These Clinical Study Results are provided for informational purposes only.

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1 These Clinical Study Results are provided for informational purposes only. The study listed may include approved and non approved uses, formulations or treatment regimens. It is not intended to promote any product or indication and is not intended to replace the advice of a health care professional. The results reported in any single clinical trial may not reflect the overall results obtained across the product development. Only a physician can determine if a specific product is the appropriate treatment for a particular patient. If you have questions, please consult a health care professional. Before prescribing any product, healthcare professionals should consult prescribing information for the product approved in their country.

2 101MS101: High Titer Comparability 2 STUDY SYNOPSIS Title of Study: An Open-Label, Multicenter, Randomized, Crossover Study in Subjects with Relapsing Forms of Multiple Sclerosis Comparing the Pharmacokinetic Properties of Produced by the Current Commercial Process and Produced by the High Titer Process Coordinating Investigator: Germany Study Period: Date of first treatment: 23 January 2007 Date of study completion: 31 March 2008 Phase of Development: 1b Study Objective(s): Primary objective(s): The primary objective of this study was to establish the pharmacokinetic (PK) comparability of commercial scale (BG00002-B) natalizumab and high-titer natalizumab (), administered IV over 60 minutes to subjects with relapsing forms of multiple sclerosis (MS). The primary PK parameters that were used to determine comparability were: The area under the curve for the serum concentration of natalizumab to the last measurable concentration (AUC last ) The area under the curve for the serum concentration of natalizumab to infinity (AUC inf ) The observed maximum concentration (C max ) Secondary objective(s): To compare the PD effects of BG00002-B and To assess the tolerability and safety BG00002-B compared to Study Design: This was an open-label, randomized study using a 2-period crossover design. Subjects were to be randomized to 1 of 2 treatment groups: Group 1 or Group 2. All subjects in each treatment group were to undergo 2 periods of treatment (Treatment Period A and Treatment Period B). Approximately 22 subjects were to be treated in each group. Group 1: 4 intravenous (IV) infusions of, 300 mg at Weeks 0, 4, 8, and 16 (Treatment Period A), and 1 IV infusion of BG00002-B, 300 mg at Week 24 (Treatment Period B). Group 2: 4 IV infusions BG00002-B, 300 mg at Weeks 0, 4, 8, and 16 (Treatment Period A). 1 IV infusion of, 300 mg at Week 24 (Treatment Period B) After completion of Treatment Period B, subjects may have been eligible to resume treatment with commercially available natalizumab, beginning at Week 32. 2

3 101MS101: High Titer Comparability Number of Subjects (Planned and Analyzed): Planned: 44 Analyzed: 43 Analysis Populations: The PK population was defined as all subjects who received the full 300 mg dose for both dose 4 (Week 16) and dose 5 (Week 24) infusions of natalizumab, who did not develop antibodies to natalizumab by Week 32 (56 days following Week 24/dose 5 infusion), and who had a sufficient number of the concentration measurements to calculate meaningful PK parameters. The pharmacodynamic (PD) population was defined as all subjects who received at least the Week 16 (dose 4) infusion of natalizumab and who had at least 1 measurement of α4 integrin after the Week 16 (Dose 4) infusion. The safety population was defined as all subjects who received at least 1 infusion of natalizumab and who had at least 1 post-infusion measurement of the safety parameter being analyzed. Since each subject was to receive both BG00002-B and, safety data was summarized according to the preparation received immediately prior to the evaluation. All safety analyses were based on the safety population. Study Population: Main inclusion criteria: Gave written informed consent and any authorizations required by local law (e.g., Protected Health Information [PHI]). Had a diagnosis of a relapsing form of MS, and falling within the therapeutic indications stated in the locally approved label for Tysabri. Aged 18 to 55 years old, inclusive, at the time of informed consent. Were natalizumab naïve. Weighed a minimum of 55 kg and have a BMI of between 18 kg/m 2 and 35 kg/m 2, inclusive. Were willing to remain free from concomitant immunosuppressive or immunomodulatory treatment (including interferon-beta [IFN-β] and glatiramer acetate [GA] for the duration of the study) Main exclusion criteria: Diagnosis of primary progressive, or secondary progressive MS without the occurrence of relapses (as defined by Lublin and Reingold, 1996). The subject was considered by the Investigator to be immunocompromised, based on medical history, physical examination, or laboratory testing, or due to prior immunosuppressive or immunomodulating treatment 3

4 101MS101: High Titer Comparability The subject was unable to have a brain MRI scan (e.g., a subject with metal clip to repair cerebral aneurysm). The subject had a history of, or available abnormal laboratory results indicative of, any significant disease that would preclude the administration of a recombinant humanized antibody immunomodulating agent for the course of the study. History of malignancy (subjects with basal cell carcinoma that has been completely excised prior to study entry remain eligible). Known history of human immunodeficiency virus infection, hepatitis C or hepatitis B infection. History of organ transplantation or anti-rejection therapy. History of severe allergic or anaphylactic reactions or known drug hypersensitivity. A clinically significant infectious illness (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to the Screening Visit. History of progressive multifocal leukoencephalopathy (PML). Previous treatment with natalizumab, any murine protein, or any other therapeutic monoclonal antibody. Treatment with immunosuppressant medications (e.g., mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate) within 3 months prior to randomization. Treatment with immunomodulatory medications (including IFNβ and GA) within 2 weeks prior to randomization. Positive urine drug screen at Screening Visit. Study Treatment, Dose, Mode of Administration, Lot Number(s): Dosing of BG00002-B and was to be consistent with the recommended dose regimen for the treatment of MS according to the currently approved label for natalizumab: 300 mg IV infusion of natalizumab over 60 minutes once every 4 weeks. At every infusion, subjects were to remain in the clinic for a minimum of 1 hour post-infusion for observation. In addition, at the Week 16 and Week 24 visits subjects were to remain in the clinic for 6 hours post-infusion for PK sampling. Lot Numbers: Duration of Treatment and Follow-Up: The study consisted of a screening period, a 32-week treatment period, and a follow-up to occur 12 weeks after the last dose of study treatment. Following the Week 32 visit, subjects may have been eligible to resume natalizumab treatment with commercially available natalizumab in the TOUCH (Tysabri Outreach Unified Commitment to Health) Prescribing Program. 4

5 101MS101: High Titer Comparability Criteria for Evaluation: Pharmacokinetics: The concentration of natalizumab in serum was determined at specified timepoints to establish the PK comparability of BG00002-B and administered IV over 60 minutes to subjects with relapsing forms of MS. The primary PK parameters used to determine comparability were: The area under the curve for the serum concentration of natalizumab to the last measurable concentration (AUC last ) The area under the curve for the serum concentration of natalizumab to infinity (AUC inf ) The observed maximum concentration (C max ) Pharmacodynamics: PD activity was assessed by measuring the degree of saturation of the VLA-4 (α4β1) receptor on peripheral blood lymphocyte/monocyte populations by natalizumab. Summary statistics for percentage saturation were calculated at specified timepoints for BG00002-B and. The mean values were plotted over time. Safety: The following safety parameters were assessed during the study: The incidence of adverse events. The occurrence of antibodies (immunogenicity) was analyzed at Weeks 0, 12, 16, 24, and 32 Laboratory evaluations Vital signs Statistical Methods: The bioequivalence of the 2 preparations was tested by constructing a 90% CI for the relative geometric mean ratio of to BG00002-B for C max, AUC last, and AUC inf. The standard 80% to 125% equivalence criterion was used. The data were transformed using natural logarithms, and the log-transformed data was analyzed using an analysis of variance model with factors for treatment group, subjects nested within treatment group (group), treatment period, and preparation. The CIs were constructed via the classical (shortest) CI approach, which is equivalent to Schuirmann s 2 one-sided tests procedure for comparability. 5

6 101MS101: High Titer Comparability Results: A total of 43 subjects at 4 investigational sites were randomized into this study, with 20 assigned to Group 1 ( followed BG00002-B), and 23 assigned to Group 2 (BG00002-B followed by ). Four subjects from each treatment group discontinued study drug prematurely (8 subjects, 19%), and withdrew from the study. All withdrawals occurred during period A. Group 1 subjects ( in Period A): 1 withdrawal due to anti-natalizumab antibodies; 1 voluntary; 1 due to an AE, and 1 per Investigator discretion. Group 2 subjects (BG00002-B in Period A): 4 subjects withdrew due to anti-natalizumab antibodies. There were no major protocol deviations, and no deviations that resulted in removal of a subject from PK, PD, or safety analyses. Demographics and baseline disease characteristics: The study population was comprised of 17 men (40%) and 26 women (60%) between 25 and 59 years of age (median 43 years), of whom 79% were Caucasian and 19% were black. Subjects weights ranged from 55.3 kg to kg, and BMI ranged from 18.2 to 35.0 (mean 26.19). There was no significant imbalance between the treatment groups for any demographic variable. MS history, relapse history, prior MS therapy, baseline Expanded Disability Safety Scale (EDSS) scores, and neurological examination findings were similar in both treatment groups. Pharmacokinetics: Thirty-five subjects (81%) received all 5 planned doses and were evaluable for pharmacokinetic analysis. Nearly identical concentration vs. time profiles were observed with and BG00002-B. Standard bioequivalence statistical comparisons for AUC inf, AUC last, and C max ratios demonstrated bioequivalence of and BG00002-B. The least squares mean ratio for to BG00002-B from baseline-corrected measurements were: AUC last : 104% (90% CI; 101% to 107%) AUC inf : 104% (90% CI; 101% to 106%) C max : 105% (90% CI; 100% to 109%) The frequency of development of anti-natalizumab antibodies was similar in subjects who received BG00002-B compared to subjects who received during Period A. Pharmacodynamics: 37 subjects (86%) were evaluable for pharmacodynamic analysis. Mean 28-day alpha-4 integrin vs. time profiles were similar for and BG00002-B. Mean saturation values at the end of a typical 28-day dosing interval exceeded 77% for both and BG00002-B. 6

7 101MS101: High Titer Comparability Safety: No significant or clinically meaningful differences were observed in the overall incidence or nature of AEs, SAEs, or infections when analyzed by natalizumab preparations or treatment sequences. In addition, small differences that were observed appeared random and not indicative of any differences between the preparations. There was no evidence of any safety concerns following the switch from either or BG00002-B to the other preparation. The overall incidence of infection was 53% (23 subjects), and was similar following treatment with each natalizumab preparation. Three serious infections occurred, 2 following treatment with (bronchitis, urinary tract infection) and 1 following treatment with BG00002-B in a subject who had previously received (pneumonia). None of these events was considered related to study drug by the Investigator, and subjects continued study participation. A total of 6 SAEs were reported by 4 subjects, 3 of which were infections (described above). The remaining 3 events were muscle spasticity, MS relapse, and left clavicle fracture and laceration of the skin, both related to a bicycle accident. Infusion reactions, defined as AEs occurring within 2 hours after the start of a natalizumab infusion, were reported by 6 subjects (14%) overall, with 4 subjects (10%) receiving and 2 subjects (5%) receiving BG00002-B at the time of the event. None of these events was serious. No infusion reactions were reported following the switch from one preparation to the other. A single hypersensitivity reaction of an allergic urticarial rash was reported in a subject during the 4 th infusion of which led to discontinuation of the infusion and withdrawal from the study. No significant differences were observed in laboratory parameters between the natalizumab preparations or treatment seuqences. Four subjects who received BG00002-B during Period A developed anti-natalizumab antibodies compared with 2 subjects who received. No subject developed anti-natalizumab antibodies following the switch from one preparation to the other. Conclusions: produced by the process was found to be bioequivalent to natalizumab produced by the BG B process across all PK and PD parameters studied. Similar safety profiles were observed for both preparations of natalizumab, and no safety concerns were identified following the switch from either or BG00002-B to the other preparation. These results confirm that and BG00002-B are equivalent. Publication(s) Based on the Study: None. Date of Report: 14 July