ALN-PCS01 / Alnylam, Novartis - LARVOL DELTA

Aegerion Pharmaceuticals: We are bullish on the lomitapide story (SeekingAlpha) - FDA's EMDAC to hold an advisory panel to review lomitapide along with Kynamro in Sep or Oct 2012; Aegerion has a PDUFA date of Dec 29, 2012; The decision by the EU is expected in H1 2013; Lomitapide has a clear edge due to its efficacy, oral-dose formulation & superior safety/tolerability profile; AMG145 & REGN727 are being developed by Amgen & Regeneron /Sanofi, respectively; Two antisense drug candidates targeting PCSK9 mRNA, ALN-PCS01 & BMS-PCSK9Rx, are developed by Alnylam & Isis in collaboration with BMS, respectively

Anticipated FDA decision • Anticipated PDUFA date • EMDAC review • Dyslipidemia

Alnylam Pharmaceuticals reports first quarter 2015 financial results and highlights recent period progress (Alnylam Press Release) - P1, N=NA; "We have also continued enrolling subjects in our ALN-PCSsc Phase 1 study…initial Phase 1 data for ALN-PCSsc expected in mid-2015…”

Anticipated P1 data • Dyslipidemia

Alnylam Pharmaceuticals Inc: Rodman morning summary (Rodman and Renshaw) - P1 proof-of-concept data for ALN-PCS expected in Q4 '11

Financial analyst: Clinical • Dyslipidemia • None

Alnylam Pharmaceuticals reports first quarter 2013 financial results (Alnylam) - "Formed Strategic Alliance with The Medicines Company to Develop and Commercialize ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Hypercholesterolemia."

Licensing / partnership • Dyslipidemia

Trial to evaluate safety and tolerability of ALN-PCS02 in subjects with elevated LDL-cholesterol (LDL-C) (clinicaltrials.gov) - P1, N=32; Sponsor: Alnylam; Active, not recruiting -> Completed

Trial completion • Dyslipidemia

The Medicines Company: Annual Report 2013 (The Medicines Company) - Anticipated initiation of P1 trial for hypercholesterolemia in Q4 2014/Q1 2015

Anticipated trial initiation date • Atherosclerosis • Dyslipidemia

The Medicines Company: Annual Report 2013 (The Medicines Company) - Anticipated patent expiry in US on general RNAi technology between 2015-2021; Anticipated patent expiry ex US on general RNAi technology between 2015-2021; Anticipated composition of matter and methods of treatment patent expiry in May 2027

Anticipated patent expiry • Atherosclerosis • Dyslipidemia

Q2 2012 Results (Alnylam) - "Rapid, dose-dependent, and durable knockdown of PCSK9 of up to 84% with mean lowering of 68% at 0.4 mg/kg group (p<0.0001); Major reductions in LDL-C of up to 50% with mean lowering of 41% at 0.4 mg/kg group (p<0.01)"

P1 data • Dyslipidemia

Alnylam: Barclays Global Healthcare Conference (Alnylam) - "ALN-PCS Phase I Study Results"; "Pharmacodynamics and Clinical Efficacy"; "PCSK9 knockdown and LDL-C reduction after single dose without statins"; "Randomized, placebo controlled, single dose escalation study in healthy volunteers with elevated LDL (n=32)"; "Rapid, dose-dependent, and durable knockdown of PCSK9 of up to 84% with mean lowering of 68% at 0.4 mg/kg group (p<0.0001)"; "Major reductions in LDL-C of up to 50% with mean lowering of 41% at 0.4 mg/kg group (p<0.01)"

P1 data • Dyslipidemia

Alynlam: Corporate Overview (Alnylam) - Anticipated partnership to initiate P2 trials for severe hypercholesterolemia in 2013

Anticipated licensing / partnership • Anticipated new P2 trial • Dyslipidemia

Alnylam Pharmaceuticals: Q2 2015 Results (Alnylam) - Anticipated presentation of initial data from P1 trial in hypercholesterolemia at ESC (Aug 30, 2015)

Anticipated P1 data • Dyslipidemia

The Medicines Company: Annual Report 2015 (The Medicines Company) - Anticipated patent expiry in US on general RNAi technology between 2016-2028; Anticipated composition of matter and methods of treatment patent expiry in May 2027; Anticipated expiry of patent in US and ex-US at end of 2033

Anticipated patent expiry • Dyslipidemia

Alnylam and collaborators publish clinical trial results with ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia, in The Lancet (Alnylam Press Release) - P1, N=32; NCT01437059; Sponsor; Alnylam Pharmaceuticals; "...announced today the publication in The Lancet of complete study results from a Phase I trial with ALN-PCS...resulted in a rapid, dose-dependent reduction in plasma PCSK9 of up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of low-density lipoprotein cholesterol (LDL-C) – a clinically validated endpoint – of up to 57% relative to baseline and placebo."

P1 data • Atherosclerosis • Dyslipidemia

ALN-PCSsc achieves quarterly and potentially bi-annual subcutaneous dose regimen profile for effective LDL-C lowering in phase 1 clinical study (Alnylam Press Release) - P1, N=69; NCT02314442; Sponsor: Alnylam; "Alnylam Pharmaceuticals...and The Medicines Company...announced today positive initial results from their ongoing Phase 1 clinical trial with ALN-PCSsc at ESC Congress 2015...initiation of the ORIONTM development program, with an initial Phase 2 study planned to begin by end-2015 and a Phase 3 study expected to begin by end-2017. ORION is also expected to include a comparative study of ALN-PCSsc with anti-PCSK9 MAbs...Reductions in LDL-C were highly durable, with a 44 ± 1% mean lowering (p < 0.001, relative to baseline) in the 300 mg cohort maintained at 140 days after a single dose; data collection beyond 140 days is ongoing."

Anticipated new P2 trial • Anticipated new P3 trial • Conference • P1 data • Dyslipidemia

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: A randomised, single-blind, placebo-controlled, phase 1 trial (Lancet) - P1, N=32; NCT01437059; Sponsor: Alnylam Pharmaceuticals; “The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%])... treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0•0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0•0001).”

P1 data • Atherosclerosis • Dyslipidemia

The Medicines Company and Alnylam form strategic alliance to develop and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia (Alnylam) - "Alnylam will continue the program for an estimated one to two years to complete certain pre-clinical and Phase I clinical studies. The Medicines Company is responsible for leading and funding development from Phase II forward and commercializing the ALN-PCS program if successful. Under the terms of the agreement, The Medicines Company will make an upfront cash payment of $25 million to Alnylam. Alnylam may also receive potential development and commercial milestone payments of up to $180 million. Alnylam will be eligible to receive scaled double-digit royalties on global products sales of ALN-PCS products."

Licensing / partnership • Dyslipidemia