Claire Harrison1, Björn Andreasson2, Nathalie Cambier3, Aaron T Gerds4, Sebastian Grosicki5, Árpád Illés6, Jean-Jacques Kiladjian7, David Lavie8, Ruben Mesa9, Jeanne Palmer10, Francesco Passamonti11, Andrew Perkins12, Tomasz Sacha13, Christof Scheid14, Doroteya Todorieva-Todorova15, Alessandro M Vannucchi16, Tomasz Woźny17, Barbara J Klencke18, Mark M Kowalski18, Srdan Verstovsek19

1Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom, 2NU Hospital Group, Uddevalla, Sweden, 3CHU, Lille, France, 4Cleveland Clinic Department of Hematology and Medical Oncology, Avon, United States, 5Medical University of Silesia, Katowice, Poland, 6University of Debrecen, Debrecen, Hungary, 7Saint-Louis Hospital (AP-HP), Paris, France, 8Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 9UT Health San Antonio Cancer Center, San Antonio, 10Mayo Clinic Hospital, Phoenix, United States, 11University of Insubria, Varese, Italy, 12Monash University, Melbourne, Australia, 13Jagiellonian University, Kraków, Poland, 14University of Cologne, Köln, Germany, 15Hematology Division, Medical University, Pleven, Bulgaria, 16AOU Careggi, University of Florence, Florence, Italy, 17Szpital MSWiA w Poznaniu, Poznań, Poland, 18Sierra Oncology Inc., Vancouver, Canada, 19The University of Texas MD Anderson Cancer Center, Houston, United States

LONG TERM SAFETY OF MOMELOTINIB IN JAKi NAÏVE AND PREVIOUSLY JAKi TREATED INTERMEDIATE/HIGH RISK MYELOFIBROSIS PATIENTS

#EP1113

BACKGROUND

BACKGROUNDMETHODS

BACKGROUNDRESULTS

CONCLUSIONS

JAK1Inhibition

Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with demonstrable clinical activity against each of the three hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly. MMB’s benefits have been demonstrated across the continuum of intermediate/high risk MF patients, whether JAKi-naïve or previously JAKi-treated.

BMP2, BMP6

ACVR1

InterleukinsInterferons

Cytokine Receptors EPOR / MPL

Ligand

JAK2JAK1JAK2JAK2

Decreased hepcidin transcription restores iron homeostasis and

increases hemoglobin leading to an array of anemia benefits

Reduced extramedullary hematopoiesis improves

splenomegaly

Decreased inflammation and aberrant cytokine signaling

reduces constitutional symptoms

JAK2Inhibition

SMAD1,5 PSTAT STAT PP

Momelotinib therapy decreases inflammation, improves splenomegaly and increases hemoglobin

Data were analyzed from two Phase 3 trials of patients with MF1 (refer to poster #EP1103 for schematics):• SIMPLIFY-1 (S1): 1:1 Randomized Treatment (RT, double-blind) of MMB vs ruxolitinib (RUX) for 24 weeks

in 432 JAKi-naïve patients, followed by extended treatment (ET) MMB. Trial duration ≈ 5.4 years. • SIMPLIFY-2 (S2), 2:1 RT of MMB vs best available therapy (BAT [88% RUX]) for 24 weeks in 156 anemic or

thrombocytopenic prior-RUX treated patients, followed by ET. Trial duration ≈ 4.8 years.• An extended access protocol (XAP) provided continued MMB treatment to 138 patients following the

completion of S1, S2 and earlier Phase 2 MMB studies. Of these, 105 remain on MMB with duration on therapy ranging up to 9.8 years.

1 Data cut April 2020

A Significant Cohort of Patients with Myelofibrosis Have Received Extended MMB Therapy Across these studies, more than 550 patients with MF have received MMB, with extended durability: 336 patients remained on therapy for ≥ 48 weeks, 212 for ≥ 96 weeks, and 148 for ≥ 144 weeks (Table 1).

SIMPLIFY-1 SIMPLIFY-2MMB RUX MMB BAT

Total Duration of Exposure to Study Drug During Randomized Treatment (weeks)N 214 216 104 52Mean (SD) 21.3 (6.36) 23.3 (3.14) 19.5 (7.71) 21.0 (6.91)Median 23.9 24.0 23.9 24.1Q1, Q3 23.3, 24.0 23.7, 24.1 15.9, 24.0 23.7, 24.3

Total Duration of Exposure to MMB (weeks) - Cumulative Randomized and Open-label Treatment (Patients Randomized to MMB) 1N 214 - 104 -Mean (SD) 102.8 (81.4) - 72.6 (76.6) -Median 81.6 - 40.0 -Q1, Q3 32.6, 163.7 - 15.9, 94.8 -

Number (%) of Patients Exposed to MMB at Each Timepoint - Cumulative Randomized and Open-label Treatment (All Patients Receiving MMB) 1Patients receiving randomized and/or open-label MMB 411 (100%) 144 (100%)≥ 24 weeks 321 (78.1%) - 88 (61.1%) -≥ 48 weeks 267 (65.0%) - 69 (47.9%) -≥ 96 weeks 176 (42.8%) - 36 (25.0%) -≥ 144 weeks 124 (30.2%) - 24 (16.7%) -≥ 192 weeks 73 (17.8%) - 17 (11.8%) -≥ 240 weeks 19 (4.6%) - 6 (4.2%) -≥ 288 weeks 3 (0.7%) - 1 (0.7%) -

Table 1: Duration of Therapy1 Includes exposure from all subjects who received randomized and/or open-label MMB therapy in S1 and S2, crossed-over to MMB from RUX or BAT, and those who enrolled in XAP. As of April 2020, 105 subjects from S1, S2 and previous Phase 2

studies remain on MMB therapy in XAP.

Disruption of Study Treatment Due to Thrombocytopenia is Uncommon on Momelotinib• In S1, dose reductions or interruptions due to thrombocytopenia were common for RUX (24.5%) and

> 4−fold higher than MMB (6.1%) in RT. This reflects the known myelosuppressive effect of RUX, which induces or exacerbates anemia and thrombocytopenia.

• MMB discontinuation due to thrombocytopenia was also infrequent in the more advanced patients in S2 at 4.8% in RT and 2.9% in ET. “No therapy” was acceptable as BAT so discontinuation rates could not be compared between treatment arms.

• Both through the RT period and during overall exposure to MMB in S2, the most common AE leading to dose reduction or interruption was thrombocytopenia: 4.8% for MMB vs 5.8% for BAT during RT, and 0% for MMB→MMB vs 5% for BAT→MMB during weeks 24-48 of ET.

Momelotinib’s Differentiated Pro-erythropoietic Pharmacology Promotes Low Hematological Toxicity and Consistent Dosing• The incidence of Grade 3/4 hematological toxicity was low for MMB (Tables 2A and 2B), even with the

duration of treatment exceeding 3.5 years for > 90 patients in S1/S2 combined. • S1 RT period: Grade 3/4 anemia occurred in only 6.1% of patients on MMB compared with an

approximate 4-fold higher rate (22.7%) for RUX. • S1 RT period: the rate of thrombocytopenia on MMB was low (7.0%) and not markedly greater than the

rate for RUX (4.6%), likely due to the starting dose for RUX being titrated by baseline PLTs to mitigate induced myelosuppression and similarly, the numerous dose reductions for thrombocytopenia observed for RUX at PLT counts < 125 × 109/L.

• The favorable tolerability of MMB facilitated consistent dose intensity (DI) in contrast to reduced DI for RUX. This comparative DI analysis is presented in poster #EP1103.

SIMPLIFY -1

TEAEs 1 by PT

RT Period ET Week 24 – Week 48Overall MMB exposure

in RT and ET (N=411)MMB(N=214)

RUX(N=216)

ContinuingMMBMMB

(N=171)

CrossoverRUXMMB

(N=197)Number of patients with Any Gr3/4 TEAE, n (%) 74 (34.6%) 94 (43.5%) 47 (27.5%) 74 (37.6%) 251 (61.1%)

Thrombocytopenia 15 (7.0%) 10 (4.6%) 6 (3.5%) 17 (8.6%) 55 (13.4%)Anemia 13 (6.1%) 49 (22.7%) 8 (4.7%) 10 (5.1%) 48 (11.7%)

Pneumonia 5 (2.3%) 3 (1.4%) 2 (1.2%) 5 (2.5%) 30 (7.3%)

SIMPLIFY-2

TEAEs 1 by PT

RT Period ET Week 24 – Week 48 Overall MMB exposure in RT and ET

(N=144)MMB

(N=104)BAT

(N=52)

ContinuingMMBMMB

(N=64)

CrossoverBATMMB

(N=40)Number of patients with Any Gr3/4 TEAE, n (%) 57 (54.8%) 22 (42.3%) 18 (28.1%) 22 (55.0%) 104 (72.2%)

Anemia 14 (13.5%) 9 (17.3%) 6 (9.4%) 6 (15.0%) 33 (22.9%)Thrombocytopenia 11 (10.6%) 3 (5.8%) 1 (1.6%) 5 (12.5%) 22 (15.3%)

Asthenia 5 (4.8%) 1 (1.9%) 1 (1.6%) 4 (10.0%) 11 (7.6%)Neutropenia 5 (4.8%) 1 (1.9%) 1 (1.6%) 3 (7.5%) 9 (6.3%)

Pneumonia 2 (1.9%) 1 (1.9%) 2 (3.1%) 1 (2.5%) 9 (6.3%)Table 2A and 2B: Most Frequent Grade 3 or 4 Adverse Events in SIMPLIFY -1 and SIMPLIFY-21 TEAEs occurring in >5% patients in the “Overall exposed to MMB”.

Momelotinib Treatment Leads to Higher Mean Hemoglobin and Platelet Levels Over Time

• Patients randomized to MMB in S1 experienced a rapid increase in Hgb which was maintained over time, in contrast to the significant decrease in Hgb for RUX-patients despite frequent transfusions on RUX (Figure 1A). Hemoglobin also increased to above baseline in patients crossing-over from RUX to MMB during ET. Platelet values were maintained over time compared to RUX (Figure 1B), and rebounded following RUX→MMB cross-over.

• Similar benefits were observed in S2, where Hgb and PLT levels improved in patients on MMB and were maintained over time (Figures 2A and 2B).

• Together, these data reinforce the low myelosuppressive potential and differentiated pro-hematopoietic pharmacology of MMB which contrasts with the hematological toxicity evident during RUX administration.

Figure 1A and 1B: SIMPLIFY-1 - Mean Hemoglobin and Platelets Over Time

0 4 8 12 16 20 24 28 32 369.0

9.5

10.0

10.5

11.0

11.5

Weeks

Mea

n He

mog

lobi

n (g

/dL)

Momelotinib Ruxolitnib Crossover: Ruxolitnib to Momelotinib

CrossoverRUX→MMB

0 4 8 12 16 20 24 28 32 36150

200

250

300

350

Weeks

Mea

n Pl

atel

ets

(x 1

03 /uL)

Momelotinib Ruxolitnib Crossover: Ruxolitnib to Momelotinib

CrossoverRUX→MMB

Figure 2A and 2B: SIMPLIFY-2 - Mean Hemoglobin and Platelets Over Time

0 4 8 12 16 20 24 28 32 368.5

9.0

9.5

10.0

10.5

Weeks

Mea

n He

mog

lobi

n (g

/dL)

Momelotinib BAT Crossover: BAT to Momelotinib

CrossoverBAT→MMB

0 4 8 12 16 20 24 28 32 3650

100

150

200

250

300

Weeks

Mea

n Pl

atel

ets

(x 1

03 /uL)

BAT Crossover: BAT to MomelotinibMomelotinib

CrossoverBAT→MMB

Momelotinib Displays a Favorable Long-term Safety ProfileThe most frequent AEs (all grades) during the RT and ET periods of S1 and S2 are summarized in Tables 3A and 3B.

SIMPLIFY-1

TEAEs 1 by PT

RT Period ET Week 24 – Week 48 Overall MMB exposure in RT and ET

(N=411)MMB

(N=214)RUX

(N=216)

ContinuingMMBMMB

(N=171)

Switch(RUXMMB

(N=197)patients with any TEAE, n (%) 198 (92.5%) 206 (95.4%) 134 (78.4%) 177 (89.8%) 397 (96.6%)

Diarrhea 39 (18.2%) 43 (19.9%) 18 (10.5%) 28 (14.2%) 99 (24.1%)Anemia 31 (14.5%) 81 (37.5%) 14 (8.2%) 21 (10.7%) 93 (22.6%)

Thrombocytopenia 40 (18.7%) 63 (29.2%) 16 (9.4%) 28 (14.2%) 94 (22.9%)Nausea 34 (15.9%) 8 (3.7%) 6 (3.5%) 28 (14.2%) 85 (20.7%)Fatigue 31 (14.5%) 26 (12.0%) 11 (6.4%) 26 (13.2%) 84 (20.4%)

Headache 38 (17.8%) 43 (19.9%) 4 (2.3%) 13 (6.6%) 68 (16.5%)Peripheral sensory neuropathy 20 (9.3%) 12 (5.6%) 7 (4.1%) 15 (7.6%) 61 (14.8%)

SIMPLIFY-2

TEAEs 1 by PT

RT Period ET Week 24 – Week 48 Overall MMB exposure in RT and ET

(N=144)MMB

(N=104)BAT

(N=52)

ContinuingMMBMMB

(N=64)

SwitchBATMMB

(N=40)patients with any TEAE, n (%) 101 (97.1%) 46 (88.5%) 60 (93.8%) 40 (100.0%) 142 (98.6%)

Diarrhea 34 (32.7%) 8 (15.4%) 13 (20.3%) 9 (22.5%) 52 (36.1%)Cough 18 (17.3%) 6 (11.5%) 12 (18.8%) 8 (20.0%) 39 (27.1%)

Pyrexia 15 (14.4%) 4 (7.7%) 9 (14.1%) 9 (22.5%) 37 (25.7%)Anemia 16 (15.4%) 10 (19.2%) 7 (10.9%) 6 (15.0%) 36 (25.0%)

Asthenia 20 (19.2%) 11 (21.2%) 4 (6.3%) 9 (22.5%) 35 (24.3%)Thrombocytopenia 18 (17.3%) 6 (11.5%) 3 (4.7%) 8 (20.0%) 34 (23.6%)

Nausea 20 (19.2%) 5 (9.6%) 7 (10.9%) 3 (7.5%) 31 (21.5%)Headache 16 (15.4%) 3 (5.8%) 2 (3.1%) 5 (12.5%) 25 (17.4%)

Peripheral sensory neuropathy 8 (7.7%) 0 2 (3.1%) 5 (12.5%) 20 (13.9%)Table 3A and 3B: Most Frequent Adverse Events in SIMPLIFY-1 and SIMPLIFY-21 TEAEs occurring in >20% patients in the “Overall exposed to MMB” group plus headache and peripheral sensory neuropathy of any frequency.

Other Safety DataDuring the overall period of exposure in S1 and S2, MMB demonstrated low rates of AEs of interest for the JAKi class: cataracts1 6.8% in S1 and 3.5% in S2; non-melanoma skin cancers2 4.9% in S1 and 4.2% in S2; opportunistic infections3 1.0% in S1 and 0.7% in S2; and thrombosis4 3.2% in S1 and 7.0% in S2.Peripheral neuropathy (PN) was notably infrequent, low grade, and often reversible across overall MMB exposure. In S1 and S2 overall, events of PN5 were ~73% Grade 1, ~23% Grade 2 and only 8 events were Grade 3, despite PN being a common background finding in MF. During the RT period of S1, PN6 was reported for 9.3% of patients receiving MMB compared to 5.6% for RUX (Table 3A). Very few patients who received MMB at any time during S1 and S2 (8/411 patients in S1 and 3/144 in S2; ≈2%) had PN5 which increased in grade but did not resolve or return to the original AE grade on-study.1HLT “Cataract conditions”, 2HLT “Skin neoplasms malignant and unspecified (excl melanoma)”, 3SMQ narrow terms “Opportunistic infections”, 4SMQ narrow terms “Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous”. 5SMQ narrow terms “Peripheral neuropathy”, 6PT “Peripheral sensory neuropathy”.

• The further analyses of data from the 550 JAKi naïve and previously JAKi-treated patients with MF who received MMB at any time during the RT and ET phases of the Phase 3 SIMPLIFY studies presented here confirm the remarkable durability and long-term tolerability of MMB therapy, with 336 patients remaining on MMB for ≥ 48 weeks and 148 patients for ≥ 2 years.

• In contrast to RUX, MMB therapy elicited sustained increases in Hgb and improved or maintained PLT counts in the RT periods of both studies, leading to low rates of hematological AEs in the MMB patients. Importantly, as noted in S1, patients who crossed-over from RUX to MMB for ET, also saw a rapid and sustained improvement in Hgb and PLT levels, despite prior RUX myelosuppression.

• This lack of hematologic toxicity is associated with substantially higher dose intensity for MMB vs RUX as described in the companion poster #EP1103.

• Overall, these findings are consistent with MMB’s differentiated pharmacological and clinical profile as an inhibitor of JAK1, JAK2 and ACVR1 which is associated with low myelosuppressive potential and consequent anemia and thrombocytopenia benefits which contrast with the hematological toxicity evident during RUX therapy.

• Importantly, no new safety signals or cumulative toxicity were observed during extended MMB dosing. Peripheral neuropathy was uncommon, of low grade, and not progressive.

• These data demonstrate MMB’s potential ability to address the unmet needs of patients with intermediate/high risk MF.

ACKNOWLEDGEMENTSThe SIMPLIFY-1 and -2 studies were sponsored by Gilead Sciences. As momelotinib’s current sponsor, Sierra Oncology would like to thank all participating patients and their families as well as participating study sites.