Colin Living with Porphyria First Quarter 2017 Financial Results May 5, 2017 1
Agenda Welcome • Christine Regan Lindenboom Vice President, Investor Relations & Corporate Communications Q1 2017 Overview • John Maraganore, Ph.D. Chief Executive Officer Alnylam Clinical Pipeline • Akshay Vaishnaw, M.D., Ph.D. Executive Vice President of R&D Financial Results • Michael Mason Vice President, Finance and Treasurer 2017 Goals Update • Barry Greene President Q&A Session 2
Alnylam Forward Looking Statements This presentation contains forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. There are a number of important factors that could cause actual results to differ materially from the results anticipated by these forward- looking statements. These important factors include our ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of our product candidates; pre-clinical and clinical results for our product candidates; actions or advice of regulatory agencies; delays, interruptions or failures in the manufacture and supply of our product candidates; our ability to obtain, maintain and protect intellectual property, enforce our intellectual property rights and defend our patent portfolio; our ability to obtain and maintain regulatory approval, pricing and reimbursement for products; our progress in establishing a commercial and ex-United States infrastructure; competition from others using similar technology and developing products for similar uses; our ability to manage our growth and operating expenses, obtain additional funding to support our business activities and establish and maintain business alliances; the outcome of litigation; and the risk of government investigations; as well as those risks more fully discussed in our most recent annual report on Form 10-K under the caption “ Risk Factors.” If one or more of these factors materialize, or if any underlying assumptions prove incorrect, our actual results, performance or achievements may vary materially from any future results, performance or achievements expressed or implied by these forward-looking statements. All forward-looking statements speak only as of the date of this presentation and, except as required by law, we undertake no obligation to update such statements. 3
John Maraganore, Ph.D. Chief Executive Officer Q1 2017 Overview 4
Strategic Context for 2017 APOLLO Phase 3 topline results expected in mid-2017 • If positive, plan to file NDA/MAA at year-end Expect to advance three additional programs into Phase 3 studies • Fitusiran, for the treatment of hemophilia • Givosiran, for the treatment of acute hepatic porphyrias • Inclisiran, for the treatment of hypercholesterolemia (in collaboration with The Medicines Company) Building world-class team and capabilities in preparation for potential transition to commercial stage • Includes Quality, Medical Affairs, Manufacturing, and Commercial teams • Buildup in North America and Western Europe, and then Global 5
Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D Alnylam Clinical Pipeline 6
Alnylam ATTR Amyloidosis Portfolio Committed to Continued Innovation for Patients Patisiran ALN-TTRsc02 • IV administration • ESC “second generation” chemistry • Phase 2 completed • Anticipate quarterly SC dose • Phase 3 trial regimen ongoing; fully enrolled with top- • Phase 1 ongoing; initial positive line results expected in mid- 2017 data presented December 2016 • APOLLO-OLE study ongoing 7
Patisiran Phase 2 OLE Final Study Results Change in mNIS+7 at 24 Months 29.6 20 out of 27* patients (74%) with no change or an improvement in 30 30 (3.1) mNIS+7 at month 24 compared to baseline 25.8 (9.4) 25 Mean (SEM) Δ mNIS+7 from baseline at 24 mos~ 25 20 20 Δ mNIS+7 from baseline to Month 24 15 15 9.2 10 (2.7) 10 5 Patisiran 5 Ph 2 OLE ^ (N=26) 0 0 // // (nonlinear; N=283) 1# Placebo (N=66) Diflunisal (N=64) Natural History -5 -5 -7.0 -10 -10 Diflunisal (2.0) Ph 3 Study 2+ -15 -15 -20 -20 -25 -25 Mean Δ mNIS+7 Across -30 -30 hATTR Amyloidosis Studies Individual Δ mNIS+7 at Month 24 (n=26) at 24 mos ~ -35 -35 Adams et al. , AAN, April 2017; SEM: Standard Error of the Mean; *One patient discontinued prior to the Month 24 assessment and is included in the denominator ~Assessments drawn from studies in patients with similar baseline neurologic impairment and not based on head-to-head studies #Predicted progression of median NIS value from Gompertz curve fit 1 +Linear interpolation from 2-year NIS progression measurement in longitudinal analysis set ^Patisiran results similar in patients with/without concurrent TTR stabilizer therapy; mNIS+7 using full mNIS+7 set; partial imputation was used to recover mNIS+7 data points where components were missing at one or more replicate measurements (per patient/visit) 8 1. Adams D et al . Neurology. 2015;85;675-682. 2. Berk JL et al . JAMA. 2013;310:2658-67.
Patisiran Phase 2 OLE Final Study Results Change in mNIS+7 at 24 Months by Baseline NIS Tertile 20 Change in mNIS+7 from Baseline to Month 24 Individual Δ mNIS+7 at Month 24 (n=26) 10 0 -10 -20 -30 -40 0 27 Mean (SEM) Δ mNIS+7 from Baseline NIS Baseline NIS Tertiles N Range Baseline to Month 24 First Tertile 7 4-13 -2.9 (2.0) Second Tertile 10 16-42 -9.4 (3.3) Third Tertile 9 46-93 -7.4 (4.3) SEM: Standard Error of the Mean Adams et al. , AAN, April 2017 9
Patisiran Phase 2 OLE Final Study Results TTR Amyloid Content in Skin: Lower Limb • Blinded analysis of tandem skin punch biopsies performed at central lab; statistical significance testing performed post-hoc • Dermal amyloid content in both distal thigh and distal leg decreased over time relative to baseline ◦ Statistically significant decrease in absolute change for distal thigh at 6, 18 and 24 months and at all time points for distal leg Distal thigh dermal amyloid content ‡ in Patient 050-0003 Mean Absolute Change from Baseline Median Relative Change from Baseline in Dermal Amyloid Content in Dermal Amyloid Content 12 months 18 months 24 months 6 months Mean Absolute Change from Baseline in 0 Median Relative Percent Distal Thigh N Change (IQR) Dermal Amyloid Content, % 6 months 22 -52.5 (-75.7, 0) 12 months † 19 -61.8 (-87.5, 0) -3.81* -5 -4.27 -4.58* N=20 18 months 20 -78.2 (-89.7, -8.3) N=20 N=22 24 months † 19 -23.8 (-78.3, 0) -6.38* Baseline -7.23* N=19 -8.01* N=22 Median Relative Percent N=20 -10 Distal Leg N Change (IQR) -9.48* N=18 -10.71* 6 months 22 -48.5 (-74.3, 0) N=19 12 months 18 -64.6 (-85.8, 0) Distal Thigh (Baseline Amyloid content (n=24): 10.9%) 18 months † 18 -67.5 (-91.3, -10) -15 Distal Leg 24 months † 18 -40.4 (-78.3, -21.6) (Baseline Amyloid content (N=24): 15.8%) * P<0.05 IQR, Interquartile Range; † 1 patient excluded due to baseline value of 0 and a non-zero post-baseline value 24months ‡ Red: Amyloid by Congo red staining 10 Adams et al. , AAN, April 2017
Patisiran Phase 2 OLE Final Study Results Summary Patisiran generally well tolerated in patients with hATTR amyloidosis out to 25 months ◦ No drug-related SAEs and majority of AEs were mild or moderate ◦ Drug- related AEs reported in ≥4 patients were infusion related reaction (22.2%) and flushing (22.2%), all of which were mild Results consistent with therapeutic hypothesis that patisiran can potentially halt or improve neuropathy progression ◦ Long-term patisiran administration resulted in improvement in neuropathy impairment score with mean 7.0-point decrease in mNIS+7 at 24 months – Compares favorably to expected mean 26-30 point increase in mNIS+7 at 24mo estimated from analyses of separate historical data sets in untreated hATTR patients with similar baseline neuropathy impairment ◦ Improvement or no change in mNIS+7 observed in 20 of 27 (74%) patients ◦ In exploratory analyses, observed an increase in sweat gland nerve fiber density and a decrease in dermal amyloid content in the distal thigh and leg relative to baseline All eligible patients have enrolled into the APOLLO-OLE study and will continue to receive patisiran dosing ◦ As of May 5, 2017, more than 20 patients received ≥ 36 months of patisiran dosing; plan to present data in late 2017 Plan to present APOLLO Phase 3 topline results in September 11
Fitusiran for Hemophilia Potential to Restore Hemostasis in Hemophilia Genetically validated, Biomarker for POC Definable path to approval liver-expressed target gene in Phase 1 and patient access Established Endpoint Plasma Biomarkers Hemophilia A FVIIa FVII Annualized Bleeding Rate (ABR) AT Lowering, FX FVIII FVIIIa Thrombin Generation 140 100 AT % Lowering Hemophilia B Peak Thrombin 120 FIX FIXa FIX 80 AT 100 Peak Thrombin (nM) AT FXa AT Activity (%) 60 80 FVa FV 60 40 Thrombin Prothrombin 40 20 20 Photo courtesy of Guy Young, M.D. Fibrinogen Fibrin Director, Hemostasis & Thrombosis Center at Children's Hospital Los Angeles and Professor of Pediatrics, USC 0 0 Keck School of Medicine -30 0 Days 60 120 Blood clot 12 Fitusiran Phase 1 results: Pasi et al. , WFH , July 2016
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