Ganaxolone is a GABAA receptor–positive modulator. It binds specifically to GABAA receptors to enhance their inhibitory effects. It is indicated for seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2 years and older. CDD, a rare developmental epileptic encephalopathy, is largely a disease of pediatric and young adult patients.
Approval was based on the phase 3 MARIGOLD trial. Patients treated with ganaxolone (n = 49) showed a median 30.7% reduction in 28-day major motor seizure frequency, compared to a 6.9% reduction for those receiving placebo (n = 51) (P=0.0036). In the open-label extension study, patients treated with ganaxolone for at least 12 months (n = 48) experienced a median 49.6% reduction in major motor seizure frequency. Prescribing Information
Other neurology approvals
Adlarity (donepezil transdermal) – New transdermal patch indicated for treatment of mild, moderate, and severe Alzheimer dementia; originally approved as tablet and oral disintegrating tablet.
Hyftor (sirolimus topical) – New dosage form indicated for treatment of facial angiofibroma associated with tuberous sclerosis in patients aged 6 years and older.
Fintepla (fenfluramine) – New indication for seizures associated with Lennox-Gastaut syndrome (previously approved for seizures associated with Dravet syndrome) in patients aged 2 years and older.
Ultomiris (ravulizumab) – C5 complement inhibitor; new indication for generalized myasthenia gravis.
Radicava ORS (edaravone) – New oral suspension dosage form for adults with ALS.
Daridorexant is a dual orexin receptor antagonist. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. Daridorexant is indicated for adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
Approval was based on two phase 3 multicenter, randomized, double-blind, placebo-controlled trials. Participants were randomized 1:1:1 to receive daridorexant 50 mg, daridorexant 25 mg, or placebo (study 1; n = 930), or daridorexant 25 mg, daridorexant 10 mg, or placebo (study 2; n = 307) every evening for 3 months. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. In study 1, the daridorexant 25-mg and 50-mg doses showed a statistically significant improvement in all endpoints, compared to placebo, at both month 1 and month 3 (P<0.0001). In study 2, the daridorexant 25-mg dose showed statistically significant improvement in WASO at month 1 (P=0.0001) and month 3 (P=0.0028) compared to placebo. Lancet Neurol. 2022 Feb;21(2):125-139
Other psychiatry approvals
Xelstrym (dextroamphetamine transdermal) – New transdermal patch indicated for treatment of attention deficit hyperactivity disorder (ADHD) in adults and children aged 6 years and older.
Nalmefene – Opioid antagonist reintroduced to US market for management of known or suspected opioid overdose.
Qelbree (viloxazine) – Indication for ADHD expanded to include adults.
Igalmi (dexmedetomidine) – New buccal dosage form and indication for acute treatment of agitation associated with schizophrenia or bipolar I or II disorder.
Zulresso (brexanolone) – Indication for postpartum depression expanded to include adolescents aged 15 years and older.
COVID-19 vaccine, adjuvanted (Novavax)
Emergency use authorization was granted for COVID-19 vaccine, adjuvanted for prevention of COVID-19 infection in adults. It is a more traditionally manufactured vaccine that contains a purified full-length protein subunit (rS). An immune response to the rS protein is elicited, which protects against COVID-19. It also contains an adjuvant (ie, saponin-based Matrix-MTM) to enhance immune response and stimulate high levels of neutralizing antibodies.
Approval was based on the PREVENT-19 phase 3 clinical trial in the United States and Mexico, which demonstrated overall efficacy of 90.4% (P<0.001). Results showed 77 cases of symptomatic COVID-19 disease that investigators observed in trial participants from January 25 through April 30, 2021. There were 63 cases in 9,868 participants who received placebo and 14 cases in 19,714 participants who received the investigational vaccine. Of the 63 COVID-19 cases in the placebo group, investigators classified 10 as moderate and 4 as severe. There were no cases of moderate or severe disease in the investigational vaccine group. It is important to note that the study was conducted before the delta and omicron variants were circulating. N Engl J Med. 2022 Feb 10;386:531-543
Spikevax (COVID-19 vaccine, mRNA-Moderna)
COVID-19 vaccine, mRNA-Moderna is the second mRNA vaccine to gain full approval for a 2-dose primary series. It is approved for adults aged 18 years and older.
Approval was based on analysis of follow-up safety and effectiveness data from the data that supported the emergency use that was granted in December 2020. The updated analyses to determine effectiveness included 14,287 vaccine recipients and 14,164 placebo recipients 18 years of age and older who did not have evidence of SARS-CoV-2 infection prior to receiving the first dose. The data used for the analyses were accrued before the omicron variant emerged. These data demonstrated that the vaccine was 93% effective in preventing COVID-19, with 55 cases of COVID-19 occurring in the vaccine group and 744 COVID-19 cases in the placebo group. The vaccine was also 98% effective in preventing severe disease. N Engl J Med 2021 Nov 4;38519):1774-1785
The emergency use authorization remains in effect for heterologous and homologous booster doses, and also for a third dose as part of the primary series for severely immunocompromised adults.
COVID-19 Approvals & Emergency Use Authorizations
Olumiant (baricitinib) – New indication approved for treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). EUA for this indication remains in place for pediatric patients aged 2 years and older.
mRNA COVID-19 vaccines
CDC interim recommendations for vaccine regimens in individuals aged 6 months and older, including additional doses for immunosuppressed individuals, adults aged 50 years and older, and otherwise healthy individuals.
CDC interim recommendations also states an 8-week interval may be optimal for some people aged 12 years and older, especially for males aged 12-39 years, because of the small risk of myocarditis associated with mRNA COVID-19 vaccines.
EUA extended to include children aged 6 months through 4 years (previously authorized for 5 years and older).
Full approval granted for adolescents aged 12 years and older.
FDA granted emergency use to prevent COVID-19 in children aged 6 months through 17 years.
Use limited to adults for whom other FDA-authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, or for those who elect to receive the Janssen COVID-19 vaccine because they would otherwise not receive a COVID-19 vaccine
Veklury (remdesivir) – Full approval gained for adults and children to allow outpatient infusions for treatment of COVID-19. The indication includes adults and children who are aged 28 days or older (weighing at least 3 kg), who require hospitalization, or who are not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death.
Two monoclonal antibodies are available in the United States. Bebtelovimab is used for postexposure prophylaxis in patients at high risk for progression to severe COVID-19 (or for whom other COVID-19 treatment options are not available or are clinically appropriate). Tixagevimab plus cilgavimab is used for preexposure prophylaxis of individuals who are moderately to severely immunocompromised because of a medical condition or treatments and would otherwise not mount a sufficient immune response to a vaccine (also for those with confirmed severe allergy to the vaccines).
Other monoclonal antibodies (ie, sotrovimab, bamlanivimab/etesevimab, casirivimab/imdevimab) previously used for postexposure prevention are no longer being distributed because of decreased efficacy against omicron variants.
Bebtelovimab – EUA issued for treatment (ie, postexposure prophylaxis) of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years or older who weigh 40 kg or more and are at high risk for progressing to severe disease.
Evusheld (tixagevimab and cilgavimab) – EUA revised for preexposure prophylaxis of COVID-19 with an increased dose of tixagevimab 300 mg IM and cilgavimab 300 mg IM administered as separate, consecutive IM injections. Patients who have already received the previously authorized dose (150 mg of tixagevimab and 150 mg of cilgavimab) should receive an additional dose of 150 mg of tixagevimab and 150 mg of cilgavimab as soon as possible to raise their monoclonal antibody levels to those expected for patients receiving the higher dose.
Other infectious disease approvals
Triumeq, Triumeq PD (abacavir/dolutegravir/lamivudine) – Indication for HIV treatment expanded to include children weighing at least 10 kg; additionally, a tablet for suspension approved for precise dosing in those weighing <25 kg.
Cabenuva (cabotegravir/rilpivirine) – New dosage regimen (every 2 months) approved for HIV-1 treatment; additionally, indication for HIV treatment expanded to include adolescents aged 12 years and older who weigh at least 35 kg; additionally, lead-in oral therapy is now optional.
TPOXX (tecovirimat) – New IV formulation approved to treat smallpox in individuals unable to swallow capsules.
Vtama (tapinarof topical)
Tapinarof is a first-in-class aryl hydrocarbon receptor (AhR) agonist for treatment of plaque psoriasis in adults. Efficacy of tapinarof in psoriasis is attributed to its binding and activation of AhR, a ligand-dependent transcription factor, leading to the downregulation of proinflammatory cytokines, including interleukin-17.
Approval was based on the PSOARING clinical trials, which compared use versus topical placebo. Approximately 35-40% of patients who received active drug had clear or almost clear scores after 12 weeks, as compared to 6% of patients on placebo. N Engl J Med 2021;385:2219-2229
Abrocitinib is an oral Janus kinase (JAK)-1 inhibitor indicated for refractory moderate-to-severe atopic dermatitis in adults whose disease is not adequately controlled with other systemic therapies or for whom those therapies are inadvisable. JAK1 inhibitors reduce interleukin-4 (IL-4) and IL-13 signaling.
Approval was based on the JADE COMPARE trial, which compared abrocitinib 200 mg or 100 mg once daily, dupilumab 300 mg SC every other week (after a 600-mg loading dose), and placebo. Additionally, all patients received topical therapy. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14% in the placebo group (P<0.001 for both abrocitinib doses vs placebo). An eczema area and severity index-75 (EASI-75) response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. N Engl J Med. 2021 Mar 25;384(12):1101-1112
Alpelisib is the first drug approved for patients aged 2 years and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Klippel-Trenaunay-Weber syndrome is part of this spectrum of diseases. FDA approval of alpelisib was supported by real-world evidence from the open-label EPIK-P1 trial. A retrospective chart review showed patients treated with alpelisib had reduced target lesion volume and improvement in PROS-related symptoms and manifestations. After 24 weeks, 27% of patients (10/37) achieved a confirmed response to treatment, defined as 20% or greater reduction in the sum of PROS target lesion volume. Also, 23 of 31 patients (74%) showed some reduction in target lesion. Prescribing Information
Baricitinib is the first systemic treatment to gain FDA approval for adults with severe alopecia areata. Baricitinib is a Janus kinase (JAK) inhibitor that blocks phosphorylation and activation of signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression involved in the inflammatory pathway.
Approval was based on two phase 3 trials, BRAVE-AA1 and BRAVE-AA2. In BRAVE-AA1, 22% of the 184 patients who received baricitinib 2 mg and 35% of the 281 patients who received 4 mg achieved adequate scalp hair coverage, compared to 5% of the 189 patients who received placebo. In BRAVE-AA2, 17% of the 156 patients who received baricitinib 2 mg and 32% of the 234 patients who received 4 mg achieved adequate scalp hair coverage, compared to 3% of the 156 patients who received a placebo. Results were statistically significant for each treatment group compared to placebo (P<0.001). N Engl J Med 2022 May 5;386(18):1687-1699
Opzelura (ruxolitinib topical)
Ruxolitinib topical cream received approval in July 2022 for treatment of adults and adolescents aged 12 years and older with nonsegmental vitiligo. Approval was based on data from two phase 3 trials (TRuE-V1 and TRuE-V2) that evaluated the safety and efficacy of ruxolitinib cream compared to vehicle in more than 600 people.
Topical ruxolitinib resulted in significant improvements in vitiligo area scoring index (VASI), which represent improvements in facial and total body repigmentation, at week 24 (primary analysis) compared to vehicle and in an open-label extension at week 52.
Results at week 24, which were consistent across both studies, showed approximately 30% of patients treated with topical ruxolitinib achieved at least 75% improvement from baseline in facial repigmentation (F-VASI75), the primary endpoint, compared to approximately 8% and 13% of patients treated with vehicle in TRuE-V1 and TRuE-V2, respectively. At week 52, approximately 50% of ruxolitinib-treated patients achieved F-VASI75.
Additionally, at week 24, more than 15% of patients treated with topical ruxolitinib achieved at least 90% improvement from baseline in F-VASI (F-VASI90), compared to approximately 2% of patients treated with vehicle. At week 52, the percentage of ruxolitinib-treated patients who achieved F-VASI90 doubled to approximately 30%. Medscape Medical News
Other dermatology approvals
Rinvoq (upadacitinib) – This JAK inhibitor gained approval for refractory moderate-to-severe atopic dermatitis, including adults and adolescents aged 12 years and older.
Skyrizi (risankizumab) – New indication approved for adults with active psoriatic arthritis.
Juvederm Volbella XC (hyaluronic acid, non-animal stabilized) – New indication approved for dermal filler for improvement of infraorbital hollowing.
Mavacamten is a first-in-class cardiac myosin inhibitor indicated for symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy to improve exercise capacity and symptoms in adults. Mavacamten modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM.
Approval of mavacamten was based on results from the multicenter, phase 3 EXPLORER-HCM trial (n = 251). Of 123 patients randomly assigned to mavacamten, 92 (75%) completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and week 30; and of the 128 patients randomly assigned to placebo, 88 (69%) completed the KCCQ at baseline and week 30. At 30 weeks, the change in KCCQ-OS (overall summary) score was greater with mavacamten than with placebo (mean score, 14.9 vs 5.4; difference +9.1; P<0.0001), with similar benefits across all KCCQ subscales. The proportion of patients with a very large change (KCCQ-OS 20 points or more) was 36% in the mavacamten group versus 15% in the placebo group, with an estimated absolute difference of 21%. These gains returned to baseline after treatment was stopped. Lancet. 2021 Jun 26
Other cardiology approvals
Jardiance (empagliflozin) – Indication to reduce the risk of cardiovascular death plus hospitalization in adults with heart failure (HF) broadened to include HF with either reduced or preserved ejection fraction.
Xigduo XR (dapagliflozin/metformin) – New indication approved to reduce risk of CV death and hospitalization for HF in adults with T2DM who have HF (NYHA class II-IV) with reduced ejection fraction.
Vutrisiran is an anti-transthyretin small interfering ribonucleic acid (siRNA) agent. It is indicated for polyneuropathy caused by hereditary transthyretin-related amyloidosis (hATTR) in adults. Amyloidogenic TTR mutations cause deposits primarily in the peripheral nerves. siRNA agents cause degradation of mutant and wild-type TTR mRNA through RNA interference.
Approval was based on results from HELIOS-A, a global, randomized, open-label, multicenter, phase 3 study. A total of 164 patients with hATTR amyloidosis were randomized 3:1 to receive either vutrisiran 25 mg SC every 3 months (n = 122) or patisiran 0.3 mg/kg IV every 3 weeks (n = 42) for 18 months. The efficacy of vutrisiran was also assessed by comparing the vutrisiran group in HELIOS-A with the placebo group (n = 77) from the APOLLO phase 3 study of patisiran.
Vutrisiran met the primary endpoint of the study, the change from baseline in the modified Neuropathy Impairment Score + 7 (mNIS+7) at 9 months. Treatment with vutrisiran (n = 114) resulted in a 2.2 point mean decrease (improvement) in mNIS+7 from baseline, compared to a 14.8 point mean increase (worsening) reported for the external placebo group (n = 67), resulting in a 17.0 point mean difference relative to placebo (P<0.0001). By 9 months, 50% of patients treated with vutrisiran experienced improvement in neuropathy impairment relative to baseline. Neurology 2021 Apr 13;96(15 suppl)
Other rheumatology approvals
Skyrizi (risankizumab) – New indication approved for adults with active psoriatic arthritis.
Rinvoq (upadacitinib) – New indication approved for adults with active ankylosing spondylitis who have had an inadequate response or intolerance to at least TNF blocker.
Krystexxa (pegloticase) – New indication for coadministration with methotrexate for people with uncontrolled gout.
Tirzepatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It acts by dually targeting glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GIP is an incretin hormone that induces insulin secretion in response to a meal (primarily by hyperosmolarity of glucose in the duodenum) to facilitate the metabolism of carbohydrates, fats, and proteins. GLP-1 receptor agonists increase insulin secretion in the presence of elevated blood glucose, suppress glucagon postprandially, delay gastric emptying to decrease postprandial glucose, and decrease glucagon secretion.
The SURPASS clinical trials investigated the use of tirzepatide. SURPASS-2 was an open-label, 40-week, phase 3 trial. The comparison by Frias et al of tirzepatide versus semaglutide in patients with type 2 diabetes mellitus (SURPASS-2) found that tirzepatide at all doses was noninferior and superior to semaglutide in lowering HbA1c. Tirzepatide was also superior to semaglutide in body-weight reductions. N Engl J Med 2021 Aug 5;385(6):503-515
Other endocrinology approvals
Imcivree (setmelanotide) – Indication for chronic weight management in patients aged 6 years and older with obesity caused by certain genetic disorders expanded to include Bardet-Biedl syndrome.
Qsymia (phentermine/topiramate) – Indication for chronic weight management expanded to include adolescents aged 12 years and older with an initial BMI in the 95th percentile or greater for age and sex.
Voquezna Triple Pak (vonoprazan/amoxicillin/clarithromycin)
Voquezna Dual Pak (vonoprazan/amoxicillin)
Vonoprazan is a first-in-class potassium-competitive acid blocker (PCAB) for treatment of H pylori in combination with clarithromycin and/or amoxicillin. It suppresses basal and stimulated gastric acid secretion at the secretory surface of the gastric parietal cell through inhibition of the H+, K+-ATPase enzyme system in a potassium-competitive manner. The combinations are supplied as prepackaged 15-day dosage regimens.
Approval of vonoprazan double (DT) and triple (TT) therapies was based on the phase 3 PHALCON-HP trial. Each proved noninferior to lansoprazole triple therapy in patients with H pylori not resistant to ampicillin or clarithromycin: vonoprazan TT (84.7%; P<0.0001) and vonoprazan DT (78.5%; P=0.0037) vs lansoprazole TT (78.8%). Am J Gastroenterol 2021 Oct;116(S634)
Other gastroenterology approvals
Rinvoq (upadacitinib) – New indication for moderate-to-severe active ulcerative colitis (UC) in adults who had inadequate response or intolerance to 1 or more TNF blockers.
Dupixent (dupilumab) – New indication approved for adults and adolescents for eosinophilic esophagitis.
Skyrizi (risankizumab) – New indication approved for adults with Crohn disease.
Obstetrics & Gynecology
Oteseconazole is an azole metalloenzyme inhibitor that targets fungal sterol 14-alpha demethylase (CYP51). Inhibition of CYP51 results in accumulation of 14-methylated sterols, which may be toxic to fungi. It is indicated to reduce incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are NOT of reproductive potential.
Approval was supported by positive results from phase 3 trials – 2 global VIOLET studies and a US-focused ultraVIOLET study, including 875 patients at 232 sites across 11 countries. Results from ultraVIOLET (n = 219) demonstrated that oteseconazole was superior to fluconazole/placebo in the proportion of women with more than 1 culture-verified acute VVC episode through week 50 in the intent-to-treat (P<0.001). Open Forum Infectious Diseases. 2021 Nov;8(suppl 1).
Tarpeyo (budesonide) – New indication to reduce proteinuria in adults with primary immunoglobulin A nephropathy.
Nephroscan (technetium Tc 99m succimer) – New technetium diagnostic imaging agent to aid in scintigraphic evaluation of renal parenchymal disorders.
Ryaltris (olopatadine/mometasone intranasal) – New fixed-dose combination indicated for seasonal allergic rhinitis in patients aged 12 years and older.
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Cite this: FDA Drug Approvals, Internal Medicine — 2022 Midyear Review - Medscape - Aug 24, 2022.