Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (September 2016)
73 slides from Alnylam Pharmaceuticals's technical presentation, Sep 27, 2016
Slide 1: ALN-GO1 Investigational RNAi Therapeutic for Primary Hyperoxaluria Type 1
ALN-GO1 Investigational RNAi Therapeutic for the Treatment of Primary Hyperoxaluria Type 1 Tuesday, September 27, 2016 1
Slide 2: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • David-Alexandre Gros, M.D., Senior Vice President, Chief Business Officer Overview of Primary Hyperoxaluria Type 1 • Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatri
Slide 3: Reminders
Reminders Event will run for approximately 60 minutes Q&A Session at end of presentation • Submit questions at bottom of webcast screen • Questions may be submitted at any time Replay, slides and audio available at www.alnylam.com 3
Slide 4: Alnylam Forward Looking Statements
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 material
Slide 5: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • David-Alexandre Gros, M.D., Senior Vice President, Chief Business Officer Overview of Primary Hyperoxaluria Type 1 • Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatri
Slide 6: RNAi Therapeutics
RNAi Therapeutics New Class of Innovative Medicines Harness natural pathway Catalytic mechanism Silence any gene in genome Upstream of today’s medicines Clinically proven approach 6
Slide 7: Alnylam Strategic Therapeutic Areas (STArs)
Alnylam Strategic Therapeutic Areas (STArs) Investigational pipeline focused in 3 STArs Genetic Medicines RNAi therapeutics for rare diseases Cardio-Metabolic Diseases RNAi therapeutics for dyslipidemia, NASH, type 2 diabetes, hypertension, and other major diseases Hepatic Infectious Diseases RNAi t
Slide 8: Alnylam Development Pipeline
Alnylam Development Pipeline 8
Slide 9: Alnylam Development Pipeline
Alnylam Development Pipeline 9
Slide 10: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • David-Alexandre Gros, M.D., Senior Vice President, Chief Business Officer Overview of Primary Hyperoxaluria Type 1 • Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatri
Slide 11: Primary Hyperoxaluria
Primary Hyperoxaluria Sally-Anne Hulton Birmingham Children's Hospital UK 11
Slide 12: Clinical presentation & diagnosis
Clinical presentation & diagnosis asymptomatic stones single nephrocalcinosis renal or recurrent impairment Stone in urine Stone to laboratory for analysis Calcium Oxalate present Specific blood and urine tests 12
Slide 13: Oxalate Synthesis
Oxalate Synthesis peroxisome GRHPR serine hydroxypyruvate hydroxypyruvate X D-glycerate NADPH NADP+ cytosol AGT pyruvate alanine X AGT LDH glycine glyoxylate H2O2 GRHPR glyoxylate GO O2 glycollate NADP+ X NADPH NAD+ oxalate NADH glycollate glycollate ?GRHPR HOGA hydroxyproline 4-OH-oxoglutate pyruva
Slide 14: Urinary metabolites to aid preliminary PH diagnosis
Urinary metabolites to aid preliminary PH diagnosis: glycerate, glycolate and HOG GCOL GCER DMG HOG Urine analysis “Ramp 1” Hewitt & Rumsby, UCLH 2013 14
Slide 15: PH mutations & diagnosis
PH mutations & diagnosis • PH1 AGXT gene chr 2 • PH1 plasma oxalate + glycollate PH1 incidence 6 to 7 per million population urine oxalate • PH2 GRHPR gene chr 9 • PH2 urine L-glyceric acid (may be absent) • PH3 HOGA1 gene chr10 • PH3 urine oxalate + glycollate urine Ca + uric acid Databas
Slide 16: Age of onset: comparative UK data
Age of onset: comparative UK data PH1, 2 and 3 50 45 40 35 30 PH1 % PH Patients 25 PH2 20 PH3 15 10 5 0 <1y 1-4.9 5-9.9 10-14.9 15-19.9 20-39.9 40-80 Age of onset in years 16
Slide 17: Consequences of PH1
Consequences of PH1 • Phenotypic variability • Systemic deposition of Ox in all organs – bones – myocardium, vasculature, AV block – cutaneous – bone marrow: EPO resistant anaemia – eyes: retina – neurological • Progressive renal impairment 17
Slide 18: Factors impacting on renal survival
Factors impacting on renal survival • Degree of hyperoxaluria • Specific mutation • Nephrocalcinosis n=68 n=355 Tang X et al. Kid Int 2015: 87(3):623-31 Mandrile G et al, Kid Int. 2014: 86(6):1197-204 18
Slide 19: Consequences of PH1
Consequences of PH1 Female aged 9 years with calcification of kidneys, marked osteopoenia. Pin in femoral neck following fracture. Oxalate crystals on fundoscopy and in retina on post mortem 19
Slide 20: Consequences of PH1
Consequences of PH1 Endomyocardial biopsy right ventricle Giant cell with crystals F Mookadam et al: Circ J 2010; 74: 2403 – 2409 20
Slide 21: Gangrene of fingers with osteolysis in secondary oxalosis
Gangrene of fingers with osteolysis in secondary oxalosis Index and middle finger Courtesy of S Arampatzis, D Fuster 21 University Hospital of Bern, Switzerland
Slide 22: Infantile Systemic Oxalosis
Infantile Systemic Oxalosis • Poorer prognosis for PH1 in neonates • Early death is common – 50% have ESRD at diagnosis and 80% develop ESRD by 3 years1 • Difficult to diagnose and treat – Normal ranges of urinary/plasma oxalate not clearly defined for neonates – Acute renal failure common problem i
Slide 23: PH1 Patient Population
PH1 Patient Population OxalEurope data • Approx 690 – 740 PH1 patients to date • 51 of 132 PH1 patients: systemic oxalosis1 European Hyperoxaluria Consortium 1Garrelfs S et al. IPNA 2016 23 23
Slide 24: PH1: age at diagnosis
PH1: age at diagnosis n=297 24 Courtesy: S Garrelfs
Slide 25: PH under diagnosed
PH under diagnosed • Diagnosis often missed or delayed – Lack of availability of adequate diagnostic tools – Highly variable age of onset, presentation and progression • Indications of significant number of undiagnosed patients in Asia and Middle East: – oxalate in urine of 24- 40% of Pakistani chil
Slide 26: PH1 patient Kaplan-Meier survival curve
PH1 patient Kaplan-Meier survival curve To be updated? n=410 with full AGXT genotype Death in 13% 64 out of 449 patients (14%) died 26 Mandrile G et al. Kid Int. 2014; 86(6):1197-204
Slide 27: Patient survival PH1: importance of ESRD
Patient survival PH1: importance of ESRD 27 J Harambat on behalf of
Slide 28: Early therapy
Early therapy • affects long term outcome • 20/27 PH1 children stable GFR over 20yrs • document genetic data • allows time to reflect on phenotypic variability Fargue S et al KI 2009; 76: 767-73 28
Slide 29: Conservative treatment
Conservative treatment 1. Minimize absorption of oxalate – Avoid Vit C / high oxalate foods – Oxalobacter formigines 2. Reduce oxalate synthesis – Vit B6 pyridoxine – Gly170Arg or Phe1 52Ile mutation 3. Minimize oxalate deposition in kidney – Fluid intake 2.5 l/m2/day minimum – Salt Na+ intake –
Slide 30: On-going management
On-going management Annual GFR ml/min/1.73m2 • If > 60 stable • If 40-60 consider isolated liver Tx review genotype Gly170Arg • If < 40 combined liver/ kidney Tx 30
Slide 31: Dialysis in PH
Dialysis in PH • Unable to reduce oxalate load • Weekly clearance = 6-9 mmol/wk/SA equivalent to 2 days of endogenous oxalate production • Haemo clearance better at 120ml/min than PD at 7ml/min Am J Kid D 1992; 19: 546-53 Perit Dial Int 1994; 14; 81-84 NDT 2001; 16: 2407-11 KI 2006; 70: 1642-8 31
Slide 32: Isolated liver transplant
Isolated liver transplant • ? Timing + genotype Gly170Arg • Drugs compromise renal function • Possible subsequent renal Tx Patient 82% at 10 yrs of age survival in pre-emptive 72% at 20 yrs of age Liver Tx 5 out of 24 (21%) patients died Perera T et al NDT 2010; 26(1)354-9 Ped Transpl 2000; 4: 177-8
Slide 33: Hepato-renal transplantation
Hepato-renal transplantation • Combined • Sequential – Total hepatectomy required – liver 1st then kidney – 80% patient 5yr survival • advantage of early liver with GFR of 40-60 replacement of AGT – Risk factors: • can delay renal Tx age < 5 yrs – cadaveric or LRD or dialysis > 2 yrs combination poo
Slide 34: Patient survival after combined hepato-renal transplant
Patient survival after combined hepato-renal transplant 82% at 5 yrs 74% at 10 yrs 66% at 20 yrs 24 out of 113 (21%) patients died 34 J Harambat on behalf of
Slide 35: Current problems
Current problems • Management of recurrent stones • Oxalate deposition systemically and in the transplanted kidney – sometimes immediate graft loss • Management of recurrent bone fractures • Coordinated care for multisystem disease 35
Slide 36: Current Research
Current Research • Gene therapy – In vivo (gene delivered by vector) – Ex vivo on induced pluripotential stem cells (iPSC) together with hepatocellular Tx • Systems development – Mouse knockout – single or multiple: AGT / GRHRP /HOGA1 / GO • RNAi therapeutics 36
Slide 37: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • David-Alexandre Gros, M.D., Senior Vice President, Chief Business Officer Overview of Primary Hyperoxaluria Type 1 • Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatri
Slide 38: The Story of George
The Story of George 38
Slide 39: And his family: Josie and George
And his family: Josie (age 14) George (age 12) 39
Slide 40: Told by his mom
Told by his mom. I am a full time working mom and adult endocrinologist 40
Slide 41: January 2013, George passed his first kidney stone
January 2013, George passed his first kidney stone • Stone passed was one of six • Probably had passed a couple prior but we mistook them for a bout of gastroenteritis or a muscle ache after playing tennis • Removal of the remaining 5 would require a series of painful surgeries and procedures 41
Slide 42: George maintained his caring spirit
George maintained his caring spirit • Recovery was difficult • In spite of pain, he kept an optimistic attitude • First remark after awakening from initial surgery: “I am glad this happened to me and not Josie” 42
Slide 43: George doing homework before surgery
George doing homework before surgery 43
Slide 44: Diagnosis of Hyperoxaluria
Diagnosis of Hyperoxaluria • Receiving the diagnosis – surreal • Paucity of treatment options and possibility of kidney – liver transplantation made diagnosis frightening • After receiving diagnosis, we found the Oxalosis and Hyperoxaluria Foundation (OHF) • Within 24 hours, we had contacted the May
Slide 45: The Power of the Patient
WELCOME TO THE OHF Oxalosis & Hyperoxaluria Foundation STEPPING STONES TO A CURE 45
Slide 46: George has been an inspiration to us
George has been an inspiration to us through this experience with his optimism and courage • Optimism and courage • Progressed to drinking three liters within a couple of weeks • Drinking continuously is not easy • Diagnosis made just weeks before his annual trip to camp • Drinking more • Medication
Slide 47: George at camp a few weeks after the diagnosis
George at camp a few weeks after the diagnosis 47
Slide 48: Everyone plays an important role
Everyone plays an important role • Josie – reminds and encourages George to drink when he gets frustrated • Parents help George reinvent plans of how to accomplish water and medications while at school • We take turns awakening him at night to empty bladder and drink • Grandparents take turns helpin
Slide 49: Slings are helpful… always carry a water bottle
Slings are helpful… always carry a water bottle for drinking 49
Slide 50: Camelbak
Camelbak 50
Slide 51: Reading to Christ Church Preschool with a bottle in sling
Reading to Christ Church Preschool with a bottle in sling 51
Slide 52: We have a variety of water bottles and slings and camelbaks
We have a variety of water bottles and slings and camelbaks 52
Slide 53: Daily prevention medications
Daily prevention medications … liquid potassium citrate 2 teaspoons three times daily and B6 53
Slide 54: Tennis – start drinking early and continuously
Tennis – start drinking early and continuously 54
Slide 55: Cross country – can not drink too close to run
Cross country – can not drink too close to run 55
Slide 56: Kidney function is the key to George's future
Kidney function is the key to George’s future 56
Slide 57: Parents want to maintain George's kidney function
As parents we want to do everything possible to maintain George's kidney function • We have committed to support the OHF • Thrilled with possibilities in treatment options companies such as Alnylam are investigating 57
Slide 58: Thank you
Thank you 58
Slide 59: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • David-Alexandre Gros, M.D., Senior Vice President, Chief Business Officer Overview of Primary Hyperoxaluria Type 1 • Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatri
Slide 60: Primary Hyperoxaluria Type 1 (PH1)
Primary Hyperoxaluria Type 1 (PH1) Retinal Oxalosis • Rare, autosomal recessive disease • Prevalence of 1-3:1,000,000 • Deficiency of hepatic alanine-glyoxylate Cardiomyopathy aminotransferase (AGT) leads to excessive hepatic oxalate production • Systemic oxalosis occurs as renal function Nephrocalc
Slide 61: Investigational Therapeutic Approach: RNAi
Investigational Therapeutic Approach: RNAi • Harness a natural pathway of gene ALN-GO1 silencing to regulate protein production ASGPR (pH>5) • Sequence-dependent degradation of Clathrin-coated pit target mRNA confers exquisite specificity X • Conjugation to the sugar GalNAc Recycling Clathrin-coated
Slide 62: PH1 Pathophysiology
PH1 Pathophysiology Healthy Pathway PH1 Pathway Peroxisome Peroxisome Glycine Glycine AGT DAO AGT Glyoxylate Glyoxylate GO GO GO GO Oxalate Glycolate Oxalate Glycolate Glycolate Glycolate 62
Slide 63: ALN-GO1 Therapeutic Hypothesis
ALN-GO1 Therapeutic Hypothesis Knockdown of Liver GO Enzyme to Reduce Oxalate Glycine Glycine AGT DAO DAO AGT ALN-GO1 Glyoxylate ALN-GO1 siRNA Glyoxylate Effect in healthy GO GO GO GO volunteers Oxalate Glycolate Oxalate Glycolate Glycine Glycine AGT AGT ALN-GO1 Glyoxylate Glyoxylate Effect in PH1 A
Slide 64: ALN-GO1 Phase 1/2 Study Design
ALN-GO1 Phase 1/2 Study Design Part A: Single-Ascending Dose (SAD) │ Randomized 6:2, Single-blind, Placebo-controlled 0.3 mg/kg x 1 SC, N=8 Healthy adult volunteers Outcome evaluations: Safety and Pharmacodynamics 1.0 mg/kg x 1 SC, N=8 3.0 mg/kg x 1 SC, N=8 6.0 mg/kg x 1 SC, N=8 Part B: Multiple-Asc
Slide 65: ALN-GO1 Phase 1/2 Interim Study Results: Demographics
ALN-GO1 Phase 1/2 Interim Study Results* Demographics: Part A (Healthy Volunteers) Demographic Number enrolled N=32 (ALN-GO1:Placebo = 24:8) Median Age (range) 29 years (22 - 42) Gender 16 females, 16 males Race (n) White / Caucasian 25 Asian 2 African 2 Other 3 *Data as of: 17 August 2016 65 Millin
Slide 66: ALN-GO1 Phase 1/2 Interim Results: Safety
ALN-GO1 Phase 1/2 Interim Study Results* Safety: Part A (Healthy Volunteers) ALN-GO1 was generally well-tolerated in healthy volunteers No drug-related SAEs or discontinuations due to AEs Total of 61 AEs reported in 5 placebo and 21 ALN-GO1 treated healthy volunteers • AEs occurring in greater than
Slide 67: ALN-GO1: Plasma Pharmacokinetics
ALN-GO1: Plasma Pharmacokinetics Part A (Healthy Volunteers) • ALN-GO1 was rapidly absorbed after subcutaneous injection with mean plasma tmax of approximately 3 to 6 hours • Plasma exposures increased proportionally with dose • Plasma concentrations declined rapidly after tmax with a short eliminat
Slide 68: Plasma Glycolate: Part A (Healthy Volunteers)
ALN-GO1 Phase 1/2 Interim Study Results* Plasma Glycolate: Part A (Healthy Volunteers) 50 Treatment Group: Placebo (N=8) Plasma Glycolate (nmol/mL) 45 40 ALN-GO1 0.3 mg/kg (N=6) ALN-GO1 1.0 mg/kg (N=6) 35 Mean [± SEM] ALN-GO1 3.0 mg/kg (N=6) 30 ALN-GO1 6.0 mg/kg (N=6) 25 20 15 Normal range: <14 nmol
Slide 69: Urine Glycolate: Part A (Healthy Volunteers)
ALN-GO1 Phase 1/2 Interim Study Results* Urine Glycolate: Part A (Healthy Volunteers) 70 Urine Glycolate (mg/g Cr) 60 Normal range: Mean [± SEM] 50 <50 mg/g Cr 40 30 Treatment Group: Placebo (N=8) 20 ALN-GO1 0.3 mg/kg (N=6) ALN-GO1 1.0 mg/kg (N=6) 10 ALN-GO1 3.0 mg/kg (N=6) 0 ALN-GO1 6.0 mg/kg (N=6)
Slide 70: ALN-GO1 Phase 1/2 Interim Study Results Summary
ALN-GO1 Phase 1/2 Interim Study Results Summary: Part A (Healthy Volunteers) • ALN GO1 is a novel, subcutaneously administered investigational RNAi therapeutic designed to reduce the hepatic production of oxalate in PH1 patients • Preliminary data in healthy adult volunteers suggest that single dose
Slide 71: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • David-Alexandre Gros, M.D., Senior Vice President, Chief Business Officer Overview of Primary Hyperoxaluria Type 1 • Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatri
Slide 72: Upcoming RNAi Roundtable
Upcoming RNAi Roundtable ALN-HBV for the treatment of Hepatitis B Virus (HBV) Infection Tuesday, October 11, 9:00 a.m. – 10:00 a.m. ET • Barry Greene, President • Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence • Guest Speaker: Heiner Wedemeyer, M.D., Managing Senior Physician
Slide 73: Thank you
Thank you www.alnylam.com 73
Alnylam Pharmaceuticals — Technical Presentation (September 2016) on 6ix