First patient enrolled in NIH/NHLBI-sponsored
Phase 1 Study of fostamatinib, Rigel's oral SYK inhibitor
SOUTH
SAN FRANCISCO, Calif., Jan. 22,
2025 /PRNewswire/ -- Rigel Pharmaceuticals,
Inc. (Nasdaq: RIGL) today announced the first patient has been
enrolled in a Phase 1 study evaluating the safety and tolerability
of escalating doses of fostamatinib, the company's oral spleen
tyrosine kinase (SYK) inhibitor, in patients with sickle cell
disease (SCD). The study is being sponsored by the National Heart,
Lung, and Blood Institute (NHLBI), part of the National Institute
of Health (NIH). Fostamatinib, marketed in the U.S. as
TAVALISSE® (fostamatinib disodium hexahydrate) tablets,
is approved for the treatment of adult patients with chronic immune
thrombocytopenia (ITP) who have had an insufficient response to a
previous treatment.
"Our Phase 1 study evaluating fostamatinib in patients with
sickle cell disease is an opportunity to explore a potential new
treatment option for a disease that is associated with a high
degree of recurrent acute pain events and other acute and chronic
potentially life-threatening complications," stated Richard Childs, M.D., scientific director of the
NHLBI. "Preclinical research conducted by NIH/NHLBI investigators
lead us to believe that SYK inhibition may have the potential to
reduce complications related to red cell sickling and
thrombo-inflammation in this patient population."
"We are excited to support another important study conducted by
the NIH/NHLBI for fostamatinib, as they investigate SYK inhibition
and its potential to benefit patients with sickle cell disease, a
devasting, lifelong condition," said Raul
Rodriguez, Rigel's president and CEO. "The study focuses on
an area of critical unmet need and contributes to Rigel's mission
to improve the lives of patients with hematologic disorders and
cancer."
This open label Phase 1 dose-escalation study is expected
to enroll approximately 20 patients with SCD (NCT05904093). The
trial is led by principal investigator Swee
Lay Thein, M.D., senior investigator and chief of the
Sickle Cell Branch at the NHLBI. Patients will receive oral
fostamatinib at a dose of 100 mg twice daily for 14 days,
which will be escalated to 150 mg twice daily for an additional 28
days if tolerated. The primary objective of the study is to
evaluate the safety and tolerability of fostamatinib. The secondary
and exploratory objectives are to assess the mechanism of action of
fostamatinib in SCD and mechanistic effects of fostamatinib
mediated SYK inhibition on red blood cell membrane integrity and
deformability, rate of sickling kinetics, platelet activation and
aggregation, and neutrophil activation and neutrophil extracellular
trap (NET) formation. The clinical study is being conducted at the
NIH Clinical Center in Bethesda,
Maryland and is being funded and sponsored by the NIH/NHLBI,
with study material provided by Rigel.
About SCD & SYK Inhibition
Sickle cell
disease (SCD) is a genetic hemoglobinopathy that leads to
the production of abnormal hemoglobin, the protein that carries
oxygen through the body. Normally, red blood cells are disc-shaped
and flexible enough to move easily through the blood vessels. In
sickle cell disease, red blood cells become rigid and crescent – or
"sickle" – shaped, leading to strokes, infections, vaso-occlusive
crises (VOC), and multi-organ dysfunction. The condition affects
more than 100,000 people in the United
States1 and an estimated 7-8 million people
worldwide.2
In preclinical studies, R406, the active metabolite of
fostamatinib, was shown to inhibit production of neutrophil
extracellular traps (NETs) by neutrophils in
vitro.3 In a humanized SCD mouse model, R406
treatment significantly decreased platelet ATP secretion and
aggregation in response to collagen without a significant effect on
bleeding time.4 Fostamatinib could potentially
ameliorate SCD-related prothrombic state without an increase in
bleeding, addressing an important unmet need. Furthermore, tyrosine
phosphorylation of red blood cell (RBC) Band 3 (the anion exchanger
1, of the SLC4A1 gene) compromises the RBC's integrity,
leading to shedding of red cell derived microparticles and release
of hemoglobin and mitochondrial DNA, key contributors to
thrombo-inflammation pathophysiology. By impacting phosphorylation
of RBC Band 3 protein, fostamatinib offers the potential for
enhanced RBC membrane stability and reduced sickling of
RBCs.5
About TAVALISSE®
Indication
TAVALISSE (fostamatinib disodium
hexahydrate) tablets is indicated for the treatment of
thrombocytopenia in adult patients with chronic immune
thrombocytopenia (ITP) who have had an insufficient response to a
previous treatment.
Important Safety Information
Warnings and Precautions
- Hypertension can occur with TAVALISSE treatment. Patients with
pre-existing hypertension may be more susceptible to the
hypertensive effects. Monitor blood pressure every 2 weeks until
stable, then monthly, and adjust or initiate antihypertensive
therapy for blood pressure control maintenance during therapy. If
increased blood pressure persists, TAVALISSE interruption,
reduction, or discontinuation may be required.
- Elevated liver function tests (LFTs), mainly ALT and AST, can
occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT
or AST increase to ≥3 x upper limit of normal, manage
hepatotoxicity using TAVALISSE interruption, reduction, or
discontinuation.
- Diarrhea occurred in 31% of patients and severe diarrhea
occurred in 1% of patients treated with TAVALISSE. Monitor patients
for the development of diarrhea and manage using supportive care
measures early after the onset of symptoms. If diarrhea becomes
severe (≥Grade 3), interrupt, reduce dose or discontinue
TAVALISSE.
- Neutropenia occurred in 6% of patients treated with TAVALISSE;
febrile neutropenia occurred in 1% of patients. Monitor the ANC
monthly and for infection during treatment. Manage toxicity with
TAVALISSE interruption, reduction, or discontinuation.
- TAVALISSE can cause fetal harm when administered to pregnant
women. Advise pregnant women the potential risk to a fetus. Advise
females of reproductive potential to use effective contraception
during treatment and for at least 1 month after the last dose.
Verify pregnancy status prior to initiating TAVALISSE. It is
unknown if TAVALISSE or its metabolite is present in human milk.
Because of the potential for serious adverse reactions in a
breastfed child, advise a lactating woman not to breastfeed during
TAVALISSE treatment and for at least 1 month after the last
dose.
Drug Interactions
- Concomitant use of TAVALISSE with strong CYP3A4 inhibitors
increases exposure to the major active metabolite of TAVALISSE
(R406), which may increase the risk of adverse reactions. Monitor
for toxicities that may require a reduction in TAVALISSE dose.
- It is not recommended to use TAVALISSE with strong CYP3A4
inducers, as concomitant use reduces exposure to R406.
- Concomitant use of TAVALISSE may increase concentrations of
some CYP3A4 substrate drugs and may require a dose reduction of the
CYP3A4 substrate drug.
- Concomitant use of TAVALISSE may increase concentrations of
BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp)
substrate drugs (eg, digoxin), which may require a dose reduction
of the BCRP and P-gp substrate drug.
Adverse Reactions
- Serious adverse drug reactions in the ITP double-blind studies
were febrile neutropenia, diarrhea, pneumonia, and hypertensive
crisis, which occurred in 1% of TAVALISSE patients. In addition,
severe adverse reactions occurred including dyspnea and
hypertension (both 2%), neutropenia, arthralgia, chest pain,
diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache,
syncope, and hypoxia (all 1%).
- Common adverse reactions (≥5% and more common than placebo)
from FIT-1 and FIT-2 included: diarrhea, hypertension, nausea,
dizziness, ALT and AST increased, respiratory infection, rash,
abdominal pain, fatigue, chest pain, and neutropenia.
Please see www.TAVALISSEUSPI.com for Full
Prescribing Information.
To report side effects of prescription drugs to the FDA,
visit www.fda.gov/medwatch or call 1-800-FDA-1088
(800-332-1088).
TAVALISSE is a registered trademark of Rigel Pharmaceuticals,
Inc.
Disclaimer
The content is solely the responsibility of
the authors and does not necessarily represent the official views
of the National Institutes of Health.
About Rigel
Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL)
is a biotechnology company dedicated to discovering, developing and
providing novel therapies that significantly improve the lives of
patients with hematologic disorders and cancer. Founded in 1996,
Rigel is based in South San Francisco,
California. For more information on Rigel, the Company's
marketed products and pipeline of potential products,
visit www.rigel.com.
- National Heart, Lung, and Blood Institute. Sickle Cell
Disease | What Is Sickle Cell Disease? Accessed
January 3,
2025. https://www.nhlbi.nih.gov/health/sickle-cell-disease
- G. B. D. S. C. D. Collaborators. Global, regional, and
national prevalence and mortality burden of sickle cell disease,
2000-2021: a systematic analysis from the Global Burden of Disease
Study 2021. Lancet Haematol. 2023 Aug;10(8):e585-e599. doi:
10.1016/S2352-3026(23)00118-7. Epub 2023 Jun 15.
- Strich JR, Ramos-Benitez MJ, Randazzo D, Stein SR, Babyak A,
Davey RT, Suffredini AF, Childs RW, Chertow DS. Fostamatinib
Inhibits Neutrophils Extracellular Traps Induced by COVID-19
Patient Plasma: A Potential Therapeutic. J Infect Dis. 2021 Mar
29;223(6):981-984.
- Vogel S, Kamimura S, Smith ML, et al. SYK inhibition
suppresses NLRP3 inflammasome activation in platelets from sickle
cell mice leading to decreased platelet secretion, aggregation,
spreading, and in vitro thrombus formation. Thromb Res.
2024;237:18-22
- Noomuna P, Risinger M, Zhou S, et al. Inhibition of Band 3
tyrosine phosphorylation: a new mechanism for treatment of sickle
cell disease. Br J Haematol. 2020;190(4):599-609.
Forward Looking Statements
This press release contains forward-looking statements relating
to, among other things, evaluating fostamatinib in patients
with sickle cell disease and the potential of SYK inhibition to
reduce complications related to red cell sickling and
thrombo-inflammation. Any statements contained in this
press release that are not statements of historical fact may be
deemed to be forward-looking statements. Forward-looking statements
can be identified by words such as "explore", "potential", "may",
"expected", "will" and similar expressions in reference to future
periods. Forward-looking statements are neither historical facts
nor assurances of future performance. Instead, they are based on
Rigel's current beliefs, expectations, and assumptions and hence
they inherently involve significant risks, uncertainties and
changes in circumstances that are difficult to predict and many of
which are outside of our control. Therefore, you should not
rely on any of these forward-looking statements. Actual results and
the timing of events could differ materially from those anticipated
in such forward looking statements as a result of these risks and
uncertainties, which include, without limitation, risks and
uncertainties associated with the development and commercialization
of fostamatinib; risks that the FDA, European Medicines Agency,
PMDA or other regulatory authorities may make adverse decisions
regarding fostamatinib; risks that clinical trials may not be
predictive of real-world results or of results in subsequent
clinical trials; risks that fostamatinib may have unintended side
effects, adverse reactions or incidents of misuses; the
availability of resources to develop Rigel's product candidates;
market competition; as well as other risks detailed from time to
time in Rigel's reports filed with the Securities and Exchange
Commission, including its Annual Report on Form 10-K for the year
ended December 31, 2023 and
subsequent filings. Any forward-looking statement made by us in
this press release is based only on information currently
available to us and speaks only as of the date on which it is made.
Rigel does not undertake any obligation to update forward-looking
statements, whether written or oral, that may be made from time to
time, whether as a result of new information, future developments
or otherwise, and expressly disclaims any obligation or undertaking
to release publicly any updates or revisions to any forward-looking
statements contained herein, except as required by law.
Contact for Investors &
Media:
Investors:
Rigel Pharmaceuticals,
Inc.
650.624.1232
ir@rigel.com
Media:
David
Rosen
Argot Partners
646.461.6387
david.rosen@argotpartners.com
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SOURCE Rigel Pharmaceuticals, Inc.
