FDA Approvals, Highlights, and Summaries: Pediatrics

February 27, 2020

Adakveo (crizanlizumab)

Crizanlizumab, a P-selectin inhibitor, was approved by the FDA to reduce frequency of vasoocclusive crisis (VOC) in adults and adolescents aged 16 years or older with sickle cell disease. Binding P-selectin on the surface of activated endothelium and platelet cells blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes. Approval was based on the SUSTAIN clinical trial, which showed crizanlizumab reduced the median annual rate of VOCs leading to healthcare visits by 45.3% compared with placebo (1.63 vs 2.98, P=.010) in patients with or without hydroxyurea.

N Engl J Med. 2017 Feb 2;376(5):429-439

Am J Hematol. 2019 Jan;94(1):55-61

Oxbryta (voxelotor)

Voxelotor is the first drug approved by the FDA for sickle cell disease based solely on data showing an increase in hemoglobin (Hb). It is indicated for treatment of sickle cell disease in adults and adolescents aged 12 years or older. Voxelotor is an HbS polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells. By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization.

Approval of voxelotor was based on results from a clinical trial that enrolled 274 patients with sickle cell disease and treated them with either 1500 mg or 900 mg PO once daily of voxelotor or placebo. Results showed 51% of patients on the higher dose of voxelotor achieved an Hb response, defined as an increase in Hb of at least 1 g/dL after 24 weeks. Just over 6% of the placebo patients had the same Hb response. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group.

N Engl J Med. 2019 Aug 8;381(6):509-519

Trikafta (elexacaftor/tezacaftor/ivacaftor)

Elexacaftor/tezacaftor/ivacaftor is indicated for cystic fibrosis in adults and children aged 12 years or older who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population. Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared with either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. The product is a co-package of fixed-dose combination tablets containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg, plus ivacaftor 150-mg tablets.

Trikafta prescribing information

Rozyltrek (entrectinib)

Entrectinib is an inhibitor of tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). It is indicated for adults and children aged 12 years or older with solid tumors that have NTRK gene fusion without a known acquired resistance mutation. It is also indicated in adults for metastatic non–small cell lung cancer with tumors that are ROS1-positive.

Efficacy for NTRK-positive solid tumors was evaluated in a pooled subgroup of 54 patients with unresectable or metastatic solid tumors with an NTRK gene fusion enrolled in one of 3 multicenter, single-arm, open-label clinical trials (ALKA, STARTRK-1, STARTRK-2). Ninety-six percent of patients had metastatic disease, including 22% with CNS metastases, and 4% had locally advanced, unresectable disease. The overall response rate was 57%, and 45% had a duration of response of at least 12 months. Entrectinib penetrates the CNS. Among the 54 adult patients, 4 had measurable CNS metastases at baseline as assessed by blinded independent central review and had not received radiation therapy to the brain within 2 months of study entry. Responses in intracranial lesions were observed in 3 of these 4 patients.

Rozyltrek prescribing information

Aklief (trifarotene)

Trifarotene is an agonist of retinoic acid receptors (RARs), with particular activity at the gamma subtype of RAR. The stimulation of RARs results in modulation of target genes that are associated with various processes, including cell differentiation and mediation of inflammation. The exact process by which trifarotene ameliorates acne is unknown. It is indicated for acne vulgaris for patients aged 9 years and older. Trifarotene is available as a cream.

Aklief prescribing information

Dengvaxia (dengue vaccine)

Dengue vaccine was approved by the FDA for individuals aged 9-16 years with laboratory-confirmed previous dengue infection and living in endemic areas. It elicits dengue-specific immune responses against the 4 dengue virus serotypes (ie, serotypes 1, 2, 3, and 4). It is only approved for individuals previously infected by any dengue virus serotype or for whom this information is unknown. Those not previously infected are at increased risk for severe dengue disease when vaccinated and subsequently infected with dengue virus.

The approval was based on data from 2 placebo-controlled studies in patients (n>35,000) living in dengue-endemic areas. Patients were randomized 2:1 to receive either the vaccine or saline placebo and monitored for symptomatic virologically confirmed dengue (VCD) starting at day 0. Vaccine efficacy was assessed beginning 28 days after the third vaccination for 12 months. The vaccine was approximately 76% effective in preventing symptomatic VCD disease among patients aged 9-16 years who were seropositive for dengue at baseline.

Dengvaxia prescribing information

Zolgensma (onasemnogene abeparvovec)

Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human survival motor neuron (SMN) protein. It is indicated for gene replacement therapy in children aged 2 years or younger with spinal muscular atrophy (SMA) type 1 (also called Werdnig-Hoffman disease) who have biallelic mutation in the survival motor neuron 1 (SNM1) gene.

Approval was based on the ongoing phase 3 STR1VE trial and the completed phase 1 START trial. Fifteen patients with SMA type 1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN-complementary DNA encoding the missing SMN protein. As of the data cutoff, all 15 patients were alive and event-free at age 20 months, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.

N Engl J Med. 2017 Nov 2;377(18):1713-1722

Interim data analysis from the ongoing phase 3 STR1VE trial described 21 (95%) of 22 patients were alive and event-free. The median age was 9.5 months, with 6 (86%) of 7 patients aged 0.5 months or older surviving event-free. Interim results also showed ongoing improvement of motor milestones (eg, holding head erect, rolling over, sitting without support).

Pediatr Pulmonol. 2019 Feb;54(2):179-185 and STR1VE interim data analysis

Additional 2019 Pediatrics approvals

Wilate (antihemophilic factor vWF complex) gained a new indication for routine prophylaxis or on-demand treatment of bleeding episodes in adults and adolescents with hemophilia A.

Crysvita (burosumab) indication for X-linked hypophosphatemia now includes children as young as 6 months.

Ravicti (glycerol phenylbutyrate) is a nitrogen-binding agent for long-term management of adults and children (including newborns) with urea cycle disorders.

GA 68 dotatoc gained approval for children in use with positron-emission tomography scans for localization of somatostatin receptor–positive neuroendocrine tumors.

Jakafi (ruxolitinib) gained approval for steroid-refractory acute graft versus host disease in patients aged 12 years or older.

Gattex (teduglutide) is now approved for children aged 1 year or older with short bowel syndrome.

Pediatric Rheumatology

Rituxan (rituximab) was approved for granulomatosis with polyangiitis and microscopic polyangiitis in children aged 2 years or older in combination with glucocorticoids.

Benlysta (belimumab) is the first drug approved for children aged 5 years or older with systemic lupus erythematosus.

Pediatric Cardiology

Entresto (sacubitril/valsartan) gained a new indication to treat symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged 1 year or older.

Lumason (sulfur hexafluoride) gained approval for children with suboptimal echocardiograms to opacify the left ventricular chamber and improve the delineation of the left ventricular endocardial border.

Livalo (pitavastatin) was approved for heterozygous familial hypercholesterolemia in children aged 8 years or older.

Corlanor (ivabradine) was approved for the treatment of children aged 6 months or older with stable symptomatic heart failure due to dilated cardiomyopathy who are in sinus rhythm with an elevated heart rate.

Fragmin (dalteparin) was approved for the treatment of symptomatic venous thromboembolism to decrease recurrence in children aged 1 month or older.

Conjupri (levamlodipine) is the pharmacologically active S-enantiomer of amlodipine and is indicated for hypertension in adults and children aged 6 years or older.

Pediatric Infectious Disease

Mycamine (micafungin) is approved for candidemia, acute disseminated candidiasis, candidal peritonitis, and abscesses without meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months.

Avycaz (ceftazidime/avibactam) was approved for complicated urinary tract infections, including pyelonephritis, in patients aged 3 months or older.

Acyclovir dosing information from the National Institutes of Health lends clarity for newborns and premature infants with herpes simplex virus infection caused by adult genital herpes following vaginal delivery.

Biktarvy (bictegravir/emtricitabine/tenofovir AF) was approved for children with HIV type 1 infection who weigh at least 25 kg.

Tybost (cobicistat) is indicated to increase systemic exposure of atazanavir in combination with other antiretroviral agents for HIV type 1–infected pediatric patients weighing at least 35 kg.

Sirturo (bedaquiline) was approved for multidrug-resistant pulmonary tuberculosis in children aged 12 years or older.

Sovaldi (sofosbuvir) is indicated for chronic hepatitis C virus infection as a component of a combination antiviral regimen in children aged 3 years or older.

Harvoni (ledipasvir/sofosbuvir) is indicated for hepatitis C virus infection as a component of a combination antiviral regimen in children aged 3 years or older.

Mavyret (glecaprevir/pibrentasvir) was approved for adolescents to treat hepatitis C viral infection.

Pediatric Pulmonology

Asmanex HFA (mometasone inhaled) is indicated for maintenance treatment of asthma in children aged 5 years or older.

Dulera (mometasone/formoterol inhaled) is indicated for asthma in children aged 5 years or older who are not adequately controlled on a long-term asthma-control medication (eg, inhaled corticosteroid [ICS]) or whose disease warrants initiation of treatment with both an ICS and long-acting beta2-adrenergic agonist.

Nucala (mepolizumab) is indicated as add-on maintenance treatment in patients aged 6 years or older with severe eosinophilic phenotype asthma.

Symdeko (tezacaftor/ivacaftor) has a new lower dosage form and an expanded indication for children with cystic fibrosis aged 6 years or older.

Kalydeco (ivacaftor) was approved for cystic fibrosis in children as young as 6 months.

Pediatric Endocrinology

Baqsimi (glucagon intranasal) is indicated for severe hypoglycemia in adults and children aged 4 years or older who have diabetes.

Gvoke (glucagon) is a ready-to-use autoinjector approved for severe hypoglycemia in adults and children aged 2 years or older.

Toujeo (insulin glargine) gained approval in children aged 6 years or older with type 1 diabetes mellitus.

Victoza (liraglutide) was approved as an adjunct to diet and exercise to improve glycemic control in children aged 10 years or older with type 2 diabetes mellitus.

Pediatric Neurology

Ultomiris (ravulizumab) was approved for atypical hemolytic-uremic syndrome in adults and children aged 1 month or older.

Dysport (abobotulinumtoxinA) was approved for pediatric upper-limb spasticity (previously approved for lower-limb spasticity).

Botox (onabotulinumtoxinA) gained approval for pediatric lower- and upper-limb spasticity.

Ruzurgi (amifampridine) is a new brand with an approved indication for children as young as 6 years with Lambert-Eaton myasthenic syndrome.

Lyrica (pregabalin) indication for partial-onset seizures was expanded to include children as young as 1 month.

Nayzilam (midazolam intranasal) was approved in children aged 12 years or older for acute treatment of intermittent, stereotypic episodes of frequent seizure activity.

Emflaza (deflazacort) is indicated for the treatment of Duchenne muscular dystrophy in patients aged 2 years or older.

Pediatric Dermatology

Enstilar Foam, Taclonex Topical Suspension (calcipotriene/betamethasone) was approved for adolescents with plaque psoriasis.

Aczone (dapsone topical) was approved for treatment of acne vulgaris in children aged 9 years or older.

Amzeeq (minocycline topical) is the first topical minocycline product for treatment of acne vulgaris in adults and children aged 9 years or older.

Arazlo (tazarotene) lotion is approved for acne vulgaris in adults and children aged 9 years or older.

Dupixent (dupilumab) was approved for patients aged 12 years or older with moderate-to-severe atopic dermatitis.


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