By Chris Berrie PRAGUE, CZECH REPUBLIC -- October 13, 2007 -- Intramuscular injection of the tolerogenic DNA plasmid vaccine BHT-3009 that encodes full-length human myelin basic protein (MBP) is safe and well tolerated, and provides significant favourable benefit on several measures of brain lesion activity in patients with relapsing-remitting multiple sclerosis. This multicentre, randomised, double-blind, placebo-controlled phase 2b trial was presented here by coinvestigator Hideki Garren, MD, PhD, Vice President of Research, Bayhill Therapeutics, Palo Alto, United States, at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). During his presentation on October 12, Dr. Garren stressed the two important aspects of construction of BHT-3009 as a DNA plasmid. "We include the antigen, MBP, as the entire molecule, rather than specific epitopes, and we include some specific changes in the DNA background to try to drive the [T-cell] tolerance." In a previous 30-patient phase 1/2 trial, BHT-3009 was shown to be safe and well tolerated (Bar-Or et al., [Arch. Neurol. 2007, 64, 1407-1415).
The current study enrolled 289 patients who were aged 18 to 55 years and had a confirmed diagnosis of MS according to McDonald criteria, at least one relapse in the previous year, and not received any treatment with disease-modifying agents in the previous 6 months. Study subjects also had screening magnetic resonance imaging (MRI) scans that were consistent with MS, with 0-5 Gd-enhancing lesions and an expanded disability status scale (EDSS) of 3.5 or greater.
The aim of the study was to evaluate the efficacy and safety of BHT-3009 in patients with relapsing-remitting MS, and to confirm that BHT-3009 causes immune tolerance.
The primary endpoint was the rate of occurrence of new Gd-enhancing lesions on cranial MRIs performed every 4 weeks from weeks 28 to 48 of treatment. Secondary endpoints were cranial MRI measures of Gd lesion volume, T2 lesion volume/number, and T1 black hole volume. The researchers monitored for relapses and disability scores. Finally, the immune response to MBP was also determined, to confirm previous results and to prospectively identify patients who respond to BHT-3009.
Patients were randomised to one of three treatment arms: 96 received placebo; 104 patients received BHT-3009 0.5 mg (low dose); 89 patients received BHT-3009 1.5 mg (high dose). Treatment was administered by intramuscular injection on weeks 0, 2 and 4, and then every 4 weeks until week 44.
Patients' baseline disease characteristics, number of relapses in the previous year, mean EDSS and MS functional composite (MSFC) overall z scores. The three treatment groups also had similar baseline MRI parameters.
In the 267 patients in per protocol cohort evaluation from weeks 28 to 48, results show that low-dose BHT-3009 achieved a near-significant 50% decrease versus placebo in median 4-week rate of new Gd+ lesions per patient (P =.07). No high-dose BHT-3009 effects seen.
However, Dr. Garren stressed that while this primary endpoint was not satisfied, when the MRI results were taken over the full treatment period (weeks 8 to 48), the 61% reduction versus placebo at low-dose BHT-3009 was significant (P =.05).
At week 48, low-dose BHT-3009 achieved a significant 51% decrease in mean Gd+ lesion volume (P =.02), although there was only a trend for decrease in T2 lesion volume.
The immunology assessment was on the 80 patients in the subgroup with cerebrospinal fluid (CSF) samples at screening and at week 44. In the screening for CSF anti-MBP reactivity, the low-dose BHT-3009 patients with the higher antibody titers (with a 1:1 low:high cut-off) showed a significant decrease versus placebo in new Gd+ lesions per MRI at week 28 (P =.02). Similarly, for CSF auto-antibody changes from screening to week 48, there were 23 fewer myelin-specific auto-antibodies in the 0.5 mg BHT-3009 group, while the placebo group had no change in auto-antibodies.
In the safety analysis on the 286 patients who received at least one dose of BHT-3009, common adverse events were mostly mild to moderate, and relatively well balanced across treatment groups. Dr. Garren indicated that psychiatric adverse events were slightly higher in the placebo group (14.7% vs 8.7% vs 9.2%), and renal and urinary events were slightly higher in the 1.5 mg BHT-3009 group (5.3% vs 8.7% vs 11.5%). Adverse events that were severe or worse were also more common in the placebo group (11 vs 7 vs 8). However, these all differences were not statistically significant.
In terms of relapse and disability, there was an overall very low rate of MS relapse, with 0.4 relapses in the placebo group, with no significant differences across the groups for relapse rates, time to relapse, or in mean EDSS and MSFC in this trial, added Dr. Garren.
The higher 1.5 mg dose of BHT-3009 had no patient benefits, potentially due to induction of four proteolipid protein peptide (PLP) antibodies, he said. However, the 0.5 mg dose did provide significantly favourable benefit for several measures of brain lesion activity, he added.
At the same time, this latter treatment showed high levels of CSF auto-antibodies as predictive for best responders for this patient subgroup analysis, with BHT-3009 causing antigen-specific tolerance, as seen by the reduction in CSF auto-antibody levels.
Funding for this study was provided by Bayhill Therapeutics.
[Presentation title: Phase 2b Trial of a MBP-Encoding DNA Plasmid (BHT-3009) for the Treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). Abstract 48]
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