Second generation JAK inhibitors: Targeting the JAK-STAT ...splenomegaly and fatigue. –Main side effect was anemia with Hgb decreased to the range of 8-9 g/dL when procrit was administered

Rami S. Komrokji, MD Clinical Director, Associate Professor Malignant Hematology Department

H. Lee Moffitt Cancer Center Tampa, Florida

Second-generation JAK inhibitors: Targeting the JAK-STAT pathway

Disclosures for Rami S. Komrokji, MD Royalty N/A

Receipt of intellectual property/ Patent holder

N/A

Consulting fee Incyte

Speakers bureau Incyte

Fees for non-CME services N/A

Contracted research Incyte

Ownership interest (stocks, stock options)

N/A

Other N/A

N/A = Not Applicable (no conflicts listed) Presentation includes discussion of investigational JAK inhibitors that are not yet FDA approved

Case presentation

69 year old Caucasian male with past medical history of hypertension: • 1986: Diagnosed with polycythemia rubra vera and treated

with periodic phlebotomy until 2008 when his counts stabilized.

• 2012: He developed progressive splenomegaly, leukocytosis, anemia, and thrombocytopenia (WBC 17 K, Hgb 10.2 g/dL, platelets 150). – A bone marrow was consistent with post PV-myelofibrosis (post

PV-MF). Normal male karyotype – PCR was positive for JAK2V617F mutation

• No suitable donor could be identified for consideration of allogeneic stem cell transplantation.

Case presentation

69 year old Caucasian male with past medical history of hypertension diagnosed with post PV-MF: • July 2012: He was started on ruxolitinib 15 mg po BID

with excellent clinical response in terms of splenomegaly and fatigue. – Main side effect was anemia with Hgb decreased to the

range of 8-9 g/dL when procrit was administered by local oncologist maintaining Hgb between 9-10 g/dL with no transfusion.

• May 2014: Progressive splenomegaly, ruxolitinib dose increased up to 25 mg po BID but with worsening of his anemia requiring red blood cell transfusion and only modest further clinical response.

Case presentation questions

• Could a 2nd generation JAK inhibitor offer an advantage over ruxolitinib as first-line therapy in patients with cytopenia?

• Can we consider treatment with a 2nd generation JAK inhibitor after ruxolitinib failure?

Outline

• Overview of JAK inhibitors highlighting the targets, differences, and stage of development.

• What can a 2nd generation JAK2 inhibitor offer beyond ruxolitinib as an upfront treatment? – Pacritinib – Momelotinib

• Is there a role for a 2nd JAK2 inhibitor after ruxolitinib failure? – Fedratinib data as 2nd line

• Novel approaches targeting JAK/Stat pathway

JAK2 inhibitors Drug Other target Phase Status

Ruxolitinib JAK-1 III Approved

Pacritinib FLT-3 III ongoing

Momelotinib JAK1, JNK1, TYK2, CDK2, RICJ2 III ongoing

Fedratinib FLT-3, RET III withdrawn

AZD1480 JAK1, JAK3, FLT4, FGFR1, TRKA II

Gandotinib (LY2784544)

I withdrawn

NS-018 SRC, FLT3, ABL I/II

XL019 I withdrawn

BMS-911543 I/II withdrawn

Cervantes F. How I treat myelofibrosis. Blood. 2014;124(17):2635-2642.

What can a 2nd generation JAK2 inhibitor offer beyond ruxolitinib as

an upfront treatment?

Pacritinib: A Selective JAK2/FLT3 Inhibitor

William AD, et al. J Med Chem 2011; 54:4638 Hart S, et al. Leukemia 2011; 25:1751

Kinase IC50 (nM)

JAK1 1280

JAK2wt 23

JAK2V617F 19

JAK3 520

TYK2 50

FLT3 22

FLT3-D835Y 6

• Pacritinib (SB1518): oral,

selective, dual JAK2/FLT3

inhibitor

• Potent inhibition of JAK2-STAT3

-STAT5 pathway without

myelosuppression in preclinical

studies

• Did not appear to be associated

with clinically significant

treatment-emergent anemia or

thrombocytopenia in early clinical

studies

Analysis of 2 Phase II Trials of Pacritinib in Patients with Baseline Platelet Counts of ≤100,000/µL

• International phase II studies (001, 003) conducted between 2010-2012 (n=65) – Pacritinib dosed 400 mg oral once daily

– Spleen size assessed by physical exam (PE) and MRI

– Patient-reported outcomes assessed using the Myelofibrosis Symptom Assessment Form (MF-SAF)1

– Standard adverse event (AE) reporting and central laboratory testing

• Databases were integrated to evaluate safety and efficacy in patients with baseline platelet counts of ≤100,000/µL or >100,000/µL

Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395

Demographics

Baseline Platelets

≤100,000/µL

(n=28)*

Baseline Platelets

>100,000/µL

(n=37)*

All

(n=65)

Age, Median (range) 69 (46-85) 68 (44-85) 68 (44-85)

Male, N (%) 19 (68%) 28 (76%) 47 (72%)

MF Diagnosis, N (%)

Primary MF 21 (75%) 19 (51%) 40 (62%)

Post-PV MF 5 (18%) 11 (30%) 16 (25%)

Post-ET MF 2 (7%) 7 (19%) 9 (14%)

DIPSS Risk Category, N (%)**

Intermediate-1 3 (11%) 11 (30%) 14 (22%)

Intermediate-2 11 (39%) 9 (24%) 20 (31%)

High 4 (14%) 10 (27%) 14 (22%)

JAK2V617F positive, N (%) 23 (82%) 29 (78%) 52 (80%)

** DIPSS was calculated post-hoc and was indeterminate on the remainder of the patients: 10 (36%), 7 (19%)

and 17 (26%), respectively Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395

* No significant differences were observed between the two groups

Baseline hematologic parameters

Baseline Platelets

≤100,000/µL

(n=28)*

Baseline Platelets

>100,000/µL

(n=37)*

All

(n=65)

Platelet Count (x103/mL)

Mean (SD) 56 (± 23) 261 (± 147) 173 (± 151)

Median (IQR) 59

(34-70)

227

(163-315)

121

(60-238)

Range 15-97 104-859 15-859

Platelet transfusions

within 180 days prior to

study screening, N (%) 3 (11%) 0 (0%) 3 (5%)

Hemoglobin (g/dL),

Median (range) 8.8 (3.7-14) 10.7 (7.4-14.4) 9.7 (3.7-14.4)

RBC transfusions within

180 days prior to study

screening, N (%) 13 (46%) 13 (35%) 26 (40%)



Endpoint Time Period

Baseline Platelets

≤100,000/µL

(n=28)*

Baseline Platelets

>100,000/µL

(n=37)*

All

(n=65)

≥ 50%

Reduction in

spleen size by

PE

Up to 24

weeks 12 / 28 (43%) 14 / 34 (41%) 26 / 62 (42%)

Up to last

visit on

treatment

13 / 28 (46%) 14 / 35 (40%) 27 / 63 (43%)

≥ 35%

Reduction in

spleen volume

by MRI

Up to 24

weeks 7 / 23 (30%) 6 / 26 (23%) 13 / 49 (27%)

Up to last

visit on

treatment

10 / 23 (44%) 8 / 26 (31%) 18 / 49 (37%)

Spleen response



Baseline Platelets

≤100,000/µL

(n=28)**

Baseline Platelets

>100,000/µL

(n=37)**

All

(n=65)

Up to 24

weeks 11 / 28 (39%) 16 / 34 (47%) 27 / 62 (44%)

Up to last

visit on

treatment

13 / 28 (46%) 17 / 34 (50%) 30 / 62 (48%)

≥50% reduction in patient-reported symptom score*

* The symptom score is the sum of the individual scores for worst fatigue, early satiety,

abdominal pain or discomfort, night sweats, itching, and bone pain reported on the MF-

SAF (Mesa RA, Schwager S, Radia D ,et al. The Myelofibrosis Symptom Assessment Form (MFSAF): An evidence-

based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res.

2009; 33(9): 1199-203).



Platelet count change over time

Baseline platelets ≤100,000/µL Baseline platelets >100,000/µL

Baseline platelets >350,000/µL

Me

an

Pe

rce

nt

Ch

an

ge

in

Pla

tele

t C

ou

nt

(± S

EM

)

Me

an

Pe

rce

nt

Ch

an

ge

in

Pla

tele

t C

ou

nt

(± S

EM

)

Me

an

Pe

rce

nt

Ch

an

ge

in

Pla

tele

t C

ou

nt

(± S

EM

)


Hemoglobin change over time

Baseline platelets ≤100,000/µL Baseline platelets >100,000/µL

Me

an

Pe

rce

nt

Ch

an

ge

in

He

mo

glo

bin

(±

SE

M)

Me

an

Pe

rce

nt

Ch

an

ge

in

He

mo

glo

bin

(±

SE

M)


Pacritinib: Conclusions

• Demonstrated encouraging spleen size and patient-reported symptom score reduction regardless of baseline platelet counts

• Duration of exposure and daily dose were unaffected by starting platelet counts

• There was no apparent association with clinically significant treatment emergent anemia or thrombocytopenia

• A phase III trial, PERSIST-2, will evaluate pacritinib in MF patients with platelet counts ≤ 100,000/µL vs. BAT, including ruxolitinib

• The PERSIST-1 phase III trial, which compares pacritinib to BAT, not including a JAK2 inhibitor, is currently enrolling, has no upper or lower limit for platelet counts

Small-molecule, ATP-competitive, JAK1 and JAK2 inhibitor

Has good selectivity over other JAK family kinases (JAK3, TYK2) and excellent selectivity over other tyrosine and serine/threonine kinases

Inhibits STAT phosphorylation downstream of constitutively active JAK2 or cytokine-stimulated JAK1 or JAK2

Orally active

Update on the long-term efficacy and safety of momelotinib, a

JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis

Pardanani A, et al. Blood 2013;122(21): abstr 108

Dose Groups

100 mg QD (n=3)

150 mg QD* (n=52)

200 mg QD (n=3)

300 mg QD* (n=60)

400 mg QD (n=6)

150 mg BID* (n=42)

Continues long-term dosing of momelotinib

48 subjects remain on study as of Oct, 2013

Data collection and analysis ongoing

Median duration of treatment (days): 627 (range 23 1294)

Core Study CCL09101 (n=166)

Treatment Duration: 9 months

Extension Study CCL09101E

(n=120)

*Dose level targeted for expansion

MTD

Dose-limiting toxicities: Grade 3

hyperlipasemia, Grade 3 headache

Studies CCL09101 and CCL09101E


Key eligibility criteria for study CCL09101

Diagnosis of PMF or Post-PV/ET MF

IPSS high risk or Int-2 risk, or Int-1 risk with

symptoms and/or unresponsive to available

therapy

AST or ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if due to

extramedullary hematopoiesis

Bilirubin ≤ 2 x ULN or direct bilirubin < 1.0

Creatinine ≤ 2.5 x ULN

ANC ≥ 500/µL, platelet ≥ 50,000/µL

4-weeks wash out for prior radiation

therapy

14-days wash out for prior systemic

therapy

Presence of peripheral neuropathy is not

allowed (amendment 3/2011)

Clinically active hepatitis B or C is not

allowed

Known positive HIV is not allowed


Baseline characteristics Characteristic Value

Number of subjects 166

Age (years)

Median (range) 68 (34-89)

Sex

Male/Female 58%/42%

Myelofibrosis

Primary 63%

Post-PV 22%

Post-ET 15%

JAK2V617F positive 77%

Prior therapy

JAK inhibitor 13%

Characteristic Value

Splenomegaly > 10 cm 79%

Palpable spleen size (cm)

Mean 18.3

Median 18

RBC transfusion dependent 43%

Median hemoglobin level (g/dL) 9.4

Transfusion independent

(n=93) 10.3

Transfusion dependent

(n=72) 8.7

Median platelet count (109/L) 182


Spleen response

Spleen Response Number of

Subjects (%)

Total enrollment 166 (100%)

Baseline spleen size > 5 cm at baseline 148 (89%)

≥ 50% reduction in splenomegaly that lasts

≥ 8 weeks for splenomegaly ≥ 10 cm at

baseline: A (A/148)

52 (35%)

Resolution of splenomegaly that lasts ≥ 8

weeks for splenomegaly > 5 and < 10 cm:

B (B/148)

6 (4%)

Spleen Response: A + B 58 (39%)


Anemia response

Anemia Response Number of

Subjects (%)

Transfusion dependent at baseline 72 (43%)

Achieved transfusion independence on study

that lasts ≥ 12 weeks: C (C/72) 49 (68%)

Transfusion independent with Hgb < 10 g/dL at

baseline 39 (24%)

Rise in Hgb ≥ 2 g/dL on study that lasts ≥ 12

weeks: D (D/39) 10 (26%)

Anemia Response: C + D 59 (53%)

Transfusion dependence at baseline is defined as ≥ 2 units of RBC transfusions in the 30 days prior to C1/D1 and/or identified as transfusion dependent in medical history


Duration of anemia response

Number of events (%): 18 (30.5)

Number of censored (%): 41 (69.5)

Median (days) (95% CI): 1,042 (514, NE)

Event Censored

Duration of anemia response (days)

Pro

ba

bili

ty

0 200 400 600 800 1000

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


Treatment-related adverse events (> 10% of subjects)

Total number of subjects enrolled 166

All Grades ≥ Grade 3

Thrombocytopenia 77 (46.4%) 49 (30%)

Neuropathy peripheral 73 (44.0%) 0 (0%)

Diarrhoea 42 (25.3%) 0 (0%)

Dizziness 40 (24.1%) 0 (0%)

Nausea 37 (22.3%) 0 (0%)

Headache 26 (15.7%) 2 (1%)

Alanine aminotransferase increased 25 (15.1%) 4 (2%)

Aspartate aminotransferase increased 20 (12.0%) 2(1%)

Lipase increased 24 (14.5%) 8 (5%)

Hyperamylasaemia 17 (10.2%) 0 (0%)

• Thrombocytopenia includes platelet count decreased, thrombocytopenia

• Neuropathy peripheral includes formication, hypoaesthesia, paraesthesia, peripheral sensory neuropathy, neuropathy

peripheral

• Lipase increased includes hyperlipasaemia, lipase increased

• Hyperamylasaemia includes amylase increased, hyperamylasaemia

• Treatment-relatedness assessed by investigator


First dose effect of momelotinib

Number (%)

Total subjects enrolled 166

Adverse event of dizziness* on C1/D1 23 (14%)

Related to study drug 16 (10%)

Unrelated to study drug 5 (3%)

Relatedness not reported 2 (1%)

Adverse event of hypotension* on C1/D1 11 (7%)

Related to study drug 8 (5%)

Unrelated to study drug 3 (2%)

• *Dizziness includes dizziness, lightheadedness

• *Hypotension includes low blood pressure, decreased blood pressure, hypotension

• 3 subjects with dizziness also reported hypotension

• Treatment-relatedness assessed by investigator


Platelet count and momelotinib starting dose

Month

525

150 mg QD

300 mg QD

150 mg BID

Doses at C1D1

Me

an

pla

tele

t co

un

t

1 2 3 4 6 5 7 8

0

25

50

75

25

100

125

150

175

200

225

250

275

300

325

350

375

400

425

450

475

500

Me

an

Pla

tele

ts

0

25

50

75

100

125

150

175

200

225

250

275

300

325

350

375

400

425

450

475

500

525

Time (Months)

1 2 3 4 5 6 7 8

Dose at C1D1: 150 mg QD 300 mg QD 150 mg BID


N=420

1:1 randomization

Screening (≤ 35 days)

Double-blind Treatment Phase Open-label Phase Long-term Follow-up

Momelotinib + placebo

Ruxolitinib + placebo

Week 24

Momelotinib QD Momelotinib

Momelotinib

Week 192

Year 4 Year 5 Day 1

Within 5 days of randomization

Phase 3 study design (GS-US-352-0101)

Is there a role for a 2nd JAK2 inhibitor after ruxolitinib failure?

Efficacy and safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with

ruxolitinib: A phase II study (JAKARTA-2)

• Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles.

• Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib.

• No consensus definition of RUX resistance/intolerance, (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX.

• Primary endpoint : spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]

Harrison CN, et al. Blood. 2013;122(21):abstr 661



• 27 patients received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4])

• Baseline Characteristics: – The median age was 69 yrs – 56% male – 67% primary MF – 63% high-risk MF – 67% JAK2V617F positive – 41% platelet count <100 × 109/L – median spleen volume 3190 mL [1072–7815].

• Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity)

• Median fedratinib exposure : 4 cycles (range 1–10); 19 patients remain on treatment.




RUX resistant (n=18)

RUX intolerant (n=9)

Overall (n=27)

Spleen response at Wk 12a, n/N (%)

6/14 (43)

2/6 (33)

8/20 (40)

Symptom response to Wk 12b, n/N (%

3/18 (17)

2/8 (25)

5/26 (19)

a7 patients not evaluable: no post-baseline MRI/CT scan (n=5); no baseline MRI/CT scan (n=1); MRI/CT scan outside time window for Wk 12 assessment (n=1). b1 patient not evaluable: no baseline and at least one post-baseline assessment of TSS.


Momelotinib: Response rates of JAK inhibitor-treated subjects

Number

Previously treated with JAK inhibitor 22

Ruxolitinib 14

TG101348 5

“JAK inhibitor study” 3

Spleen evaluable1 20

Spleen response2: A (A/20) 2 (10%)

Transfusion independence evaluable3 13

Transfusion independence response4: B (B/13) 7 (54%)

(1) Spleen evaluable: baseline palpable splenomegaly > 5 cm and had completed ≥ 8 weeks of treatment

(2) Spleen response: ≥ 50% decrease from baseline in palpable spleen length for baseline splenomegaly ≥

10 cm or resolution of palpable splenomegaly for baseline splenomegaly > 5 and < 10 cm

(3) Transfusion independence evaluable: transfusion dependent at baseline and had completed ≥ 12

weeks of treatment

(4) Transfusion independence response: For those who are transfusion dependent at baseline,

achievement of transfusion independence that lasts ≥ 12 weeks


Novel approaches targeting JAK/Stat pathway

Targets of intervention by putative small-molecule inhibitors around the cytokine receptor,

JAK-STAT, MAPK, and PI3K-mTOR pathways.

Constantinescu S N , and Vainchenker W. Hematology Am Soc

Hematol Educ Program 2012;2012:553-560

Copyrighted Figure

Searching for “mutant”-specific JAK2 inhibitors by targeting a predicted mechanism of

activation of JAK2 kinase domain (JH1) by the V617F pseudokinase (JH2) mutation.

Constantinescu S N , and Vainchenker W. Hematology Am Soc

Hematol Educ Program 2012;2012:553-560

Copyrighted Figure

Conclusions

• 2nd generation JAK2 inhibitors may offer advantages as first-line therapy in term of efficacy or toxicity based on different 2ndry targets.

• Responses to 2nd generation JAK2 inhibitors may be observed after failure of ruxolitinib and should be further pursued in clinical trials.

• Novel approaches targeting JAK-STAT pathway include search for mutant specific inhibitors, non-competitive inhibitors, and targeting downstream signaling.

Thank You

[email protected]

Documents

Second generation JAK inhibitors: Targeting the JAK-STAT ...splenomegaly and fatigue. –Main side effect was anemia with Hgb decreased to the range of 8-9 g/dL when procrit was administered