Slide 1: Top-line Results of a Study of Rilonacept (IL-1 Trap) for Prevention of Gout Flares
Top-line Results of a Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability, and Efficacy of Rilonacept (IL-1 Trap) for the Prevention of Gout Flares During Initiation of Allopurinol Therapy Regeneron Pharmaceuticals, Inc. Investors' Webcast September 3, 2008
Slide 2: Safe Harbor Statement
Except for historical information, the matters contained in this presentation may constitute forward-looking statements that involve risks and uncertainties, such as risks associated with preclinical and clinical development of Regeneron's drug candidates, determinations by regulatory and administra
Slide 3: Gout
Gout Gout: a disease resulting from the deposition of monosodium urate crystals in the joints caused by excess serum uric acid (a bodily waste product normally excreted by the kidneys) Clinical manifestations: acute and chronic pain/inflammation of joints and surrounding tissue tophi development (de
Slide 4: Allopurinol in the Treatment of Gout
Allopurinol in the Treatment of Gout Role: reduces the production of uric acid to help normalize serum uric acid levels with chronic use Usage: over 1.3 million gout patients receive allopurinol treatment each year over 750,000 new gout patient starts are initiated with allopurinol each year Major t
Slide 5: Gout: Evidence for Role of IL-1
Gout: Evidence for Role of IL-1 Gout has IL-1-associated clinical features inflammation, fever, elevated acute phase response IL-1 is a major product of human white blood cells stimulated by monosodium urate crystals (Duff, 1983, Malawista 1985, Martinon, 2006) The NLRP-3 (cryopyrin) inflammasome is
Slide 6: Gout: Evidence for Role of IL-1 (Continued)
Monosodium urate crystals internalized by monocytes activate the NLRP3 inflammasome which leads to the processing and release of IL-1^ IL-1^ induces the expression of adhesion molecules and chemokines which are critical for the recruitment of PMNs into the site of acute inflammation Martinon, 2006 G
Slide 7: Rilonacept (ARCALYST): Structure and Characteristics
Rilonacept (ARCALYST(r))): Structure and Characteristics Rilonacept: a dimeric fusion protein Specific blocker of IL-1, incorporating extracellular domains of the 2 receptor components required for IL-1 signalling IL-1RI (IL-1 receptor sub-type 1) IL-1RAcP (IL-1 receptor accessory protein) Molecular
Slide 8: Mechanism of Action of Rilonacept
Mechanism of Action of Rilonacept Certain inflammatory responses arise from excessive release of activated IL-1^ Rilonacept blocks IL-1 signaling by acting as a soluble decoy receptor that binds IL-1 and prevents its interaction with cell surface receptors IL-1 and inflammation Mechanism of action o
Slide 9: Cryopyrin-Associated Periodic Syndromes (CAPS)
Cryopyrin-Associated Periodic Syndromes (CAPS): Rare, Inherited, Auto-inflammatory Diseases with Life-long, Debilitating Consequences CAPS are characterized by lifelong, recurrent symptoms of rash, chills/fever, joint pain, fatigue, and eye redness/pain Intermittent, debilitating disease flares/ exa
Slide 10: CAPS: Generally Caused by a Mutation Resulting in Overproduction of IL-1
Cryopyrin PYD CARD CARD CARD CARD Inflammasome NBS LRR Monocyte/Macrophage CAPS: Generally Caused by a Mutation in a Gene that Helps Regulate the Body's Innate Immune Response, Resulting in Overproduction of Interleukin-1^ (IL-1^) PYD Autosomal-dominant mutation of NLRP-3/CIAS1 gene (in many patient
Slide 11: Phase Program Showed Marked Reduction in CAPS Symptoms with Rilonacept
Phase 3 Program Showed Marked Reduction in CAPS Symptoms with Rilonacept, but Not with Placebo - -3 0 3 6 (n=23) (n=24) 5 4 3 2 1 0 Rilonacept Placebo 3rd Qtr 4th Qtr Pre-treatment Baseline 3.1 2.4 90 20.4 Endpoint 0.5 2.1 34.6 31.6 North 45.9 46.9 45 43.9 Pre-treatment Baseline Period Part A Treatm
Slide 12: Important Information about Rilonacept
Important Information about Rilonacept Rilonacept is not indicated for use in gout. It is currently being studied in a Phase 2 exploratory trial in gout Rilonacept is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FC
Slide 13: Gout Pilot Study of Rilonacept: Single-Blind, Placebo Run-In
Gout Pilot Study of Rilonacept: Single-Blind, Placebo Run-In Study in Patients with Chronic Active Gout S D0 W2 W4 W6 W8 W14 xx xx xx x x x x x Two week placebo run-in Loading dose of rilonacept at Week 2 [2X 160 mg subcutaneously (SC)] followed by five weekly 160 mg SC injections of rilonacept Eval
Slide 14: Gout Pilot Study Findings: Pain Score Improved with Rilonacept
Gout Pilot Study Findings: Patients' Pain Score Improved with Rilonacept but not with Placebo (0 = normal/none to 10 = severe) (LOCF; N = 10) -1 0 2 4 6 8 14 Placebo Rilonacept Screening Off Treatment ns* P<0.02** * - Wk 2 v D0 ** - Wk 8 v Wk 2
Slide 15: Phase 2 Study Objectives
Phase 2 Study Objectives Primary Objective To assess the activity of rilonacept in reducing the frequency of acute gout flares in hyperuricemic patients initiating allopurinol therapy compared to placebo Secondary Objective To assess the severity and duration of gout flares during initiation of allo
Slide 16: Phase 2 Study Design
Phase 2 Study Design Multi-center, randomized double-blind, placebo- controlled trial in 83 hyperuricemic (serum uric acid > 7.5 mg/dL) patients with inter-critical gout Group 1- rilonacept 320mg on day 1, followed by rilonacept 160mg once a week for 16 weeks Group 2- placebo Patients in both treatm
Slide 17: Study Scheme
Study Scheme Rilonacept 160 mg subcutaneously weekly Rilonacept 160 mg subcutaneously weekly Rilonacept 160 mg subcutaneously weekly Rilonacept 160 mg subcutaneously weekly Rilonacept 160 mg subcutaneously weekly Rilonacept 160 mg subcutaneously weekly Rilonacept 160 mg subcutaneously weekly Rilonac
Slide 18: Patient Population
Patient Population Patients 18 years of age or older : Meeting the criteria of the American Rheumatism Association (ARA) for the classification of the acute arthritis of primary gout Serum uric acid ^ 7.5 mg/dL A self-reported history of ^ 2 gout flares in the year prior to the Screening Visit
Slide 19: Key Exclusion Criteria
Key Exclusion Criteria Acute gout flare within 2 weeks before Screening Visit Allergy to allopurinol Use of glucocorticoids or colchicine within 4 weeks before Screening Visit Use of NSAIDs within 2 weeks prior to the Screening Visit Use of allopurinol, probenecid, or sulfinipyrazone within 3 months
Slide 20: Efficacy Endpoints
Efficacy Endpoints Primary Endpoint: The mean number of gout flares assessed from Day 1 to Week 12 * A gout flare was defined as patient-reported acute joint pain deemed by the patient and/or investigator to require rescue anti-inflammatory therapy (NSAIDs or glucocorticoids) Secondary Endpoints: Th
Slide 21: Patient Disposition
Patient Disposition Placebo Rilonacept 160mg/kg Patients randomized & dosed 42 41 Patients who completed Week 12 33 40 Withdrawals before Week 12 9 1 Reasons for withdrawal before Week 12 [n(%)] - Lost to follow up - Lack of efficacy - Adverse event - Consent withdrawn - Other 4 (9.5%) 2 (4.8%) 2 (4
Slide 22: Baseline Characteristics
Baseline Characteristics Placebo Rilonacept 160mg/kg Patients randomized 42 41 Male (%) 95.0 98.0 Age yrs mean (median) 50 (52) 52 (50) Prior mean number of gout flares/yr 4.4 4.7 Prior mean duration of gout flare (days) 5.4 6.0 Tophi present 6 2
Slide 23: Efficacy Findings
EFFICACY FINDINGS REGENERON
Slide 24: Primary Endpoint: Mean Number of Gout Flares Per Patient Through Week 12
Primary Endpoint: Mean Number of Gout Flares Per Patient Through Week 12 Placebo (n=42) Rilonacept (n=41) 0.79 0.15 Mean number of gout flares per patient 0.15 p < 0.0011 (33 flares) (6 flares) 0.79 81% ^
Slide 25: Time to First Gout Flare
Time to First Gout Flare Placebo Rilonacept Placebo Rilonacept censored Treatment Proportion of Subjects Gout-Flare Free 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 40 30 50 60 70 90 80 p=0.0003 Time to First Gout Flare (days)
Slide 26: Proportion of Patients with a Gout Flare Through Week 12
Proportion of Patients with a Gout Flare Through Week 12 Placebo (n=42) Rilonacept (n=41) 45 15 Proportion of patients with a grout flare p < 0.004 45.2% 14.6% (19 patients) (6 patients)
Slide 27: Proportion of Patients with a Gout Flare Through Week 12
Proportion of Patients with a Gout Flare Through Week 12 Placebo (n=42) Rilonacept (n=41) 45 15 Proportion of patients with a grout flare p < 0.004 45.2% 14.6% (19 patients) (6 patients) 47.4% > 1 flare 0 % > 1 flare
Slide 28: Mean Number of Days with a Pain Score >5 Through Week 12
Mean Number of Days with a Pain Score > 5 (0-10 scale) Through Week 12 Placebo (n=42) Rilonacept (n=41) 2.02 0.22 Mean number of days with pain score > 5 0.22 days p < 0.001 2.02 days
Slide 29: Safety Findings
SAFETY FINDINGS REGENERON
Slide 30: Safety Summary
Safety Summary No serious drug-related adverse events were reported with rilonacept Injection-site reaction was the most commonly reported adverse event reported with rilonacept treatment
Slide 31: Adverse Events Through Week 12
Adverse Events Through Week 12 Placebo (n=42) Rilonacept (n=41) Any Adverse Event [n(%)] 23 (55%) 17 (42%) Number of patients who discontinued due to an AE [n (%)] 3 (7.1%) 1 (2.4%) Serious AEs [n (%)] 2 (4.8%) 1 (2.4%)
Slide 32: Treatment-Emergent Adverse Events Through Week 12
Number of Patients with ^ 1 Treatment-Emergent Adverse Event Through Week 12 (reported in at least 5% of patients in either group treated) High-level Term AE Category Placebo (n=42) Rilonacept (n=41) Injection/infusion site reaction 1 (2.4%) 4 (9.8%) Upper respiratory tract infections 4 (9.5%) 1 (2.
Slide 33: Infections
10% of rilonacept-treated patients and 19% of placebo- treated patients reported 1 infection or more 1 rilonacept-treated patient reported pyleonephritis 2 placebo-treated patients reported bronchitis 1 rilonacept-treated patient and 4 placebo-treated patients reported upper respiratory tract infect
Slide 34: Conclusions
Conclusions In a Phase 2 study of gout patients initiating therapy with allopurinol to lower their uric acid levels Rilonacept produced an 81% statistically significant reduction in the mean incidence of gout flares per patient versus placebo over the first 12 weeks of therapy 45.2% of patients trea