ANAGRELIDE CONTROLLED RELEASE (GALE-401) SAFETY PROFILE CONSISTENTLY WELL TOLERATED IN MYELOPROLIFERATIVE NEOPLASMS PATIENTS AND HEALTHY VOLUNTEERS
Author(s): ,
S Verstovsek
Affiliations:
University of Texas, MD Anderson Cancer Center,Houston TX,United States
,
M Saltzman
Affiliations:
Innovative Medical Research of South Florida,Miami FL,United States
,
S Dakhil
Affiliations:
Cancer Center of Kansas,Wichita KS,United States
,
J Lee
Affiliations:
Galena Biopharma Inc.,San Ramon CA,United States
,
L Chance
Affiliations:
Galena Biopharma Inc.,San Ramon CA,United States
,
PF Gildden
Affiliations:
Galena Biopharma Inc.,San Ramon CA,United States
,
A Pilgrim
Affiliations:
BioVascular, Inc.,San Diego CA,United States
,
S Flores
Affiliations:
Galena Biopharma Inc.,San Ramon CA,United States
,
V Fernandez
Affiliations:
Galena Biopharma Inc.,San Ramon CA,United States
,
B Nejadnik
Affiliations:
Galena Biopharma Inc.,San Ramon CA,United States
GS Choy
Affiliations:
Galena Biopharma Inc.,San Ramon CA,United States
EHA Library. Verstovsek S. Jun 11, 2016; 133563; P675
Dr. Srdan Verstovsek
Dr. Srdan Verstovsek
Contributions
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Abstract
Abstract: P675

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
The most frequently reported AEs leading to treatment discontinuation with anagrelide (Agrylin®, Shire) were headache, diarrhea, edema, palpitations, and abdominal pain. Of the 942 subjects treated with anagrelide for a mean duration of approximately 65 wks, 161 (17%) were discontinued due to AEs or abnormal laboratory test results (PI, Agrylin). These effects may be attributable to anagrelide’s inhibitory effects on human PDE3. Modification of the PK profile of anagrelide to reduce peak plasma levels while maintaining therapeutic blood levels may offer a means to retain platelet lowering activity while reducing potential side-effects. In the Phase 1 HV study, BIO-ANA101, 2 such novel controlled release formulations of anagrelide (CR and IR/CR) were compared with the EU marketed formulation (Xagrid®, Shire) in a single dose cross-over study at a dose of 0.5 mg. The CR formulation demonstrated Cmax/AUC0-inf values that were 23%/72% of Xagrid’s, respectively leading to the development program of anagrelide CR (GALE-401).

Aims
Characterize the safety profile of GALE-401 in HV and MPN subjects.

Methods
To date, 98 HV and 18 MPN subjects have been enrolled among 5 Phase 1 clinical trials (BIO-ANA101, 102, 103, 104, 105) and a Phase 2 single arm, open label pilot study (NCT02125318) of GALE-401, respectively. All studies were conducted in accordance with ICH Guidelines and GCP principles. Safety events were compared across HV vs. MPN subjects treated with GALE-401 compared to historical Agrylin published data.

Results
In the HV studies, single and multiple doses of GALE-401 were safe and well tolerated and there were no clinically relevant changes in vital signs, ECGs, and safety laboratory parameters other than a reduction in platelet counts. The most frequent TEAEs reported included headache, pain in extremities or back, palpitations and gastrointestinal disturbances. In particular, in BIO-ANA105, with 20 subjects randomized to receive either GALE-401 or Agrylin (0.5 mg BID for 7d) after which they were washed out for a minimum of 21d and received the alternative drug product for an equal period, the overall AEs considered by the Investigator to be related to treatment were observed [GALE-401 (7 events/6 subjects) vs. Agrylin (12 events/8 subjects)]. With the exception of GI disorders (15%, GALE-401 vs. 10.5%, Agrylin), the incidence of TEAEs across SOCs was higher during Agrylin treatment compared to GALE-401 treatment. In the Phase 2 MPN study, subjects treated with GALE-401 exhibited fewer of the more common AEs associated with Agrylin (cardiac; general; gastrointestinal; respiratory, thoracic, and mediastinal; skin and subcutaneous tissue; nervous system) or equivalent (musculoskeletal and connective tissue) AEs associated with Agrylin. Some of the less common AEs of Agrylin were comparatively more frequent for GALE-401 (vascular; hepatobiliary; blood and lymphatic). Additionally, fewer moderate to severe (Grade 3/4) AEs and fewer AEs per patient (2.3 vs. 3.3) were observed with GALE-401 vs. Agrylin, respectively. Further, based on treatment discontinuation due to an AE, 5 subjects who were previously intolerant to Agrylin (because of AEs) have continued their treatment with GALE-401. Overall, 3 of these 5 subjects were on study for a longer duration [mean time on study, 106d, (47–196d)] compared to their experience with Agrylin prior to enrollment into the Phase 2 study (~7d). Two subjects (40%) have remained in the study and have been able to continue their treatment with GALE-401 for 15 and 22m, respectively. Given this information, GALE-401 seems to confer an improved overall safety profile and potentially offers patients improved tolerability compared to the licensed product.

Conclusion
Across HV and MPN subjects, GALE-401 consistently demonstrated a well-tolerated safety profile. Moreover, in a small subset of subjects enrolled in the Phase 2 MPN pilot study, some previously treated Agrylin intolerant subjects, demonstrated a continued prolonged clinical benefit with GALE-401. A randomized trial comparing Agrylin vs. GALE-401 is needed, alternatively or together with a trial evaluating Agrylin intolerant subjects is warranted.

Session topic: Myeloproliferative neoplasms - Clinical 2 (Poster)

Keyword(s): Anagrelide, Essential Thrombocytemia, Myeloproliferative disorder

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