Drug Authorizations: OXBRYTA and ADAKVEO for sickle cell, XCOPRI for partial-onset seizures, CALQUENCE for leukemia/lymphoma, GIVLAARI for acute hepatic porphyria
OXBRYTA (voxelotor) tablets
Global Blood Therapeutics
INDICATION FOR USE: Treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older.
ADDRESSING UNMET NEED: Treatment option for 100,000 people in the U.S., and the more than 20 million globally, who live with this debilitating blood disorder
MECHANISM OF ACTION: Hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs) – increasing the affinity of Hb for oxygen
EFFICACY:
- Randomized, double-blind, placebo-controlled, multicenter trial, n=274 patients with sickle cell disease, OXBRYTA vs. placebo
- Endpoint: Hb response rate defined as a Hb increase of >1 g/dL from baseline to Week 24
- 51.1% (OXBRYTA) vs. 6.5% (placebo), (p < 0.001); no outlier subgroups observed
SAFETY:
- Common side effects: Headache, diarrhea, abdominal pain, nausea, fatigue, rash and pyrexia
REGULATORY PATHWAY: NDA
- Accelerated Approval, Fast Track designation. Orphan Drug designation
- Accelerated approval requirements: Phase 3, randomized, doubleblind, placebo-controlled trial in pediatric patients (age 2 years to < 15 years) with Sickle Cell Disease , long-term (5 years) followup
ADAKVEO (crizanlizumab-tmca) injection
Novartis
INDICATION FOR USE: Reduce the frequency of vasoocclusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease.
ADDRESSING UNMET NEED: First targeted therapy approved for sickle cell disease, specifically inhibiting selectin, a substance that contributes to cells sticking together and leads to vaso-occlusive crisis- a painful condition
MECHANISM OF ACTION: Humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.
EFFICACY:
- 52-week, randomized, multicenter, placebo-controlled, double-blind study, n=198 patients with sickle cell disease, any genotype, ADAKVEO vs placebo
- Endpoint: Annual rate of vaso-occlusive crisis (VOC) to a healthcare visit
- Median annual rate of 1.63 visits (ADAKVEO) vs. 2.98 visits (placebo)
- 36% on Adakveo did not experience VOC during the study, delayed the time of first VOC experience
SAFETY:
- Common side effects: Back pain, nausea, pyrexia, arthralgia
- Need to monitor patients for infusion-related reactions, interference with automated platelet counts or platelet clumping
REGULATORY PATHWAY: BLA
- Priority Review and Breakthrough Therapy designation, Orphan Drug designation
- Postapproval requirements: Further evaluation of immune mediated safety
XCOPRI® (cenobamate tablets)
SK Lifesciences
INDICATION FOR USE: Treatment of partial-onset seizures in adult patients
ADDRESSING UNMET NEED: New option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life
MECHANISM OF ACTION: Precise mechanism unknown; demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents
EFFICACY:
- Two multicenter, randomized, double-blind, placebo-controlled studies, N=655 adult patients
- Endpoint: % change from baseline in seizure frequency per 28 days in the treatment period
- 55.6% reduction (XCOPRI 200 mg) vs 21.5% reduction (placebo), p< 0.0001
SAFETY:
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), shortening of the QT interval and ventricular fibrillation – dose needs to be titrated
- Increased risk of suicidal thoughts or behavior and other neurological adverse reactions
- Most common side effects: Somnolence (sleepiness), dizziness, fatigue, diplopia (double vision), headaches
REGULATORY PATHWAY: NDA
- Contains cenobamate – (Controlled substance schedule to be determined after review by the Drug Enforcement Administration
- Required pediatric assessments
CALQUENCE® (acalabrutinib) capsules
AstraZeneca
INDICATION FOR USE: treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
EFFICACY & SAFETY:
- Two randomized, actively controlled trials in patients with CLL
- Endpoint: Progression-free survival (PFS) as assessed by independent review; significantly improved in both acalabrutinib arms, p<0.0001
- Most common adverse reactions: Anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, diarrhea
REGULATORY PATHWAY: Supplemental NDA
- First approved in 2017
- This review conducted under Project Orbis, framework for concurrent submission and review by FDA, the Australian Therapeutic Goods Administration, and Health Canada
- FDA review used the Real-Time Oncology Review (RTOR) and Assessment Aid pilot programs, to sreamline data submission, Priority Review and Breakthrough Therapy designation
GIVLAARI (givosiran) injection
Alnylam Pharmaceuticals
INDICATION FOR USE: Treatment of adults with acute hepatic porphyria (AHP)
MECHANISM OF ACTION: Double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes; leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid
(ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP
EFFICACY:
- Randomized, double‑blind, placebo‑controlled, multinational trial, n=94 patients with AHP, GIVLAARI vs placebo
- Endpoint: Rate of porphyria attacks requiring hospitalizations, urgent healthcare visit, or intravenous hemin administration at home
- 1.9 (95% CI:1.3,2.8) with GIVLAARI vs, 6.5 (95% CI:4.5, 9.3) with placebo
- 70% (95% CI: 60%, 80%) fewer porphyria attacks with GIVLAARI
SAFETY:
- Most common adverse reactions: Nausea and injection site reactions
- Warnings for anaphylactic reactions, hepatic and renal toxicities, and injection site reactions
REGULATORY PATHWAY: NDA
- Priority Review, Orphan product, Breakthrough Therapy designations
- Postmarketing commitments: Trial in pediatric patients age greater than or equal to 12 years to less than 17 years with AHP
Image credit: Global Blood Therapeutics, Novartis, SK Lifesciences, AstraZeneca, Alnylam