A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in β-thalassaemia intermedia and HbE/β-thalassaemia

British Journal of Haematology

Volumn 161, Issue 4, 2013, Pages 587-593

  Fucharoen, Suthat ^a   Inati, Adlette ^b   Siritanaratku, Noppadol ^a   Thein, Swee L ^c   Wargin, William C ^d   Koussa, Suzanne ^b   Taher, Ali ^b   Chaneim, Nattawara ^a   Boosalis, Michael ^e   Berenson, Ronald ^f   Perrine, Susan P ^e  

^a MAHIDOL UNIVERSITY   (Thailand)

^b Rafik El Hariri University Hospital   (Lebanon)

^c KING S COLLEGE HOSPITAL   (United Kingdom)

^d PK PM Associates LLC   (United States)

^e BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f HemaQuest Pharmaceuticals   (United States)

Author keywords

Beta thalassaemia intermedia; Clinical trial; Fetal haemoglobin; Pharmacokinetics

Indexed keywords

HEMATOLOGIC AGENT; HEMOGLOBIN; HEMOGLOBIN F; HQK 1001; PLACEBO; SODIUM 2,2 DIMETHYLBUTYRATE; UNCLASSIFIED DRUG;

ABDOMINAL PAIN; ADULT; AREA UNDER THE CURVE; ARTICLE; BACKACHE; BETA THALASSEMIA; BETA THALASSEMIA INTERMEDIA; CLINICAL ARTICLE; CONTROLLED STUDY; DIZZINESS; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; FATIGUE; FEMALE; GASTRITIS; GASTROENTERITIS; HEADACHE; HEMOGLOBIN DETERMINATION; HUMAN; MALE; MAXIMUM PLASMA CONCENTRATION; NAUSEA; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PR INTERVAL; PRIORITY JOURNAL; QRS COMPLEX; QT INTERVAL; RANDOMIZED CONTROLLED TRIAL; RR INTERVAL; SIDE EFFECT; THALASSEMIA; TREATMENT OUTCOME; UPPER ABDOMINAL PAIN; UPPER RESPIRATORY TRACT INFECTION; VOMITING; WEIGHT GAIN;

ADMINISTRATION, ORAL; ADOLESCENT; ADULT; BETA-THALASSEMIA; BUTYRATES; FEMALE; FETAL HEMOGLOBIN; GENE EXPRESSION REGULATION; HUMANS; MALE; MIDDLE AGED; SPLENECTOMY; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84876810376     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.12304     Document Type: Article

References (35)

1. Boosalis, M.S., Castenada, S., Bohacek, R., Trudel, M., Mabaera, R., Emery, D., Lowrey, C., Shen, L., Faller, D.V. & Perrine, S.P. (2011) Novel therapeutic candidates, identified by molecular modeling, induce fetal globin gene expression in vivo. Blood Cells, Molecules & Diseases, 47, 107-116.
2. Bourantas, K., Economou, G. & Georgiou, J. (1997) Administration of high doses of recombinant human erythropoietin to patients with beta- thalassemia intermedia: a preliminary trial. European Journal of Haematology, 58, 22-25.
3. Cappellini, M.D. & Marelli, S. (2004) Approaches to therapy of thalassemia intermedia. In: Clinical Aspects and Therapy of Hemoglobinopathies (eds by Maggio, A., Hoffbrand, A.V.), pp. 203-213. SEE Societa Editrice Europea di Nicodemo Maggiulli & C. snc, Firenze.
4. Cappellini, D., Graziadei, M.G., Ciceri, L., Comino, A., Bianchi, P., Porcella, A. & Fiorelli, G. (2000) Oral isobutyramide therapy in patients with thalassemia intermedia: results of a phase II open study. Blood Cells, Molecules and Diseases, 26, 105-111.
5. Castaneda, S., Boosalis, M.S., Emery, D., Thies, A., Faller, D.V. & Perrine, S.P. (2005) Enhancement of growth and survival and alterations in Bcl-family proteins in beta-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives. Blood Cells, Molecules and Diseases, 35, 217-226.
6. Collins, A.F., Pearson, H.A., Giardina, P., McDonagh, K.T., Brusilow, S.W. & Dover, G.J. (1995) Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood, 85, 43-49.
7. 0 -thalassaemic patient unable to be transfused due to multiple alloantibodies. British Journal of Haematology, 72, 467-468.
8. Fucharoen, S., Siritanaratkul, N., Winichagoon, P., Chowthaworn, J., Siriboon, W., Muangsup, W., Chiacharoen, S., Poolsup, P., Piankijagum, A., Schechter, A.N. & Rodgers, G.P. (1996) Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease. Blood, 87, 887-892.
9. Galanello, R., Perseu, L., Satta, S., Demartis, F.R. & Campus, S. (2011) Phenotype-genotype correlation in beta thalassemia. In: Thalassemia Reports, Proceedings of the 12th International Conference on Thalassemia and Hemoglobinopathies; 2011 May 11-14 Antalya, Turkey. (ed. by A. Maggio ), Vol. 1 (s2):e6, pp. 16-20. PagePress, Italy.
10. Gallo, E., Massaro, P., Miniero, R., David, D. & Tarella, C. (1979) The importance of the genetic picture and globin synthesis in determining the clinical and haematological features of thalassaemia intermedia. British Journal of Haematology, 41, 211-221.
11. Garner, C., Mitchell, J., Hatzis, T., Reittie, J., Farrall, M. & Thein, S.L. (1998) Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23. American Journal of Human Genetics, 62, 1468-1474.
12. Hajjar, F.M. & Pearson, H.A. (1994) Pharmacologic treatment of thalassemia intermedia with hydroxyurea. The Journal of Pediatrics, 125, 490-492.
13. Jiang, J., Best, S., Menzel, S., Silver, N., Lai, M.I., Surdulescu, G.L., Spector, T.D. & Thein, S.L. (2006) cMYB is involved in the regulation of fetal hemoglobin production in adults. Blood, 108, 1077-1083.
14. Labie, D., Pagnier, J., Lapoumeroulie, C., Rouabhi, F., Dunda-Belkhodja, O., Chardin, P., Beldjord, C., Wajcmman, H., Fabry, M.E. & Nagel, R.L. (1985) Common haplotype dependency of high G gamma- globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proceedings of the National Academy of Sciences of the United States of America, 82, 2111-2114.
15. Ley, T.J., DeSimone, J., Anagnou, N.P., Keller, G.H., Humphries, R.K., Turner, P.H., Young, N.S., Keller, P. & Nienhuis, A.W. (1982) 5- azacytidine selectively increases gamma-globin synthesis in a patient with beta+ Thalassemia. The New England Journal of Medicine, 307, 1469-1475.
16. Lowrey, C.H. & Nienhuis, A.W. (1993) Brief report: treatment with azacitidine of patients with end-stage beta-thalassemia. The New England Journal of Medicine, 329, 845-848.
17. Nisli, G., Kavakli, K., Vergin, C., Ōztop, S. & Çetingül, N. (1996) Recombinant human erythropoietin trial in thalassemia intermedia. Journal of Tropical Pediatrics, 42, 330-334.
18. 0- thalassemia/hemoglobin E. Human Genetics, 127, 303-314.
19. Olivieri, N.F., Saunthararajah, Y., Thayalasuthan, V., Kwiatowski, J., Ware, R.E., Kuypers, F.A., Kim, H., Trachtenberg, F.L., Vichinsky, E.P. & for the Thalassemia Clinical Network (2011) A pilot study of subcutaneous decitabine in beta-thalassemia intermedia. Blood, 118, 2708-2711.
20. Pace, B.S., White, G.L., Dover, G.J., Boosalis, M.S., Faller, D.V. & Perrine, S.P. (2002) Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo. Blood, 100, 4640-4648.
21. Perrine, S.P. (2005) Fetal globin induction-can it cure beta thalassemia? Hematology/the Education Program of the American Society of Hematology, 1, 38-44.
22. Perrine, S.P., Ginder, G.D., Faller, D.V., Dover, G.H., Ikuta, T., Witkowska, H.E., Cai, T., Vichinsky, E.P. & Olivieri, N.F. (1993) A short- term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. The New England Journal of Medicine, 328, 81-86.
23. Perrine, S.P., Mankidy, R., Boosalis, M.S., Bieker, J.J. & Faller, D.V. (2009) Erythroid Krüppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. European Journal of Haematology, 82, 466-476.
24. Perrine, S.P., Wargin, W.A., Boosalis, M.S., Wallis, W., Case, S., Keefer, J.R., Faller, D.V., Welch, W.C. & Berenson, R.J. (2011) Evaluation of safety and pharmacokinetics of sodium 2, 2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single- and repeat- dose studies in healthy volunteers. The Journal of Clinical Pharmacology, 51, 1186-1194.
25. Rachmilewitz, E.A. & Aker, M. (1998) The role of recombinant human erythropoietin in the treatment of thalassemia. Annals of the New York Academy of Sciences, 850, 129-138.
26. Reich, S., Buhrer, C., Henze, G., Ohlendorf, P., Mesche, M., Sinha, P., Kage, A., Müller, C., Vetter, B. & Kulozik, A.E. (2000) Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta-thalassemia. Blood, 96, 3357-3363.
27. Schrier, S.L. (1997) Pathobiology of thalassemic erythrocytes. Current Opinion in Hematology, 4, 75-78.
28. 0 thalassaemia: clinical and haematological outcome. British Journal of Haematology, 131, 378-388.
29. Steinberg, M.H. & Rodgers, G.P. (2001) Pharmacologic modulation of fetal hemoglobin. Medicine, 80, 328-344.
30. Taher, A., Mussallem, K.M., Karimi, M., El-Beshlaway, A. & Cappellini, M. (2010) Overview on practices in thalassemia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood, 115, 1886-1892.
31. Thein, S.L. & Menzel, S. (2009) Discovering the genetics underlying foetal haemoglobin production in adults. British Journal of Haematology, 145, 455-467.
32. Thein, S.L., Menzel, S., Lathrop, M. & Garner, C. (2009) Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Human Molecular Genetics, 18, R216-R223.
33. Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V.G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M.G., Sestu, N., Lai, S., Dei, M., Mulas, A., Crisponi, L., Naitza, S., Asunis, I., Deiana, M., Naqaraja, R., Perseu, L., Satta, S., Cipollina, M.D., Sollainoc, C., Moi, P., Hirshhom, J.N., Orkin, S.H., Abecasis, G.R., Schlessinger, D. & Cao, A. (2008) Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta- thalassemia. Proceedings of the National Academy of Sciences of the United States of America, 105, 1620-1625.
34. Weatherall, D.J. (2010) The inherited diseases of hemoglobin are an emerging global health burden. Blood, 115, 4331-4336.
35. Wilkinson, G.R. (2005) Drug metabolism and variability among patients in drug response. The New England Journal of Medicine, 352, 2211-2221.