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FDA Approves Crizanlizumab-tmca and Voxelotor for Sickle Cell Disease

Evidence for efficacy for crizanlizumab-tmca is based on the results from the SUSTAIN trial and for voxelotor on the results from the HOPE study
05 Dec 2019
Haematologic malignancies

On 15 November 2019, the US Food and Drug Administration (FDA) approved crizanlizumab-tmca (ADAKVEO, Novartis) to reduce the frequency of vaso-occlusive crises (VOCs) in adults and paediatric patients aged 16 years and older with sickle cell disease.

On 25 November 2019, the FDA granted accelerated approval to voxelotor (Oxbryta, Global Blood Therapeutics) for adults and paediatric patients 12 years of age and older with sickle cell disease.

FDA approves crizanlizumab-tmcafor sickle cell disease

Efficacy for crizanlizumab-tmcawas evaluated in 198 patients with sickle cell disease in SUSTAIN (NCT01895361), a 52-week, randomised, multicentre, placebo-controlled, double-blind trial. Patients were randomised (1:1:1) to crizanlizumab-tmca 5 mg/kg (n = 67), crizanlizumab-tmca 2.5 mg/kg (n = 66), or placebo (n = 65) administered intravenously over 30 minutes on week 0, 2, and every 4 weeks thereafter. Randomisation was stratified by prior hydroxyurea and by the number of VOCs in the prior 12 months.

The primary efficacy outcome measure was the annual rate of VOCs leading to a healthcare visit, defined as an acute episode of pain with no cause other than a vaso-occlusive event requiring a medical facility visit and oral or parenteral opioids, or parenteral NSAIDs. Patients receiving crizanlizumab-tmca, 5 mg/kg, had a lower median annual rate of VOC compared to those receiving placebo (1.63 vs. 2.98, p = 0.010). Reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype and/or hydroxyurea use. Thirty-six percent of patients treated with crizanlizumab-tmca 5 mg/kg did not experience a VOC compared to 17% in the placebo arm. The median time to first VOC from randomisation was 4.1 vs. 1.4 months in the crizanlizumab-tmca 5mg/kg and placebo arm, respectively.

The most common adverse reactions (>10%) in patients receiving crizanlizumab-tmca were nausea, arthralgia, back pain, and pyrexia.

The recommended dose is 5 mg/kg intravenously over a period of 30 minutes on week 0, 2, and every 4 weeks thereafter.

Full prescribing information for ADAKVEO is available here.

FDA granted this application priority review and orphan product and Breakthrough Therapy designations.

FDA approves voxelotor for sickle cell disease

Efficacy for voxelotor was evaluated in 274 patients with sickle cell disease in HOPE (NCT 03036813), a randomised, double-blind, placebo-controlled, multicentre trial. Patients were randomised to voxelotor 1500 mg (n = 90), 900 mg (n = 92), or placebo (n = 92). The median age was 24 years (range 12, 64). Approximately 65% of patients were taking hydroxyurea at trial entry. Patients were enrolled if their baseline haemoglobin (Hb) ≥5.5 to ≤10.5 g/dL. Patients on stable hydroxyurea doses continued the drug throughout the trial. Randomisation was stratified by whether the patient was already receiving hydroxyurea, by geographic region, and by age.

The primary efficacy outcome measure was Hb response rate defined as an Hb increase of >1 g/dL from baseline to week 24. The response rate for voxelotor was 51.1% (46/90) compared to 6.5% (6/92) in the placebo group (p < 0.0001). Additional efficacy evaluation included change in Hb, percentage change in indirect bilirubin and percentage reticulocyte count during this time period. In the voxelotor 1,500 mg group, the mean change for Hb, indirect bilirubin, and percentage reticulocyte count were 1.14g/dL, ‑29.08%, and -19.93%, respectively. In the placebo group, the mean change during this time period for Hb, indirect bilirubin, and percentage reticulocyte count were ‑0.08g/dL, ‑3.16%, and 4.54%, respectively. 

The most common adverse reactions (>10%) to voxelotor are headache, diarrhoea, abdominal pain, nausea, rash, fatigue and pyrexia. Product information includes a warning for hypersensitivity and potential laboratory interference. Voxelotor may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by high performance liquid chromatography.

The recommended voxelotor dose is 1,500 mg orally once daily with or without food.

Full prescribing information for OXBRYTA is available here.

This indication is approved under accelerated approval based on increase in haemoglobin. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). FDA granted this application priority review, fast track, and Breakthrough Therapy designation.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA Oncology Center of Excellence’s Project Facilitate.

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