan after first injection of study medication (n=39 placebo, n=35 ATL1102). ATL1102 showed a significant reduction, 54.4%, in CNNAL (6.2 placebo, 3.0 ATL1102; p=0.01). A reduction of 66.7% (p=0.002) was observed in the cumulative number (weeks 4,8,12) of new T1-Gd lesions with ATL1102. A reduction in CVT1L was also observed under ATL1102 but did not reach significance (589.4 mm3 placebo, 358.0 mm3 ATL1102; p=0.1068). Adverse events that were more frequent under ATL1102 included mild to moderate injection site reactions and a tendency for decreased platelet counts which were reversible after treatment interruption. Conclusions: This proof-of-concept study of a drug designed to inhibit VLA-4 mRNA showed a significant reduction of the cumulative number of new active lesions in RR-MS patients following 8 weeks of treatment. These promising results warrant further investigation.
Interventions
Patients receive 200 mg ATL1102 (VLA-4 antisense oligonucleotide) by subcutaneous injection three times in the first week, then twice weekly for the next seven weeks. The patients are monitored for a further eight weeks following completion of dosing.
Sponsors
Antisense Therapeutics Limited
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Males and females aged 18 to 55 years Diagnosis of Relapsing Remitting Multiple Sclerosis (RRMS) At least 9 T2 lesions or at least 4 if one is gadolinium-enhancing Last relapse in the previous 12 months No relapse in the previous four weeks Score of EDSS 0 to 6.0 Reliable contraception (e.g. surgical sterilisation, oral contraceptives) Written informed consent to participate in the study by signature on the Patients Consent Form
Exclusion criteria
Administration of any investigational drug within the previous 2 months before enrolment (4 months if the previous drug was a new chemical entity). Progressive disease. Concomitant clinically relevant other findings on MRI that may interfere with outcome assessment. Previous treatment with VLA-4 antibodies, anti-CD4 antibodies, or other monoclonal antibodies. Total lymphoid irradiation at any time. Treatment with immune-modulating drugs in the previous two months or treatment with immune-suppressive drugs in the previous six months. HIV positive patients. Detectable levels of JC Virus in the blood measured by quantitative PCR. Patients with renal impairment with serum creatinine greater than or equal to 2,0 mg/dl. History of clinically relevant gastrointestinal, hepatic, renal, endocrine, haematological, metabolic, neurologic (other than multiple sclerosis (MS)) and psychiatric disease. Patients with infections (lymphocytes greater than 3000/microL). History of any bleeding. History of coagulation abnormalities. Concomitant medication acetyl salicylic acid (greater than 300 mg/day) and phenprocoumon. Clinically relevant abnormalities in physical findings at screening examination if interfering with the study objective. Pregnant or breast-feeding women. History of drug or alcohol abuse. Epileptics. Suicidal subjects. History of drug allergy and/or known drug hypersensitivity. Inability to communicate or cooperate with the Investigator due to language problem, poor mental development or impaired cerebral function. Any medical condition which, in the judgement of the Investigator, might interfere with the objectives of the study. Repeated participation in this study. Contraindication for application of study drug. Corticoid-treatment in the previous six weeks and during the study period, exceptions are corticoid-treatment before the study period (not in the previous six weeks) and of relapses during the study period: Relapses are characterised by the occurrence of neurological dysfunction symptoms, appearing after a 30-day period of stability or improvement and lasting for more than 24 hours (no infection, no fever). A 5-day methylprednisolone treatment 1000 mg intravenous (i.v) is allowed in this case followed by a reducing procedure. Corticoid-treatment if applied locally (e.g. inhaled products) is allowed. Additionally MRI exclusion criteria: Metal residing in the body (e.g. implants), Cardiac pacemaker, valves, cochlear implants, CNS vascular clips. Contrast medium allergy Gadolinium Diethylenetriamine Penta-Acetic Acid (Gd-DTPA). No MRI exclusion criteria but caution is advised in case of: Cardiovascular disease including coronary heart disease, Immune deficiency, Haematologic disorder.
Outcome results
None listed