Results of a Phase 2b Multi-Center, Randomized, Double ... Slide 2 •Sponsored institutional grants...
Transcript of Results of a Phase 2b Multi-Center, Randomized, Double ... Slide 2 •Sponsored institutional grants...
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A. Glanville1, M. Musk2, M. Zamora3, T. Hodges4, S. Arcasoy5, U. Sommerwerck6, J. DeVincenzo7, V. Karsten8, S. Shah8, J. Cehelsky8, S. Nochur8, J. Gollob8, A. Vaishnaw8, A. Simon8,
Jens Gottlieb9 (1Sydney, 2Perth, Australia, 3Aurora, 4Phoenix, 5New York, 7Memphis, 8Cambridge, US, 6Essen, 9Hannover, Germany)
Results of a Phase 2b Multi-Center, Randomized,
Double-Blind, Placebo-Controlled Study of an RNAi
Therapeutic, ALN-RSV01, in Respiratory Syncytial
Virus (RSV)-Infected Lung Transplant Patients
Disclosure Slide
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• Sponsored institutional grants for Alnylam
Pharmaceuticals for $10,001–$50,000
• Consultancy fees for Chiesi, Novartis for $5,001–$10,000
• Lecture fees from Roche, Astellas, Boehringer, Astra-
Zeneca, Novartis, Merck for $ 5,001–$10,000
• Travel and accommodation grants for Astellas, Nycomed,
Merck, Novartis $5,001–$10,000.
• BOS is major cause of morbidity and
mortality in lung transplant patients
• Re-transplantation remains only
definitive BOS treatment
• Community acquired respiratory virus
(CARV) infections occur in 8-10% of
transplant patients annually
• Up to 25% of CARV infections are
due to RSV
• Three prospective studies confirm
role of CARV, including RSV, in BOS
development in lung transplant
patients
Gottlieb J et al., Transplantation, 2009
Gottlieb J et al., Transplant, 87: 1530-37 (2009)
Hopkins P et al., Am J Respir Crit Care Med ., 178: 876-81 (2008)
Kumar D et al, Am J Transplant, 5:2031-36 (2005)
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Bronchiolitis Obliterans Syndrome (BOS) The Role of RSV Infection
RNA Interference (RNAi) ALN-RSV01
• Natural biologic process regulating gene expression mediated by small
interfering RNA (siRNA)
• Utilize siRNA to silence endogenous (host genes) or exogenous (infectious
organism gene) disease-causing targets
• ALN-RSV01: inhaled siRNA directed against nucleocapsid (N) gene of RSV
required for RSV replication
• Hypothesis: decreasing RSV viral load will decrease infection severity and
ameliorate airway injury and chronic allograft dysfunction, i.e. BOS
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Zamore Nat Struct Biol. 8(9):746-50. (2001); Bartel Cell 116(2): 181-197 (2004)
ALN-RSV01
siRNA targeting
RSV N gene
RNAi-mediated cleavage
of RSV mRNA
Cleaved
RSV
mRNA
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 11 Study Day
ALN-RSV01 Placebo
% I
nfe
cte
d
P=0.0069
Human experimental infection study showed ALN-RSV01 significantly decreased infection
rate in healthy volunteers infected with RSV intranasally (p=0.0069)1
Randomized, double-blind, PBO-controlled trial (n=24) in RSV-infected lung transplant
patients demonstrated significantly decreased BOS at Day 90 (p=0.02)2
1. PNAS;107:8800-5 (2010)
2. Am J Respir Crit Care Med.; 183:531-8 (2011)
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Incidence of Infection
Phase IIa Experimental Infection Study1 Incidence of BOS
0
10
20
30
40
50
ALN-RSV01 Placebo
% N
ew
or
Pro
gre
ssiv
e B
OS
Phase IIa Lung Transplant Study2
P=0.02
ALN-RSV01 RNAi Therapeutic for RSV Infection; Key Prior Studies
ALN-RSV01 Phase IIb Study Design Eligibility Criteria and Endpoints
Key Inclusion Criteria • Adults ≥ 18 yo
• Greater than 90 days post-transplant
• Rejection-free ≥ 30 days
• Confirmed RSV by local or central lab
Key Exclusion Criteria • Rx for other acute lung infection
• BOS Grade 3
• Unstable FEV1 over prior 3 months
• Mechanical intubation
• Use of alemtuzumab within 9 mo of screen; anti-thymocyte globulin within 90 days of
screen
Stratification Factors at Randomization • Time from symptom onset (< 5 days vs > 5days)
• Pre-infection BOS grade (BOS 0 vs BOS 0P,1 or 2)
Primary Endpoint • Effect of ALN-RSV01 on incidence of new or progressive BOS at Day 18 BOS
• BOS adjudicated by independent committee blinded to study site and treatment
Key Secondary Endpoints • BOS at Day 90, anti-viral activity, symptom score, survival, acute lung rejection
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ALN-RSV01 Phase IIb Study Schema and Analysis Populations
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CARV
Infection
N=3985
RSV+
N=218
Days 0 1 2 3 4
Placebo + SOC*
(N=42)
ALN-RSV01 + SOC*
(N=45)
Primary Endpoint
New/ Progressive
BOS Day180
Secondary Endpoint
New/Progressive
BOS Day 90
N=87
Rx: 0.6 mg/kg/d x 5d aerosolized *SOC-Standard of care per site protocol
Study Metrics • 33 sites from 6 countries (Australia, Austria, Germany, France, Canada, USA) screened
lung transplant patients with respiratory symptoms
• Enrollment occurred from Feb 2010-Nov 2011
Pre-specified Analysis Populations • ITT: Randomized patients that received at least one dose of study medication (missing
Day 180 data = treatment failure
• ITT central (ITTc): ITT patients who are RSV positive by central laboratory (missing Day
180 data = treatment failure
• PP: ITTc patients with Day 180 BOS assessment and no major protocol violations
• Enrollment occurred from Feb 2010-Nov 2011
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Baseline Characteristic Placebo (N=33) ALN-RSV01 (N=44)
Age Median (Range) 56 (28 – 72) 53.5 (20 – 72)
Sex Male
Female
20 (61%)
13 (39%)
23 (52%)
21 (48%)
Type of Lung Transplant Bilateral
Single
27 (82%)
6 (18%)
36 (82%)
8 (18%)
Transplant Indication Emphysema/COPD
Idiopathic Pulmonary Fibrosis
Cystic Fibrosis
Other
12 (36%)
9 (27%)
7 (21%)
5 (15%)
10 (23%)
14 (32%)
10 (23%)
10 (23%)
Years from Transplant Median (Range) 2.9 (0.6-16.8) 3.1 (0.3 – 21.5)
Pre-infection BOS Grade 0
0p
1
2
14 (42%)
14 (42%)
4 (12%)
1 (3%)
19 (43%)
16 (36%)
6 (14%)
3 (7%)
FEV1 Change from Pre-Infection to Screening
Median (Range)
-13.4% (-48.1 - 8.6)
-9.4% (-56.3 - 10.1)
Mean Viral Load (SD) Nasal Swab
[Log10 Copies/ml] Oropharyngeal Wash
6.9 (2.3)
4.3 (1.4)
6.7 (2.3)
4.2 (1.5)
Days from Symptom Onset to Treatment
<5 Days
≥5 Days
7 (21%)
26 (79%)
12 (27%)
32 (72%)
RSV Treatment Pulse Dose Steroids*
Ribavirin
IVIG
Palivizumab
21 (64%)
27 (82%)
4 (12%)
3 (9%)
34 (77%)
33 (75%)
4 (9%)
3 (7%)
ALN-RSV01 Phase IIb Study Results Baseline Patient Characteristics (ITTc)
No statistically significant differences in baseline characteristics between groups
* Pulse Dose Steroids: steroids above standard maintenance regimen
ALN-RSV01 Phase IIb Study Results Incidence of Day 90 and Day 180 BOS
Treatment effect of ALN-RSV01 on Day 90 and Day 180 BOS ranges from 52-65%
Per Protocol
0
10
20
30
40
% N
ew
or
Pro
gre
ss
ive
BO
S
Day 90 Day 180
Placebo ALN-RSV01 Placebo ALN-RSV01
p=0.044 p=0.058
ITTc
30.3%
13.6%
33.3%
15.9%
0
10
20
30
40
Day 90 Day 180
Placebo ALN-RSV01 Placebo ALN-RSV01
% N
ew
or
Pro
gre
ss
ive
BO
S
p=0.028 p=0.025
28.1%
9.8%
29.0%
10.3%
p-value from Cochran-Mantel-Haenszel (CMH) test adjusting for randomization strata 9
ALN-RSV01 Phase IIb Study Results Ribavirin Pulse and Dose Steroids: Impact on Day 180 BOS (ITTc)
ALN-RSV01 treatment effect was preserved in patients who received pulse dose steroids
Subgroup
Placebo
N=33
ALN-RSV01
N=44 p-value
Ribavirin 9/27
(33%)
6/33
(18%) 0.098^^
No Ribavirin 1/6
(17%)
0/11
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* Pulse Dose Steroids: steroids above standard maintenance regimen
^^ CMH Test (adjusted for steroid or ribavirin use)
Subgroup
Placebo
N=33
ALN-RSV01
N=44 p-value
Pulse Dose Steroid*
9/21
(43%)
6/34
(18%) 0.028^^
No Pulse Dose Steroid 1/12
(8%)
0/10
PBO
N=33
RSV01
N=44 p-value
< 5 Days from Symptom Onset to
First Dose
5/7
(71%)
1/12
(8%) 0.0095^
≥ 5 Days from Symptom Onset to First
Dose
5/26
(19%)
5/32
(16%) 0.740^
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ALN-RSV01 Phase IIb Study Results Time to Treatment: Impact on Day 180 BOS (ITTc)
Strong treatment effect (88%) observed in patients treated with ALN-RSV01 < 5 days from symptom onset
^Fisher’s Exact Test
Multiple Logistic Regression Model: Determines effect of each individual variable on odds of developing
Day 180 BOS while adjusting for effects of other variables
Conclusion
• ALN-RSV01 treatment effect is robust – the most significant variable among 18 considered
• When only early pulse steroids (Day 0-4) was evaluated in the LR model, steroid treatment no longer had a
significant impact on BOS, but the ALN-RSV01 treatment effect remained (OR=4.7, CI 0.9, 22.7)
Log (Odds Ratio)
Pulse Steroids*
5% FEV1 Drop
ALN-RSV01
-1 0 1 2
Day 180 BOS Risk: DECREASED INCREASED
OR 8.5 (CI 1.7,41.7)
OR 1.2 (CI 1.0,1.6)
OR 17.5 (CI 1.6,187.9)
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ALN-RSV01 Phase IIb Study Results Logistic Regression Model
*Pulse steroids: any dose above maintenance given during the study
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Study Outcome
PBO
N=33
RSV01
N=44 p-value
Cumulative Total Symptom Score Day 0-14Ϯ
Median (range)
73.0
(7 – 246)
85.0
(4 – 638)
NS
Overall Viral Load (AUC 0-6) (SD)
[Log10 copies/ml x Day]
Nasal Swabs
Oropharyngeal Wash
33.1 (13.8)
21.3 (9.2)
33.4 (14.6)
20.6 (9.5)
NS
NS
Duration of Hospitalization for RSV Infection
[Days] Median (range)
6.5 (5-18)
8.0 (2-52)
NS
Respiratory Infection after D30 7 (21%) 10 (23%) NS
Acute Rejection 2 (6% ) 5 (11%) NS
Survival* 33 (100% ) 43 (98% ) NS
*3 deaths occurred during the study in the ITT population :
• 1 in ALN-RSV01 and 2 in Placebo (neither were RSV+)
• None related to study drug
• None related to BOS as determined by Clinical Adjudication Committee
ALN-RSV01 Phase IIb Study Results Key Secondary Endpoints (ITTc)
ϮScale of 10 symptoms with max. 60 points per day
Serious Adverse Events • 12 SAEs in 9 patients between Day 0-30: ALN-RSV01 n=5 (11%);
Placebo n=7 (17%)
• 1 SAE considered possibly related to study drug
Deaths • 3 deaths: 1 in ALN-RSV01 and 2 in Placebo (neither RSV+)
• No deaths study drug related, as determined by study investigators
• No deaths BOS-related, as determined by adjudication committee
ALN-RSV01 Phase IIb Study Results Safety (ITT)
Treatment Emergent Respiratory
Events > 5%
Placebo
N=42
n (%)
ALN-RSV01
N=45
n (%)
Wheezing^ 0 4 (9%)
Cough 1 (2%) 3 (7%)
Dyspnea 3 (7%) 2 (4%)
Epistaxis 3 (7%) 0
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Serious Adverse Events (SAEs) (ITT)
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Treatment
Arm Description of SAE ID Start Stop Severity
Relationship to
study drug
ALN-
RSV01
Deep vein thrombosis 011-001 Day 17 Day 168 Moderate Unrelated
Atrial flutter 031-003 Day 3 Day 67 Severe Unrelated
Right pneumothorax 201-018 Day 0 Day 10 Severe Possibly
Worsening anemia 400-008 Day 24 Day 28 Moderate Unrelated
Pseudomonas LRTI 404-001 Day 8 Day 19 Severe Unrelated
Placebo
Abdominal pain 005-002 Day 5 Day 10 Severe Unrelated
Bronchitis 005-002 Day 13 Day 23 Moderate Unrelated
Kidney Stones 005-002 Day 27 Day 43 Moderate Unrelated
GI infection 202-001 Day 3 Day 8 Moderate Unrelated
Pulmonary embolism 306-002 Day 20 Day 29 Moderate Unrelated
Deep vein thrombosis 306-002 Day 20 Day 29 Moderate Unrelated
RSV bronchiolitis 401-003 Day 3 Day 9 Mild Unrelated
12 SAEs were reported in 9 patients between Day 0 and Day 30
1 SAE considered possibly related to ALN-RSV01: pneumothorax in patient with prior history of spontaneous
pneumothorax 12 hrs post-study drug administration
ALN-RSV01 Phase IIb Study Results Summary
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ALN-RSV01 is a promising therapeutic for RSV-induced
BOS, a significant cause of morbidity and mortality in lung
transplant patients ● Effective in reducing BOS in RSV-infected lung transplant patients
» Reduced incidence of new or progressive BOS at Days 90 and 180
by 50% or more
» Treatment effect enhanced when given < 5 days from symptom
onset
» Significant treatment effect observed in logistic regression analysis
adjusting for multiple other variables
» Results consistent with prior Phase IIa study showing decreased
Day 90 BOS
● No significant differences on viral parameters or symptom scores
● Safe and well tolerated