Relyvrio (sodium phenylbutyrate/taurursodiol)
Sodium phenylbutyrate/taurursodiol is indicated for treatment of amyotrophic lateral sclerosis (ALS) in adults. The precise mechanism is unknown. Sodium phenylbutyrate is a histone deacetylase inhibitor shown to upregulate heat-shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress. Taurursodiol recovers mitochondrial bioenergetics deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the cell’s apoptotic threshold. The precise mechanism of action in patients with ALS is unknown.
Approval was based on the CENTAUR trial. The phase 2 CENTAUR trial (n = 89 treatment; n = 48 placebo) showed patients treated with sodium phenylbutyrate/taurursodiol had slower progression of disease compared to those randomized to placebo. Also, the ALS functional rating scale revised (ALSFRS-R) score showed the highest score preservation in fine motor skill subscales. N Engl J Med. 202 Sep 3:383(10):919-930
The open-label extension (OLE) of the CENTAUR trial included 56 participants from the treatment group (ie, early start group) and 34 from the placebo group. In the early start group subjects, the risk of any key event was 47% lower (p = 0.003), and the risk of death or tracheostomy or permanent assisted ventilation was 49% lower (p = 0.007). Also, first hospitalization was 44% lower in this group (p = 0.03). J Neurol Neruosurg Psychiatry. 2022 May 16;93(8):871-875
The CENTAUR OLE showed the median survival in the early start group was 25 months compared to 18.5 months for the group starting treatment during the extension. Muscle Nerve. 2021 Jan;63(1):31-39
Ublituximab is a CD20-directed monoclonal antibody indicated for relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Approval was supported by results from the ULTIMATE I (n = 549) and ULTIMATE II (n = 545) trials. Compared with teriflunomide, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (p < 0.001); in the ULTIMATE II trial, the annualized relapse rates were 0.09 and 0.18, respectively (p = 0.002). N Engl J Med. 2022 Aug 25;387(8):704-714
Skysona (elivaldogene autotemcel)
Elivaldogene autotemcel is a one-time gene therapy designed to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells, resulting in the production of the adrenoleukodystrophy protein (ALDP). It is indicated to slow the progression of neurologic dysfunction in boys aged 4 to 17 years with early, active cerebral adrenoleukodystrophy (CALD), a rare, X-linked, peroxisomal disorder that affects production of ALDP.
Accelerated approval from the FDA was supported by interim results from the phase 2/3 STARBEAM study, which concluded that elivaldogene autotemcel may be an effective alternative to allogeneic stem-cell transplantation in boys with early stage CALD. N Engl J Med. 2017 Oct 26;377(17):1630-1638
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
DaTscan (ioflupane I 123) – New indication as an adjunct to other diagnostic evaluations for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging in adult patients with suspected Lewy body dementia
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
Dextromethorphan/bupropion is a new fixed-dose combination product indicated for treatment of adults with major depressive disorder (MDD). Dextromethorphan is an antagonist of the N-methyl-D-aspartate (NMDA) receptor. The tablet is formulated to increase the bioavailability and half-life of dextromethorphan by utilizing the bupropion component to increase plasma dextromethorphan concentrations by inhibiting its metabolism.
In the phase 3 GEMINI (glutamatergic and monoaminergic modulation in depression) study, there were significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation. J Clin Psychiatry 2022 May 30;83(4)
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
Vraylar (cariprazine) – New indication for adjunctive therapy for major depressive disorder
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 the 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
Xenpozyme (olipudase alfa)
Olipudase alfa is indicated for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults and children. It is a recombinant enzyme for replacement therapy. ASMD is a lysosomal storage disease that results from reduced activity of the enzyme acid sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. ASM degrades sphingomyelin to ceramide and phosphocholine. ASM deficiency causes intra-lysosomal accumulation of sphingomyelin (and cholesterol and other cell membrane lipids) in various tissues.
Approval of olipudase alfa was established by the ASCEND and ASCEND-Peds trials. The ASCEND trial assessed 31 adults with ASMD type A/B or type B and their percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume. The olipudase alfa group demonstrated improved lung function and reduced splenomegaly compared to the placebo group from baseline to week 52 (increased predicted diffusing capacity for carbon monoxide, 22% vs 3%; spleen volume, 39% decrease vs 0.5% increase). In the ASCEND-Peds trial, 9 patients treated with olipudase alfa who were able to perform test at baseline saw improvement in lung performance from baseline to week 52 (mean increase of 33% predicted diffusing capacity for carbon monoxide). Genet Med. 2022 Jul;24(7):1425-1436 and Genet Med. 2021 Aug;23(8):1543-1550
Teplizumab is a humanized monoclonal antibody that targets the cluster of differentiation 3 (CD3) antigen, which is coexpressed with the T-cell receptor (TCR) on the surface of T-lymphocytes. It is indicated to delay the onset of stage 3 type 1 diabetes mellitus (T1DM) in adults and children aged 8 years and older who currently have stage 2 T1DM.
FDA approval was based on a phase 2, randomized, placebo-controlled trial involving 76 at -risk children and adults. The study demonstrated that a single 14-day regimen of daily IV infusions of teplizumab in 44 patients delayed clinical T1DM by a median of 2 years compared to 32 participants who received placebo (p = 0.006). N Engl J Med. 2019 Aug 15;381(7):603-613
Data from 3 years of follow-up (median 923 days) showed 50% of the teplizumab group remained diabetes free, compared to 22% of the placebo group (p = 0.01). Those who received teplizumab had a greater average C-peptide AUC compared to those given placebo, reflecting improved beta-cell function (1.96 vs 1.68 pmol/mL; p = 0.006). C-peptide levels declined over time in the placebo group, but they stabilized in patients who received teplizumab (p = 0.0015). Sci Transl Med. 2021 Mar 3;13(583)
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
Tymlos (abaloparatide) – New indication to increase bone density in men with osteoporosis at high risk for fracture or patients who have failed on or are intolerant to other available osteoporosis therapy
Olpruva (sodium phenylbutyrate) – New oral pellets for suspension indicated as an adjunct to dietary protein restriction and essential amino acid supplementation for the chronic management of patients who weigh at least 20 kg with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS)
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
Mavacamten is a first-in-class cardiac myosin inhibitor indicated for symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) 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
Furoscix (furosemide) – New formulation and administration method: SC delivery by on-body infusor for treatment of congestion due to fluid overload in adults with NYHA class II/III CHF
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.
Deucravacitinib is an oral tyrosine kinase 2 (TYK2) inhibitor. TYK2 pairs with JAK1 to mediate multiple cytokine pathways and pairs with JAK2 to transmit signals shown in cell-based assays. The precise mechanism linking inhibition of TYK2 enzyme to therapeutic effectiveness is unknown. It is indicated for moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
Approval was supported with results from the POETYK PSO-1 trial. At week 16, the PASI 75 (Psoriasis Area and Severity Index showing at least 75% reduction of symptoms from baseline) response rates were significantly higher with deucravacitinib than with placebo or apremilast (58.4% vs 12.7% vs 35.1%; p<0.0001). The static physician’s global assessment score 0 / 1 (sPGA 0/1) also favored deucravacitinib (53.6% vs 7.2% vs 32.1%; p<0.0001). Efficacy improved beyond week 16 and was maintained through week 52. J Am Acad Dermatol. 2022 Jul 9
Spesolimab is an anti-interleukin-36 (IL-36) monoclonal antibody. Binding to the IL-36 receptor decreases release of proinflammatory and profibrotic pathways in patients with inflammatory dermatoses. It is indicated for treatment of generalized pustular psoriasis (GPP) flares.
Evidence from the Effisayil 1 trial supported the approval. The Effisayil 1 trial assessed 53 adults with GPP based on the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation score at 1 week after receiving spesolimab or placebo. At the end of 1 week, the spesolimab treatment group saw improved pustulation. In patients treated with spesolimab, GPPGA pustulation subscore of 0 was observed in 54% compared to 6% in the placebo group. GPPGA total score of 0 or 1 was 43% with spesolimab compared to 11% for placebo. N Engl J Med. 2021;385(26):2431-2440
DaxibotulinumtoxinA is the first peptide-formulated, long-acting neuromodulator approved for temporary improvement of moderate-to-severe glabellar lines in adults. As a botulinum toxin, it blocks cholinergic transmission at neuromuscular junctions by inhibiting the release of acetylcholine.
Approval was supported by the SAKURA phase 3 trial, which included more than 2700 adults who received approximately 4200 treatments. The median duration of effect was 6 months, with some patients maintaining results at 9 months, compared to 3-4 months with other botulinum toxins. Dermatol Surg. 2021 Jan 1;47(1):48-54
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 gained 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
Dupixent (dupilumab) – New indication approved for adults with prurigo nodularis
Rinvoq (upadacitinib) – JAK inhibitor that gained approval by the FDA 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
Zoryve (roflumilast topical) – New dosage form approved for adults and adolescents with plaque psoriasis
Juvederm Volbella XC (hyaluronic acid, non-animal stabilized) – New indication approved for dermal filler for improvement of infraorbital hollowing
NexoBrid (anacaulase) – Proteolytic enzymes indicated for eschar removal (debridement) in adults with deep partial-thickness and/or full-thickness thermal burns
Omlonti (omidenepag isopropyl ophthalmic)
Omidenepag isopropyl is a prodrug of omidenepag and a selective prostaglandin E2 (EP2) receptor agonist, which increases aqueous humor drainage. Omidenepag isopropyl is indicated for primary open-angle glaucoma (POAG) or ocular hypertension.
Approval was supported by data from a phase 3 open-label trial, RENGE, which evaluated the safety and efficacy of omidenepag isopropyl ophthalmic solution 0.002% in 125 patients with primary open-angle glaucoma or ocular hypertension. Omidenepag isopropyl ophthalmic solution demonstrated noninferiority to timolol ophthalmic solution 0.5% in the duration of the 52-week study. Japanese Journal of Ophthalmology. 2021 65:810–819
Additionally, prostaglandin-associated periorbitopathy in patients with glaucoma has been reported not to be caused by EP2 receptor agonists but, rather, to be a cosmetic problem with prostaglandin F receptor (FP) agonists. Alleviation of periorbitopathy symptoms were reported after switching from an FP agonist to omidenepag isopropyl. Objective deepening of the upper eyelid sulcus improved by 76% at 7 months, and subjective questionnaires reported improvement in 95%. J Ocul Pharamcol Ther. 2022 Oct 31
Vabysmo (faricimab) – First bispecific antibody for treatment of adults with neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME). Faricimab targets 2 distinct pathways – angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). By inhibiting VEGF-A, faricimab suppresses endothelial cell proliferation, neovascularization, and vascular permeability. By inhibiting Ang-2, faricimab promotes vascular stability and desensitizes blood vessels to the effects of VEGF-A. Ang-2 levels are increased in some patients with nAMD and DME.
Approval was based on the phase 3 TENAYA and LUCERNE studies for wet AMD and the YOSEMITE and RHINE studies for DME. The multicenter trial sites (n = 271) randomly assigned patients with wet AMD (TENAYA: n = 334 faricimab; n = 337 aflibercept) (LUCERNE: n = 331 faricimab; n = 327 aflibercept) to determine noninferiority. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline. BCVA with faricimab was noninferior to aflibercept in both studies, and ocular adverse events were comparable between faricimab and aflibercept. Lancet 2022 Jan 21
The YOSEMITE and RHINE studies (353 worldwide sites) randomized adults with vision loss due to center-involving diabetic macular edema to receive intravitreal faricimab 6 mg every 8 weeks, faricimab 6 mg per personalized treatment interval (PTI), or aflibercept 2 mg every 8 weeks up to week 100. The primary endpoint was mean change in best-corrected visual acuity at 1 year. Patients were randomly assigned to faricimab every 8 weeks (YOSEMITE, n = 315; RHINE, n = 317), faricimab PTI (n = 313; n = 319), or aflibercept every 8 weeks (n = 312; n = 315). Vision gains and anatomic improvements with faricimab were achieved with adjustable dosing up to every 16 weeks. Lancet 2022 Jan 21
Tebentafusp is the first drug approved for treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma (mUM). It is a first-in-class bispecific protein comprising a soluble T-cell receptor (TCR) fused to an anti-CD3 immune-effector function that specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. Immune-mobilizing monoclonal TCRs against cancer (ImmTAC) molecules bind cells that present a peptide derived from an antigen of interest, and they recruit T-cells to lyse the target cells.
Approval of tebentafusp was based on the results of the phase 3 IMCgp100-202 clinical trial, which evaluated overall survival (OS) of tebentafusp compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in patients with previously untreated mUM. The trial randomized 378 patients in a 2:1 ratio to either tebentafusp or investigator’s choice. Results demonstrated OS was 73% in the tebentafusp group compared to 59% in the investigator’s-choice group (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine) at 1 year (p<0.001). Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; p=0.01). N Engl J Med. 2021 Sep 23;385(13):1196-1206
Other ophthalmology approvals
Iheezo (chloroprocaine ophthalmic) – New topical ophthalmic gel indicated for ocular surface anesthesia
Acuvue Theravision with Ketotifen (ketotifen, drug-eluting contact lens) – Daily disposable contact lenses indicated for the prevention of ocular itch caused by allergic conjunctivitis and to provide vision correction in patients aged 11 years and older who do not have red eyes, who are suitable for contact lens wear, and who do not have more than 1.00 D of astigmatism
Beovu (brolucizumab intravitreal) – New indication approved for diabetic macular edema
Iyuzeh (latanoprost) – Preservative-free ophthalmic solution approved for elevated intraocular pressure
Terlipressin is a synthetic vasopressin with twice the selectivity for V1 receptors compared to V2 receptors. V1 vasopressin receptors are abundantly expressed in the mesenteric arteries as compared to other vascular areas, whereas V2 receptors are expressed in the renal tubules. The primary actions of V1 and V2 are stimulation of vasoconstriction and water resorption, respectively, resulting in decreased portal blood inflow and reduced portal hypertension. It is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.
Approval by the FDA in September 2022 was established by the CONFIRM trial, a phase 3, randomized, controlled trial that included patients with type 1 hepatorenal syndrome (HRS-1) and rapidly worsening renal function. This trial accessed percentage of patients with improved renal function via verified HRS reversal, without need for renal replacement therapy for 10 days after treatment. Verified HRS reversal was observed in 32% of those treated with terlipressin compared to 17% of those in the placebo group (p = 0.0006). Deaths due to respiratory disorders were higher in the terlipressin group compared to the placebo group after 90 days (11% vs 2%). Use of terlipressin is not recommended in patients with hypoxia (SpO2 <90%), and oxygenation levels should be monitored during treatment. N Engl J Med. 2021 Mar 4;384(9):818-828
Rebyota (microbiota rectal)
Microbiota rectal is a live biotherapeutic delivered rectally to provide a broad consortium of diverse microbes to the gut to reduce recurrent Clostridioides difficile infection (CDI) after antibiotic treatment.
Approval was based on the PUNCH CD3 phase 3 clinical trial. Adults who had at least 1 CDI recurrence with a positive stool assay for C difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of microbiota or placebo. The primary endpoint was treatment success, defined as the absence of CDI diarrhea within 8 weeks of study treatment. In 267 patients who received blinded treatment (n = 180, microbiota; n = 87, placebo), successful treatment was 70.6% versus 57.5% with microbiota and placebo, respectively. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the microbiota and the placebo groups. Drugs. 2022 Oct;82(15):1527-1538
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
Lenacapavir is a first-in-class, twice-yearly capsid inhibitor indicated for treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant infection. Lenacapavir directly binds to the interface between capsid protein (p24) subunits in hexamers, thereby interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation.
Approval was supported by data from the phase 2/3 CAPELLA trial, which evaluated lenacapavir in combination with an optimized background regimen in people with multidrug-resistant HIV-1. At week 26, a viral load of less than 50 copies/mL was reported in 81% of the patients in cohort 1 (blinded lenacapavir) and in 83% in cohort 2 (open-labeled lenacapavir. N Engl J Med. 2022 May 12;386;(19):1793-1803
Other infectious disease approvals
Jynneos (smallpox and monkeypox vaccine) is approved by the FDA as a 2-dose subcutaneous injection for prevention of smallpox and monkeypox disease in adults aged 18 years and older who are at high risk for smallpox or monkeypox infection. Because of limited global supply of the vaccine during the 2022 outbreak, emergency use authorization (EUA) was granted for adults to receive a lower 2-dose intradermal dosage. Additionally, the EUA allows children at risk to receive a 2-dose subcutaneous regimen.
Xofluza (baloxavir marboxil) – Indication expanded for acute uncomplicated influenza in otherwise healthy patients to include children as young as 5 years
Boostrix (tetanus & reduced diphtheria toxoids/ acellular pertussis vaccine) – New indication approved for pregnant women during 3rd trimester to protect newborns younger than 2 months from whooping cough (Bordetella pertussis)
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
Vemlidy (tenofovir AF) – Indication for chronic hepatitis C infection expanded to include adolescents aged 12 years and older
Avycaz (ceftazidime/avibactam) – Indication for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) now include children aged 3 months to 18 years
TPOXX (tecovirimat) – New IV formulation approved to treat smallpox in individuals unable to swallow capsules
Kineret (anakinra) – EUA granted for treatment of COVID-19 in hospitalized adults with COVID-19 pneumonia requiring supplemental oxygen who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR)
Actemra (tocilizumab) – New indication approved for hospitalized adults with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation; emergency use authorization remains for children aged 2 years and older
Olumiant (baricitinib) – New indication approved by the FDA 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.
Bivalent COVID-19 vaccines
– EUAs were issued for 2 updated booster vaccine with broadened protection against omicron BA.4/BA.5 in addition to the original vaccine
– The Pfizer bivalent vaccine and Moderna bivalent vaccine are authorized for patients aged 6 months and older
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
Krystexxa (pegloticase) – New indication for coadministration with methotrexate for people with uncontrolled gout
– New indication approved for adults with active ankylosing spondylitis who have had an inadequate response or intolerance to at least 1 TNF blocker
– New indication for active non-radiographic axial spondyloarthritis (nr-axSpA) in adults
Myfembree (relugolix/estradiol/norethindrone acetate) – New indication approved for pain associated with endometriosis
Mirena (levonorgestrel intrauterine) – Use extended up to 8 years to prevent pregnancy
Brexafemme (ibrexafungerp) – Indication expanded to include reducing incidence of recurrent vulvovaginal candidiasis (RVVC) in adult and postmenarchal pediatric females
Xenoview (xenon Xe 129 hyperpolarized) – Prepared xenon gas blend indicated for use with MRI for evaluation of lung ventilation in adults and pediatric patients aged 12 years and older
Elucirem, Vueway (gadopiclenol) – New imaging agent for use with MRI in patients aged 2 years and older to detect and visualize lesions with abnormal vascularity in the central nervous system and the body
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Cite this: Mary L. Windle. FDA Approvals, Highlights, and Summaries - Medscape - Mar 02, 2023.