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1148 Initial Results in a Phase 1b Trial of PB-04 in Sickle Cell Disease Demonstrate Fetal Hemoglobin Induction, Additive Activity with Hydroxyurea, and Improved Red Blood Cell Sickling Parameters

Program: Oral and Poster Abstracts
Session: 114. Sickle cell Disease, Sickle Cell Trait and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Sickle Cell Disease, adult, Clinical Research, Thalassemia, Hemoglobinopathies, drug development, Diseases, Therapies, Biological Processes, Study Population, Human
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Kevin H.M. Kuo, MD, FRCPC, MSc1,2,3, Sylvia Titi Singer, MD4, Gershwin Theophilus Blyden, MD, PhD5*, Lanetta Bronté-Hall, MD, MPH, MSPH6, Aidan Faller, BS7*, Abdullah Kutlar, MD8, Frans A. Kuypers, PhD9*, Aliya U. Zaidi, PhD10*, Patrick C. Hines, MD, PhD10, Niren Patel, MBBS11*, Sandra Larkin, MS12*, Hanny Al-Samkari, MD13, Sujit Sheth, MD14, Seyed Mehdi Nouraie, MD15* and Susan Perrine, MD16

1Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, Canada
2Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
3Division of Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada
4UCSF Benioff Childrens Hospital Oakland, Oakland, CA
5Foundation for Sickle Cell Disease Research, Miami, FL
6The Foundation for Sickle Cell Disease Research, Hollywood, FL
7Phoenicia Biosciences, Boston, MA
8Medical College of Georgia, Augusta, GA
9Children's Hospital Oakland Research Institute, Oakland, CA
10Functional Fluidics Inc., Detroit, MI
11Department of Medicine, Augusta University, Augusta, GA
12University of California San Francisco, Oakland, CA
13Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
14Division of Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY
15Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
16Phoenicia Biosciences, Inc., Boston, MA

Extensive evidence has shown fetal hemoglobin (HbF) is a major modulator of sickle cell disease (SCD) phenotype. Clinical benefit with any increment of HbF was shown in the NIH-sponsored Natural History Study and the Multicenter Study of Hydroxyurea (HU), with mean HbF increases of 3.6% above baseline (BL), to improve survival, reduce painful vaso-occlusive crises, and recently stroke prevention and improved cardiac and neurocognitive function with HU are reported. As some patients do not tolerate optimal HU doses due to cytopenias, additional inducers suitable for combined use are desirable. Proportions of F-cells and HbF-quantity/cell have been cited as important.

PB-04, a repurposed drug with a well-known safety profile, is an oral fetal globin stimulant identified in high throughput screening, which suppresses 4 repressors of the HMG gene promoter, (BCL-11A, LSD-1, HDAC-3, KLF-1). PB-04 induces fetal globin in nonhuman primates, transgenic mice, with additive effect when combined with HU in SCD erythroid progenitors, and was shown to reduce infarcts in multiple organs with preserved splenic function in transgenic sickle mice.

An ongoing Phase 1b trial in beta thalassemia intermedia (BTI) (NCT04432623) of 3 doses (1,3, or 5 mg/kg QD) given 3 (TIW) or 5 times/week (Wk) for 12 or 24 Wks in 18 courses in 10 subjects demonstrates a favorable safety profile, dose-proportional PK with 5 >3 mg/kg doses and 5 >3 doses/Wk, Median fold-increases from baseline (BL) in F-cells of 4.4x BL (range 2.3-7x), 2.8x F-reticulocytes (1.6-14.8x), and 6.5x (range 3-11x) increases in mean fluorescence intensity (MFI, representing amount of HbF/RBC). Mean increases in % HbF were 6.5%.

Evaluation of PB-04 has now begun in 7 subjects with SCD, 19-51 yrs; 3 were receiving HU with HbF responses (12-22%). Adverse events, F-cells, F-reticulocytes, MFI (amount of HbF/RBC or HbF/reticulocyte) by FACS and ImageStream Analysis and % HbF are assessed Q 4 wks; flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) and sickling kinetics are assessed q 12 wks. In 4 subjects on 3 mg/kg QD TIW for 24 wks, changes observed from BL values included mean increases of 6% F-cells and 27% F-reticulocytes (2-fold). In 3 ongoing subjects receiving 5 mg/kg QD TIW for 12 wks, mean changes above BL are currently 13% F-cells, 15% F-reticulocytes; HbF/cell or HbF/reticulocyte have increased up to 10-fold. Mean % HbF has increased above HU effects in 2/3 pts on the second dose by 5-12.6% (mean 8.8%), producing 81-95% F-cells, and 35-38% HbF. Decline in FA-WB-VCAM) was observed ± HU and with both doses in 3 subjects. Correlation of HbF quantity/cell with RBC survival and sickling dynamics is being explored.

These early results with not-yet-optimized doses of PB-04 suggest additive activity with HU, producing significant HbF and F-cell levels, and support further PK-optimized studies in patients with SCD.

Disclosures: Kuo: Agios Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Forma Therapeutics: Consultancy; Pfizer: Consultancy; Bioverativ/Sanofi/Sangamo: Membership on an entity's Board of Directors or advisory committees; Novo/Nordisk: Consultancy, Honoraria; Vertex Pharmaceuticals: Consultancy. Kutlar: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma/Novo-Nordisk: Research Funding; Akira Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT/Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuypers: Forma/NovoNordisk: Research Funding; GBT/Pfizer: Research Funding. Zaidi: Functional Fluidics: Current Employment. Hines: Functional Fluidics: Current Employment, Current equity holder in private company. Al-Samkari: Novartis: Consultancy; Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; argenx: Consultancy; Pharmacosmos: Consultancy; Moderna: Consultancy. Sheth: Fulcrum: Consultancy; Chiesi: Consultancy; Bluebird bio: Consultancy, Other: Travel support; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/ Celegene: Consultancy, Other: Travel support, Research Funding; Agios: Consultancy, Other: Travel support, Research Funding; CRISPR: Membership on an entity's Board of Directors or advisory committees. Perrine: Emmaus: Consultancy.

*signifies non-member of ASH