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Navigate the Alnylam $ALNY Notes Pages

  • Introduction (valuation, milestones, pipeline, general commentary)
  • RNAi Background (science, delivery technologies, patents, litigation)
  • ALN-TTR (lead 5x15 program for transthyretin amyloidosis)
  • 5x15 Programs (details on 5x15 strategy and info on additional preclinical programs)
  • Partnered Programs (partnered clinical and preclinical assets falling outside the 5x15 focus area)
  • Alliances and Licensing (RNAi platform deals and other licensing agreements with pharma companies)

VaxiRNA Collaboration with GSK

alny gsk vaccine rnai
11/1/11 3q2011 earnings CC

ALN-RSV01

  • RNAi therapeutic being developed for respiratory syncytial virus infection (click for scientific article). 
  • Market Opportunity: “RSV is a highly contagious virus that causes infections in both the upper and lower respiratory tract. RSV infects nearly every child by the age of two years and is responsible for a significant percentage of hospitalizations of infants, children with lung or
  • congenital heart disease, the elderly and adults with immune-compromised systems, including lung transplant recipients. RSV infection typically results in cold-like symptoms, but can lead to more serious respiratory illnesses in these populations such as croup, pneumonia and bronchiolitis, and in extreme cases, severe illness and death. A study published in 2005 in the New England Journal of Medicine estimates that over 170,000 elderly adults are hospitalized with RSV each year. In addition, experts estimate that the overall prevalence of lung transplants in the United States is between 8,000 to 10,000. The annual incidence of RSV infection in lung transplant patients can be up to ten percent.”
  • Current Treatments: “The only product currently approved for the treatment of RSV infection is Ribavirin, which is marketed as Virazole® by Valeant Pharmaceuticals. However, this product is approved only for treatment of hospitalized infants and young children with severe lower respiratory tract infections due to RSV. Administration of this product is complicated and requires elaborate environmental reclamation devices because of potential harmful effects on healthcare personnel exposed to the drug. In addition, Ribavirin is used by some centers in the treatment of RSV in lung transplant patients. Two other products, a monoclonal antibody known as Synagis® (palivizumab) and an immune globulin known as RespiGamtm, have been approved for the prevention of severe lower respiratory tract disease caused by RSV in infants at high risk of such disease. Neither of these products is approved for treatment of an existing RSV infection.”
  • 2/2010 initiated global RDBPC p2b trial of aerosolized formulation in adult lung transplant pts. Up to 76 pts 1:1 w/ placebo. “The primary endpoint is a reduction in the incidence of new or progressive bronchiolitis obliterans syndrome, or BOS, a potentially life-threatening complication in lung transplant patients”- at day 
  • 5/2/11: Announced that they received approval to conduct interim analysis (blinded to ALNY) to adaptively adjust sample size, could increase to 120 pts. Will do this analysis when 75% pts are evaluable. Accrual rate has exceeded expectations, have reached target of 76, still enrolling until interim analysis later this yr and data 2012
  • 5/2/11 Question: Why do the interim look? We had always wanted to do an interim look. We recently completed discussions about this w/ FDA. This trial is based on a very small p2a study (~25pts), want to reproduce those data w/ more robustness. CEO did not answer whether there is alpha burn for the interim.
  • 5/2/11 question: What would size of p3 RSV trial be? This is life-threatening complication w/ 50% mortality...which could affect FDA's desired study size...There is some small chance this study is sufficient for filing, but FDA may well want data reproduced in similar sized study...current one is largest p2b ever among this transplant patient population.
  • Partnered w/ Cubist 1/2009 for RSV01 and several 2nd generation backups, $20m upfront [$1m paid to ISIS] and up to $82.5m milestones, plus double digit royalties (equal split in NA).  Jointly develop in North America, CBST does ROW except Asia. ALNY is developing at own risk and expense for lung transplant, CBST has right to opt in to this program for a specified period of time after completion of p2b by paying an undisclosed, prespecified % of pgm costs. Can convert NA to same royalty model and get up to $130m more milestones. 
  • 11/2009 decided to focus on RSV02 for pediatric use and then 12/2010 jointly decided to put development on hold 
  • 6/2008 Partnered with Kyowa Hakko Kirin for RSV in Japan/Asia for RSV01 and all other RSV directed programs, $15m upfront and up to $78m milestones, plus royalties, KHK pays for development, focus first on Japan, can terminate on 180 days notice). 
  • 2/2008 reported positive RDBPC GEMINI p2 data in 88 (1:1) adults experimentally infected w/ RSV- safe and well tolerated, 40% decrease in viral infection rate and 95% increase in RSV-free pts vs placebo. 
  • 7/2009 (w/ CBST) reported p2a data RDBPC trial of aerosolized formulation in 24 adult lung transplant pts. No safety issues. Baseline imbalances in viral load made it hard to interpret data, but trends favor RSV01. 7% new or progressive BOS vs 50% in placebo – this differece was statistically significant

ALN-VSP

  • RNAi therapeutic consisting of two siRNAs, one against VEGF (a potent angiogenic factor that drives the development of blood vessels that are critical to ensuring adequate blood supply to the growing tumor) and one against kinesin spindle protein (KSP-a key component of the cellular machinery that mediates chromosome separation during cell division, which is critical for tumor proliferation)
  • Utilizes 1st generation LNP formulation and being developed for primary (700k per yr worldwide) and secondary (500k per yr) liver cancer (at best is 20% 5 yr survival if detected early-represents 15% of total, most=fatal in 3-6 months). 
  • First systemically delivered RNAi to enter clinic. 
  • 3/2009 initiated multicenter open label p1 trial in up to 55pts with advanced cancers with liver involvement. Interim data 2010 and 2011 shows was generally well tolerated and signs of biological activity. 5/2/11: enrollment completed 4/2011, with multiple pts still receiving therapy.
  • 11/2010 reported interim safety data from Phase I clinical trial “showing that 127 doses of ALN-VSP at dose levels of 0.1 to 1.25 mg/kg had been administered to 28 patients, with two to 13 doses administered per patient, and was generally well tolerated. The majority of the patients treated had colorectal cancer, a primary tumor that often metastasizes to the liver. No dose-dependent trends were observed in clinical or laboratory adverse events, including liver function tests. A patient with advanced pancreatic neuroendocrine cancer with extensive involvement of the liver developed hepatic failure five days following the second dose at 0.7 mg/kg, and subsequently died; this was deemed possibly related to the study drug. At 1.25 mg/kg, a patient experienced grade three thrombocytopenia after the first dose; this was deemed related to the study drug and was resolved within five days. There have been three acute infusion reactions at 0.4, 0.7 and 1.25 mg/kg; all three patients tolerated further treatment with prolongation of infusion duration.” 
  • 6/2010 data showed anti-VEGF activity in pt tumor samples. 
  • 1/2011 data showed detection of siRNA in nearly all tumor tissues at pharmacologically relevant concentrations. 
  • 6/2011 at ASCO: presented phase 1 data. 41 pts received 182 doses ranging from 0.1 to 1.5 mg/kg. Multiple pts achieved SD or better (12 of 24 SD at 0.7 or higher doses, one ongoing PR). Adverse evens included fever, fatigue, and nausea in 25-25% of pts, no dose dependent changes in liver function tests. One liver failure leading to death ruled "possibly drug related." Recommend 1.0 mg/kg every two weeks as phase 2 dose. also measured siRNA presence in nearly all tumor biopsies taken, at concentrations that lead to meaningful gene silencing in preclinical studies. Click here for PR.
  • Plan to partner before p2 trials (6/2011 - goal to initiate in 2012).
  • 8/2011 Phase 1 trial completed - click for PR - click to download complete slide deck (protected so I can't extract images). See detailed ASCO data above. Average disease control was 5 months (range 2-14 months). 5 patients with controlled disease remain on extension trial (one ongoing PR and 4 SD greater than 4 months)

ALN-HTT

  • RNAi therapeutic targeting huntingtin gene for Huntington’s disease (30k pts in US, 150k carriers at 50% risk of developing. No tx slow disease progression/nervous system deterioration).  Novel implantable infusion drug-device combo partnered w/ Medtronic 2/2005 and amended 7/2007 (50/50 co-development and profit share in US, Medtronic develops and commercializes ROW…could expand to other neurological diseases to be treated w/ similar combo)
  • 11/2010: program is now also partnered with CHDI Foundation, which will fund 50% of program up until IND filing- about $10m value (no royalties or milestones, but repay with interest if commercialized)
  • 5/2011: continuing to advance toward the clinic in 2012
  • 5/25/11 webcast: currently in tox studies