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Percent of at-risk placebo who crossed over or discontinued
*
• Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo
ASH 2013
Overall Survival: Rank-Preserving Structural Failure Time (RPSFT) Analysis
1.0
0.8
0.6
0.4
0.2
00 8 24 40 56 72 88 104 120 136 168 176
Pro
bab
ilit
y
Weeks16 32 48 64 80 96 112 128 152144 160
HR=0.36 (95% CI: 0.204, 1.035)
Placebo Ruxolitinib
Ruxolitinib
Placebo-RPSFT
22
• RPSFT is a recognized method to estimate HR after adjusting for crossover1-5
• Hazard ratio of 0.36 is consistent with the hypothesis that ITT analysis underestimates the survival benefit of ruxolitinib relative to “true placebo”
(1) Robins J, Tsiatis A. Commun Stat Theory Methods. 1991;20:2609-31; (2) Demetri GD, et al. Clin Cancer Res. 2012;18:3170-79; (3) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance 179. http://guidance.nice.org.uk/TA179. Issued September 23, 2009; (4) Sternberg CN, et al. Eur J Cancer. 2013;49:1287-96; (5) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance 215. http://guidance.nice.org.uk/TA215/Guidance/pdf/English. Issued February 2011.
ASH 2013
Mean Platelet Count and Hemoglobin Level Over Time
Platelet Count Hemoglobin
23
85
90
95
100
105
110
115
0 12 24 36 48 60 72 84 96 108 120 132 144
WeeksM
ea
n H
em
og
lob
in (
g/L
)120
170
220
270
320
0 12 24 36 48 60 72 84 96 108 120 132 144
Weeks
Me
an
Pla
tele
ts (
x1
09/L
)
128 82PBO
144 136 112 107 100 88RUX
Number of patients
151
155
112 37
143 124 110 104 94 79
132 83
145 136 113 107 100 88
151
155
113 37
143 124 110 104 94 79
Number of patients
370Ruxolitinib Placebo Ruxolitinib Placebo
ASH 2013
Incidence of New Onset All Grade Non-hematologic Adverse Events Regardless of Causality
24
Incidence (%)Ruxolitinib
0–<12 months (n=155)
12–<24 months (n=130)
24–<36 months (n=103)
≥36 months(n=82)
Fatigue 29.0 15.2 15.3 7.7
Diarrhea 27.8 6.7 10.8 3.9
Ecchymosis 21.2 10.4 5.7 0
Peripheral edema 21.3 8.4 12.6 0
Dyspnea 19.2 10.2 2.9 3.3
Dizziness 18.1 10.4 3.0 3.5
Pain in extremity 18.0 6.2 4.2 3.3
Headache 16.6 5.1 2.7 0
Nausea 16.6 6.8 5.1 5.9
Constipation 14.5 8.6 10.1 9.0
Abdominal pain 13.8 5.7 3.6 0
Insomnia 13.8 5.7 3.7 0
Vomiting 13.7 2.8 2.4 5.5
Pyrexia 13.5 7.3 8.5 2.9
Cough 13.1 13.3 4.0 6.0
Arthralgia 11.8 5.8 6.6 6.3
Upper respiratory tract infection
7.7 11.1 4.0 3.2
• There was no change in the rate, distribution, or severity of nonhematologic adverse events in the ruxolitinib group with longer-term treatment; most nonhematologic adverse events were grade 1 or 2
Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval). Adverse event is included if the incidence was >10% at any yearly interval.
ASH 2013
Incidence of New Onset Grade 3 or 4 Non-hematologic Adverse Events Regardless of Causality
25
Incidence (%)
Ruxolitinib
0–<12 months (n=155)
12–<24 months (n=130)
24–<36 months (n=103)
≥36 months(n=82)
Fatigue 6.2 0.9 3.3 0
Pneumonia 5.6 3.6 3.5 0
Abdominal pain 4.2 0 3.2 0
Arthralgia 2.1 0 0 0
Diarrhea 2.1 0 0 0
Dyspnea 2.1 0.9 2.2 2.5
Pain in extremity 2.1 0 1.1 0
Hyperuricemia 1.4 0.9 0 2.5
Fall 1.4 0.9 0 0
GI hemorrhage 1.4 0.9 0 0
Septic shock 1.4 0 0 0
Muscular weakness 1.4 0 1.1 0
Hypoxia 1.4 0 2.2 0
Sepsis 0.7 1.7 2.2 0
Epistaxis 0.7 1.7 0 0
Renal failure acute 0.7 0.9 2.2 2.4
Abdominal pain upper 0.7 0 2.2 0
Myocardial infarction 0 0.9 0 4.8
Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval).Adverse event is included if the incidence was ≥2 patients at any yearly interval.
ASH 2013
BM Morphology in a Ruxolitinib-Treated Patient: A Case Demonstrating Improvement on Ruxolitinib
26
Baseline BiopsyGrade 3
24 MoPost Ruxolitinib
Grade 2
48 MoPost Ruxolitinib
Grade 0
Kvasnicka HM, et al. ASCO. 2013 (abstr 7030). Permission to use images from Kvasnicka, HM
ASH 2013
Dynamics of BM Changes Following Ruxolitinib Treatment at 48 Mo
27
Kvasnicka, et al. ASH 2013. Abstract 4055.ASH 2013
JAK1 & 2 Inhibitors in MPNs – Efficacy Summary – As of ASH 2013
Myelofibrosis PolycythemiaVera
EssentialThrombocythemia
Spleen Const.Sympt.
Anemia Survival Counts
Const.Sympt.
VascEvents
Counts
Const.Sympt.
VascEvents
Ruxolitinib - Approved P III P III P III P III P II P II P II P II P II P II
STUDY (Interferons)Peg Interferon α2b in “Early” MF
Cornell Lead: NCT01758588
STUDY (Activin - ActRIIA-IgG1Fc) Sotatercept (ACE 011)MDACC: NCT01712308
STUDY (Telomerase Inhibitor)Imetelstat (GRN163L)
Mayo Clinic (Rochester): NCT01731951
STUDY (JAK1 Inhibitor) INCB039110 (PH II)
NCT01633372
Imetelstat: A Telomerase Inhibitor
imetelstat binds to RNA template preventing maintenance of telomeres
Telomerase enzyme:• Reverse transcriptase comprised of an RNA component (hTR) and
a reverse transcriptase catalytic protein subunit (hTERT)
• Binds to the 3’ strand of DNA and adds TTAGGG nucleotide repeats to offset the loss of telomeric DNA occurring with each replication cycle
• Not active in somatic cells; transiently upregulated in normal hematopoietic progenitor cells to support controlled proliferation
• Highly upregulated in malignant progenitor cells, enabling continued and uncontrolled proliferation
Imetelstat:
• Proprietary: 13-mer thio-phosphoramidate oligonucleotide complementary to hTR, with covalently-bound lipid tail to increase cell permeability/tissue distribution
• Long half-life in bone marrow, spleen, liver (estimated human t½ = 41 hr with doses 7.5 – 11.7 mg/kg);
Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis
– 10 –
Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study
Tefferi et. al. ASH 2013
Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis
– 10 –
Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study
Tefferi et. al. ASH 2013
100 mg BID 200 mg BID 600 mg QD-20
0
20
5.0
-14.1
-9.9
Change in Spleen Volume at Week 12 by Dose Cohort
40
Per
cen
tag
e C
han
ge
Fro
m
Bas
elin
e at
Wee
k 12
n=7
n=9
*Only patients with baseline and week 12 data were included.
Median % Change in Spleen Volume*
n=38
INCB039910 ASH 2013- Mascarenhas et. al
Improvement in TSS at Week 12 by Dose Cohort
100 mg BID 200 mg BID 600 mg QD0
10
20
30
40
50
60
22.2
34.9
50.0
41
Per
cen
tag
e o
f P
atie
nts
Per
cen
tag
e C
han
ge
Fro
m
Bas
elin
e at
Wee
k 12
n=9 n=43
*Patients who discontinued prior to the week 12 visit were considered nonresponders; 20%-33% of patients in each group discontinued prior to week 12.†Only patients with baseline and week 12 data were included.
Acknowledgements Argentina Ana Clara Kneese, MDFederico Sackmann, MD Australia David M Ross MBBS, PhDCecily Forsyth John Seymour, MBBS, PhD Karen Hall, MD Kate Burbury MD Tam Constantine, MD Canada Lynda Foltz, MDVikas Gupta, MD China Hsin-An Hou, MD Huan-Chau Lin, MD Hung Chang, MDMing-Shen Dai, MD Yuan-Bin Yu, MD Yung-Chen Su, MD Zhijian Xiao, MD Denmark Christen Lykkegaard Andersen, MD Hans Hasselbalch, MDFrance Brigitte Dupriez, MD Jean-Jacques Kiladjian, MD Jean-Loup Demory MDMagali Demilly, PhD Germany Heike L. Pahl, PhD
Ireland
Mary Francis McMullen, MDIsraelMartin Ellis, MD Italy Alessandro M. Vannucchi, MD Francesco Passamonti, MD Giovanni Barosi, MD Tiziano Barbui, MD Netherlands Harry Schouten, MD, PhD Jan Jacques Michiels, MDKarin Klauke, MDPeter te Boekhorst, MD Sonja Zweegman, MD PhD Stephanie Slot, MD Suzan Commandeur, MD New Zealand Hilary Blacklock, MD Panama Francis Guerra, MDSingapore Wee Joo Chng, MB ChB Spain Ana Kerguelen Fuentes, MD Carlos Besses, MD Francisco Cervantes, MD Dolores Fernandez-Casados
Sweden Andreasson Bjorn, MD
Elisabeth Ejerblad, MD Gunnar Birgegard, MD Jan Samuelsson, MD Johanna Ablesson, MD Peter Johansson, MD UK Anthony Green, MD Claire N. Harrison, MD Deepti Radia, MD Uruguay Pablo Muxi, MD USAAlison Moliterno, MD Brady Stein, MD MHS Casey O'ConnellCatriona Jamieson Daniel Rubin, ND Elizabth Hexner Hala Simm Jason Gotlib, MD Jeff Sloan, PhD Jessica Altman, MD Joseph Prchal, MD Kimberly Hickman Martin Tallman, MD Mike Boxer, MD Olatoyosi Odenike, MD Robert Silver, MD Ross Levine, MD Soo Jin Kim Srdan Verstovsek, MD