In the second half of 2007, Bayhill completed a Phase II clinical trial of BHT-3009 in RR-MS. Patients received intramuscular injections of either BHT-3009 (0.5 mg or 1.5 mg) or placebo at two week intervals for the initial three doses, followed by a monthly dosing regimen thereafter for up to 13 doses (44 weeks). Many patients from this trial continue to be evaluated for up to 18 months after dosing and follow-up data on these findings are expected in the second half of 2008. In addition, Bayhill plans to initiate a Phase IIb study of BHT-3009 in RR-MS patients during the fourth quarter of 2008.
Completed Phase II Clinical Trial
Results from a completed Phase II clinical trial in RR-MS patients demonstrated BHT-3009’s efficacy and ability to induce antigen-specific tolerance with limited side effcts in a pre-specified set of 80 patients. Characterized as the immunology group, these patients had high CNS immune activity as measured by high levels of antibodies in their CSF at enrollment. Prior to initiation of the trial and based on BHT-3009’s mechanism, Bayhill anticipated that these patients would respond best to BHT-3009 therapy because high levels of immune activity are evidence of a strong immune response to the MBP and other myelin self-antigens.
At the end of treatment, patients in the immunology group who received 0.5 mg of BHT-3009 showed a decrease in brain lesions measured with magnetic resonance imaging (MRI) and a reduction in relapse rates versus placebo.
Design: Randomized, double-blind, placebo-controlled trial in patients with RR-MS who had minimal or no prior therapy for MS.Patients were randomized on a 1:1:1 basis to receive 0.5 mg of BHT-3009, 1.5 mg of BHT-3009 or placebo via Intramuscular injection at weeks 0, 2, 4 and once every 4 weeks thereafter for up to 13 doses. Brain MRIs were scheduled throughout the trial in weeks 8, 16, 28, 32, 36, 40, 44 and 48.
Primary Objective: Changes in brain inflammation assessed by brain MRI, gadolinium-enhancement and other radiological measures. Brain gadolinium-enhancing lesions are a measurement of acute central nervous system inflammation
Safety Results: Among the three treatment groups (0.5 mg, 1.5 mg, and placebo) in the ITT population, there were no significant differences in the number or severity of adverse events. Most adverse events were mild or moderate and lasted for a short period of time. All three treatment groups had similar incidences of local injection site and post-injection systemic reactions, and showed no significant differences in clinical laboratory abnormalities.
Efficacy Results: BHT-3009 is effective in patients with high CNS immune activity and induces antigen-specific tolerance with limited side effects.
Detailed Analysis:
Immunology Group
As part of the trial, all of the patients enrolled in two of the study’s sites, a total of 80 patients, which we refer to as the “immunology group,” underwent baseline lumbar punctures to evaluate the immune activity in the cerebral spinal fluid as measured by Immunoglobulin G, or IgG, antibodies, which include antibodies to MBP and other myelin antigens. High levels of immune activity as measured by IgG indicate a strong immune response. The measurement of IgG has been in use for the past 40 years, is well understood in the medical community and, we believe, is readily available to physicians treating patients with RR-MS.
BHT-3009 was designed to decrease the autoimmune response to myelin antigens. It was reasonable to expect that patients’ clinical and radiographic responses to BHT-3009 would depend upon their pre-treatment immune activity. Patients having strong pre-treatment immune activity would be expected to respond well to BHT-3009 treatment while patients with low immune activity would be expected to respond less well.
Patients whose baseline IgG levels were greater than or equal to 2.5 mg/dl, representing 73% of the 80 patients in the immunology group, demonstrated a statistically significant response to the 0.5 mg dose of BHT-3009. In this population, the number of new gadolinium-enhancing lesions shown on MRIs from weeks 28 to 48 was reduced by 44% (p=.04) versus placebo. Additionally, a statistically significant response to BHT-3009 was demonstrated in each sub-group of patients when stratified by IgG levels in 0.5 mg/dl increments from 2.5 mg/dl to 5.5 mg/dl. These data support our hypothesis that patients who are more immunologically active are more likely to respond to BHT-3009. In addition, increasing pretreatment levels of IgG across the range from 2.5 mg/dl to 5.5 mg/dl correlated with a greater likelihood of response to the 0.5mg dose of BHT-3009.Annualized relapse rates for patients whose baseline IgG levels were greater than or equal to 2.5 mg/dl were reduced by 36%. In addition, this favorable trend in relapse rates was demonstrated in each sub-group of patients when stratified into IgG levels in 0.5 mg/dl increments from 2.5 mg/dl to 5.5 mg/dl.
Additional analyses of the immunology group revealed trends for improvement in other measures of brain inflammation, including T2 lesion number, T2 lesion volume and T1 black hole volume after treatment with the 0.5 mg dose of BHT-3009.
Induction of Tolerance
In the immunology group, BHT-3009 was shown to induce antigen-specific tolerance by the reduction of antibodies to MBP and other myelin-specific self-antigens in the CSF. An evaluation of changes in CSF antibodies to myelin antigens from pre-treatment to week 44 in the immunology group demonstrated no significant net change among the 28 patients who received placebo. In contrast, there were significant decreases in antibodies to MBP and other disease-associated self-antigens, including PLP, OSP, MOG, alpha-b crystallin and MOBP, in the 27 patients who received the 0.5 mg dose of BHT-3009. These data demonstrate the induction of disease-associated antigen-specific tolerance, which could be fundamental to improving the outcome in autoimmune disease.
Overall Trends in MRI Activity
In the Per Protocol Population, defined as patients who met pre-specified eligibility, treatment and analysis criteria, the evaluation of all post-randomization MRIs indicated a statistically significant reduction (p=0.05) of new gadolinium-enhancing lesions among patients in the 0.5 mg BHT-3009 group on the evaluation of all post-randomization MRIs compared to placebo.
In the overall ITT population, MRI scans showed fewer new brain gadolinium-enhancing lesions in patients treated with 0.5 mg of BHT-3009 compared to placebo, or the primary endpoint. The overall results for the ITT population, which included both patients with high levels of immune activity as well as patients with low levels of immune activity, showed a trend in favor of BHT-3009. This trend was not statistically significant.
In addition to measuring brain gadolinium-enhancing lesions as the primary endpoint, the study looked at other measures of brain inflammation in the ITT population, which revealed trends for improvement in T2 lesion number and volume and T1 black hole volume after treatment with 0.5 mg of BHT-3009. Although encouraging, the trial was not designed to detect changes in the number of relapses and disability scores and, as anticipated, the number of relapses was too low to determine if BHT-3009 affected relapse rates.
In contrast to the trends for improved MRI measures on the 0.5 mg BHT-3009 arm, there were no signifcant differences with respect to the primary endpoint in patients treated with the 1.5 mg dose of BHT-3009 compared with placebo.
Based on data from the clinical trial, Bayhill plans to evaluate 0.5 mg BHT-3009 and one additional dose < 0.5 mg in a Phase IIb clinical trial. The administration schedule is expected to mirror that of the Phase II trial, with intramuscular injections of either BHT-3009 or placebo scheduled at weeks zero, two, four and monthly thereafter throughout the duration of the treatment period.
Phase I Trial
Design: Randomized, double-blind, placebo-controlled, dose-finding Phase I trial evaluating BHT-3009 administered as monotherapy, or in conjunction with atorvastatin, in RR-MS or secondary progressive MS (SP-MS) patients who had failed standard therapy.
Primary Objective: Safety
Secondary Objectives: Ability of BHT-3009 to induce tolerance to myelin antigens.
Safety Results: BHT-3009 was safe and well-tolerated. Most adverse events were brief in duration and mild or moderate in severity among both the treatment and placebo groups, with each experiencing a similar number of events. At three years, patients who received BHT-3009 had no observable side effects.
Efficacy Results: BHT-3009 demonstrated immunological activity. Blood T cell responses to myelin self-antigens decreased without altering responses to normal stimuli, which suggest that BHT-3009 acts selectively without inhibiting other normal immune system functions.
