stand strong - horizon virtual venue

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IndicationTAVALISSE is a kinase inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Select Important Safety InformationWarnings and Precautions· Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects.

Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required.

Please see additional Important Safety Information throughout, complete Important Safety Information on page 19, and accompanying full Prescribing Information.

PROTECTING PLATELETS.DEFENDING PATIENTS.

STAND STRONGAGAINST PLATELET DESTRUCTION

For adults with chronic ITP

2 3

IMMUNE THROMBOCYTOPENIA IS A HETEROGENEOUS DISEASE WITH A COMPLEX, MULTIFACTORIAL PATHOGENESIS

Immune thrombocytopenia (ITP) is driven by two factors: immune-mediated platelet destruction and limited platelet production1

CONVENTIONAL ITP TREATMENT OPTIONS ARE DEFINED BY COMPLEXITIES

Current ITP treatment approaches either decrease platelet destruction or stimulate platelet production3

Corticosteroids Suppress systemic function and reduce antibody production,

resulting in decreased platelet destruction1

Standard first-line therapy for recently diagnosed patients5

Over time, treatment side effects may outweigh the potential benefits5

Most patients relapse upon discontinuation of treatment5

Thrombopoietin receptor agonists (TPO-RAs) Stimulate megakaryocytes in bone marrow to produce platelets3

Associated with potential increases in bone marrow fibrosis5

Evidence of increased thrombotic events with use of certain TPO-RA agents5

Anti-CD20 Depletes B cells3

Increased response when used with concomitant corticosteroids5

A meta-analysis of 5 trials showed that rituximab was not associated with reductions in bleeding5

In a study of response durability, only 21% maintained remission at 5 years5

Immune-mediated platelet destruction Limited platelet production

Dysregulation of the immune system leads to production of anti-platelet antibodies2

1 Platelet destruction causes decreased levels of thrombopoietin (TPO)1 1

Macrophage recognition of antibody-coated platelets results in unregulated platelet destruction3

2Anti-platelet antibodies may also target megakaryocytes, resulting in impaired megakaryocyte function3

2

Lysis process results in an amplified production of anti-platelet antibodies33

Irregular T-cell response may destroy platelets in bone marrow and impede platelet production4

3

An individualized treatment strategy is needed for patients since ITP is a distinctly heterogeneous disease.

– Shih et al. Presse Med. 2014.2

Heterogeneous D

isease

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Please see Important Safety Information throughout, complete Important Safety Information on page 19, and accompanying full Prescribing Information.

THE INTERNATIONAL CONSENSUS REPORT ON IMMUNE THROMBOCYTOPENIA (ITP) ENDORSES FOSTAMATINIB AS A SECOND-LINE TREATMENT FOR CHRONIC ITP

*Adapted from the 2019 publication of the International Consensus Report on ITP.†Recommended first-line treatments are defined as corticosteroids, IVIG, and anti-D.

Select Important Safety Information

Warnings and Precautions (continued)• Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT or AST

increase to >3 x upper limit of normal, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation.

TAVALISSE PRESENTS AN OPPORTUNITY TO REDEFINE THE TREATMENT LANDSCAPE

Limiting platelet destruction with the targeted mechanism of TAVALISSE is a novel way to treat chronic ITP (cITP)6,7

TAVALISSE is the first spleen tyrosine kinase (SYK) inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.6,7

STIMULATE PLATELETPRODUCTION

LIMIT PLATELETDESTRUCTION

TARGETED(DISEASE

MECHANISM)

TAVALISSE7

SYSTEMIC(IMMUNE

SUPPRESSION)

Splenectomy8

Intravenous immune globulin10,11

Corticosteroids9

Anti-CD2012,13

TPO-RAs14-16

[TAVALISSE] has a unique mechanism of action, dissimilar to other approved ITP therapies, and produced responses in patients who had relapsed or not responded to TPO-RA agents, rituximab, and/or splenectomy.

– Bussel et al. Am J Hematol. 2018.6

After first-line treatments fail in adults with ITP, the International Consensus Report recommends5,*,†:

MEDICAL OPTIONS

SUBSEQUENT TREATMENT

SURGICAL OPTION

Splenectomy

FOSTAMATINIB

Eltrombopag

Romiplostim

Avatrombopag

Rituximab

ROBUST EVIDENCE

Azathioprine

Cyclosporin A

Cyclophosphamide

Danazol

Dapsone

Mycophenolate mofetil

Vinca alkaloids

LESS ROBUST EVIDENCE

Treating cITP

✔

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INHIBITING SPLEEN TYROSINE KINASE (SYK) MAY HELP LIMIT IMMUNE-MEDIATED PLATELET DESTRUCTION

*The active metabolite of TAVALISSE is R406.

TAVALISSE is the first and only agent that targets SYK in macrophages to inhibit downstream signaling in cITP3,6


Warnings and Precautions (continued)• Diarrhea occurred in 31% of patients and severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the

development of diarrhea and manage using supportive care measures early after the onset of symptoms. If diarrhea becomes severe (≥Grade 3), interrupt, reduce dose or discontinue TAVALISSE.

STAND STRONG AGAINST PLATELET DESTRUCTION

TAVALISSE is an opportunity for

patients to

Downstream signaling pathways (Arp2/3, p38, JNK)

Platelet bound by autoantibodies

SYK

SLP76

Rac

PI3K

Macrophage

Fcγ receptor

Anti-platelet autoantibody

TAVALISSE (the active metabolite) inhibits spleen tyrosine kinase (SYK)7,*

3. The Fcγ cascade, which includes spleen tyrosine kinase (SYK), leads to platelet destruction2,17

2. Antibody-coated platelets binding to Fcγ receptors on the macrophage surface induces intracellular signaling2

1. Dysregulation of the immune system leads to production of anti-platelet antibodies2

4. Fcγ activation results in a continuous cycle of autoimmune- mediated platelet destruction2,17


MO

A

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Stable response (primary endpoint)

To observe stability and response variability (during weeks 14-24)

Platelet count ≥50 x 109/L on at least 4 of the 6 visits without need for rescue treatment

Overall response (post hoc endpoint)†

To assess efficacy signal during the first 3 months/ 12 weeks

Platelet count ≥50 x 109/L at one or more check-ins without need for rescue treatment in the preceding 4 weeks

THE FOSTAMATINIB IN ITP (FIT) PROGRAM WAS DESIGNED TO EVALUATE SHORT- AND LONG-TERM TREATMENT EFFECTS

The FIT-1, FIT-2, and FIT-3 phase 3 clinical trials assessed TAVALISSE efficacy, safety, and durability6,18,*

* Duration of response analysis endpoint: the number of days from achieving a platelet count ≥50 x 10⁹/L to reaching a platelet count <30 x 10⁹/L at two consecutive visits. Patients were classified as losing response if platelet counts dropped below 30 x 10⁹/L for two consecutive visits 28 days apart, or if rescue medication was used.

†Overall response: the initial 12 weeks were selected since most nonresponding patients from both arms discontinued FIT-1 and FIT-2 and entered the open-label extension study at or very soon after week 12.

‡Stable concurrent ITP therapies permitted in clinical trials: glucocorticoids (<20 mg prednisone equivalent per day), azathioprine, or danazol.

All patients with platelets <50 x 109/L, regardless of treatment arm, were eligible to enter FIT-3 (open-label extension) at or after week 12

In clinical trials, stable concurrent ITP therapy was allowed, and rescue therapy was permitted if needed. Visits where rescue medication was used were excluded from the efficacy analysis7,‡

FIT-1 and FIT-2Double-blind, placebo-controlled (short-term)

FIT-3Open-label extension (long-term)

Ongoingefficacy and safety evaluation

Patients eligible to enter FIT-3 at ≥week 12

Weeks 14-24biweekly check-ins

Day 1–week 12biweekly check-ins

Treatment initiated

150patients

randomized 2:1

FIT-1 and FIT-2Double-blind, placebo-controlled (short-term)

FIT-3Open-label extension (long-term)

ONGOINGThe median duration of response

has not been reached

Patients eligible to enter FIT-3 at ≥week 12§

Weeks 14-24biweekly check-ins

Day 1–week 12biweekly check-ins

Treatment initiated

150patients

randomized 2:1

THE FIT PROGRAM INCLUDED ADULT PATIENTS WITH CHRONIC ITP WHO HAD RECEIVED ≥1 PRIOR THERAPY

FIT program patients were representative of the general adult chronic ITP population, including exposure to prior therapies

Median time since diagnosis 8.5 years

Median age 54 years

Gender 61% female; 39% male

Median platelet count 16 x 109/L

Platelet counts <15 x 109/L 45%

Splenectomy (time since splenectomy) 35% (all >6 months, except for 1 patient)

Median number of prior therapies 4

Corticosteroids 94%

Immunoglobulins 53%

TPO-RAs 48%

Immunosuppressants 44%

Rituximab 32%

Select baseline patient characteristics in FIT-1 and FIT-27,19 Prior treatment exposure among patients in FIT-1 and FIT-26,7,19

TAVALISSE dosing7

Starting dose of TAVALISSE: One 100 mg tablet BID

Based on platelet count and tolerability, the dose could be increased to one 150 mg tablet BID at or after week 4

Patients who had a platelet count ≥50 x 109/L at the time of rollover to the FIT-3 open-label extension study maintained their existing dose of TAVALISSE


Warnings and Precautions (continued)• Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC

monthly and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction, or discontinuation.

Trial Design

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Warnings and Precautions (continued)• TAVALISSE can cause fetal harm when administered to pregnant women. Advise pregnant women the potential risk to a fetus. Advise females

of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Verify pregnancy status prior to initiating TAVALISSE. It is unknown if TAVALISSE or its metabolite is present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during TAVALISSE treatment and for at least 1 month after the last dose.

MEDIAN PLATELET COUNTS BY STUDY VISIT (POOLED FIT-1 + FIT-2)

PLAT

ELET

CO

UN

T (

109 /L

)

STUDY VISIT IN WEEKS

200

0

0 2 4 6 8 10 12 14 16 18 20 22 24

38

49

45

Overall Responders

Nonresponders

Placebo

38

48

43

41

45

41

40

41

35

40

40

31

38

39

33

37

42

32

31

7

11

27

7

6

26

5

3

23

4

4

21

3

2

20

4

3

100

150

50

PlaceboTAVALISSE NonrespondersTAVALISSE Overall Responders50%

40%

30%

20%

10%

0

14%17%

43%

Stable ResponseOverall Response

2%Stable Response

Overall Response

TAVALISSE (n=101) PLACEBO (n=49)

STABLE RESPONSE ANALYSIS7

FIT-1: 18% stable response rate FIT-2: 16% stable response rate FIT-1 + FIT-2: 17% stable response rate (pooled)

Response rates achieved in the 24-week evaluation period (double-blind, placebo-controlled trials)

Overall response observations from a 3-year post hoc interim analysis19,*,†

* 1 month = 4 weeks. Data cutoff date: March 8, 2018.

†Overall response: achievement of a platelet count ≥50 x 109/L at least once during the first 3 months/12 weeks without need for rescue treatment.

TAVALISSE DELIVERED RAPID AND ROBUST IMPROVEMENTS IN PLATELET COUNTS TAVALISSE DEMONSTRATED DURABLE BENEFIT BEYOND 3 YEARS

TAVALISSE overall response summary — day 1 to 24 weeks19

First platelet count measurement at week 2 and every 2 weeks thereafter.18

A total of 102 patients exited the placebo-controlled trials early (at or after week 12) and entered the open-label extension study.7

Stable response (primary endpoint)7,18,19,*

Median post-baseline platelet count: 97 x 109/L

Platelet counts ≥50 x 109/L during weeks 14-24 (at least 4 of 6 consecutive visits)

Overall response (post hoc endpoint)6,19,†

Median post-baseline platelet count: 49 x 109/L

At least one platelet count ≥50 x 109/L during weeks 0-12

Median time to first response: 15 days6,‡

110

130

90

70

50

30

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

PLAT

ELET

CO

UN

T (x

109 /L

)

STUDY VISIT IN MONTHS

6353 62 56 53 47 4046 47 37 40 35 35 37 31 33 36 34 33 34 35 32 28 24 21 17 13 9Overall

Responders

MEDIAN PLATELET COUNTS OVER TIME(OVERALL RESPONDERS IN THE PHASE 3 CLINICAL STUDIES—FIT-1 + FIT-2 + FIT-3)

Median platelet count: 60 x 109/L

*Stable platelet response: achievement of a platelet count ≥50 x 10⁹/L on ≥4 of the 6 visits during weeks 14-24 without need for rescue treatment.

†Overall response: achievement of a platelet count ≥50 x 10⁹/L at least once during the first 3 months/12 weeks without need for rescue treatment.

‡Time to first response was a post hoc analysis.

Efficacy

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PATIENT SUBGROUP DIFFERENCE (95% CI)

POPULATION All patients (N=150) 28.29 (14.54, 42.04)

BASELINE PLATELET COUNT

≥15 x 10⁹/L (n=82)

<15 x 10⁹/L (n=68)

35.85

20.26

(16.40, 55.29)

(2.14, 38.39)

PRIOR SPLENECTOMY

Yes (n=53)

No (n=97)

13.62

35.92

(-8.81, 36.06)

(18.85, 52.99)

PRIOR RITUXIMAB*Yes (n=48)

No (n=102)

21.01

31.98

(-3.36, 45.38)

(15.34, 48.62)

PRIOR TPO-RAYes (n=71)

No (n=79)

22.78

32.42

(4.03, 41.54)

(12.50, 52.35)

AGE<65 years (n=111)

≥65 years (n=39)

30.68

21.10

(15.02, 46.33)

(-7.99, 50.20)

FAVORS PLACEBO FAVORS TAVALISSE

-75 -50 -25 0 25 50 75

TAVALISSE DEMONSTRATED EFFICACY ACROSS PATIENT SUBGROUPS COMPARED TO PLACEBO

Treatment benefit favored TAVALISSE in the phase 3 clinical trials (FIT-1 + FIT-2)19

*Post hoc subgroup.

A post hoc analysis of the phase 3 clinical studies was conducted to evaluate patient response by line of therapy20

ALL LINES OF THERAPY(N=145)

3RD LINE OF THERAPY AND BEYOND

(n=113)

47%

54%

0

10

20

30

40

50

60

70

80

2ND LINE OF THERAPY(n=32)

78%

PATI

ENTS

, %

PERCENTAGE OF PATIENTS WITH PLATELET COUNT ≥50 x 109/L AT ANY VISIT(PATIENTS WHO RECEIVED TAVALISSE IN FIT-1 + FIT-2 + FIT-3)

RESPONSE TO TAVALISSE WAS ASSESSED BY LINE OF THERAPY

2nd line of therapy: patients who had received only steroids (with or without immunoglobulins) prior to treatment with TAVALISSE in the FIT program

Durability of response by line of therapy* (in patients with a platelet count ≥50 x 109/L at any visit):

2nd line: 84%

3rd line and beyond: 79%


Drug Interactions• Concomitant use of TAVALISSE with strong CYP3A4 inhibitors increases exposure to the major active metabolite of TAVALISSE (R406),

which may increase the risk of adverse reactions. Monitor for toxicities that may require a reduction in TAVALISSE dose.• It is not recommended to use TAVALISSE with strong CYP3A4 inducers, as concomitant use reduces exposure to R406.

Adverse events among patients in these subgroups were consistent with those in patients treated with TAVALISSE in the placebo-controlled trials7,18,20

* Median percentage of time on treatment with platelet counts not ≤30 x 109/L on two consecutive visits, at least 28 days apart or use of rescue therapy.

Subgroup Analysis

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aIncludes diarrhea and frequent bowel movement. bIncludes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP diastolic increased. c Includes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection, and viral upper respiratory tract infection. dIncludes rash, rash erythematous, and rash macular. eIncludes abdominal pain and abdominal pain upper. fIncludes neutropenia and neutrophil count decreased.

No new or more frequent toxicities or intolerabilities were detected with prolonged use of TAVALISSE in the FIT-3 open-label extension study18

The most common adverse reactions reported in TAVALISSE and placebo patients were categorized as mild, moderate, and severe7

ADVERSE REACTIONSTAVALISSE (n=102) PLACEBO (n=48)

Mild % Moderate % Severe % Mild % Moderate % Severe %

Diarrheaa 21 10 1 13 2 0

Hypertensionb 17 9 2 10 0 2

Nausea 16 3 0 8 0 0

Dizziness 8 2 1 6 2 0

ALT increased 5 6 0 0 0 0

AST increased 5 4 0 0 0 0

Respiratory infectionc 7 4 0 6 0 0

Rashd 8 1 0 2 0 0

Abdominal paine 5 1 0 2 0 0

Fatigue 4 2 0 0 2 0

Chest pain 2 3 1 2 0 0

Neutropeniaf 3 2 1 0 0 0

Incidence of common adverse reactions (≥5% of patients)—FIT-1+ FIT-27

THE MOST COMMON ADVERSE REACTIONS OBSERVED IN FIT-1 AND FIT-2

Observations from the placebo-controlled trials (FIT-1 + FIT-2)

Diarrhea was the most common adverse reaction observed7

– Diarrhea should be managed with supportive measures (eg, dietary changes, hydration, and/or antidiarrheal medication). If diarrhea becomes severe, interrupt, reduce, or discontinue TAVALISSE (see dose modification guidelines)

10 patients discontinued treatment with TAVALISSE due to adverse reactions19

– 5 severe AEs led to treatment withdrawal in the TAVALISSE arm: syncope, pneumonia, chest pain, thrombocytopenia, and neutropenia

– Nonsevere adverse events leading to withdrawal in the TAVALISSE arm included: alanine aminotransferase increased, diarrhea, neutropenia, abdominal pain, and headache

Most AEs were mild/moderate and resolved or were managed with dose reduction, dose interruption, and/or secondary medication.

—Bussel et al. Am J Hematol. 2019.18

TAVALISSE PATIENTS HAD FEWER BLEEDING EPISODES AND REQUIRED LESS RESCUE MEDICATION COMPARED TO PLACEBO

0%

MODERATEANY MILD SEVERE

6%

SERIOUS

0

10

20

30

40

12%

18%

9% 10%

0%

10%

21%

35% Placebo (n=49)

TAVALISSE Overall Responder (n=43)

PATI

ENTS

, %

TAVALISSE patients had a lower incidence of bleeding episodes than placebo patients7,19

TAVALISSE patients required less rescue medication than placebo patients6

In the placebo-controlled trials, the incidence of bleeding in patients who received TAVALISSE (regardless of responder status) was 29%, compared with 37% in patients who received placebo

In the placebo-controlled trials, 30% of patients who received TAVALISSE (regardless of responder status) required rescue medication, compared with 45% of patients who received placebo

Of patients treated with TAVALISSE in the phase 3 clinical studies (FIT-1 + FIT-2 + FIT-3)19,*:

59% had no bleeding episodes

59% did not require rescue medication at any visit

* Compiled from interim analysis. Data cutoff: March 8, 2018.

PATI

ENTS

, %

0

10

20

30

40

50

PLACEBO (n=49)TAVALISSE OVERALL RESPONDER (n=43)

16%

45%


Drug Interactions (continued)• Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs and may require a dose reduction

of the CYP3A4 substrate drug.• Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp)

substrate drugs (eg, digoxin), which may require a dose reduction of the BCRP and P-gp substrate drug.

Bleeding, Rescue, Safety

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TAVALISSE OFFERS THE CONVENIENCE OF ORAL DOSING WITHOUT FOOD RESTRICTIONS

When starting TAVALISSE, a 12-week evaluation period is recommended—evaluate clinical benefit at weeks 4, 8, and 127,*,†

Continue treatment at therapeutic dose

- OR -If patient has not derived

clinical benefit after 12 weeks, discontinue treatment‡

MAINTAIN

150 mg BID

100 mg BID

WEEK 4WEEK 1 WEEK 8 WEEK 12

TAVALISSE INITIATION

Increase dose from 100 mg BID to 150 mg BID if patient is not deriving clinical benefit

MAINTAIN

PMAM

AM PM

*12-week evaluation period recommended per product labeling.†Clinical benefit: platelet count increase to a level sufficient to avoid clinically important bleeding. ‡ Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding.

As a part of chronic ITP care, patient monitoring is recommended with TAVALISSE7

Complete blood counts (CBCs), including platelet counts and neutrophilsBaseline plus monthly monitoring until a stable platelet count (≥50 x 10⁹/L) is achieved, then regular monitoring

Liver function tests (LFTs) (eg, ALT, AST, and bilirubin) Baseline plus monthly monitoring

Blood pressure Baseline plus monitoring every 2 weeks until a stable dose is reached, then monthly thereafter

USING TAVALISSE IN YOUR PRACTICE

Patient response may vary—adjust dose to achieve target platelet count

Target platelet count

Baseline 2 4 6 8 10 12


Baseline 2 4 6 8 10 12


Baseline 2 4 6 8 10 12


Baseline 2 4 6 8 10 12

POTENTIAL PLATELET COUNT RESPONSE TRENDS

WEEKS

Early and consistent response observed at 100 mg BID dose

Response maintained at 100 mg BID dose

Initial response observed at 100 mg BID dose

Loss of response observed at week 4

Dose increased to 150 mg BID

Response is recovered and maintained at 150 mg BID dose

Slight response observed at 100 mg BID dose

Dose increased to 150 mg BID at week 4

Response increased and maintained at 150 mg BID dose

No response observed at 100 mg BID dose

Dose increased to 150 mg BID at week 4

No response or clinical benefit observed

Treatment discontinued after week 12

TAVALISSE is an oral medication taken twice daily with or without food7

TAVALISSE is available as 100 mg and 150 mg tablets7

If a dose is missed, the next dose should be taken at its regularly scheduled time7

In clinical trials, stable concurrent ITP therapy was allowed and rescue therapy was permitted if needed7

Use the lowest dose of TAVALISSE to achieve and maintain a platelet count of at least 50 x 109/L as necessary to reduce the risk of bleeding7

In addition to supportive care measures, management of some adverse reactions may require dose interruption, reduction, or discontinuation7

– See section 2.3 of the full Prescribing Information for specific guidance on dose modifications and recommendations for treatment discontinuations regarding hypertension, hepatotoxicity, diarrhea, and neutropenia

88% of patients in the phase 3 clinical trials were maintained at the 150 mg BID dose7


Adverse Reactions• Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis,

which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%).

• Common adverse reactions (≥5% and more common than placebo) from FIT-1 and FIT-2 included: diarrhea, hypertension, nausea, dizziness, ALT and AST increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia.

Dosing

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ROBUST PLATELET COUNT INCREASES

Platelet counts ≥50 x 109/L were observed beyond the

24-week trials19,†

DURABLE BENEFIT

Demonstrated improvements in platelet counts beyond

3 years19,‡

ORAL DOSING WITH NO FOOD RESTRICTIONS

The convenience of an oral medication that can be

taken with or without food7

MILD TO MODERATE ADVERSE REACTIONS

The majority of adverse reactions observed in clinical trials were mild or moderate18

15

EARLY ONSET OF EFFICACY

Median time to first response was 15 days6,*

TAVALISSE is the first and only targeted agent that helps prevent immune-mediated platelet destruction6,7

PROVIDE YOUR PATIENTS WITH AN OPPORTUNITY FOR A LASTING DEFENSE


*Post hoc analysis; first platelet count measurement at 2 weeks.

† 17% of patients (FIT-1 + FIT-2 pooled [n=17]; FIT-1 = 18%, FIT-2 = 16%) achieved a stable platelet count defined as ≥50 x 109/L at 4 of 6 visits in the absence of rescue medication during weeks 14-24. Fifty-four percent of patients treated with TAVALISSE (N=145) achieved a platelet count ≥50 x 109/L at any visit (FIT-1 + FIT-2 + FIT-3).18,20

‡Interim analysis, March 2018.

PROTECTING PLATELETS. DEFENDING PATIENTS.

© 2020 Rigel Pharmaceuticals, Inc. All rights reserved. TAVA_ITP-19261 0120TAVALISSE is a registered trademark and RIGEL ONECARE is a trademark of Rigel Pharmaceuticals, Inc.

INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Important Safety Information

Warnings and Precautions• Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension

may be more susceptible to the hypertensive effects. Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required.

• Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT or AST increase to >3 x upper limit of normal, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation.

• Diarrhea occurred in 31% of patients and severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea and manage using supportive care measures early after the onset of symptoms. If diarrhea becomes severe (≥Grade 3), interrupt, reduce dose or discontinue TAVALISSE.

• Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC monthly and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction, or discontinuation.

• TAVALISSE can cause fetal harm when administered to pregnant women. Advise pregnant women the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Verify pregnancy status prior to initiating TAVALISSE. It is unknown if TAVALISSE or its metabolite is present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during TAVALISSE treatment and for at least 1 month after the last dose.

Drug Interactions • Concomitant use of TAVALISSE with strong CYP3A4 inhibitors increases exposure to the

major active metabolite of TAVALISSE (R406), which may increase the risk of adverse reactions. Monitor for toxicities that may require a reduction in TAVALISSE dose.

• It is not recommended to use TAVALISSE with strong CYP3A4 inducers, as concomitant use reduces exposure to R406.

• Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs and may require a dose reduction of the CYP3A4 substrate drug.

• Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp) substrate drugs (eg, digoxin), which may require a dose reduction of the BCRP and P-gp substrate drug.

Adverse Reactions• Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia,

diarrhea, pneumonia, and hypertensive crisis, which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%).


References: 1. Raj AB. Immune thrombocytopenia: pathogenesis and treatment approaches. J Hematol Transfus. 2017;5(1):1056-1065. 2. Shih A, Nazi I, Kelton JG, Arnold DM. Novel treatments for immune thrombocytopenia. Presse Med. 2014;43:e87-e95. 3. Newland A, Lee E, McDonald V, et al. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018;10(1):9-25. 4. Olsson B, Ridell B, Carlsson L, et al. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood. 2008;112(4):1078-1084. 5. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. 6. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930. 7. TAVALISSE® [package insert]. South San Francisco, CA: Rigel Pharmaceuticals, Inc.; April 2018. 8. Ghanima W, Godeau B, Cines DB, et al. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012;120(5):960-969. 9. Mizutani H, Furubayashi T, Imai Y. Mechanisms of corticosteroid action in immune thrombocytopenic purpura (ITP): experimental studies using ITP-prone mice, (NZW x BXSB) F1. Blood. 1992;79(4):942-947. 10. Kistanguri G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):495-520. 11. WinRho® SDF [package insert]. Berwyn, PA: Aptevo BioTherapeutics, LLC.; August 2016. 12. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001;98(4):952-957. 13. Rituxan® [package insert]. South San Francisco, CA: Genentech, Inc.; April 2019. 14. Doptelet® [package insert]. Durham, NC: Dova Pharmaceuticals, Inc.; June 2019. 15. Nplate® [package insert]. Thousand Oaks, CA: Amgen, Inc.; October 2017. 16. Promacta® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2019. 17. Nimmerjahn F, Ravetch J. Fc receptors as regulators of immune responses. Nature. 2008;8:34-47. 18. Bussel JB, Arnold DM, Boxer MA, et al. Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program. Am J Hematol. 2019;94(5):546-553. 19. Data on file, Rigel Pharmaceuticals, Inc. April 2018. 20. Boccia R, Boxer MA, Ghanima W, et al. Enhanced responses to fostamatinib as second-line therapy and in persistent immune thrombocytopenia (ITP) patients. Abstract presented at: 61st ASH Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

Please see accompanying full Prescribing Information.To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (1-800-332-1088).






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RIGEL OFFERS SUPPORT FOR PATIENTS AND PRACTICES

Reimbursement specialists assist with reimbursement approval, including benefit investigations, prior authorizations, and appeals

Copay and financial assistance programs are available for eligible patients

Nurse navigators facilitate communication, guiding patients through treatment initiation and notifying you and your staff about relevant medical concerns

RIGEL ONECARE is designed to fit within your practice needs

Flexible: TAVALISSE can be fulfilled through in-office dispensing or through specialty pharmacies

Customized: Choose services and method of contact based on what works best for your staff

TAVALISSE Copay Assistance can help eligible patients pay as little as $15 per prescription*

How to enroll

Visit TAVALISSEcopay.com

Follow the steps to complete the enrollment process to determine if patient is eligible

VISIT TAVALISSEcopay.com TO LEARN MORE

RIGEL ONECARE is a patient support center sponsored by Rigel Pharmaceuticals, Inc.

Limitations may apply.*

* Qualifications: Patient has been diagnosed with low platelet counts due to cITP when a prior treatment for ITP has not worked well enough; Patient is 18 years of age or older; Patient has a commercial insurance plan and is not participating in state or federal programs like Medicare Part D, Medicaid, VA/DOD, or Tricare or other state or federal assistance plans. Eligible patients, age 18 or older and with a valid prescription, may receive TAVALISSE at a $15 copay for each prescription if they pay through commercial insurance. The patient will be responsible for any out-of-pocket expenses after the $15,000 annual cap. This offer is not valid for cash-paying patients. This offer is not insurance and offer is valid only for prescriptions filled in the United States and Puerto Rico. Rigel reserves the right to rescind, revoke, or amend this program without notice. Other restrictions may apply. Patient is responsible for applicable taxes, if any.

RIGEL ONECARE provides services dedicated to helping your patients get started and stay on track with TAVALISSE


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ROBUST PLATELET COUNT INCREASES

Platelet counts ≥50 x 109/L were observed beyond the

24-week trials19,†

DURABLE BENEFIT

Demonstrated improvements in platelet counts beyond

3 years19,‡

ORAL DOSING WITH NO FOOD RESTRICTIONS

The convenience of an oral medication that can be

taken with or without food7

MILD TO MODERATE ADVERSE REACTIONS

The majority of adverse reactions observed in clinical trials were mild or moderate18

15

EARLY ONSET OF EFFICACY

Median time to first response was 15 days6,*

TAVALISSE is the first and only targeted agent that helps prevent immune-mediated platelet destruction6,7

PROVIDE YOUR PATIENTS WITH AN OPPORTUNITY FOR A LASTING DEFENSE


*Post hoc analysis; first platelet count measurement at 2 weeks.

† 17% of patients (FIT-1 + FIT-2 pooled [n=17]; FIT-1 = 18%, FIT-2 = 16%) achieved a stable platelet count defined as ≥50 x 109/L at 4 of 6 visits in the absence of rescue medication during weeks 14-24. Fifty-four percent of patients treated with TAVALISSE (N=145) achieved a platelet count ≥50 x 109/L at any visit (FIT-1 + FIT-2 + FIT-3).18,20

‡Interim analysis, March 2018.

PROTECTING PLATELETS. DEFENDING PATIENTS.

© 2020 Rigel Pharmaceuticals, Inc. All rights reserved. TAVA_ITP-19261 0120TAVALISSE is a registered trademark and RIGEL ONECARE is a trademark of Rigel Pharmaceuticals, Inc.

INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Important Safety Information

Warnings and Precautions• Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension

may be more susceptible to the hypertensive effects. Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required.

• Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT or AST increase to >3 x upper limit of normal, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation.

• Diarrhea occurred in 31% of patients and severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea and manage using supportive care measures early after the onset of symptoms. If diarrhea becomes severe (≥Grade 3), interrupt, reduce dose or discontinue TAVALISSE.

• Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC monthly and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction, or discontinuation.

• TAVALISSE can cause fetal harm when administered to pregnant women. Advise pregnant women the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Verify pregnancy status prior to initiating TAVALISSE. It is unknown if TAVALISSE or its metabolite is present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during TAVALISSE treatment and for at least 1 month after the last dose.

Drug Interactions • Concomitant use of TAVALISSE with strong CYP3A4 inhibitors increases exposure to the

major active metabolite of TAVALISSE (R406), which may increase the risk of adverse reactions. Monitor for toxicities that may require a reduction in TAVALISSE dose.

• It is not recommended to use TAVALISSE with strong CYP3A4 inducers, as concomitant use reduces exposure to R406.

• Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs and may require a dose reduction of the CYP3A4 substrate drug.

• Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp) substrate drugs (eg, digoxin), which may require a dose reduction of the BCRP and P-gp substrate drug.

Adverse Reactions• Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia,

diarrhea, pneumonia, and hypertensive crisis, which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%).


References: 1. Raj AB. Immune thrombocytopenia: pathogenesis and treatment approaches. J Hematol Transfus. 2017;5(1):1056-1065. 2. Shih A, Nazi I, Kelton JG, Arnold DM. Novel treatments for immune thrombocytopenia. Presse Med. 2014;43:e87-e95. 3. Newland A, Lee E, McDonald V, et al. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018;10(1):9-25. 4. Olsson B, Ridell B, Carlsson L, et al. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood. 2008;112(4):1078-1084. 5. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. 6. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930. 7. TAVALISSE® [package insert]. South San Francisco, CA: Rigel Pharmaceuticals, Inc.; April 2018. 8. Ghanima W, Godeau B, Cines DB, et al. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012;120(5):960-969. 9. Mizutani H, Furubayashi T, Imai Y. Mechanisms of corticosteroid action in immune thrombocytopenic purpura (ITP): experimental studies using ITP-prone mice, (NZW x BXSB) F1. Blood. 1992;79(4):942-947. 10. Kistanguri G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):495-520. 11. WinRho® SDF [package insert]. Berwyn, PA: Aptevo BioTherapeutics, LLC.; August 2016. 12. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001;98(4):952-957. 13. Rituxan® [package insert]. South San Francisco, CA: Genentech, Inc.; April 2019. 14. Doptelet® [package insert]. Durham, NC: Dova Pharmaceuticals, Inc.; June 2019. 15. Nplate® [package insert]. Thousand Oaks, CA: Amgen, Inc.; October 2017. 16. Promacta® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2019. 17. Nimmerjahn F, Ravetch J. Fc receptors as regulators of immune responses. Nature. 2008;8:34-47. 18. Bussel JB, Arnold DM, Boxer MA, et al. Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program. Am J Hematol. 2019;94(5):546-553. 19. Data on file, Rigel Pharmaceuticals, Inc. April 2018. 20. Boccia R, Boxer MA, Ghanima W, et al. Enhanced responses to fostamatinib as second-line therapy and in persistent immune thrombocytopenia (ITP) patients. Abstract presented at: 61st ASH Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

Please see accompanying full Prescribing Information.To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (1-800-332-1088).






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