On June 6, 2023 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported an expert review article in Blood Advances examining the development path and positioning of REZLIDHIA (olutasidenib), a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase-1 (mIDH1)1, in the mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML) treatment landscape (Press release, Rigel, JUN 6, 2023, View Source [SID1234632523]).
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"The compelling safety and efficacy results observed in REZLIDHIA trials to date, marked by encouragingly durable responses, represent an important advance for mIDH1 R/R AML patients and treating physicians," said Justin Watts, M.D., Lead Author and Associate Professor of Medicine, Division of Hematology, Chief, Leukemia Section at the University of Miami Health System. "These data are particularly supportive of the use of REZLIDHIA in mIDH1 R/R AML patients who have failed intensive chemotherapy or venetoclax plus HMA combination therapy. The results validate ongoing studies evaluating olutasidenib in frontline and R/R settings as a monotherapy and in combination with azacitidine with or without prior exposure to HMA or IDH1 inhibitor."
"We are pleased with the growing body of evidence and thought leader support for REZLIDHIA as a differentiated and potentially market-leading therapy for mIDH1 R/R AML patients," said Raul Rodriguez, Rigel’s president and CEO. "We remain committed to delivering this important treatment option to mIDH1 R/R AML patients and look forward to data from the ongoing studies of REZLIDHIA in broader mIDH1 AML treatment settings."
Key points from the paper are summarized below:
REZLIDHIA demonstrated highly durable remission rates, representing a critical addition to the mIDH1 AML treatment landscape
The available data support the use of REZLIDHIA as monotherapy in R/R AML patients who have failed intensive chemotherapy or venetoclax plus HMA combination therapy
The authors state that the choice of which IDH1 inhibitor to use first in these patients is not yet clear, although given the available data REZLIDHIA is recommended in venetoclax plus HMA failures
Among the 12 patients with prior exposure to venetoclax, the ORR was 50% with four patients achieving CR/CRh (33%; 95% CI, 9.9–65.1) and two patients had CRi
Ongoing studies (NCT02719574) could clarify the role of REZLIDHIA in treatment naïve mIDH1 AML (including when given in combination with azacitidine) and in R/R mIDH1 AML with prior IDH1 inhibitor exposure. Further studies assessing maintenance, triplet therapy, and sequencing with venetoclax and azacitidine are being considered.
The paper, titled "Olutasidenib: from Bench to Bedside," was published online in Blood Advances and can be accessed here.
Rigel announced a peer-reviewed publication of data in Blood Advances in February 2023, which summarizes clinical results from the Phase 2 registrational trial of REZLIDHIA in patients with mIDH1 R/R AML.
On December 1, 2022, the U.S. Food and Drug Administration (FDA) approved REZLIDHIA (olutasidenib) capsules for the treatment of adult patients with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test. REZLIDHIA became commercially available in the U.S. on December 22, 2022. REZLIDHIA was added to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute myeloid leukemia (AML) on January 13, 2023 as a recommended targeted therapy for adult patients with R/R AML with isocitrate dehydrogenase-1 (IDH1) mutation.
About AML
Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that in the United States alone, there will be about 20,380 new cases, most in adults, in 2023.2
Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.3 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.4 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need.
About REZLIDHIA
INDICATION
REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME
Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS
Differentiation Syndrome
REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.
If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.
Hepatotoxicity
REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.
Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.
ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.
DRUG INTERACTIONS
Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
LACTATION
Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.
GERIATRIC USE
No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.
HEPATIC IMPAIRMENT
In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.
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REZLIDHIA is a registered trademark of Rigel Pharmaceuticals, Inc.