Lonafarnib, an oral farnesyltransferase inhibitor, is indicated to reduce the risk of mortality in Hutchinson-Gilford progeria syndrome (HGPS). It was also approved for processing-deficient progeroid laminopathies with heterozygous LMNA mutation with progerinlinke protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations.
Farnesyltransferase is an enzyme involved in modification of proteins through a process called prenylation. Mutation in the LMNA gene causes over-production of progerin, a farnesylated-aberrant protein. Persistent farnesylation causes progerin accumulation in the inner nuclear membrane and is, at least partly, responsible for HGPS.
Accumulation of the defective lamin A protein makes the nucleus unstable, leading to the process of premature aging in children with progeria.
A multinational, observational study (n=258) showed treatment with lonafarnib monotherapy was associated with a lower mortality rate compared with no treatment after 2.2 years of follow-up. ( JAMA. April 24, 2018;319(16):1687-1695)
Setmelanotide is a melanocortin-4 receptor agonist. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. Setmelanotide is the first drug indicated for long-term weight management in patients aged at least 6 years with obesity due to rare genetic conditions (eg, proopiomelanocortin [POMC], proprotein convertase subtilisin/kexin type 1 [PCSK1], or leptin receptor [LEPR] deficiency).
Phase 3 clinical trials observed 80% of patients with obesity owing to POMC or PCSK1 deficiency achieved greater than 10% weight loss and 45.5% of patients with obesity due to LEPR deficiency achieved greater than 10% weight loss after 1 year of treatment. Additionally, hunger scores improved from baseline to 1 year. ( Lancet Diabetes Endocrinol. December 2020;8(12):960-970 and Imcivree prescribing information)
Triheptanoin is indicated as a source of calories and fatty acids for molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAODs) in adults and children. It is a medium-chain triglyceride consisting of 3 odd-chain 7-carbon length fatty acids (heptanoate) that provide a source of calories and fatty acids to bypass the LC-FAOD enzyme deficiencies for energy production and replacement.
For this rare disease, a small double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long–chain acylCoA dehydrogenase, trifunctional protein, or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) were randomly assigned a diet containing 20% of their total daily energy from either triheptanoin or trioctanoin. At 4 months, patients in the triheptanoin group increased left ventricular (LV) ejection fraction by 7.4% (P=.046) while experiencing a 20% (P=.041) decrease in LV wall mass on their resting ECG. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared with patients taking trioctanoin. ( J Inherit Metab Dis. November 2017;40(6):831-843)
Other notable pediatric endocrinology approval
Saxenda (liraglutide) - Indication for adjunctive use for long-term weight management expanded to include adolescents
Pediatric Infectious Diseases
Remdesivir is an antiviral agent that inhibits SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. It was the first drug approved by the FDA for treating the SARS-CoV-2 virus infection. It is indicated for adults and pediatric patients aged 12 years and older who weigh at least 40 kg for treatment of coronavirus disease 2019 (COVID-19) requiring hospitalization. An Emergency Use Authorization has also been issued for younger children.
Approval was based on data from the Adaptive COVID-19 Treatment Trial (ACTT). Final analysis included 1,062 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients treated with 10 days of remdesivir recovered faster than similar patients who received placebo. Results showed that patients who received remdesivir had a 31% faster time to recovery compared with those who received placebo (P <.001). Specifically, the median time to recovery was 10 days in patients treated with remdesivir compared with 15 days in those who received placebo (P <.001). Patients with severe disease (n=957) had a median time to recovery of 11 days compared with 18 days for placebo. A statistically significant difference was not reached for mortality by day 15 (remdesivir 6.7% vs placebo 11.9%) or by day 29 (remdesivir 11.4% vs placebo 15.2%). ( N Engl J Med. October 8, 2020)
Nifurtimox is an antiprotozoal agent that until recently, was available as an orphan drug in the United States for Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi. Approval for Chagas disease is specifically for children and adolescents younger than 18 years who weigh at least 2.5 kg.
Approval for nifurtimox was based on the number of treated patients who became IgG antibody negative or who showed an at least 20% decrease in optical density on two different IgG antibody tests against antigens of T cruzi. ( PLoS Negl Trop Dis. January 7, 2021)
Atoltivimab/maftivimab/odesivimab is a monoclonal combination that simultaneously binds to the glycoprotein on the Ebola virus surface and blocks attachment and entry of the virus on the host cell membranes. It is indicated for treatment of Zaire ebolavirus (Ebola virus) infection in adult and pediatric patients, including neonates born to mothers who are reverse-transcriptase polymerase chain reaction positive for Zaire ebolavirus infection.
Ansuvimab is a recombinant human IgG1 monoclonal antibody that binds to the glycoprotein on the Ebola virus surface and blocks attachment and entry of the virus on the host cell membranes. It is indicated for treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to mothers who are reverse-transcriptase polymerase chain reaction positive for Zaire ebolavirus infection.
Artesunate is an antimalarial artemisinin derivative. It is rapidly metabolized to the active metabolite, dihydroartemisinin (DHA). Artesunate and DHA, like other artemisinins, contain an endoperoxide bridge that is activated by heme iron that leads to oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes, and decreased parasite growth and survival. Artesunate and DHA are active against the blood-stage asexual parasites and gametocytes of Plasmodium species, including the chloroquine-resistant strains.
Artesunate is administered intravenously and is indicated for adults and children for initial treatment of severe malaria. It should always be followed by a complete treatment course of an appropriate oral antimalarial regimen.
Artesunate IV was officially approved by the FDA in May 2020 (it was previously available from the CDC through an Investigative New Drug protocol). Approval was based the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine Artesunate Malaria Trial (AQUAMAT). These 2 studies examined a total of 6886 patients and included adults, children, and pregnant women. Artesunate IV reduced mortality by 34.7% (P=.0002) and 22.5% (P=.002) compared with quinine in the SEAQUMAT and AQUAMAT studies, respectively. ( Lancet. August 27-Spetember 2, 2005;366(9487):717-25; Lancet. November 13, 2010;376(9753):1647-57)
Pediatric emergency use authorizations (EUAs) issued for COVID-19
COVID-19 vaccine, mRNA-Pfizer (BNT-162b2) - EUA for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals aged 16 years and older
Bamlanivimab - EUA issued for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 2 years and older who weigh at least 40 kg with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization
Casirivimab/imdevimab - EUA issued for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 2 years and older who weigh at least 40 kg with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization
Baricitinib - EUA for use, in combination with remdesivir, for treatment of suspected or laboratory-confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation
Veklury (remdesivir) - EUA issued for antiviral treatment of coronavirus disease 2019 (COVID-19) in hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg
Other notable pediatric infectious disease approvals
Eraxis (anidulafungin) - Indication expanded to include children as young as 1 month for treatment of candidemia and other forms of candidal infections (intra-abdominal abscess and peritonitis)
Xofluza (baloxavir marboxil) - New indication approved for postexposure prophylaxis in persons aged 12 years and older following contact with an individual who has influenza; additionally, an oral suspension has been approved
Selzentry (maraviroc) - Indication expanded for treatment of only CCR5-tropic HIV infection to include patients weighing at least 2 kg
Prezcobix (darunavir/cobicistat) - Indication for treatment of HIV infection expanded to include patients weighing at least 40 kg
Evotaz (atazanavir/cobicistat) - Indication for treatment of HIV infection expanded to include patients weighing at least 35 kg
Sivextro (tedizolid) - Indicated for acute bacterial skin and skin structure infections in patients aged 12 years or older
Tivicay PD (dolutegravir) - Indicated for HIV infection in children aged 4 weeks or older who weigh at least 3 kg
Zosyn (piperacillin/tazobactam) - Indication for nosocomial pneumonia expanded to include children as young as 2 months
Epclusa (sofosbuvir/velpatasvir) - Indicated for chronic hepatitis C virus infection in children aged 6 years or older or weighing at least 17 kg
Sirturo (bedaquiline) - Indication for multidrug-resistant pulmonary tuberculosis expanded to include children aged 5 years or older
Veklury (remdesivir) - FDA granted an emergency use authorization for remdesivir to treat hospitalized patients with suspected or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe coronavirus disease 2019 (COVID-19)
Pralsetinib is another kinase inhibitor of rearranged during transfection (RET) alterations and mutations. Some RET fusion proteins can drive tumorigenic potential, which leads to uncontrolled cell proliferation. Pralsetinib has also exhibited antitumor activity. Pralsetinib is indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET-fusion–positive thyroid cancers in adults and children aged 12 years or older.
The initial approval for NSCLC was based the ARROW study, a nonrandomized, open-label phase 1/2 study (n=114). The study separated patients into separate cohorts, patients with metastatic RET-fusion–positive NSCLC who had progressed on platinum-based chemotherapy (n=87) and treatment-naïve patients with metastatic NSCLC (n=27). The overall response rate for patients who had progressed on platinum-based chemotherapy was 57%, with 5.2% of patients having a complete response and 52% having a partial response. The overall response rate for treatment-naïve patients was 70%, with 11% of patients having a complete response and 59% having a partial response. ( J Clin Oncol. May 20, 2020;38(15 suppl):9515-9515)
Naxitamab is indicated for relapsed or refractory high-risk neuroblastoma in the bone or bone marrow, in patients aged 1 year and older who have demonstrated a partial response, minor response, or stable disease with prior therapy. It is a humanized anti-GD2 3F8 monoclonal antibody that stimulates antibody-dependent cell-mediated cytotoxicity against GD2-expressing tumor cells.
Approval was based on two trials in combination with granulocyte-macrophage colony-stimulating factor. Among 22 patients treated in the multicenter Study 201, the overall response rate (ORR) was 45% and 30% of responders had a duration of response (DOR) of at least 6 months. Among 38 patients treated in the single-center Study 12-230, the ORR was 34% with 23% of patients having a DOR of at least 6 months. Both trials observed responses in bone, bone marrow, or both. (FDA grants accelerated approval to naxitamab)
Selpercatinib is a kinase inhibitor of wild-type rearranged during transfection (RET) and multiple mutated RET isoforms, as well as vascular endothelial growth factor receptors (VEGFR1, VEGFR3). Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. Selpercatinib is indicated for metastatic RET fusion-positive non–small cell lung cancer (NSCLC) in adults. It is also indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in adults and children aged 12 years or older who required systemic therapy.
In the open-label LIBRETTO-001 phase 1/2 clinical trial (n=144) for adults with NSCLC, the overall response rate was 64% in treatment-experienced patients (n=105) and 85% in treatment-naïve patients (n=39). Results for patients with MTC (n=143) showed the overall response rate was 69% in cabozantinib/vandetanib treatment-experienced patients (n=55) and 73% in treatment-naïve patients (n=88). (Retevmo prescribing information)
Tazemetostat is an enhancer of zeste homolog 2 (EZH2) inhibitor. Uncontrolled EZH2 enzyme activity results in poorly regulated genes that control cancer cell proliferation. Tazemetostat is indicated for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection in adults and adolescents aged 16 years or older. It is also indicated for adults with relapsed or refractory follicular lymphoma in patients whose tumors are positive for EZH2 mutation and who have received at least 2 prior systemic therapies, or those who have no satisfactory treatment options.
Approval for epithelioid sarcoma was based on a phase 2 trial (n=62). The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the 9 patients who had a response, 6 (67%) patients had a response lasting 6 months or longer. Approval for follicular lymphoma was based on a phase 2 study. In the 53 patients treated with at least 2 prior systemic therapies, the overall response rate was 34% (4% complete response, 30% partial response). The median duration of response was 13 months. Tazverik prescribing information
Other notable pediatric oncology approvals
Nucala (mepolizumab) - Indicated for adults and pediatric patients aged 12 years and older with hypereosinophilic syndrome with a duration of 6 months without an identifiable nonhematologic secondary cause
Opdivo (nivolumab) - Indicated as a single agent or in combination with ipilimumab for patients aged 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
ProHance (gadoteridol) - Now approved for MRI use in newborns and toddlers to visualize lesions with disrupted blood-brain barrier and/or abnormal vascularity of intracranial lesions, spine, and associated tissues
Crysvita (burosumab) - Indicated for FGF23-related hypophosphatemia in tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors
Mylotarg (gemtuzumab) - Indication for newly-diagnosed CD33+ acute myeloid leukemia expanded to include pediatric patients aged 1 month or older
Gardasil 9 (human papillomavirus vaccine nonavalent) - Indication now includes prevention of head and neck cancers
Risdiplam is a mRNA-splicing modifier of survival of motor neuron 2 (SMN2) designed to treat mutations in band 5q that lead to SMN protein deficiency. It is indicated for treatment of spinal muscular atrophy (SMA), including types 1, 2, and 3, in adults and children aged 2 months and older.
FIREFISH was an open-label, 2-part pivotal clinical trial in infants aged 2-7 months with type 1 SMA. Results showed 7 (41%) of 17 infants achieved the ability to sit without support for at least 5 seconds and 19 (90%) of 21 were alive without permanent ventilation at 12 months. After a minimum of 23 months of treatment and reaching age 28 months or older, 17 (81%) of 21 were alive without permanent ventilation. ( Neurology. April 14, 2020;94(15 suppl))
The SUNFISH study was a 2-part, double-blind, placebo-controlled pivotal clinical trial in children and young adults (aged 2-25 years) with type 2 or 3 SMA. A clinically meaningful and statistically significant improvement in motor function among children and adults was observed as measured by a change from baseline in the Motor Function Measure 32 (MFM-32) total score. Improved upper limb motor function compared with baseline, as measured by the Revised Upper Limb Module (RULM), a secondary independent motor function endpoint of the study, also showed statistically significant improvement. (Evrysdi prescribing information)
Viltolarsen is indicated for Duchenne muscular dystrophy (DMD) in adults and children with a confirmed DMD gene mutation that is amenable to exon 53 skipping. It is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. Viltolarsen binds to exon 53 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein. The underlying cause of DMD is a mutation or error in the gene for dystrophin, an essential protein involved in muscle fiber function.
Results were from the phase 2, two-period study in patients aged 4 to less than 10 years conducted in North America (N=16) and a multicenter, open-label study in boys aged 5 to less than 18 years conducted in Japan (N=16). In the North American study, of those patients who received the recommended dose of 80 mg/kg/wk (N=8), 100% of patients showed an increase in dystrophin levels after treatment. (Viltepso prescribing information)
Selumetinib is an inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2). MEK 1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Inhibition of ERK phosphorylation is thought to reduce neurofibroma numbers, volume, and proliferation. Selumetinib is indicated for neurofibromatosis type 1 (NF1) in pediatric patients aged 2 years or older who have symptomatic, inoperable plexiform neurofibroma.
FDA approval was based on results from the phase 2 SPRINT Stratum 1 trial, in which 50 patients with NF1 received selumetinib as twice-daily oral monotherapy. Of this group, 33 (66%) patients had a partial response of at least a 20% reduction in tumor volume. ( N Engl J Med. April 9, 2020;381(15):1430-1442)
Other notable pediatric neurology approvals
Epidiolex (cannabidiol) - Indicated for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients aged 1 year and older
Xeomin (incobotulinumtoxinA) - Indication for spasticity expanded to include upper limb spasticity (except cerebral palsy) in children aged 2-17 years
Vimpat (lacosamide) - New indication for adjunctive therapy of primary generalized tonic-clonic seizures in patients aged 4 years and older
Fintepla (fenfluramine) - Reintroduced to US market with new indication for seizures associated with Dravet syndrome in patients aged 2 years or older
Cymbalta (duloxetine) - Indication for fibromyalgia now includes adolescents aged 13-17 years
VESIcare LS (solifenacin) - New liquid formulation approved for neurogenic detrusor over-activity in children aged 2 years or older
Abametapir, a metalloproteinase inhibitor and topical pediculicide, is indicated for head lice infestation in adults and children aged 6 months and older.
Approval was supported in part by a double-blind, phase 2 trial in 50 patients with active head lice infestation who were randomized to receive a single treatment of abametapir lotion or vehicle (control) applied to scalp and hair for 10 minutes. Ovicidal efficacy was measured by recording the hatch rate of eggs collected from each subject’s hair before and after treatment and incubated for 14 days. With abametapir, 100% of treated eggs remained unhatched, compared with 64% for vehicle. Accounting for pretreatment hatch rates, the absolute reduction in egg hatching was 92.9% for abametapir versus 42.3% for vehicle (P <.0001). ( Glob Pediatr Health. February 22, 2019;6)
Two studies (n=704) showed that 81.5% of abametapir-treated individuals were free of lice 2 weeks after a single application, compared with 49.1% treated with vehicle (P <.001). ( Pediatr Dermatol. 2018;35(5):616-621)
Winlevi (clascoterone topical)
Clascoterone topical is an androgen-receptor inhibitor indicated for acne vulgaris in patients aged 12 years and older. The exact mechanism of action by which it clascoterone is effective for acne is unknown. Laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles.
Approval of clascoterone topical was supported by 2 phase 3 randomized trials including 1,440 patients. At week 12, treatment success rates showed statistically significant improvement for patients receiving clascoterone (18.4% and 20.3%) compared with the vehicle alone (9% and 6.5%). ( JAMA Dermatol, June 1, 2020;165(6):621-30)
Other notable pediatric dermatology approvals
Vectical (calcitriol topical) - Indication for plaque psoriasis expanded to include children aged 2 years and older (previously approved for adults)
Stelara (ustekinumab) - Indication for plaque psoriasis expanded to include children aged 6 years and older (previously approved for aged ≥12 years)
Ultravate lotion (halobetasol topical) - Indication expanded to include adolescents aged 12 years and older
Dupixent (dupilumab) - Indicated for moderate-to-severe atopic dermatitis not adequately controlled with topical prescription therapies or when those therapies are not advisable in children aged 6 years or older
Jublia (efinaconazole) - Indication for onychomycosis expanded to include children as young as 6 years
Taltz (ixekizumab) - Indication for plaque psoriasis expanded to include children aged 6 years or older
Eucrisa (crisaborole topical) - Indicated for mild-to-moderate atopic dermatitis in infants and children aged 3 months or older
Berotralstat is the first oral kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients aged 12 years and older. Kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE caused by C1-inhibitor deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks.
The APeX-2 phase 3 trial demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P=.024) and 150 mg (1.31 attacks per month; P <.001) compared with placebo (2.35 attacks per month). ( J Allergy Clin Immunol. October 21, 2020;S0091-6749)
Arcalyst (rilonacept) - New indication for maintenance of remission of deficiency of interleukin-1 receptor antagonist (DIRA) in adults and pediatric patients weighing at least 10 kg
Other notable pediatric approvals
Lumasiran is a small interfering ribonucleic acid (RNAi) agent that reduces levels of glycolate oxidase (GO) enzyme by targeting hydroxyacid oxidase 1 mRNA in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. It is the first drug approved by the FDA for primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels.
Approval was based on the ILLUMINATE-A and ILLUMINATE-B phase 3 trials. The randomized, placebo-controlled ILLUMINATE-A trial (n=39; ages 6-61 years) demonstrated a 65% reduction of 24-hour urinary oxalate levels in the lumasiran-treated group, compared with an average of 12% reduction in the placebo group. By month 6 of the study, 52% of the lumasiran-treated group reached a normal 24-hour urinary oxalate level, compared with no patients in the placebo group. ILLUMINATE-B, which was an open-label study of lumasiran treatment in 16 patients with PH1 younger than 6 years, showed an average 71% decrease in urinary oxalate by 6 months. (Oxlumo prescribing information)
Xeljanz (tofacitinib) - Active polyarticular course juvenile idiopathic arthritis for children aged 2 years and older
Simponi Aria (golimumab) - New indication for polyarticular course juvenile idiopathic arthritis in children aged 2 years and older; additionally, indication for psoriatic arthritis extended to include patients aged 2 years and older
Suprep (sodium sulfate/potassium sulfate/magnesium sulfate) - Indication for colonoscopy bowel preparation expanded to include children aged 12 years and older
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Cite this: FDA Approvals, Highlights, and Summaries: Pediatrics - Medscape - Feb 24, 2021.