FDA Approvals, Highlights, and Summaries: Family Medicine

February 27, 2020

Accrufer (ferric maltol)

Ferric maltol is indicated for adults with iron deficiency anemia. The approval was based on 3 placebo-controlled trials (AEGIS 1 and 2, AEGIS 3). Ferric maltol improved hemoglobin from baseline by 2.18 g/dL in AEGIS 1 and 2 in patients with inflammatory bowel disease (P<.0001). Patients with chronic kidney disease were studied in AEGIS 3, which showed hemoglobin improvement from baseline by 0.52 g/dL (P=.0149).

Inflamm Bowel Dis. 2015 Mar;21(3):579-88

Accrufer prescribing information

Reblozyl (luspatercept)

Luspatercept is an erythroid maturation agent. The drug is a recombinant fusion protein that diminishes Smad2/3 signaling by binding several endogenous transforming growth factor-beta superfamily ligands. In a model of beta-thalassemia, luspatercept decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis. It is indicated for anemia in adults with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Approval of luspatercept was based on the BELIEVE phase 3 clinical trial that included adults with beta-thalassemia who require regular RBC transfusions (defined as 6-20 RBC units per 24 weeks, with no transfusion-free period >35 days during that period). Patients (n=336) were randomized 2:1 to receive luspatercept (n=224) or placebo (n=112) at a starting dose of 1 mg/kg SC every 21 days for up to 48 weeks. In the patients who received luspatercept, 21.4% achieved a 33% or greater reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) during weeks 13-24 after randomization, compared with 4.5% (n=5) in the placebo arm (risk difference [95% confidence interval]: 17.0 [10.4, 23.6], P<.0001).

[Cappellini MD, Viprakasit V, Taher A, et al. The Believe trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. Abstract #163. Presented at the 2018 American Society of Hematology (ASH) Annual Meeting, December 1, 2018; San Diego, CA.]

Givlaari (givosiran)

Givosiran is a small-interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. It is approved for adults with acute hepatic porphyrias (AHPs), in which attacks are caused by induction of the enzyme 5-aminolevulinic acid synthase 1 (ALAS1).

Approval of givosiran was based on the ENVISION phase 3 trial (n=94). Givosiran resulted in a 74% mean reduction in annualized composite rate of porphyria attacks in acute intermittent porphyria patients relative to placebo. A corresponding 90% reduction in median annualized attack rate (AAR), with 50% of patients on givosiran who were attack-free compared with 16.3% for placebo was also observed. A 73% reduction in mean AAR was observed in patients with any AHP relative to placebo. Givosiran resulted in a reduction in days of hemin use of 77% compared with placebo. It also led to sustained (~90%) lowering from baseline of ALA and porphobilinogen, the neurotoxic liver heme intermediates that cause attacks and other AHP disease manifestations.

[Balwani M, Gouya L, Rees DC, Stein P, Stolzel U, Aguilera Peiro P, et al. ENVISION, a Phase 3 Study to Evaluate the Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase 1, in Acute Hepatic Porphyria Patients. Presented at EASL (European Association for the Study of the Liver) meeting. 13 April 2019, Vienna, Austria.]

Nourianz (istradefylline)

Istradefylline, a selective adenosine A2A antagonist, is indicated as adjunctive treatment to levodopa/carbidopa in adults with Parkinson disease experiencing OFF episodes. Approval was based on several randomized, placebo-controlled trials (n=1143) in patients stabilized on levodopa/carbidopa with or without other medications for their Parkinson disease. Results showed statistically significant decreases in OFF time in the istradefylline treatment groups compared with placebo.

Mov Disord. 2013 July;28(8):1138-1141

Clin Neuropharmacol. 2015 Mar-Apr;38(2):41-6

Mov Disord. 2010 Jul 30;25(10):1437-43

Reyvow (lasmiditan)

Lasmiditan is the first of a new serotonin agonist drug class that binds to 5-HT1F. Serotonin 5-HT1F agonists (ie, ditans) do not elicit a vasoconstrictive effect. It is indicated for treatment of acute migraine with or without aura. Approval was based on 2 phase 3 studies, SAMURAI and SPARTAN, and an open-label GLADIATOR trial, totaling nearly 4000 patients. Collectively, the trials found the percentage of patients who were free of migraine pain at 2-hours postdose ranged from 28.2-38.8%, as compared to the rate with placebo of 15.3-21.3% (P<.001 to .003).

Neurology. 2018 Dec 11;91(24):e2222-32232

Brain. 2019 Jul 1;142(7):1894-1904

Cephalalgia. 2019 Oct;39(11):1343-1357

Ubrelvy (ubrogepant)

Ubrogepant is the first drug in the class of calcitonin gene–related peptide (CGRP) antagonists approved for treatment of acute migraine. Ubrogepant is administered orally. Previously approved CGRP antagonists are indicated for migraine prophylaxis.

Approval was based on 2 randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine headache. The percentage of participants who had freedom from pain at 2 hours in the ACHIEVE I study was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P=.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<.001).

N Engl J Med. 2019 Dec 5;381(23):2230-2241

The ACHIEVE II trial had similar results of 14.3% in the placebo group and 21.8% in the 50-mg ubrogepant group (P=.01).

JAMA. 2019 Nov 19;322(19):1887-1898

Sunosi (solriamfetol)

Solriamfetol is a dopamine/norepinephrine reuptake inhibitor indicated to improve wakefulness in adults with excessive daytime sleepiness caused by narcolepsy or obstructive sleep apnea (OSA).

In a phase 3 randomized clinical trial, 239 patients with narcolepsy were randomized to receive solriamfetol 75 mg, 150 mg, or 300 mg (2 times the maximum recommended daily dose), or placebo, once daily. Compared with the placebo group, patients randomized to 150 mg showed statistically significant improvements on the maintenance of wakefulness test (MWT) and on the Epworth Sleepiness Scale (ESS) at week 12. These effects were apparent at week 1 and consistent with the results at week 12. At week 12, a higher percentage of patients treated with solriamfetol 150?mg (78.2%) reported patient global impression of change (PGIc) scale improvement relative to placebo (39.7%; P<.0001).

Ann Neurol. 2019 Mar;85(3):359-370

Approval for excessive daytime sleepiness in adults with OSA was based on the TONES 3 randomized controlled trial. A total of 476 patients with OSA were randomized to receive solriamfetol 37.5 mg, 75 mg, or 150 mg, or placebo, once daily. Coprimary endpoints (MWT and ESS) were met at all solriamfetol doses (P<.05), with dose-dependent effects observed at week 1 maintained over the 12-week study duration. All doses except 37.5 mg resulted in higher percentages of participants reporting improvement on PGIc (key secondary endpoint; P<.05).

Am J Respir Crit Care Med. 2019 Jun 1;199(11):1421-1431

Aklief (trifarotene)

Trifarotene is an agonist of retinoic acid receptors (RARs), with particular activity at the gamma subtype of RAR. 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

Scenesse (afamelanotide)

Afamelanotide is a subcutaneously implantable alpha-melanocyte–stimulating hormone analog that increases melanin production in the skin independent of sunlight exposure or artificial light sources. It is indicated for prevention of photoxicity and anaphylactoid reactions in adults with erythropoietic protoporphyria (EPP).

EPP is a rare disorder caused by mutations leading to impaired activity of ferrochelatase, an enzyme involved in heme production; decreased ferrochelatase activity leads to protoporphyrin IX (PPIX) accumulation in the body; light reaching the skin can react with PPIX, causing intense skin pain and skin changes (eg, redness, thickening). Afamelanotide, a melanocortin-1 receptor (MC1-R) agonist, increases production of eumelanin (the most common type of melanin) in the skin independent of exposure to sunlight or artificial light sources. It is indicated to increase pain-free light exposure in adults with a history of phototoxic reactions from EPP.

US approval was based on 2 multicenter, randomized, double-blind, placebo-controlled trials in patients residing in the European Union (n=74) and the United States (n=94). Patients were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of 5 implants in the European Union study and 3 in the US study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. In the US study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hr vs 40.8 hr in the placebo group; P=.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6 hr vs 0.8 hr; P=.005), and the number of phototoxic reactions was lower in the afamelanotide group (77 vs 146, P=.04).

N Engl J Med. 2015 Jul 2;373(1):48-59 .

Jeuveau (prabotulinumtoxinA-xvfs)

PrabotulinumtoxinA, an acetylcholine-release inhibitor and neuromuscular blocker, is indicated for temporary improvement in the appearance of moderate-to-severe glabellar facial lines associated with corrugator and/or procerus muscle activity in adults.

Approval was based on 2 randomized, multicenter, double-blind, placebo-controlled trials of identical design (n=654). At day 30, 67-71% of patients treated with prabotulinumtoxinA achieved grade 2 or higher improvement for the glabellar line scale from baseline at maximum frown compared with 1% of those treated with placebo.

Dermatol Surg. 2019 Nov;45(11):1381-1393

Aesthet Surg J. 2019 Apr 5

Skyrizi (risankizumab)

Risankizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the p19 subunit of the human interleukin 23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor. It was approved for treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

Approval was based on the UltlMMa-1 and UltlMMa-2 replicate phase 3, randomized, double-blind, placebo-controlled and active comparator–controlled international trials (n=997). Coprimary endpoints were proportions of patients achieving a 90% improvement in the Psoriasis Area Severity Index (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16 (nonresponder imputation). Risankizumab showed superior efficacy to both placebo and ustekinumab in the treatment of moderate-to-severe plaque psoriasis.

At week 16 of each study, PASI 90 was achieved by 74.8-75.3% patients receiving risankizumab compared with 2-4.9% receiving placebo and 42-47.5% receiving ustekinumab (P<.0001 vs placebo and ustekinumab). Results from each trial for sPGA 0 or 1 at week 16 was achieved by 83.7-87.8% patients receiving risankizumab compared with 5.1-7.8% receiving placebo and 61.6-63% receiving ustekinumab (P<.0001 vs placebo and ustekinumab).

Lancet. 2018 Aug 25;392(10148):650-661

Recarbrio (imipenem/cilastatin/relebactam)

Imipenem/cilastatin/relebactam contains previously approved imipenem/cilastatin and relebactam, a new beta-lactamase inhibitor. It is indicated for complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intra-abdominal infections (cIAIs) in adults with limited or no other treatment options.

Imipenem is a carbapenem that inhibits bacterial cell-wall synthesis by binding to penicillin-binding proteins, resulting in bacterial cell lysis. Cilastatin prevents renal metabolism of imipenem by competing with dehydropeptidase in the renal tubules to improve systemic exposure of imipenem. Relebactam has no intrinsic antibacterial activity. It protects imipenem from degradation by certain serine beta-lactamases such as sulfhydryl variable (SHV), temoneira (TEM), cefotaximase-Munich (CTX-M), E cloacae P99 (P99), Pseudomonas-derived cephalosporinase (PDC), and Klebsiella pneumoniae carbapenemase (KPC).

Efficacy of the antibiotic combination was supported in part by the findings of the efficacy and safety of imipenem-cilastatin for the treatment of cUTIs and cIAIs. Relebactam was assessed based on data from in vitro studies and animal models of infection. Safety was studied in 2 clinical trials, one each for cUTIs and cIAIs. The cUTI trial included 298 adult patients, with 99 treated with the proposed dose. The cIAI trial included 347 patients, with 117 treated with the proposed dose. Dosage modifications are necessary for patients who have renal impairment.

Recarbrio prescribing Information

Pretomanid

Pretomanid, a nitroimidazooxazine, is indicated for adults with extensively drug-resistant, treatment-intolerant, or nonresponsive multidrug-resistance tuberculosis. Pretomanid kills actively replicating Mycobacterium tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell-wall production. Efficacy was primarily demonstrated in a study of 109 patients who were treated with pretomanid plus bedaquiline and linezolid. Of the 107 patients who were evaluated 6 months after the end of therapy, 95 (89%) had successful treatment, far exceeding success rates of available treatments.

Pretomanid prescribing information

Egaten (triclabendazole)

Triclabendazole is an antihelmintic agent indicated for the treatment of fascioliasis caused by Fasciola hepatica or Fasciola gigantica in patients aged 6 years or older. The mechanism by which triclabendazole exhibits its effect against Fasciola species is not fully elucidated. Studies in vitro and/or in infected animals suggest that triclabendazole and its active metabolites (sulfoxide and sulfone) are absorbed by the tegument of the immature and mature worms, leading to a decrease of the resting membrane potential and inhibition of tubulin function and protein and enzyme synthesis.

Prior to its approval in 2019, triclabendazole was available for many years via investigational protocols from the US Centers for Disease Control and Prevention. An open-label, randomized trial conducted in Vietnam compared the efficacy of triclabendazole (two 10 mg/kg doses given 12 hours apart with food) with oral artesunate (4 mg/kg, given once daily for 10 days) (n=100). Patients (age range, 9-74 years) with acute symptomatic fascioliasis were randomized, 50 in each treatment group. At 3 months after treatment, 92% and 76% (difference 16%; 95% confidence interval, 1.7-30.8; P=.035) of patients in the triclabendazole and artesunate arms, respectively, reported no clinical symptoms. Six open-label studies showed the dose response at 20 mg/kg was superior to that of lower doses.

Egaten prescribing information

Fetroja (cefiderocol)

Cefiderocol is a cephalosporin antibiotic with activity against gram-negative aerobic bacteria. Cefiderocol functions as a siderophore and binds to extracellular free ferric iron. In addition to passive diffusion via porin channels, cefiderocol is actively transported across the outer cell membrane of bacteria into the periplasmic space using a siderophore iron uptake mechanism. It is indicated to treat complicated urinary tract infections, including pyelonephritis, caused by susceptible gram-negative microorganisms in adults who have limited or no alternative treatment options.

Fetroja prescribing information

Xenleta (lefamulin)

Lefamulin is a first-in-class pleuromutilin antibacterial. It inhibits bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center (PTC) in domain V of the 23s rRNA of the 50S subunit. It is indicated for adults with bacterial community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae. It is administered twice daily as either an intravenous infusion or an oral tablet. Approval was based on LEAP 1 and 2 trials.

In LEAP 1, patients (n=551) were randomized to either lefamulin 150 mg IV q12h or moxifloxacin 400 mg IV q24h. After 6 doses, patients could be switched to the oral study drug if prespecified improvement criteria were met. If methicillin-resistant S aureus was suspected, linezolid or placebo was added to moxifloxacin or lefamulin, respectively. Lefamulin was noninferior to moxifloxacin for early clinical response. Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin.

Clin Infect Dis. 2019 Nov 13;69(11):1856-1867

The LEAP 2 study (n=738) found oral lefamulin 600 mg q12h for 5 days was noninferior to moxifloxacin 400 mg/day for 7 days for treating bacterial CAP.

Presented at IDWeek 2018 Oct 4. San Francisco, CA

Jynneos (smallpox and monkeypox vaccine)

Smallpox and monkeypox vaccine is an attenuated, live, nonreplicating vaccine for immunization of adults at high risk for smallpox or monkeypox infection. Approval was determined in a clinical study comparing the immune responses in study participants who received either Jynneos or ACAM2000, an FDA-approved vaccine for the prevention of smallpox. The study included approximately 400 healthy adults, aged 18-42 years, who had never been vaccinated for smallpox. Half of the study participants received 2 doses of Jynneos administered 28 days apart, and half received 1 dose of ACAM2000. The group vaccinated with Jynneos had an immune response that was not inferior to immune responses to ACAM2000.

Jynneos prescribing information

Wakix (pitolisant)

Pitolisant is a nonscheduled, first-in-class histamine 3 (H3) receptor antagonist/inverse agonist indicated for excessive daytime sleepiness in adults with narcolepsy. The efficacy of pitolisant was evaluated in 2 multicenter, randomized, double-blind, placebo-controlled studies in patients (n=261) with narcolepsy with or without cataplexy. In both studies, pitolisant demonstrated a statistically significant improvement in the Epworth Sleepiness Scale score.

Lancet Neurology. 2017 Mar;16(3):200-207

Wakix prescribing information

Dayvigo (lemborexant)

Lemborexant is an orexin antagonist indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Orexins are neuropeptides that regulate the sleep-wake cycle by promoting wakefulness when bound to G-protein–coupled receptors, OX1R and OX2R.

Approval of lemborexant was based on results from the phase 3 studies, SUNRISE 1 and SUNRISE 2, that included nearly 2000 patients. Sleep onset and maintenance were improved compared with placebo. Middle-of-the-night safety (including wakening to sound) and next-day postural stability and memory studies over 12 months were also conducted. There were no meaningful differences between lemborexant 5 mg, 10 mg, or placebo with ability to wake to sound in the middle of the night; however, balance impairment at 4 hours postdose was evident with lemborexant compared with placebo.

JAMA Netw Open. 2019; 2(12):e1918254

Zulresso (brexanolone)

Brexanolone is the first drug to be approved by the FDA for the treatment of postpartum depression (PPD). The mechanism by which brexanolone works for PDD is not fully understood, but it is believed to be related to positive allosteric modulation of both synaptic and extrasynaptic GABA-A receptors.

The drug is available only through a restricted program called the Zulresso Risk Evaluation and Mitigation Strategy (REMS) Program that requires the drug be administered by a healthcare provider in a certified healthcare facility. The REMS requires that patients be enrolled in the program prior to administration of the drug. Brexanolone is administered as a continuous intravenous infusion over a total of 60 hours (2.5 days). Because of the risk of serious harm resulting from the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring.

Approval was based on 2 randomized, placebo-controlled phase 3 clinical trials that investigated the efficacy and safety of brexanolone injection in 246 women with moderate-to-severe PPD at 30 US centers.

In study 1, Hamilton Rating Scale for Depression (HAM-D) total scores decreased to a significantly greater extent at the end of the 60-hour infusion in the group receiving brexanolone 60 mcg/kg/hour (mean reduction, 19.5 points; P=.0013) and in the group on brexanolone 90 mcg/kg/hour (17.7 points; P=.0252) than in the placebo group (14 points). Similarly, in study 2, HAM-D scores improved significantly more in the higher-dose group (mean, 14.6 points; P=.016) compared with the placebo group (12.1 points).

Lancet. 2018 Sep 22;392(10152):1058-1070

Depression scores had not returned to baseline by day 30 in any of the brexanolone groups and remained significantly lower in both treatment groups compared with the placebo group of study 1 at day 30.

Data from a lactation study in 12 women indicate that brexanolone is transferred to breastmilk in nursing mothers; however, the relative infant dose is low, 1-2% of the maternal weight-adjusted dosage. Available data do not suggest a significant risk of adverse reactions to breastfed infants from exposure.

Zulresso prescribing information

Spravato (esketamine intranasal)

Esketamine intranasal is indicated in conjunction with an oral antidepressant for treatment-resistant depression (TRD). It is administered in a physician’s office, and the patient must be carefully monitored for at least 2 hours because of the risk of sedation, dissociation, and elevated blood pressure following the dose. Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor). The mechanism by which esketamine exerts its antidepressant effect is not fully understood.

Efficacy of esketamine was evaluated in 3 short-term (4-week) clinical trials and 1 longer-term maintenance-of-effect trial. In the short-term studies, patients were randomized to receive esketamine intranasal or a placebo nasal spray. Because of the serious nature of TRD and the need for patients to receive some form of treatment, all patients started a new oral antidepressant at the time of randomization, and the new antidepressant was continued throughout the trials. Primary efficacy was measured by the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) used to assess the severity of depressive symptoms. In one of the short-term studies, esketamine nasal spray demonstrated statistically significant effect compared with placebo on the severity of depression, and some effect was seen within 2 days. The 2 other short-term trials did not meet the prespecified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with esketamine intranasal plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.

Am J Psychiatry. 2018 Jul 1;175(7):620-630

JAMA Psychiatry. 2018 Feb 1;75(2):139-148

Evenity (romosozumab)

Romosozumab is a monoclonal antibody that binds with and inhibits sclerostin, a regulatory factor in bone metabolism. Sclerostin inhibition increases bone formation and, to a lesser extent, decreases bone resorption. Romosozumab is indicated for osteoporosis treatment in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture. It is also indicated for patients who have failed or are intolerant of other available osteoporosis therapy.

A boxed warning is included in the prescribing information to warn of an increased risk of major adverse cardiovascular events, including myocardial infarction, stroke, and death. Patients who have had a myocardial infarction or stroke within the past year should not receive romosozumab.

FDA approval was based on the FRAME study, which included over 7000 women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive romosozumab subcutaneous injections (210 mg) or placebo monthly for 12 months. Thereafter, patients in each group received denosumab 60 mg subcutaneously every 6 months for 12 months. Results showed that romosozumab was associated with a lower risk of vertebral fracture compared with placebo at 12 months (representing a 73% lower risk with romosozumab; P<.001). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group compared with the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<.001).

N Engl J Med. 2016 Oct 20;375(16):1532-1543

Vyleesi (bremelanotide)

Bremelanotide is a melanocortin receptor (MCR) agonist that nonselectively activates several receptor subtypes with the following order of potency: MC1R, MC4R, MC3R, MC5R, MC2R. MCR agonists with high affinity for the type-4 receptor have potential to modulate brain pathways involved in sexual response. It is indicated for acquired, generalized hypoactive sexual desire disorder in premenopausal women.

It is administered as a subcutaneous injection about 45 minutes before an anticipated sexual activity. Approval was based on the RECONNECT clinical trials (n=1247). Results from these trials showed approximately 25% of patients treated with bremelanotide had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2-6, with higher scores indicating greater sexual desire) compared with about 17% of those who took placebo. Additionally, about 35% of the bremelanotide group had a decrease of 1 or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.

RECONNECT study

Rinvoq (upadacitinib)

Upadacitinib, a Janus kinase-1 (JAK1) selective inhibitor, is indicated for moderately to severely active rheumatoid arthritis (RA) in adults who have had an inadequate response to or are intolerant of methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiological disease-modifying antirheumatic drugs.

JAK1 is essential for certain cytokines to elicit signals from various interleukins, cardiotrophin, neurotrophin, and interferons. These signals are crucial in maintaining the inflammatory condition in RA. Inhibition of JAK reduces production of and modulates proinflammatory cytokines central to RA.

Approval was based on data from the SELECT phase 3 RA program that enrolled over 4000 patients with moderate-to-severe RA across 5 studies. In the SELECT-MONOTHERAPY study, 598 of 648 patients completed the study. At week 14, an American College of Rheumatology 20% (ACR20) response was achieved by 89 (41%) of 216 patients in the continued-methotrexate group, 147 (68%) of 217 patients receiving upadacitinib 15 mg, and 153 (71%) of 215 patients receiving upadacitinib 30 mg (P<.0001 for both doses vs continued methotrexate).

Lancet. 2019 Jun 8;393(10188):2303-2311

The SELECT-COMPARE study evaluated safety and effectiveness of upadacitinib compared with adalimumab (each with methotrexate) over 48 weeks. Results showed that low disease activity, clinical remission, and improvements in pain and function remained superior for upadacitinib compared with adalimumab at 26 weeks and from weeks 26-48.

Ann Rheum Dis. 2019 Nov;78(11):1454-1462

Ibsrela (tenapanor)

Tenapanor, a sodium-hydrogen exchange 3 (NHE3) inhibitor, is indicated for adults with irritable bowel syndrome with constipation. NHE3 inhibition reduces sodium absorption from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool consistency.

Approval of tenapanor was based on 2 phase 3 trials (n=1226) that showed a statistically significant improvement in stool frequency and abdominal pain compared with placebo.

Am J Gastroenterol. 2020 Jan 13 .

Beovu (brolucizumab intravitreal)

Brolucizumab is indicated for treatment of neovascular (wet) age-related macular degeneration (nAMD). It is a vascular endothelial growth factor (VEGF) inhibitor. By inhibiting VEGF-A, brolucizumab suppresses endothelial cell proliferation, neovascularization, and vascular permeability.

Approval of brolucizumab was based on the HAWK and HARRIER phase 3 trials (n=1817) that compared intravitreal brolucizumab with aflibercept for nAMD. At 48 weeks, brolucizumab was demonstrated to be noninferior to aflibercept in mean best-corrected visual acuity. At week 16, after identical treatment exposure, fewer brolucizumab 6 mg–treated eyes had disease activity compared with aflibercept in HAWK (24% vs 34.5%; P=.001) and HARRIER (22.7% vs 32.2%; P=.002).

Ophthalmology. 2019 Dec;126(12):e95-e96

Additional 2019 Approvals

Dupixent (dupilumab) was approved as add-on maintenance treatment in adults with inadequately controlled severe chronic rhinosinusitis with nasal polyps.

Ofev (nintedanib) was approved to slow the rate of decline in pulmonary function in adults with interstitial lung disease associated with systemic sclerosis (scleroderma).

Baqsimi (glucagon intranasal) was approved 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.

 

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