FDA Drug Approvals — 2021 Midyear Review 

August 20, 2021


Evkeeza (evinacumab)

Evinacumab is a recombinant human monoclonal antibody that binds to and inhibits angiopoietin–like 3 (ANGPTL3). ANGPTL3 inhibits lipoprotein lipase and endothelial lipase, thereby reducing lipid metabolism. Evinacumab inhibits ANGPTL3 and results in increased lipid metabolism, leading to decreased low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Evinacumab is indicated as an adjunct to other LDL-C–lowering therapies for homozygous familial hypercholesterolemia in adults and adolescents aged 12 years and older.

Approval was based on the phase 3 ELIPSE trial (n = 65). The study found that patients undergoing stable lipid-lowering treatment in whom an intravenous infusion of evinacumab was administered every 4 weeks achieved, by week 24, a 47.1% relative reduction in their LDL-C level compared with a 1.9% increase seen in patients treated with a placebo (P <.001). N Engl J Med. 2020;383:711-720

Verquvo (vericiguat)

Vericiguat stimulates soluble guanylate-cyclase (sGC), the intracellular receptor for endogenous nitric oxide (NO), which catalyzes cyclic guanosine monophosphate (cGMP) production; cGMP plays a role in the regulation of vascular tone, cardiac contractility, and cardiac remodeling. By directly stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cGMP, leading to smooth muscle relaxation and vasodilation. Vericiguat is indicated to reduce risk of cardiovascular death and heart failure (HF) hospitalization, following a hospitalization for HF or need for outpatient intravenous diuretics, in adults with symptomatic chronic HF and ejection fraction less than 45%.

Results from the phase 3 VICTORIA trial (n = 5050) study showed that in patients with symptomatic chronic HF (New York Heart Association class II-IV) and left ventricular ejection fraction of less than 45%, vericiguat was superior to placebo in reducing the risk of cardiovascular death or heart failure hospitalization. These results were based on a time-to-event analysis (hazard ratio, 0.9; 95% confidence interval, 0.82-0.98; P = .02) and demonstrated an adverse event profile similar to placebo. N Engl J Med. 2020; 382:1883-1893

Other cardiology approvals

Praluent (alirocumab) - Indicated as an adjunct to other low-density lipoprotein cholesterol (LDL-C)–lowering therapies in adults with homozygous familial hypercholesterolemia to reduce LDL-C.

Entresto (sacubitril/valsartan) - Indication for heart failure expanded to include adults with preserved left ventricular ejection fraction.

Arcalyst (rilonacept) - Interleukin-1 inhibitor for treatment of recurrent pericarditis and to reduce risk of future recurrence in adults and children aged 12 years and older.

Roszet (rosuvastatin/ezetimibe) - New combination indicated to reduce low-density lipoprotein cholesterol in patients with primary nonfamilial hyperlipidemia or homozygous familial hypercholesterolemia.


Ponvory (ponesimod)

Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator that binds with high affinity to S1P receptor 1 and blocks the capacity of lymphocytes to regress from lymph nodes, reducing number of lymphocytes in peripheral blood. Ponesimod is indicated for relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Approval for ponesimod was based on a head-to-head phase 3 trial (n = 1133). In that trial, ponesimod demonstrated superior efficacy in significantly reducing annual relapse by 30.5% compared with teriflunomide in patients with relapsing MS. Over the study period, 71% of patients treated with ponesimod had no confirmed relapses, compared with 61% in the teriflunomide group. JAMA Neurol. 2021 May 1;78(5):558-567

Amondys 45 (casimersen)

Casimersen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMO binds to exon 45 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. Casimersen is indicated for Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 45 skipping.

The ESSENCE trial—a placebo-controlled confirmatory trial to support the casimersen approval—is ongoing and expected to conclude in 2024. In the study, patients who received casimersen showed a significantly greater increase in dystrophin protein levels from baseline to week 48 of treatment compared with those who received placebo. Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE)

Aduhelm (aducanumab)

Aducanumab is a monoclonal antibody that targets beta-amyloid and binds to aggregated forms of beta-amyloid. The FDA granted accelerated approval for aducanumab based on the reduction in amyloid-beta plaques observed in patients treated for Alzheimer disease. The prescribing information specifies approval for patients with mild cognitive impairment or a mild dementia stage of disease, the population studied in the clinical trials. The prescribing information states that continued approval is contingent upon verification of clinical benefit in confirmatory trial(s).

Accelerated approval was based on 2 phase 3 trials. In a letter released by the FDA, the rationale for approval was explained. One of the clinical trials (EMERGE) was the first to show that high-dose aducanumab reduced amyloid-beta plaques—a hallmark finding in the brain of patients with Alzheimer disease—and slowed cognitive decline. The second trial (ENGAGE) showed no benefit of aducanumab versus placebo, at low or high doses. Debate continues regarding this approval. The materials for the FDA Peripheral and Central Nervous System Drugs Advisory Committee Meeting provide detailed analyses of these phase 3 trials.

Nulibry (fosdenopterin)

Fosdenopterin is indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency type A (MoCD-A), a rare disease. Fosdenopterin provides an exogenous source of cyclic pyranopterin monophosphate (cPMP). MoCD-A is caused by a mutation in the molybdenum cofactor synthesis 1 gene (MOCS1), which causes a deficiency in molybdenum cofactor production. The exogenous intermediate substrate cPMP provided by the drug is subsequently converted to molybdenum cofactor, which is required for the activation of essential enzymes (eg, sulfite oxidase) to reduce the levels of neurotoxic sulfites. Decreased sulfite oxidase activity is thought to cause the severe and rapidly progressive CNS damage observed in patients with MoCD-A.

Other neurology approvals

Gocovri (amantadine) - Gained FDA approval as adjunctive treatment to levodopa/carbidopa for Parkinson disease in patients experiencing "off" episodes.

Nurtec ODT (rimegepant) - Indication for migraine expanded to include preventive therapy. Originally approved for acute treatment.

Infectious Disease

Cabenuva (cabotegravir/rilpivirine) and Vocabria (cabotegravir)

Cabotegravir/rilpivirine is a combination of HIV-1 integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI), which are copackaged as 2 separate intramuscular (IM) injections. Cabotegravir/rilpivirine is indicated as a complete regimen for treatment of HIV-1 infection in adults to replace a current stable antiretroviral therapy regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. It is initiated as a once-monthly IM injection following lead-in therapy with oral cabotegravir (Vocabria) plus rilpivirine (Edurant) for a least 1 month.

The safety and efficacy of cabotegravir/rilpivirine were established through 2 randomized, open-label, controlled clinical trials in 1182 HIV-infected adults who were virologically suppressed (HIV-1 RNA <50 copies/mL) before initiation of the treatment. Patients in both trials continued to show virologic suppression at the conclusion of each study, and no clinically relevant change from baseline in CD4+ cell counts was observed. N Engl J Med. 2020 Mar 19;382(12):1112-1123; N Engl J Med. 2020 Mar 19;382(12):1124-1135

Tembexa (brincidofovir)

Brincidofovir is a prodrug of cidofovir. Brincidofovir effectively penetrates cells via its lipid conjugate, releasing the nucleotide analog cidofovir, which then acts to inhibit viral replication. Cidofovir diphosphate selectively inhibits orthopoxvirus DNA polymerase–mediated viral DNA synthesis by incorporation of cidofovir into the growing viral DNA chain. This results in reductions in the rate of viral DNA synthesis. It is indicated for treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates.

The drug gained approval under the FDA's animal rule. Approval was based on efficacy data in 2 lethal orthopoxvirus animal models of human smallpox disease, the rabbit pox model (New Zealand white rabbits infected with rabbit pox virus) and the mouse pox model (BALB/c mice infected with ectromelia virus). In the pivotal studies in each model, brincidofovir resulted in statistically significant survival benefit versus placebo following delayed treatment after animals were infected with a lethal viral dose. Tembexa prescribing information

Infectious disease emergency use authorizations (EUAs)


Sotrovimab was granted an EUA for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients aged 12 years or 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 progression to severe COVID-19, including hospitalization or death.

The phase 3 trial COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial – Intent to Care Early) demonstrated that sotrovimab significantly reduced the risk of hospitalization or death by 79% at day 29 among 1057 high-risk outpatients (P <.001). Day 29 analysis from COMET-ICE clinical trial

Etesevimab (plus bamlanivimab)

Etesevimab was issued an EUA for use in combination with bamlanivimab for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 12 years and older weighing at least 40 kg. Treatment is dependent on positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing in patients who are at high risk for progressing to severe COVID-19 and/or hospitalization.

NOTE: Owing to the increase in variants of concern (VOCs) in the United States, monoclonal antibodies that have gained EAU have been tested to evaluate activity against VOCs. As of March 24, 2021, US distribution ceased for bamlanivimab alone. On June 25, 2021, US distribution ceased for bamlanivimab plus etesevimab as the P.1/Gamma and B.1.351/Beta variants (first identified in Brazil and South Africa) exceeded 11% of cases throughout the United States. Consider use of casirivimab plus imdevimab or sotrovimab in outpatients who qualify for monoclonal antibodies.

In this arm of the phase 3 BLAZE-1 trial, the change in log viral load from baseline at day 11 was -3.72 for bamlanivimab 700 mg, -4.08 for bamlanivimab 2800 mg, -3.49 for bamlanivimab 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Among nonhospitalized patients with mild-to-moderate COVID-19 illness, treatment with bamlanivimab plus etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; however, no significant difference in viral load reduction was observed for bamlanivimab monotherapy. No difference in hospitalization rate was observed between bamlanivimab monotherapy or with the combination. Based on an analysis of available data, the authorized dosage regimen of the combination is bamlanivimab 700 mg plus etesevimab 1400 mg administered together as a single intravenous infusion.This regimen is expected to have similar clinical effects as the 2800-mg dosages evaluated in the study. JAMA. 2021;325(7):632-644

Ad26.COV2.S vaccine

Ad26.COV2.S vaccine was issued an 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 18 years or older.

This decision was based on the totality of scientific evidence, including data from the phase 3 ENSEMBLE study, which demonstrated that the vaccine was 85% effective in preventing severe disease across all regions studied and showed protection against COVID-19–related hospitalization and death, beginning 28 days after vaccination. N Engl J Med. 2021 Apr 21

Other infectious disease approvals

Natroba (spinosad) - New indication approved for scabies in adults and children aged 4 years and older.

Vaxchora (cholera vaccine) - Use for immunization against Vibrio cholera serogroup 01 expanded to include children aged 2 years and older.

Rapivab (peramivir) - Indication for acute uncomplicated influenza expanded to include children as young as 6 months.

BNT-162b2 (COVID-19 vaccine, mRNA-Pfizer) - Emergency use authorization for prevention of SARS-CoV-2 infection expanded to include adolescents aged 12 years and older.


Lybalvi (olanzapine/samidorphan)

Olanzapine/samidorphan is indicated for treatment of schizophrenia in adults. It is also approved for bipolar I disorder as monotherapy or as an adjunct to lithium or valproate. Olanzapine acts through a combination of dopamine and serotonin type 2 antagonism. Samidorphan is an opioid antagonist and mitigates weight gain associated with olanzapine.

Approval was based on the ENLIGHTEN clinical trials. Olanzapine is associated with metabolic changes, including hyperglycemia, dyslipidemia, and weight gain. The ENLIGHTEN trials showed the combination provided sustained antipsychotic efficacy with minimal effects on weight, waist circumference, and metabolic parameters. Am J Psychiatry. 2020 Dec 1;177(12):1168-1178

Azstarys (serdexmethylphenidate/dexmethylphenidate)

Serdexmethylphenidate/dexmethylphenidate is a fixed-dose combination of the prodrug of dexmethylphenidate, serdexmethylphenidate, and immediate-release dexmethylphenidate. This combination provides extended drug levels. It is indicated for attention deficit hyperactivity disorder in adults and children aged 6 years and older. Efficacy was assessed by Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)–combined scores compared with baseline and at 0.5, 1, 2, 4, 8, 10, 12, and 13 hours post dose. Results showed statistically significant improvement of SKAMP-combined scores compared with placebo. Azstarys prescribing information

Qelbree (viloxazine)

Viloxazine is indicated for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents aged 6-17 years. The mechanism of action by which viloxazine affects ADHD is unclear; however, it may be by selectively inhibiting norepinephrine reuptake. Approval was based on 3 phase-3 placebo-controlled trials that included over 1000 participants. Patients taking viloxazine had statistically significant improvement in ADHD Rating Scale 5 and Clinical Global Impressions I scores compared with placebo. Qelbree prescribing information

Other psychiatry approval

Kloxxado (naloxone intranasal) - New formulation that delivers 8 mg per actuation, compared with older products that deliver 2 mg or 4 mg per actuation.


Zegalogue (dasiglucagon)

Dasiglucagon is a ready-to-use, stable glucagon analog indicated for severe hypoglycemia in pediatric and adult patients with diabetes. It is a glucagon receptor agonist that increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver.

Other endocrinology approval

Wegovy (semaglutide) - New distinct brand and indication as an adjunct to a reduced-calorie diet and increased physical activity for long-term weight management in adults who are obese (body mass index [BMI] ≥30 kg/m2) or overweight (BMI 27 kg/m2) with at least 1 weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, dyslipidemia).

Nephrology and Urology

Lupkynis (voclosporin)

Voclosporin is an oral calcineurin inhibitor indicated in combination with a background immunosuppressive regimen for treatment of active lupus nephritis in adults.

The AURA-LV phase 3 trial randomized patients to placebo or an induction regimen that combined voclosporin with mycophenolate mofetil and low-dose oral corticosteroids. At 24 weeks, 32.6% of the low-dose voclosporin group achieved complete renal response (CRR) and 27.3% in the high-dose voclosporin group, compared with 19.3% in the placebo group. CRR rate in the low-dose and high-dose voclosporin groups was also higher than with placebo at 48 weeks. Kidney Int. Jan;95(1):219-231

The AURORA phase 3 trial compared the efficacy and safety of voclosporin (23.7 mg twice daily) with placebo in combination with mycophenolate and low-dose oral corticosteroids. At 1 year, the renal response rate was higher in the voclosporin group compared with placebo (40.8% vs 22.5%; odds ratio, 2.65; P <.001). In addition, the median time to the achievement of a urine protein-to-creatinine ratio below 0.5 mg/mg showed significant clinical improvement with voclosporin compared with placebo (169 vs 372 days; P <.001). Lancet. 2021 May 29;397(10289):2070-2080

Other nephrology and urology approvals

Farxiga (dapagliflozin) - Indication approved to reduce risk of sustained estimated glomerular filtration rate decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease who are at risk of progression.

Myrbetriq (mirabegron) - FDA approval gained for neurogenic detrusor overactivity in children aged 3 years and older.

Botox (onabotulinumtoxinA) - New indication approved for neurogenic detrusor overactivity in children aged 5 years and older who have an inadequate response to or are intolerant of anticholinergic medications.

Additional Approvals

Additional approvals across specialties

Anavip (Crotalidae immune FAB equine) - Indication for treatment of snake envenomation expanded to include additional North American pit vipers.

Nplate (romiplostim) - New indication for treatment of adults and pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation.

Humira (adalimumab) - Indication for treatment of moderately to severely active ulcerative colitis to include children 5 years of age and older.

Zeposia (ozanimod) - New indication approved for adults with moderately to severely active ulcerative colitis.

Tyvaso (treprostinil inhaled) - New indication granted for treatment of adults with pulmonary hypertension associated with interstitial lung disease (World Health Organization Group 3) to improve exercise ability.

Actemra (tocilizumab) - New indication approved for adults to slow the rate of decline in pulmonary function in adults with systemic sclerosis–associated interstitial lung disease.

Carbaglu (carglumic acid) - Approval granted for adjunctive therapy to standard of care for acute hyperammonemia due to propionic acidemia or methylmalonic acidemia in adults and children.


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