11

RomiplostimRomiplostimFDA OverviewFDA Overview

Oncologic Drugs Advisory Oncologic Drugs Advisory Committee MeetingCommittee Meeting

Faranak Jamali, MDFaranak Jamali, MD

March 12, 2008March 12, 2008

22

Chronic ITP efficacy and safetyChronic ITP efficacy and safety– Faranak Jamali, MDFaranak Jamali, MD

Exploratory study in MDSExploratory study in MDS– Steven Lemery, MDSteven Lemery, MD

Risk management considerationsRisk management considerations– Suzanne Berkman, PharmDSuzanne Berkman, PharmD

FDA Overview

33

Proposed indicationProposed indication

……for the treatment of thrombocytopenia for the treatment of thrombocytopenia in adult patients with chronic ITP:in adult patients with chronic ITP:

who are non-splenectomized and have an who are non-splenectomized and have an insufficient response or are intolerant to insufficient response or are intolerant to corticosteroids and/or immunoglobulins.corticosteroids and/or immunoglobulins.

who are splenectomized and have an who are splenectomized and have an insufficient response to splenectomy.insufficient response to splenectomy.

44

Romiplostim DatabaseRomiplostim Database

14 Studies supply data14 Studies supply data

– Healthy subjects: 2 studiesHealthy subjects: 2 studies

– ITP: 2 phase 3 studies, 8 supportiveITP: 2 phase 3 studies, 8 supportive

– MDS: 1 studyMDS: 1 study

– CIT: 1 studyCIT: 1 study

Ongoing studies in ITP, MDS, CITOngoing studies in ITP, MDS, CIT

Romiplostim exposure in BLA: Romiplostim exposure in BLA:

– n = 271 in ITPn = 271 in ITP

– n = 121 in other settingsn = 121 in other settings

55

Phase 3: Studies 20030Phase 3: Studies 20030105105 and and 2003020030212212

Study “105:” SplenectomyStudy “105:” Splenectomy

Study “212:” Spleen intact + completed 1 prior Study “212:” Spleen intact + completed 1 prior treatment “e.g., prednisone”treatment “e.g., prednisone”

Study “213:” an open label extensionStudy “213:” an open label extension

66

Phase 3 Design FeaturesPhase 3 Design Features

R (2:1), DB, PC, 24 week treatment period R (2:1), DB, PC, 24 week treatment period with 12 wk f/u (off med)with 12 wk f/u (off med)

R stratified by con meds (yes/no)R stratified by con meds (yes/no)

Starting dose 1 mcg/kg, SC; max 15 mcg/kgStarting dose 1 mcg/kg, SC; max 15 mcg/kg

Target plt 50 to 200 K/mcLTarget plt 50 to 200 K/mcL

– Dose reduction for > 200KDose reduction for > 200K

– Dose held for > 400KDose held for > 400K

Weekly Plt ct; regular lab/antibodyWeekly Plt ct; regular lab/antibody

PRO: ITP QuestionnairePRO: ITP Questionnaire

77

Phase 3 study endpointsPhase 3 study endpointsPrimary endpoint: Primary endpoint:

– Durable plt responseDurable plt response

– Weekly plt ct ≥ 50 K/mcL for ≥ 6 weeks Weekly plt ct ≥ 50 K/mcL for ≥ 6 weeks of the last 8 weeksof the last 8 weeks

Secondary endpoints:Secondary endpoints:

– Overall platelet responseOverall platelet response

– Number of weekly platelet responsesNumber of weekly platelet responses

– Patients requiring rescue medicationPatients requiring rescue medication

– Durable plt response on stable doseDurable plt response on stable dose

Multiple other supportive endpointsMultiple other supportive endpoints

88

Disposition Disposition GroupGroup 105105 212212

PlPl Romi-Romi-plostimplostim

PlPl Romi-Romi-

plostimplostim

RandomizedRandomized 2121 4242 2121 4141

DiscontinuedDiscontinued 22 22 44 22

D/C CauseD/C Cause

DeathDeath 22 -- -- --

AEAE -- 11 11 22

PregnancyPregnancy -- -- 11 --

Consent w/dConsent w/d -- 11 22 --

99

Baseline CharacteristicsBaseline Characteristics

CxCx

105105 212212

Pl, Pl,

n = 21n = 21

Romi-Romi-plastimplastim

n = 42n = 42

PlPl

n = 21n = 21

Romi-Romi-plastimplastim

n = 41n = 41

Age, medAge, med 5656 5151 4646 5252

Female (%)Female (%) 5252 6464 7676 6666

Med Plt (10Med Plt (1099/L)/L) 14.714.7 13.513.5 19.319.3 18.718.7

Med Hgb (g/L) Med Hgb (g/L) 145145 137137 125125 136136

Med WBC (10Med WBC (1099/L)/L) 8.48.4 8.98.9 7.77.7 5.95.9

1010

Prior TherapiesPrior TherapiesCxCx 105105 212212

Pl, Pl, n = 21n = 21

Romi-Romi-plostimplostimn = 42n = 42

PlPln = 21n = 21

Romi-Romi-plostimplostimn = 41n = 41

Subjects w prior ITP Treatment (n)Subjects w prior ITP Treatment (n)

SteroidSteroid 2020 4242 1919 3737

Anti-DAnti-D 99 1919 66 2020

IVIGIVIG 2020 3939 1515 2626

Vinc/VinblastinVinc/Vinblastin 1010 1717 00 00

CyclophosCyclophos 1414 2121 77 66

AzathioprineAzathioprine 55 1010 11 22

DanazolDanazol 1010 1313 11 66

RituximabRituximab 1515 3030 55 1313

OtherOther 1111 2121 66 1010

1111

Primary Endpoint: Durable Platelet Primary Endpoint: Durable Platelet ResponseResponse

StudyStudy PlPl Romi-Romi-

plostimplostim

p-p-

valuevalue

105105

(splenectomy)(splenectomy)0/21 0/21 (0%)(0%)

16/42 16/42 (38%)(38%) < 0.01< 0.01

212212

(no splenectomy)(no splenectomy)1/21 1/21 (5%)(5%)

25/41 25/41 (61%)(61%) < 0.01< 0.01

1212

Secondary EndpointsSecondary Endpoints

OutcomeOutcomeStudy 105Study 105

splenectomysplenectomyStudy 212Study 212

no splenectomyno splenectomy

PlPln = 21n = 21

Romi-Romi-n = 42n = 42

PlPln = 21n = 21

Romi-Romi-n = 41n = 41

Overall Plt RespOverall Plt Respn (%)n (%) 00

33 33 (79%)(79%)

3 3 (14%)(14%)

36 36 (88%)(88%)

Wks w Plt Resp,Wks w Plt Resp,mean mean

0.20.212.312.3 1.31.3 15.215.2

Rescue Med, Rescue Med, n (%)n (%)

1212(57%)(57%)

11 11 (26%)(26%)

13 13 (62%)(62%)

7 7 (17%)(17%)

Dur Plt Resp & Dur Plt Resp & Stable Dose, n (%)Stable Dose, n (%) 00

13 13 (31%)(31%) 00

21 21 (51%)(51%)

All p-values < 0.01

1313

Safety Data in Phase 3 StudiesSafety Data in Phase 3 Studies

Adverse events Adverse events

Specific risks:Specific risks:

1)1) Reticulin formation and potential for Reticulin formation and potential for fibrosisfibrosis

2)2) Thrombotic eventsThrombotic events

3)3) Severe thrombocytopenia after Severe thrombocytopenia after discontinuation of Romiplostimdiscontinuation of Romiplostim

4)4) ImmunogenicityImmunogenicity

5)5) NeoplasiaNeoplasia

1414

Adverse Events in Phase 3 Studies, n (%)Adverse Events in Phase 3 Studies, n (%)

Adverse eventAdverse eventPlPl

n = 41n = 41

Romi-Romi-

n = 84n = 84

AnyAny 39 (95%)39 (95%) 84 (100%)84 (100%)

Any seriousAny serious 8 (20%)8 (20%) 14 (17%)14 (17%)

FatalFatal 3 (7%)3 (7%) 1 (1%)1 (1%)

Any bleedAny bleed 25 (61%)25 (61%) 48 (57%)48 (57%)

Any serious bleedAny serious bleed 4 (10%)4 (10%) 5 (6%)5 (6%)

1515

Adverse Events in Phase 3 Studies (%)Adverse Events in Phase 3 Studies (%)

TermTerm Pl Pl n = 41n = 41

Romi-Romi-n = 84n = 84

ArthralgiaArthralgia 20%20% 26%26%

DizzinessDizziness 00 17%17%

InsomniaInsomnia 7%7% 16%16%

MyalgiaMyalgia 2%2% 14%14%

Extremity painExtremity pain 5%5% 13%13%

Abdominal painAbdominal pain 00 11%11%

Shoulder painShoulder pain 00 8%8%

DyspepsiaDyspepsia 00 7%7%

ParesthesiaParesthesia 00 6%6%

1616

Specific Safety Risks: Safety DatabaseSpecific Safety Risks: Safety Database

• ITP: n = 271 • ≤ 6 months: phase 3 and other studies

• Extension study 213 & SOC study 131

• Median exposure ~ 37 weeks

• 36 subjects exposed for 2 years

• Healthy: n = 56

• MDS: n = 44

• CIT: n = 21

1717

1) Reticulin Formation and Risk for Fibrosis1) Reticulin Formation and Risk for Fibrosis

Reticulin in marrow: “reticulin fibrosis”Reticulin in marrow: “reticulin fibrosis”– identified with silver stainidentified with silver stain– associated with benign and malignant associated with benign and malignant

conditionsconditions– thought to be reversiblethought to be reversible

Collagen in marrow: “collagen fibrosis”Collagen in marrow: “collagen fibrosis”– identified with trichrome stainidentified with trichrome stain– “ “less likely” reversibleless likely” reversible– myelofibrosis/cytopeniasmyelofibrosis/cytopenias

Could long term Romiplostim exposure Could long term Romiplostim exposure result in marrow fibrosis/cytopenia?result in marrow fibrosis/cytopenia?

1818

Romiplostim and Reticulin FormationRomiplostim and Reticulin Formation

Repeat Romiplostim dose studies in rats: Repeat Romiplostim dose studies in rats:

– marrow fibrosis on H and E stainsmarrow fibrosis on H and E stains

– reversible after drug discontinuationreversible after drug discontinuation

Prior study in rats with a TPO (Yanagida):Prior study in rats with a TPO (Yanagida):

– repeat dose resulted in myelofibrosisrepeat dose resulted in myelofibrosis

– predominance of reticulinpredominance of reticulin

– marrow TGFß content paralleled reticulinmarrow TGFß content paralleled reticulin

– suggested megakarycocyte TGFß may suggested megakarycocyte TGFß may stimulate reticulin formationstimulate reticulin formation

1919

““Increased Reticulin” in ITP StudiesIncreased Reticulin” in ITP Studies

Phase 3 (controlled) studies:Phase 3 (controlled) studies:

– One Romiplostim group/none PlaceboOne Romiplostim group/none Placebo

Uncontrolled studies:Uncontrolled studies:

– Nine patientsNine patients

Follow-up information:Follow-up information:

– 2 patients had marrows “improved” with 2 patients had marrows “improved” with Romiplostim discontinuation; 2 others “stable” Romiplostim discontinuation; 2 others “stable”

– 2 remained on Romiplostim or dose interrupted2 remained on Romiplostim or dose interrupted

– Not available or pending as of 120 day updateNot available or pending as of 120 day update

2020

Patient Features from Detailed Review of Six Patient Features from Detailed Review of Six AE with “Increased Reticulin”AE with “Increased Reticulin”

All had nucleated RBC in peripheral bloodAll had nucleated RBC in peripheral blood

All had undergone splenectomyAll had undergone splenectomy

All received “high” doses: 7 to 18 mcg/kgAll received “high” doses: 7 to 18 mcg/kg

5 had no collagen on trichrome; 1 had 5 had no collagen on trichrome; 1 had “localized collagen” assessed as “localized collagen” assessed as “inconsistent with chronic idiopathic “inconsistent with chronic idiopathic myelofibrosis”myelofibrosis”

2121

Aplastic AnemiaAplastic Anemia

75 y o female with ITP, DM, CAD & breast 75 y o female with ITP, DM, CAD & breast cancer historycancer history

Six months Romiplostim Six months Romiplostim

Marrow at time of AA diagnosis: “…only focal Marrow at time of AA diagnosis: “…only focal erythropoiesis and myelopoiesis…convincing erythropoiesis and myelopoiesis…convincing marrow megakaryocytes not identified”marrow megakaryocytes not identified”

No JAK2 V617F point mutation detectedNo JAK2 V617F point mutation detected

Con meds: azathioprine, carvedilol, Con meds: azathioprine, carvedilol, amlodipine, losartan, acyclovir, ezetimibe and amlodipine, losartan, acyclovir, ezetimibe and fenfibratefenfibrate

Died 54 days laterDied 54 days later

2222

2) Thrombotic Events2) Thrombotic Events

• Phase 3 (controlled) studies:

• Placebo group: PE

• Romi group: CVA and arterial embolus

• Other studies: 12 patients

• DVT (3), PE (3)

• MI (2), Portal V thrombosis (2), Superficial thrombophlebitis (2), Thrombosis (2)

2323

3) Severe Thrombocytopenia after 3) Severe Thrombocytopenia after Romiplostim DiscontinuationRomiplostim Discontinuation

Potential risk: suppression of TPOPotential risk: suppression of TPO

Early phase studies:Early phase studies:

– 4/57 patients experienced decreased plts 4/57 patients experienced decreased plts

– Approximated baseline within 14 days Approximated baseline within 14 days

Notable case:Notable case:

– 80 y o male received six months Romiplostim80 y o male received six months Romiplostim

– CVA 3 days after Romiplostim discontinuation CVA 3 days after Romiplostim discontinuation

(plt count 107K/mcL), aspirin therapy(plt count 107K/mcL), aspirin therapy

– 7 days later ICH (plt ct 5K/mcL)7 days later ICH (plt ct 5K/mcL)

– Plt transfusion and died next dayPlt transfusion and died next day

2424

4) Immunogenicity4) Immunogenicity

Developed: Developed: ITP subjects ITP subjects

testedtestedn = 225n = 225

““Binding” AbsBinding” Abs

RomiplostimRomiplostim 23 (10%)23 (10%)

TPOTPO 12 (5%)12 (5%)

““Neutralizing” AbsNeutralizing” Abs

RomiplostimRomiplostim 11

TPOTPO 00

2525

5) Neoplasia5) Neoplasia

Subjects with neoplasms, nSubjects with neoplasms, nPl Pl

n = 41n = 41

RomiRomi

n = 84n = 84

AnyAny 55 22

B cell lymphomaB cell lymphoma 00 11

Basal cell caBasal cell ca 00 11

M myelomaM myeloma 11 00

Liver metastasisLiver metastasis 11 00

Benign lung neoplasmBenign lung neoplasm 11 00

Fibroma (arm)Fibroma (arm) 11 00

Benign ovarian tumor/ Benign ovarian tumor/ Uterine leiomyomaUterine leiomyoma 11 00

Phase 3 Studies, Pooled

2626

Romiplostim in Chronic ITPRomiplostim in Chronic ITPSummarySummary

Increases and sustains platelet counts in Increases and sustains platelet counts in patients who have failed prior therapiespatients who have failed prior therapies

Long term safety data limited: Long term safety data limited:

– marrow events/reticulin/potential fibrosismarrow events/reticulin/potential fibrosis

– thrombotic eventsthrombotic events

– severe thrombocytopenia after severe thrombocytopenia after discontinuationdiscontinuation

– immunogenicityimmunogenicity

– neoplasianeoplasia