Polycythemia Vera. Linkesch et al., 1985; Gisslinger et al., ) Hasselbalch 1988; Silver et al.,1988 3) Kiladjian et al.

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

2 Polycythemia Vera Philadelphia chromosome negative MPN characterized by aberrant hematopoesis of the myeloid lineage driven by mutated 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 from phlebotomy, improvement of pruritus and sustained mtjak2-allele burden reduction have been reported 2) Interferons are the only known drugs with potential for disease modification by specific targeting the malignant clone 3) 1) Linkesch et al., 1985; Gisslinger et al., ) Hasselbalch 1988; Silver et al.,1988 3) Kiladjian et al., 2008, 2011

3 Ropeginterferon alfa-2b (/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 selfadministration AOPs Clinical Development Program ongoing since 2010 PEGINVERA Study (Phase II): showed that long-term maintenance treatment of PV patients is feasible, efficacious and well tolerated 1) PROUD-PV Study (Phase III): demonstrated non-inferiority of Complete Hematological Response of Ropeginterferion alfa-2b to HU after 12 months of treatment 2) 1) Gisslinger et al. EHA ) Gisslinger et al. ASH 2016

4 Design PROUD- & CONTINUATION-PV

5 Patient Disposition No selection bias identified (at Month 12: comparison of complete hematological response rates between patients that completed PROUD-PV and patients enrolled in CONTINUATION-PV)

6 Patient Characteristics All patients enrolled in CONTINUATION-PV at treatment start (Month 0) (n=95) (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) No selection bias identified (comparison baseline parameters between PROUD-PV full cohort and patients enrolled in CONTINUATION-PV) *) confirmed by bone marrow biopsy ** ) 12 cm for females, 13 cm for males

7 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 10 9 /L, WBCs<10 x 10 9 /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

8 Efficacy Results (24 month analysis) RR [95% CI] (/) P-value Complete Hematologic Response at M % (67/95) 49.3% (33/67) 1.42 [ ] CHR & Improvement in Disease Burden at M % (47/95) 36.6% (26/71) 1.34 [ ] Partial Molecular Response at M24 (LOCF) 68.1% (64/94) 34.7% (26/75) 1.85 [ ] Ropeginterferon alfa-2b induces high rates of hematological, clinical and molecular responses after 24 months of treatment

9 Full Analysis Set Complete Hematological Response 24 MONTH DATA (stat. significant RR) (stat. significant RR)

10 Full Analysis Set CHR & Improvement in Disease Burden 24 MONTH DATA (stat. significant RR) (stat. significant RR)

11 Full Analysis Set (LOCF) Partial Molecular Response 24 MONTH DATA (stat. significant RR) (stat. significant RR)

12 Individual Clinical Parameters

13 Safety Profile Overview Long-term Safety (up to 3.6 years of treatment; mean 2.7 years) (n=127) (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%)

14 All grade, related AEs > 10% of patients Long-term Safety (up to 3.6 years of treatment; mean 2.7 years) (n=127) (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= ggt increased 14 (11.0%) 0 (0.0%) p< n.s. not significant

15 Adverse Events of Special Interest (IFNs) Long-term Safety (up to 3.6 years of treatment; mean 2.7 years) (n=127) (n=127) Endocrine disorders* 5 (3.9%) 1 (0.8%) Psychiatric disorders** 3 (2.4%) 1 (0.8%) Cardiac/Vascular disorders Stroke Thrombotic event Cardiac failure Atrial fibrillation Others 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

16 Malignancies Long-term Safety (up to 3.6 years of treatment; mean 2.7 years) AOP 2014 (n=127) (n=127) Acute leukemia 2 Basal cell carcinoma Malignant melanoma Adrenal neoplasm* Glioblastoma Spermatocytic seminoma * No additional information on type of neoplasm available

17 Full Analysis Set (LOCF) JAK-2 allele burden over time 24 MONTH DATA

18 Variant Allele Frequency Burden changes of non-jak2 mutations Treatment duration in months

19 Summary Hematological, clinical and molecular response rates increase between 12 and 24 month of Ropeginterferon alfa-2b treatment, whereas decrease in the arm At Month 24 of treatment, response rates are higher in the Ropeginterferon alfa-2b arm compared to 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)

20 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.

21 Thank you to all participants 101, Petrozavodsk 102, Syktyvkar 104, Tula 011 Wien, Gisslinger 012 Innsbruck, Willenbacher 013 Salzburg, Greil 014 Wien, Schloegl 015 Linz, Buxhofer-Ausch 017 Graz, Bauer 021 Varna, Gercheva 022 Sofia, Mihaylov 023 Plovdiv, Georgiev 024 Vratsa, Sivcheva 031 Prague, Schwarz 032 Brno, Mayer 033 Hradec Kralove, Dulicek 034 Prague, Cerna 041 Paris, Kiladjian 042 Poitiers, Roy 043 Marseille, Rey 051 Bonn, Wolf 052 Aachen, Koschmieder 053 Dresden, Platzbecker 061 Kaposvar, Egyed 062 Budapest, Masszi 063 Debrecen, Illes 064 Szeged, Borbenyi 065 Gyula, Jakucs 072 Pavia, Cazzola 081 Rzeszow, Starzak-Gwozdz 082 Warsaw, Warzocha 083 Torun, Calbecka 085 Lublin, Soroka-Wojtaszko 086 Krakow, Skotnicki/Krochmalcyk 091 Bucharest, Berbec 092 Bucharest, Bumbea 093 Cluj-Napoca, Cucuianu 094 Brasov, Gheorghita 101 Petrozavodsk, Myasnikov 102 Syktyvkar, Sokolova 104 Tula, Volodicheva 105 Samara, Rossiev 106 Yaroslavl, Yablokova 111 Banska Bystrica, Vallova 112 Bratislava, Hrubisko 122 Barcelona, Besses 131 Cherkasy, Pylypenko 132 Dnipropetrovsk, Kaplan 133 Lviv, Masliak 134 Kyiv, Klymenko 136 Zhytomyr, Lysa 1 122, Barcelona 042, Poitiers 041, Paris , Marseille 052, Aachen 051, Bonn , Pavia 053, Dresden Prague , Torun 033, Hradec Kralove 032, Brno ,Bratislava Krakow 082, Warsaw 063, Debrecen 062, Budapest 065, Gyula 061, Kaposvar 064, Szeged 085, Lublin 081, Rzeszow 133, Lviv 111, Banska Bystrica 093, Cluj-Napoca 9 022, Sofia , Brasov 091, 092, Bucharest 024, Vratsa , Plovdiv 136, Zhytomyr 021, Varna 105, Samara 106, Yaroslavl 134, Kyiv , Cherkasy 132, Dnipropetrovsk Sponsor of the study and owner of the data: AOP Orphan Pharmaceuticals AG, Vienna, Austria