Ropeginterferon Alfa-2b Induces High Rates of Clinical, Hematological and Molecular Responses in Polycythemia Vera: Two-Year Results from the First

Prospective Randomized Controlled Trial

Heinz Gisslinger, Christoph Klade, Pencho Georgiev, Dorota Krochmalczyk, Liana Gercheva-Kyuchukova, Miklos Egyed, Viktor

Rossiev, Petr Dulicek, Arpad Illes, Halyna Pylypenko, Lylia Sivcheva, Jiri Mayer, Vera Yablokova, Kurt Krejcy, Barbara Grohmann-Izay,

Hans C. Hasselbalch, Robert Kralovics and Jean-Jacques Kiladjian

Polycythemia Vera

Philadelphia chromosome negative MPN characterized by aberrant hematopoesis of the myeloid lineage driven bymutated constitutive-active JAK2

PV Treatment aims at managing• Long-term risk for disease progression (MF, AML/MDS)• Mid to long-term thrombohemorrhagic risk• Disease symptom burden, quality-of-life

Interferons in PV• IFNs have been successfully applied since 1980s 1)

• Consistently, high rates of hematologic response, independence fromphlebotomy, improvement of pruritus and sustained mtJAK2-allele burdenreduction have been reported 2)

• Interferons are the only known drugs with potential for diseasemodification by specific targeting the malignant clone 3)

1) Linkesch et al., 1985; Gisslinger et al., 1989 2) Hasselbalch 1988; Silver et al.,1988 3) Kiladjian et al., 2008, 2011

Ropeginterferon alfa-2b (AOP2014/P1101)

• A novel monopegylated Interferon alfa-2b, composed of only one single isoform due to an innovative pegylation technology

• Administration frequency once every 14 days (once monthly in long-term maintenance) by a pre-filled, dose-adjustable pen suitable for self-administration

AOPs Clinical Development Program ongoing since 2010

• PEGINVERA Study (Phase II): showed that long-term maintenance treatmentof PV patients is feasible, efficacious and well tolerated 1)

• PROUD-PV Study (Phase III): demonstrated non-inferiority of CompleteHematological Response of Ropeginterferion alfa-2b to HU after 12 monthsof treatment 2)

1) Gisslinger et al. EHA 2017 2) Gisslinger et al. ASH 2016

Design PROUD- & CONTINUATION-PV

Patient Disposition

No selection bias identified(at Month 12: comparison of complete hematological response ratesbetween patients that completed PROUD-PV and patients enrolled in

CONTINUATION-PV)

Patient Characteristics

*) confirmed by bone marrow biopsy **) ≤12 cm for females, ≤13 cm for males

No selection bias identified (comparison baseline parameters between PROUD-PV full cohort and patients enrolled in CONTINUATION-PV)

All patients enrolled in CONTINUATION-PV at treatment start (Month 0)

AOP2014 (n=95) Control (n=76)Caucasian 100% 100%

WHO2008 PV *) 100% 100%

Female 48 (50.5%) 40 (52.6%)

Age (median, range) [years] 58 (30-85) 59 (32-79)

HU pretreated 30 (31.6%) 20 (26.3%)

Disease duration (median, range) [months]HU naive/HU pretreated 1.2 (0-102)/3.1 (0-146) 1.2 (0-70)/8.9 (0-92)

Hematocrit (mean, SD) 48.3% (5.3) 49.9% (±5.5)

Spleen normal **) 39 (41.1%) 36 (47.4%)

Splenomegaly (per Investigator assessment) 7 (7.4%) 8 (10.5%)

Disease-related symptoms present 15 (15.8%) 17 (22.4%)

Mean JAK2V617F burden 42.8% (±23.4) 42.9% (±23.0)

Efficacy Assessment (24 month analysis)

(1) Complete Hematologic Response (CHR) - ELN

Hct<45% without phlebotomy (at least 3 months since the last phlebotomy),

PLTs<400 x 109/L,

WBCs<10 x 109/L

(2) CHR & Improvement in Disease Burden

Disease-related signs (clinically significant splenomegaly reported as AE by the Investigator) and

Disease-related symptoms

(3) Partial Molecular Response - ELN

Efficacy Results (24 month analysis)

AOP2014 Control RR [95% CI] (AOP2014/Control)

P-value

Complete Hematologic Response at M2470.5%

(67/95)49.3%

(33/67)1.42 [1.09-1.87] 0.0101

CHR & Improvement in Disease Burden at M24

49.5% (47/95)

36.6% (26/71)

1.34 [0.93-1.92] 0.1183

Partial Molecular Response at M24 (LOCF)68.1%

(64/94)34.7%

(26/75)1.85 [1.33-2.56] 0.0002

Ropeginterferon alfa-2b induces high rates of hematological, clinical andmolecular responses after 24 months of treatment

Complete Hematological Response

AOP2014ControlAOP2014 (stat. significant RR)Control (stat. significant RR)

Fu

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Set24 MONTH DATA

CHR & Improvement in Disease Burden

24 MONTH DATA

Fu

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ysis

Set

AOP2014ControlAOP2014 (stat. significant RR)Control (stat. significant RR)

Partial Molecular Response

24 MONTH DATA

Fu

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(L

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AOP2014ControlAOP2014 (stat. significant RR)Control (stat. significant RR)

Individual Clinical Parameters

Safety Profile – Overview

Long-term Safety (up to 3.6 years of treatment; mean 2.7 years)

AOP2014(n=127)

Control(n=127)

Patients with AE 114 (89.8%) 113 (89.0%)

Patients with treatment-related AE 89 (70.1%) 98 (77.2%)

Patients with ≥ Grade 3 AE 35 (27.6%) 33 (26.0%)

All grade, related AEs > 10% of patients

Long-term Safety (up to 3.6 years of treatment; mean 2.7 years)

AOP2014(n=127)

Control(n=127)

P-value

Thrombocytopenia 25 (19.7%) 34 (26.8%) n.s.

Leukopenia 24 (18.9%) 28 (22.0%) n.s.

Anaemia 12 (9.4%) 28 (22.0%) p=0.0091

gGT increased 14 (11.0%) 0 (0.0%) p<0.0001

n.s. not significant

Adverse Events of Special Interest (IFNs)

Long-term Safety (up to 3.6 years of treatment; mean 2.7 years)

AOP2014(n=127)

Control(n=127)

Endocrine disorders* 5 (3.9%) 1 (0.8%)

Psychiatric disorders** 3 (2.4%) 1 (0.8%)

Cardiac/Vascular disordersStroke

Thrombotic eventCardiac failure

Atrial fibrillationOthers§

13 (10.2%)2 (1.6%)2 (1.6%)0 (0.0%)5 (3.9%)4 (3.2%)

7 (5.5%)0 (0.0%)2 (1.6%)2 (1.6%)3 (2.4%)0 (0.0%)

Tissue disorders*** 2 (1.6%) 0 (0.0%)

* Autoimmune thyroiditis, Hypo-/Hyperthyroidism** Anxiety, Depression, Mood altered *** Rheumatoid arthritis, Sjogren‘s Syndrom§ additional events reported: peripheral arterial occlusive disease (presented already in medical history), hematemesis, phlebitis

Malignancies

Long-term Safety (up to 3.6 years of treatment; mean 2.7 years)

AOP 2014(n=127)

Control(n=127)

Acute leukemia 2

Basal cell carcinomaMalignant melanoma

21

Adrenal neoplasm*Glioblastoma

Spermatocytic seminoma

111

* No additional information on type of neoplasm available

JAK-2 allele burden over time

Fu

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24 MONTH DATA

Burden changes of non-JAK2 mutationsV

aria

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Alle

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Control

AOP2014

0 12 24

Treatment duration in months

Summary

• Hematological, clinical and molecular response rates increase between

12 and 24 month of Ropeginterferon alfa-2b treatment, whereas

decrease in the Control arm

• At Month 24 of treatment, response rates are higher in the

Ropeginterferon alfa-2b arm compared to Control

CHR: 70.5% vs 49.3% (RR 1.42; p=0.0101)

CHR & Improvement of Disease Burden: 49.5% vs 36.6% (RR 1.34;

p=0.1183)

Partial Molecular Response: 68.1% vs 34.7% (RR 1.85; p=0.0002)

• Safety and tolerability of Ropeginterferon alfa-2b consistent with 12

month data (PROUD-PV Study)

Conclusion PROUD/CONTINUATION-PV 24 month analysis

• Ropeginterferon alfa-2b appears more efficacious than HU

in the long run, showing high and durable hematological response and

symptom improvement (i.e. after 18 months).

• The Safety/Tolerability profile of Ropeginterferon alfa-2b remains

excellent beyond the second year of treatment.

• The unique disease modification capability of Interferon and its potential

to improve progression-free survival are suggested by the observed

effects on mutant JAK2 and other molecular markers.

021,

Varna022, Sofia

023 , Plovdiv

041, Paris

042, Poitiers

043, Marseille

051, Bonn

052, Aachen

062, Budapest

063, Debrecen

064, Szeged

072, Pavia

081, Rzeszow

082, Warsaw

083, Torun

085, Lublin

086 Krakow

093, Cluj-Napoca

094, Brasov

101, Petrozavodsk

102, Syktyvkar

104, Tula

105, Samara

106, Yaroslavl

122, Barcelona

131, Cherkasy

132, Dnipropetrovsk

133, Lviv

134, Kyiv

136, Zhytomyr

111, Banska Bystrica

112,Bratislava

061, Kaposvar

033, Hradec

Kralove

Prague

015

017

011

014

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19

27

35

10

1

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024, Vratsa

053, Dresden

065, Gyula

091, 092,

Bucharest

031034

032, Brno

011 Wien, Gisslinger012 Innsbruck, Willenbacher013 Salzburg, Greil014 Wien, Schloegl015 Linz, Buxhofer-Ausch017 Graz, Bauer021 Varna, Gercheva022 Sofia, Mihaylov023 Plovdiv, Georgiev024 Vratsa, Sivcheva031 Prague, Schwarz032 Brno, Mayer033 Hradec Kralove, Dulicek034 Prague, Cerna041 Paris, Kiladjian042 Poitiers, Roy043 Marseille, Rey051 Bonn, Wolf052 Aachen, Koschmieder053 Dresden, Platzbecker061 Kaposvar, Egyed062 Budapest, Masszi063 Debrecen, Illes064 Szeged, Borbenyi065 Gyula, Jakucs072 Pavia, Cazzola081 Rzeszow, Starzak-Gwozdz 082 Warsaw, Warzocha083 Torun, Calbecka085 Lublin, Soroka-Wojtaszko086 Krakow, Skotnicki/Krochmalcyk091 Bucharest, Berbec092 Bucharest, Bumbea093 Cluj-Napoca, Cucuianu094 Brasov, Gheorghita101 Petrozavodsk, Myasnikov102 Syktyvkar, Sokolova104 Tula, Volodicheva105 Samara, Rossiev 106 Yaroslavl, Yablokova111 Banska Bystrica, Vallova112 Bratislava, Hrubisko122 Barcelona, Besses131 Cherkasy, Pylypenko132 Dnipropetrovsk, Kaplan133 Lviv, Masliak134 Kyiv, Klymenko136 Zhytomyr, Lysa

Thank you to all participants

Sponsor of the study and owner of the data: AOP Orphan Pharmaceuticals AG, Vienna, Austria