PHASE 3 TRIAL TEAM-ET IN 106 HIGH-RISK ESSENTIAL THROMBOCYTHEMIA PATIENTS, DEMONSTRATING NON-INFERIORITY OF ANATHROMB, A NOVEL, EXTENDED-RELEASE ANAGRELIDE FORMULATION, TO THE LICENSED COMPARATOR
Author(s): ,
Heinz Gisslinger
Affiliations:
Hematology and Hemostaseology,Medical University Vienna,Vienna,Austria
,
Atanas Radinoff
Affiliations:
Clinic of Oncology and Hematology,Tokuda Hospital Sofia,Sofia,Armenia
,
Elena Karyagina
Affiliations:
Institute of Medical Research,Saint-Petersburg,Russian Federation
,
Sławomira Kyrcz-Krzemień
Affiliations:
Department of Hematology and Bone Marrow Transplantology,SP Szpital Kliniczny im. A. Mielęckiego Śląskiego Uniwersytetu Medycznego w Katowicach,Katowice,Poland
,
Kudrat Abdulkadyrov
Affiliations:
Russian Scientific-Research Institute for Haematology and Transfusiology,Saint-Petersburg,Russian Federation
,
Rolandas Gerbutavicius
Affiliations:
Haematology Clinic,LSMU hospital Kauno Clinics,Kaunas,Lithuania
,
Anait Melikyan
Affiliations:
Haemotology Research Center,Moscow,Russian Federation
,
Sonja Burgstaller
Affiliations:
Abteilung für Innere Medizin IV,Klinikum Wels-Grieskirchen,Wels,Austria
,
Marek Hus
Affiliations:
Klinika Hematoonkologii i Transplantacji Szpiku,Samodzielny Publiczny Szpital Kliniczny,Lublin,Poland
,
Janusz Kłoczko
Affiliations:
Klinika Hematologii z Pododziałem Chorób Naczyń,Uniwersytecki Szpital Kliniczny w Białymstoku,Białystok,Poland
,
Vera Yablokova
Affiliations:
Yaroslavl Regional Clinical Hospital,Yaroslavl,Russian Federation
,
Nikolay Tzvetkov
Affiliations:
Clinic of Hematology,MHAT “Dr. Georgi Stranski” Pleven,Pleven,Australia
,
Małgorzata Całbecka
Affiliations:
Oddział Hematologii,Specjalistyczny Szpital Miejski im. M. Kopernika w Toruniu,Toruń,Poland
,
Tatyana Shneyder
Affiliations:
Leningrad Regional Clinical hospital,Saint-Petersburg,Russian Federation
,
Krzysztof Warzocha
Affiliations:
Instytut Hematologii i Transfuzjologii,Warszawa,Poland
,
Mindaugas Jurgutis
Affiliations:
Klaipeda Seamen’s Hospital,Klaipeda,Lithuania
,
Kamil Kaplanov
Affiliations:
Volgograd Regional Clinical Oncology Dispensary,Volgograd,Russian Federation
,
Juri Hodisch
Affiliations:
Hematology and Hemostaseology,Medical University Vienna,Vienna,Austria
,
Christoph Klade
Affiliations:
AOP Orphan Pharmaceuticals AG,Vienna,Austria
Veronika Buxhofer-Ausch
Affiliations:
Hematology Department,Hospital Elisabethinen Linz,Linz,Austria
EHA Library. Gisslinger H. 06/10/16; 133284; P297
Prof. Dr. Heinz Gisslinger
Prof. Dr. Heinz Gisslinger
Contributions
Abstract
Abstract: P297

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Anathromb (AR) is a novel, extended-release formulation of anagrelide hydrochloride (ana), a well-known compound used to selectively normalize platelet counts (plc) by inhibiting megakaryocyte development and maturation in high-risk patients suffering from the myeloproliferative neoplasm Essential Thrombocythemia (ET). Common side-effects of licensed formulations may be largely due to ana and its 3OH-metabolite peak plasma concentrations, whereas efficacy is proportional to AUC. Moreover, licensed formulations need to be dosed twice daily.

Aims
The aim of this study was to demonstrate the non-inferiority of Anathromb in comparison to the licensed comparator in a phase 3, randomized, active-control, double-blind, parallel group non-inferiority setting.

Methods
AR was compared to a commercially available ana formulation, Thromboreductin (TR) in a phase 3, randomized, active-control, double-blind, parallel group non-inferiority trial in high-risk ET patients, either ana-naïve or ana-experienced. After a 6 to 12 weeks titration period, the primary endpoint was the mean plc in the maintenance phase (3 consecutive measurements, centrally assessed, each 2 weeks apart).

Results
106 patients (91 ana-naïve) were randomized and treated. All patients fulfilled the WHO 2008 diagnostic criteria, the median age was 61, roughly two-thirds were female, and both treatment arms were well balanced. The mean plc at screening was 821 for AR and 797 for TR groups, during the maintenance phase mean plc was 283 for AR and 316 for TR. Thus, both treatments were highly effective in normalizing plc, and the primary endpoint was met formally demonstrating non-inferiority of AR to the licensed TR (p<0,0001). Time from randomization to maintenance phase and number of responders were similar in both treatment arms. Results were consistent between ana-naïve and –experienced patients. Importantly, plc normalization was achieved in three-quarters of patients with a dosing corresponding to 1-2 tablets AR once daily, whereas >90% of the patients required 3 or more capsules TR per day divided in two doses morning and evening. Treatment was well-tolerated, in line with the known side effect profile of ana, the most frequent adverse events were cardiac, CNS and GI disorders. There was no statistically significant difference between the two treatment arms, numerically cardiac disorders occurred less frequently in the AR arm, whereas the opposite trend was observed for CNS and GI. Evaluation of potential differences between AR and TR regarding tolerability requires additional studies with more patients and longer exposure.

Conclusion
In summary, the novel extended-release formulation AR was well tolerated and equally effective as the licensed comparator TR in normalizing plc. AR provides a more convenient once-daily dosing schedule and may offer an alternative to licensed immediate-release ana formulations in particular for patients not well tolerating ana side effects.

Session topic: Myeloproliferative neoplasms - Clinical 1 (Poster)
Abstract: P297

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Anathromb (AR) is a novel, extended-release formulation of anagrelide hydrochloride (ana), a well-known compound used to selectively normalize platelet counts (plc) by inhibiting megakaryocyte development and maturation in high-risk patients suffering from the myeloproliferative neoplasm Essential Thrombocythemia (ET). Common side-effects of licensed formulations may be largely due to ana and its 3OH-metabolite peak plasma concentrations, whereas efficacy is proportional to AUC. Moreover, licensed formulations need to be dosed twice daily.

Aims
The aim of this study was to demonstrate the non-inferiority of Anathromb in comparison to the licensed comparator in a phase 3, randomized, active-control, double-blind, parallel group non-inferiority setting.

Methods
AR was compared to a commercially available ana formulation, Thromboreductin (TR) in a phase 3, randomized, active-control, double-blind, parallel group non-inferiority trial in high-risk ET patients, either ana-naïve or ana-experienced. After a 6 to 12 weeks titration period, the primary endpoint was the mean plc in the maintenance phase (3 consecutive measurements, centrally assessed, each 2 weeks apart).

Results
106 patients (91 ana-naïve) were randomized and treated. All patients fulfilled the WHO 2008 diagnostic criteria, the median age was 61, roughly two-thirds were female, and both treatment arms were well balanced. The mean plc at screening was 821 for AR and 797 for TR groups, during the maintenance phase mean plc was 283 for AR and 316 for TR. Thus, both treatments were highly effective in normalizing plc, and the primary endpoint was met formally demonstrating non-inferiority of AR to the licensed TR (p<0,0001). Time from randomization to maintenance phase and number of responders were similar in both treatment arms. Results were consistent between ana-naïve and –experienced patients. Importantly, plc normalization was achieved in three-quarters of patients with a dosing corresponding to 1-2 tablets AR once daily, whereas >90% of the patients required 3 or more capsules TR per day divided in two doses morning and evening. Treatment was well-tolerated, in line with the known side effect profile of ana, the most frequent adverse events were cardiac, CNS and GI disorders. There was no statistically significant difference between the two treatment arms, numerically cardiac disorders occurred less frequently in the AR arm, whereas the opposite trend was observed for CNS and GI. Evaluation of potential differences between AR and TR regarding tolerability requires additional studies with more patients and longer exposure.

Conclusion
In summary, the novel extended-release formulation AR was well tolerated and equally effective as the licensed comparator TR in normalizing plc. AR provides a more convenient once-daily dosing schedule and may offer an alternative to licensed immediate-release ana formulations in particular for patients not well tolerating ana side effects.

Session topic: Myeloproliferative neoplasms - Clinical 1 (Poster)

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