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Updated Efficacy Data from GBT’s Phase 3 Study Show Statistically Significant and Sustained Improvements in Hemoglobin with Voxelotor

AMSTERDAM, The Netherlands, June 14, 2019 (GLOBE NEWSWIRE) — Global Blood Therapeutics, Inc. (GBT) (Nasdaq: GBT) today announced new results from its Phase 3 HOPE Study of voxelotor in patients ages 12 and older with sickle cell disease (SCD). The findings from 274 adolescents and adults treated with voxelotor showed the HOPE Study met its primary endpoint of an improvement in hemoglobin greater than 1 g/dL at 24 weeks with voxelotor 1500 mg compared with placebo, with a favorable safety and tolerability profile. In the study, voxelotor provided a rapid, statistically significant and sustained improvement in hemoglobin levels and reduced the incidence of worsening anemia and hemolysis.

The data were published today in The New England Journal of Medicine and featured in the press briefing prior to presentation at 4:15 p.m. CEST as part of the Presidential Symposium at the 24thEuropean Hematology Association (EHA) Congress in Amsterdam.

“These additional data from our multi-national, Phase 3 HOPE Study support and strengthen the 24-week findings from 154 patients that were presented at the American Society of Hematology Annual Meeting in December 2018. These updated results form the basis of the rolling submission of our New Drug Application for voxelotor, which we are on track to complete in the second half of this year for review under an accelerated approval pathway,” said Ted W. Love, M.D., president and chief executive officer of GBT. “We are excited about the potential for voxelotor to improve the major morbid outcomes for people with SCD, given that lower levels of hemoglobin are associated with greater risk of overt stroke, silent infarct and increased mortality. We are also pleased to announce that we have reached final agreement with the FDA on the design of our transcranial doppler post-approval confirmatory study, which we will share more information about during our corporate update webcast later today.”

“These positive data from more than 270 patients enrolled in the HOPE Study provide strong evidence that voxelotor, by significantly improving anemia and hemolysis, has the potential to be a disease-modifying treatment for SCD by preventing chronic organ damage and prolonging survival,” said Jo Howard, MB BChir, MRCP, FRCPath, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London and a HOPE Study investigator. “Given the observed ability of voxelotor to reduce anemia, hemolysis and red blood cell sickling, as well as a favorable safety profile, I am confident that voxelotor could potentially become a new standard-of-care for treating adolescents and adults with SCD.”

New HOPE Study Results Show Robust Improvements in Anemia with Voxelotor (Abstract #S147)
The new results from the HOPE Study include 24-week efficacy data from 274 patients ages 12 and older with SCD enrolled in the study from 60 institutions across 12 countries. The data showed that patients treated with once-daily oral voxelotor demonstrated rapid, robust and sustained improvements in anemia, as measured by the increase in hemoglobin from baseline to 24 weeks compared to placebo (see Table 1). The mean increase in hemoglobin levels with voxelotor compared to placebo was similar with or without concurrent hydroxyurea treatment.

These results from the HOPE Study are reported using both intention-to-treat (ITT) and per-protocol (PP) analyses. The PP analysis is based on patients who completed the primary endpoint visit of 24 weeks, whereas the more conservative ITT analysis defines all patients with missing data at 24 weeks as non-responders. Previously, GBT had reported HOPE Study results as assessed only in the PP population. As discussed with the U.S. Food and Drug Administration (FDA), the HOPE Study primary endpoint – hemoglobin response at 24 weeks – is to be assessed in an ITT population for the New Drug Application (NDA). The benefit of voxelotor is highly statistically significant irrespective of ITT or PP analysis, and both analyses are presented below.

Table 1

  Intention-To-Treat (ITT) Analysis Per-Protocol (PP) Analysis
  N % with
 >1 g/dL 
Increase in Hb


 
Mean* 
Change in Hb 
from Baseline 
to 24 Weeks

 
N % with 
>1 g/dL 
Increase in Hb

 
Mean 
Change in Hb 
from Baseline 
to 24 Weeks

 
1500 mg 
voxelotor
90 51.1% 
(p<0.001)
1.1 g/dL
(p<0.001)
 
74 59.5% 
(p<0.001)
1.3 g/dL
(p<0.001)
900 mg 
voxelotor
92 32.6% 
(p<0.001)
0.6 g/dL
(p<0.001)
79 38.0% 
(p<0.001)
0.7 g/dL
(p<0.001)
 
Placebo 92 6.5% -0.1 g/dL 76 9.2% 0 g/dL
 
*Adjusted for baseline stratification factors.
P-value is for comparison versus placebo; not adjusted for multiplicity.

The ITT analysis of all 274 patients at 24 weeks showed:

  • Hemoglobin improved rapidly from baseline to the earliest timepoint measured (2 weeks) with voxelotor 1500 mg and was sustained through 24 weeks (p<0.001 vs. placebo). The improvement in hemoglobin was similar in patients with or without background use of hydroxyurea.
  • Voxelotor 1500 mg increased hemoglobin levels to a mean of 9.8 g/dL at 24 weeks from a baseline of 8.6 g/dL, consistent with a clinically meaningful improvement in anemia.
  • Improvements from baseline in hemoglobin, percent reticulocytes and indirect bilirubin occurred with both voxelotor doses, further demonstrating an improvement in hemolysis consistent with a dose-related inhibition of hemoglobin polymerization.
  • There were numerically fewer vaso-occlusive crises (VOCs) and a lower annualized incidence rate (per person-year) of VOCs in both voxelotor dose groups than in the placebo group, despite the significant increases in hemoglobin with voxelotor treatment.
  • Voxelotor was generally safe and well tolerated, with both doses having similar safety profiles. Treatment discontinuation rates did not differ substantially among the three trial groups. There was no evidence of impairment of tissue oxygenation at either dose of voxelotor.

Additional data presented in poster sessions at the 2019 EHA Congress further support GBT’s voxelotor program in SCD:

  • Clinical data from an investigator-initiated ancillary study of three adolescents with SCD enrolled in the HOPE-KIDS 1 Study showed that all participants had unchanged or lower cerebral blood flow as measured by functional MRI with angiography while receiving voxelotor, suggesting that cerebral blood flow was maintained or improved with administration of voxelotor. Lower cerebral blood flow with rising hemoglobin levels suggests improved oxygen delivery to the brain. (Abstract #PF740)
  • An in vitro study of the mechanism of voxelotor showed that oxygen is released from voxelotor-modified hemoglobin under deoxygenated conditions and that normal physiological compensatory mechanisms to enhance oxygen delivery are not disrupted. This finding suggests that treatment with voxelotor maintains oxygen delivery to tissues and supports the safety of this investigational treatment. (Abstract #PS1522)

Corporate Update Webcast Details                                                                                                             
Today, Friday, June 14, 2019, at 7:00 p.m. CEST / 1:00 p.m. ET, members of GBT’s management team and Jo Howard, MB BChir, MRCP, FRCPath, Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London, will review the HOPE Study data being presented at the 2019 EHA Congress. Additional presentations by Robert J. Adams, M.D., Medical University of South Carolina, and Jeremie H. Estepp, M.D., St. Jude Children’s Research Hospital, will provide an overview on the use of transcranial doppler (TCD) ultrasonography in SCD patients and the final trial design for GBT’s post-approval confirmatory TCD study, respectively. The event will be webcast live from GBT’s website at www.gbt.com in the Investors section. A replay will be available for 30 days following the event.

About Sickle Cell Disease 
SCD is a lifelong inherited blood disorder caused by a genetic mutation in the beta-chain of hemoglobin, which leads to the formation of abnormal hemoglobin known as sickle hemoglobin (HbS). In its deoxygenated state, HbS has a propensity to polymerize, or bind together, forming long, rigid rods within a red blood cell (RBC). The polymer rods deform RBCs to assume a sickled shape and to become inflexible, which causes hemolytic anemia (low hemoglobin due to RBC destruction) that can lead to multi-organ damage and early death. This sickling process also causes blockage in capillaries and small blood vessels. Beginning in childhood, SCD patients typically suffer unpredictable and recurrent episodes or crises of severe pain due to blocked blood flow to organs, which often lead to psychosocial and physical disabilities.

About Voxelotor in Sickle Cell Disease
Voxelotor (previously called GBT440) is being developed as an oral, once-daily therapy for patients with SCD. Voxelotor works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, GBT believes voxelotor blocks polymerization and the resultant sickling and destruction of red blood cells. With the potential to improve hemolytic anemia and oxygen delivery, GBT believes that voxelotor may potentially modify the course of SCD. In recognition of the critical need for new SCD treatments, the U.S. Food and Drug Administration (FDA) has granted voxelotor Breakthrough Therapy, Fast Track, Orphan Drug and Rare Pediatric Disease designations for the treatment of patients with SCD. The European Medicines Agency(EMA) has included voxelotor in its Priority Medicines (PRIME) program, and the European Commission (EC) has designated voxelotor as an orphan medicinal product for the treatment of patients with SCD.

GBT is currently evaluating voxelotor in the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) Study, a Phase 3 clinical study in patients age 12 and older with SCD. Additionally, voxelotor is being studied in the ongoing Phase 2a HOPE-KIDS 1 Study, an open-label, single- and multiple-dose study in pediatric patients (age 4 to 17) with SCD. The HOPE-KIDS 1 Study is assessing the safety, tolerability, pharmacokinetics and exploratory treatment effect of voxelotor.

About GBT
GBT is a clinical-stage biopharmaceutical company determined to discover, develop and deliver innovative treatments that provide hope to underserved patient communities. GBT is developing its lead product candidate, voxelotor, as an oral, once-daily therapy for sickle cell disease. To learn more, please visit www.gbt.com and follow the company on Twitter @GBT_news.

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