Division of General Medicine

Division of Hematology-Oncology

Ming Chung Wang, M.D.

一般內科血液腫瘤科王銘崇醫師

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Pralatrexate: mechanism of action

2

Cell membrane

Extracellular

Cytosol

FOLOTYN®

10-formyl

THF

5.10-methenyl

THF

FOLOTYN®

THF

Folate

DHF

PRPP

GARFT

FOLOTYN®-Glu(n)

IMP

AICARFT

AMP

GMP

dUMP

dTMP

DHFRTS

FPGS

RFC-1

Reduced flux due to decreased THF levels

DNA

RNADNA

Antifolate to improve cellular uptake and retention

FOLOTYN®

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Pralatrexate: a novel folate analog metabolic inhibitor

DHFR inhibitionKi (pM)

Influx (RFC-1)Vmax/Km

FPGS activityVmax/Km

Pralatrexate 13.4 12.6 23.2

Methotrexate 5.4 0.9 2.2

> 100-fold Improvement in influx and polyglutamation1,2

A 10-propargyl derivative of 10-deazaaminopterin

1. Sirotnak et al. Cancer Chemother Pharmacol. 1998;42(4):313-318.

2. Krug LM, et al. Clin Cancer Res. 2000;6:3493-3498.

3. Wang ES, et al. Leuk Lymphoma. 2003;44:1027-1035.

4. Izbicka E, et al. Cancer Chemother Pharmacol 2009;64:993–999.

FOLOTYN® (pralatrexate) exhibit increased anti-tumor activity compared with methotrexate and pemetrexed. 3,4

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FOLOTYN® Administration in PROPEL

Treatment FOLOTYN® (pralatrexate) 30 mg/m2 IV x 6 weeks followed by 1 week rest1

7 week cycle of treatment is repeated until disease progression2

Administration

Outpatient setting

3-5 minute IV push

Vitamin supplementation (vitamin B12 and folic acid)

No pre-medications required

1 Dose omission or reduction to 20 mg/m2/week was permitted for adverse events (AEs)2 Or other study defined criteria

Response

assessment

1 2 3 4 5 6 7

Cycle 1

Subsequent cycles

= dosing day

Week

O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

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FOLOTYN® Pivotal Study-PROPEL trial

Pralatrexate in patients with

Relapsed

Or refractory

PEripheral T-cell

Lymphoma

5

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PROPEL trial for Rel/Ref PTCL

Design:

– The first multi-centre, international, prospective, single-

arm, phase II clinical study

Patients:

– 115 patients with relapsed or refractory PTCL

Endpoints:

– Primary end point: ORR = CR+CRu+PR

– Secondary end points: DoR, PFS, and OS

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FOLOTYN® Administration in PROPEL

Treatment FOLOTYN® (pralatrexate) 30 mg/m2 IV x 6 weeks followed by 1

week rest1

7 week cycle of treatment is repeated until disease progression2

Administration

Outpatient setting

3-5 minute IV push

Vitamin supplementation (vitamin B12 and folic acid)

No pre-medications required

1 Dose omission or reduction to 20 mg/m2/week was permitted for adverse events (AEs)2 Or other study defined criteria

Responseassessment

1 2 3 4 5 6 7

Cycle 1

Subsequent cycles

= dosing day

Week

O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

7

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Eligible Histologies

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The PROPEL PTCL patient population

Heterogeneity of PTCL histologic subtypes evaluated for efficacy in the PROPEL study1

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1. O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

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The PROPEL Patients Were Heavily-pretreated

PROPEL patients had received a median of 3 prior therapies (range 1-12)

53% had more than 3 lines of therapy prior to receiving FOLOTYN®

63% of patients had no response to the most recent line of prior therapy

24% of patients had no f response to any prior therapy

Number of regimensPrior systemic regimens

n (%)

1 23 (21)

2 29 (27)

3 23 (21)

4 14 (13)

≥5 21 (19)

Median (range) 3.0 (1–12)

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1. O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

53%

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70% of PROPEL Patients Had Prior CHOP Therapy

Systemic therapyPatients (N=111)

No. %

CHOP 78 70

Platinum-containing multi-agent chemotherapy 45 41

Non–platinum-containing multi-agent chemotherapy 43 39

Single-agent chemotherapy 36 32

Autologous stem-cell transplant 18 16

Bexarotene 15 14

Other 13 12

Corticosteroids alone* 8 7

HyperCVAD 8 7

Denileukin diftitox 7 6

Systemic investigational agents 7 6

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*Patients treated with corticosteroids alone received other systemic therapiesO'Connor OA, et al. J Clin Oncol 2011;29:1182–1189.

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Primary End Points: ORR

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UE = Unable to evaluate for response by central review; DoR: Duration of response; IWC: International Workshop Criteria

*IWC + PET confirmed 14 CRs; ** Long follow-up data (Data on File, Mundipharma International Ltd)

n = 109Central Review IWC*, 2

n (%) 95% CI DoR (m)

CR + CRu + PR 32 (29) (19%, 36%) 10.1 / 12.6**

CR 11 (10) 44.2**

CRu 1 (1)

PR 20 (18)

SD 21 (19)

PD 40 (37)

UE 2 (2)

Missing: off treatment in cycle 1 14 (13)

1.O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

2.Cheson BD, et al. J Clin Oncol. 1999;17(4):1244-1253.

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FOLOTYN® Response Rate in PROPEL-Subset analysis

FOLOTYN® achieved an ORR of 40% post-ICE in subset analyses of PTCL patients from the PROPEL study2, 3

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FOLOTYN® administered as second-line therapy achieved an ORR of 47% post-CHOP in subset analyses of PTCL patients from the PROPEL study3, 4

1. O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

2. Goy A, et al. Poster# 1753 Presented at 52nd American Society of Hematology meeting; December 4-7, 2010; Orlando, FL.

3. Horowitz SM. Clin Advan Hematol Oncol 2011; 9(8), Supplement 16: 1–13.

4. Shustov A, et al. Abstract# 4882 Presented at 52nd American Society of Hematology meeting; 4–7 December 2010; Orlando, FL.

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FOLOTYN® Demonstrated Efficacy in Different Key Subsets

N = 109n %

Response Rate IWC 95% CI

Region North America 85 78% 32% 22-43

Europe 24 22% 21% 7-42

Age < 65 70 64% 27% 17-39

≥ 65 39 36% 33% 19-50

Prior systemictherapy

1 regimen 23 21% 35% 16-57

2 regimens 29 27% 24% 10-44

> 2 regimens 57 52% 30% 18-43

Prior methotrexate

Yes 21 19% 24% 8-47

No 88 81% 31% 21-41

Prior transplantYes 18 17% 33% 13-59

No 91 83% 29% 20-39

Histology PTCL NOS 59 54% 32% 21-46

Angioimmunoblastic 13 12% 8% 0-36

Anaplastic LC 17 16% 35% 14-62

Transformed MF 12 11% 25% 5-57

Other 8 7% 38% 9-76

1. O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

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63% FOLOTYN responders did so within 1st

Cycle in PROPEL

63% of responders did so at Cycle 1

37% of responses occurred between cycle 2 and 7

0

10

20

30

40

50

60

70

0 1 2 3 4 5 6 7

Cycle Number

% o

f r

es

po

nd

ers

First Response (IWC)

1. O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

Median time to response (IWC) Days (range)

First response 46 (37–349)

Best response 141 (37–726)

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Patients who respond to FOLOTYN® can achieve a significant duration of benefit in PROPEL

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● The median DoR* for heavily pre-treated PTCL patients treated with FOLOTYN ® was 10.1 months1

● The median OS* of heavily pre-treated PTCL patients treated with FOLOTYN® was 14.5 months1

1. O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

• DoR and OS were secondary end points of the PROPEL study

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Comparison of Median PFS* and ORR with Previous Lines of Therapy in Relapsed or Refractory PTCL patients

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1. Coiffier B, et al. Poster# 361 Presented at 11th International Conference of

Malignant Lymphoma; 15–18 June 2011; Lugano, Switzerland.

Pralatrexate reverses the trend of progressive resistance

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FOLOTYN® AEs in ≥10% of patients

EventTotal Grade 3 Grade 4

No. % No. % No. %

Any event 111 100 47 42 35 32

General events and administration site conditions

Mucositis* 79 71 20 18 4 4

Fatigue 40 36 6 5 2 2

Pyrexia 38 34 1 1 1 1

Edema* 34 31 1 1 0 0

Hematologic events

Thrombocytopenia*† 45 41 15 14 21 19

Anemia* 38 34 18 16 2 2

Neutropenia* 28 25 15 14 9 8

Leukopenia* 12 11 4 4 4 4

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*Included a grouping of similar preferred terms†Platelet count <10,000 µL was seen in five patients

O'Connor OA, et al. J Clin Oncol 2011;29:1182–1189.

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EventTotal Grade 3 Grade 4

No. % No. % No. %

Gastrointestinal events

Nausea 46 41 4 4 0 0

Constipation 38 34 0 0 0 0

Vomiting 28 25 2 2 0 0

Diarrhea 25 23 2 2 0 0

Dyspepsia* 11 10 0 0 0 0

Respiratory, thoracic and mediastinal events

Cough 32 29 1 1 0 0

Epistaxis 29 26 0 0 0 0

Dyspnea 21 19 8 7 0 0

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*Included a grouping of similar preferred terms

O'Connor OA, et al. J Clin Oncol 2011;29:1182–1189.

FOLOTYN® AEs in ≥10% of patients

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FOLOTYN® Discontinuation in PROPEL

68% of patients remained at FOLOTYN® dose of 30mg/m2 for the entire duration of treatment1

23% of patients discontinued pralatrexate due to adverse events1

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Most common causes for discontinuation due to AEs

1. O’Connor O et al. J Clin Oncol 2011; 29:1182-1189

Adverse Event term listed(N=111)

n %

Mucosal inflammation 7 6

Thrombocytopenia 5 5

Neutropenia 3 3

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Japanese phase I/II n (%)

N (phase I / II) 3 / 22 Phase II: 2 excluded due to lack of confirmed PTCL by central review

Median of prior therapy 3

SubtypesPTCL-NOSAITLALK-ALCL

1091

Response (phase II)ORR (CR+PR)SDPD

9 (45%)=2 (10%)+ 7 (35%)4 (20%)7 (35%)

PTCL-NOS: 50% (6 of 12)AITL : 44% (4 of 9)ALK-ALCL: 50% (1 of 2)

Median PFS 150 days (5 months)

Toxicities Mucositis: 84% (grade 3:20%, grade 4:0%); G3/4 hema toxicities:20-52%

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Efficacy Results

● ORR: 45%

● All 9 responders achieved response in Cycle 1

● AITL:

‒ PROPEL study: ORR 8% (1 of 13)

‒ Japan’s study: ORR 44% (4 of 9)

2016 ASH abstract

4157

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Pralatrexate Case Sharing

(1) 65 Y/O male patient, AITL

(2) 50 Y/O male patient,

primary cutaneous NK/T cell lymphoma

(3) 40 Y/O female patient, ATLL