Apadamtase Alfa: First Approval.

Apadamtase alfa (ADAMTS13, recombinant-krhn; ADZYNMA), a human recombinant form of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), is being developed by Takeda under license from KM biologics for thrombotic thrombocytopenic purpura (TTP) and sickle cell disease. On 9 November 2023, apadamtase alfa was approved in the USA for prophylactic and on-demand enzyme replacement therapy (ERT) in paediatric and adult patients with congenital TTP. Apadamtase alfa is under regulatory review for congenital TTP in the EU and Japan, and is under clinical development for immune-mediated TTP in several countries worldwide. Clinical development of apadamtase alfa for vaso-occlusive crisis related to sickle cell anaemia is underway in the USA. This article summarizes the milestones in the development of apadamtase alfa leading to this first approval in the USA for congenital TTP.

Zuranolone: First Approval.

Zuranolone (ZURZUVAE™) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABAA) receptor being developed by Sage Therapeutics and Biogen for the treatment of mood disorders. In August 2023, zuranolone received its first approval in the USA for the treatment of adults with postpartum depression [pending scheduling by the US Drug Enforcement Administration (DEA)]. This article summarizes the milestones in the development of zuranolone leading to this first approval.

Vutrisiran: A Review in Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis.

Silencing the transthyretin (TTR) gene is an effective strategy in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis. Vutrisiran (Amvuttra®), an RNA interference (RNAi) therapeutic targeting TTR mRNA, is approved in the USA and EU for the treatment of adults with polyneuropathy of hATTR amyloidosis. N-acetylgalactosamine conjugation and enhanced stabilisation chemistry are utilised to target vutrisiran to the liver and increase stability, respectively, allowing for subcutaneous administration once every 3 months. In a pivotal phase 3 study in patients with hATTR amyloidosis with polyneuropathy, subcutaneous vutrisiran 25 mg every 3 months significantly reduced neuropathy impairment versus external placebo. Vutrisiran was also associated with significant improvements in neuropathy-specific quality of life, gait speed, nutritional status and disability scores. Vutrisiran was generally well tolerated; the only common adverse events to occur at a greater incidence than with external placebo were pain in extremity and arthralgia. Vutrisiran reduces serum vitamin A levels and vitamin A supplementation is recommended. In conclusion, vutrisiran is an efficacious and generally well-tolerated alternative option for the treatment of polyneuropathy of hATTR amyloidosis, which has the potential advantage of infrequent subcutaneous dosage.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive and disabling disease caused by variants in the transthyretin (TTR) gene, which cause destabilisation and misfolding of the TTR protein. Deposition of misfolded TTR protein (amyloid) around nerves causes a range of neuropathic symptoms. Vutrisiran (Amvuttra^®) silences the TTR gene via RNA interference (RNAi). Vutrisiran, administered subcutaneously once every 3 months, is approved in the USA and EU for the treatment of polyneuropathy of hATTR amyloidosis in adults. In a phase 3 study in patients with hATTR amyloidosis with polyneuropathy, vutrisiran significantly reduced neuropathy impairment and improved other disease-related outcomes versus external placebo. Vutrisiran was generally well tolerated, with most adverse events being mild or moderate in severity. As vutrisiran decreases vitamin A levels, patients undergoing vutrisiran treatment should supplement with vitamin A. In conclusion, vutrisiran is an efficacious and generally well-tolerated alternative option for the treatment of polyneuropathy of hATTR amyloidosis, with a convenient dosage regimen.

Birch Bark Extract: A Review in Epidermolysis Bullosa.

Birch bark extract (Filsuvez®; also known as the developmental name Oleogel-S10), a topical gel consisting of 10% dry birch bark extract and 90% sunflower oil, is the first therapy approved in the EU and UK for the treatment of partial thickness wounds associated with dystrophic and junctional epidermolysis bullosa (EB) in patients aged ≥ 6 months old. In the pivotal double-blind, randomized, vehicle-controlled, phase III EASE trial in patients with EB, the primary endpoint was met, in which birch bark extract relative to control gel significantly increased the proportion of patients with first complete target wound closure within 45 days. Moreover, patients treated with birch bark extract demonstrated several other positive findings in improving wound burden and wound-associated symptoms. The clinical benefits of birch bark extract were maintained in the 24-month open-label extension period of the EASE trial. Birch bark extract was generally well tolerated in patients with EB, with the tolerability profile being similar to that of control gel. Current evidence indicates that birch bark extract is an effective, emerging treatment option for patients with dystrophic and junctional EB.

Epidermolysis bullosa (EB) is a rare, heterogenous genetic disorder characterized by extreme skin fragility and trauma-induced blister formation of the skin, mucosa or internal epithelial linings of organs. Due to lack of disease-modifying therapies, the mainstay treatment options for EB remain supportive in nature, such as wound care, skin protection, itch and pain management, infection control and trauma prevention. With various therapies being investigated as a potential treatment option for EB, birch bark extract (Filsuvez^®; also known as the developmental name Oleogel-S10) topical gel has been approved in the EU and UK for the treatment of partial thickness wounds associated with dystrophic and junctional EB in patients aged ≥ 6 months old. Birch bark extract has demonstrated anti-inflammatory, antibacterial, antiviral, antimycotic and wound-healing properties. In patients with EB, birch bark extract relative to control gel significantly accelerated wound healing within 45 days, together with other positive findings in improving wound burden and wound-associated symptoms. The clinical benefits of birch bark extract in improving wound burden were maintained for up to 24 months of continued treatment. Birch bark extract was generally well tolerated in patients with EB, with most adverse events being mild to moderate in severity. Current evidence indicates that birch bark extract is an effective, emerging treatment option for patients with dystrophic and junctional EB.

Flotufolastat F 18: Diagnostic First Approval.

Flotufolastat F 18 (POSLUMA®) is an 18F-labelled radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted imaging agent being developed by Blue Earth Diagnostics, a subsidiary of Bracco Imaging, for prostate cancer imaging. In May 2023, flotufolastat F 18 received its first approval in the USA as a radioactive diagnostic agent for positron emission tomography (PET) of PSMA positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level. This article summarizes the milestones in the development of flotufolastat F 18 leading to this first approval.

Omidubicel: First Approval.

Omidubicel (omidubicel-onlv; Omisirge®) is a nicotinamide-modified stem cell graft derived from cord blood that is being developed by Gamida Cell for the treatment of haematological malignancies and haemoglobinopathies. In April 2023, omidubicel received its first approval in the USA for use in adults and children aged ≥ 12 years with haematological malignancies who are planned for cord blood transplantation following myeloablative conditioning to reduce the incidence of infection and the time to neutrophil recovery. This article summarizes the milestones in the development of omidubicel leading to this first approval.

Efgartigimod Alfa in Generalised Myasthenia Gravis: A Profile of Its Use.

Intravenous efgartigimod alfa (also known as efgartigimod alfa-fcab in the USA; Vyvgart®) is the first neonatal Fc receptor antagonist approved in several countries worldwide, including the USA and EU for the treatment of generalised myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive, and in Japan for the treatment of gMG regardless of antibody status. In the double-blind, placebo-controlled phase 3 ADAPT trial in patients with gMG, efgartigimod alfa significantly and rapidly reduced disease burden and improved muscle strength and quality of life compared with placebo. The clinical benefits of efgartigimod alfa were durable and reproducible. Furthermore, in an interim analysis of the ongoing open-label phase 3 ADAPT+ extension trial, efgartigimod alfa provided consistent clinically meaningful improvements in patients with gMG. Efgartigimod alfa was generally well tolerated, with most adverse events being mild to moderate in severity.

Generalised myasthenia gravis (gMG) is a chronic, autoimmune neuromuscular disorder that can significantly impair quality of life. Several novel targeted therapeutic approaches have emerged to provide faster onset of action compared with conventional immunosuppressive therapy, favourable tolerability profile and the potential for a sustained disease control for patients with gMG. Intravenous efgartigimod alfa (also known as efgartigimod alfa-fcab in the USA; Vyvgart^®) is the first neonatal Fc receptor antagonist approved in several countries worldwide, including the USA and EU for the treatment of gMG in adults who are anti-acetylcholine receptor (AChR) antibody positive, and in Japan for the treatment of gMG regardless of antibody status. In the pivotal clinical trial in patients with gMG, efgartigimod alfa rapidly reduced disease burden and improved muscle strength and quality of life. The beneficial effects of efgartigimod alfa occurred early and were durable and reproducible. Longer term, efgartigimod alfa provided consistent clinically meaningful improvements in patients with gMG. Efgartigimod alfa is generally well tolerated, with most adverse events being mild to moderate in severity. Thus, efgartigimod alfa is a novel, effective and generally well-tolerated treatment option for patients with gMG.

Etranacogene Dezaparvovec: First Approval.

Etranacogene dezaparvovec (etranacogene dezaparvovec-drlb; Hemgenix®) is an adeno-associated virus vector-based gene therapy being developed by uniQure and CSL Behring for the treatment of haemophilia B. In November 2022, etranacogene dezaparvovec was approved in the USA for the treatment of haemophilia B [congenital factor IX (FIX) deficiency] in adults who are currently using FIX prophylaxis therapy, have current or historical life-threatening haemorrhage or have repeated, serious spontaneous bleeding episodes. In December 2022, etranacogene dezaparvovec also received positive opinion in the EU for the treatment of haemophilia B. This article summarizes the milestones in the development of etranacogene dezaparvovec leading to this first approval.

Mirvetuximab Soravtansine: First Approval.

Mirvetuximab soravtansine (mirvetuximab soravtansine-gynx; Elahere™) is an antibody-drug conjugate (ADC), which is comprised of a folate receptor α (FRα) directed antibody conjugated to a microtubule inhibitor via a cleavable linker. The ADC is being developed by ImmunoGen for the treatment of FRα expressing cancers. In November 2022, mirvetuximab soravtansine was approved in the USA for the treatment of adult patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens. This article summarizes the milestones in the development of mirvetuximab soravtansine leading to this first approval.

Pegcetacoplan: A Review in Paroxysmal Nocturnal Haemoglobinuria.

Subcutaneous pegcetacoplan (EMPAVELI® in the USA and ASPAVELI® in the EU) is the first complement component 3 (C3) inhibitor approved for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH) in the USA, and in adults with PNH who are anaemic after ≥ 3 months of treatment with a C5 inhibitor in the EU. In the phase III PRINCE trial in adults with PNH who were anaemic and naïve to a complement inhibitor therapy, pegcetacoplan was superior to the control group (supportive care, excluding complement inhibitors) in achieving haemoglobin stabilization and reducing lactate dehydrogenase levels. Similarly, in the phase III PEGASUS trial in adults with PNH who had a haemoglobin level < 10.5 g/dL despite eculizumab therapy, pegcetacoplan was superior to eculizumab in improving haemoglobin levels. In both trials, pegcetacoplan also improved other clinical and haematological parameters of haemolysis, as well as quality of life (QOL) outcomes. Clinical benefits of pegcetacoplan were sustained for up to 48 weeks of treatment. Pegcetacoplan was generally well tolerated in patients with PNH, with its tolerability profile being similar in patients previously treated with eculizumab and in complement inhibitor-naïve patients. Long-term data would be beneficial to further support the safety profile of pegcetacoplan. Current evidence indicates that pegcetacoplan is a valuable treatment option for adults with PNH.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematological disorder that is characterized by complement-mediated haemolysis, fatigue and thrombotic events. Complement component 5 (C5) inhibitors eculizumab and ravulizumab have demonstrated substantial efficacy in reducing intravascular haemolysis and improving quality of life (QOL) in patients with PNH; however, many patients continue to exhibit anaemia and require transfusions because of uncontrolled extravascular haemolysis. Subcutaneous pegcetacoplan (EMPAVELI^® in the USA and ASPAVELI^® in the EU) is the first C3 inhibitor approved in the USA and EU for the treatment of PNH. Pegcetacoplan targets C3 in the complement cascade, upstream of C5, thereby providing control over both intravascular and extravascular haemolysis. Pegcetacoplan was superior to supportive care in improving clinical and haematological outcomes in patients with PNH who were naïve to a complement inhibitor therapy. Similarly, pegcetacoplan was superior to eculizumab in improving clinical and haematological outcomes in patients with uncontrolled PNH despite eculizumab therapy. Pegcetacoplan also improved QOL and fatigue symptoms. Pegcetacoplan was generally well tolerated, with most adverse events being mild to moderate in severity. Current evidence indicates that pegcetacoplan is a valuable treatment option for adults with PNH.

Sodium Phenylbutyrate and Ursodoxicoltaurine: First Approval.

An oral, fixed-dose coformulation of sodium phenylbutyrate and ursodoxicoltaurine (ALBRIOZA™; hereafter denoted sodium phenylbutyrate/ursodoxicoltaurine) is being developed by Amylyx Pharmaceuticals for the treatment of neurodegenerative diseases. In June 2022, the coformulation received its first approval with conditions in Canada for the treatment of amyotrophic lateral sclerosis (ALS) in adults. The approval was based on results from the multicentre, phase II CENTAUR trial, in which slowing of ALS progression was demonstrated with sodium phenylbutyrate/ursodoxicoltaurine relative to placebo. This article summarizes the milestones in the development of sodium phenylbutyrate/ursodoxicoltaurine leading to this first approval.

Calcium, Magnesium, Potassium and Sodium Oxybates (Xywav®) in Sleep Disorders: A Profile of Its Use.

Calcium, magnesium, potassium and sodium oxybates (Xywav®; hereafter referred to as lower-sodium oxybate), a new oxybate formulation with a greatly reduced sodium burden compared with previously approved sodium oxybate (Xyrem®), is approved for the treatment of cataplexy and excessive daytime sleepiness (EDS) in adults and children aged ≥ 7 years with narcolepsy, and is the first drug approved for the treatment of idiopathic hypersomnia in adults in the USA. In two pivotal, double-blind, placebo-controlled, phase 3 trials of randomized-withdrawal design, lower-sodium oxybate effectively improved cataplexy and EDS in adults with narcolepsy, and EDS and overall idiopathic hypersomnia symptoms in adults with idiopathic hypersomnia during open-label titration and optimization periods. At the end of the double-blind, randomized withdrawal period, participants randomized to switch to placebo experienced significant worsening in these symptoms compared with those randomized to continue lower-sodium oxybate. Furthermore, worsening in patient- and clinical-rated global scales, as well as measures of health-related quality of life were also seen with placebo versus lower-sodium oxybate. Lower-sodium oxybate is generally well tolerated, with the tolerability profile being largely consistent to that seen with sodium oxybate.

Narcolepsy and idiopathic hypersomnia are rare, chronic sleep disorders that can debilitate patients' cognitive function, social functioning and health-related quality of life. They are primarily characterized by excessive daytime sleepiness (EDS) and often require long-term (even life-long) treatment to reduce symptoms and improve functioning. Sodium oxybate (Xyrem^®) is an effective treatment option for cataplexy and EDS in patients with narcolepsy; however, its high sodium content may put patients at higher risk of increased blood pressure and cardiovascular disease. To reduce the excessive sodium intake associated with long-term therapy, lower-sodium oxybate (Xywav^®), a new oxybate formulation with 92% less sodium content, has been developed. In the USA, it is approved for the treatment of cataplexy or EDS in adults and children aged ≥ 7 years with narcolepsy, and is the first drug approved for the treatment of idiopathic hypersomnia in adults. In pivotal phase 3 trials, following dose titration and optimization periods, participants randomized to discontinue lower-sodium oxybate and take placebo showed significant worsening in narcolepsy- and idiopathic hypersomnia-related symptoms, as well as health-related quality of life outcomes compared with participants randomized to continue lower-sodium oxybate. Lower-sodium oxybate is generally well tolerated, with its safety profile similar to that of sodium oxybate. Lower-sodium oxybate is a valuable treatment option for children and adults with narcolepsy and adults with idiopathic hypersomnia.

Sotrovimab: First Approval.

Sotrovimab (Xevudy®) is a recombinant human monoclonal antibody targeted against the severe acute respiratory syndrome coronavirus 2. It is being developed by Vir Biotechnology in collaboration with GlaxoSmithKline for the treatment of coronavirus disease 2019 (COVID-19). Sotrovimab received its first emergency use authorization in May 2021 for the treatment of COVID-19 in the USA, with interim, emergency or conditional authorizations subsequently granted in several other countries. In December 2021, sotrovimab received its first full approval in the EU for use in adolescents (aged ≥ 12 years and weighing ≥ 40 kg) and adults with COVID-19 who do not require oxygen supplementation and who are at high risk of progressing to severe COVID-19. This article summarizes the milestones in the development of sotrovimab leading to this first approval.

Efgartigimod: First Approval.

Efgartigimod (efgartigimod alfa-fcab, Vyvgart™) is a first-in-class neonatal Fc receptor antagonist being developed by argenx for the treatment of autoimmune diseases including myasthenia gravis. In December 2021, intravenous efgartigimod received its first approval in the USA for the treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor (AChR) antibody positive. Intravenous efgartigimod has also been evaluated for generalized myasthenia gravis in various other countries, with the agent subsequently approved in Japan in January 2022 for generalized myasthenia gravis patients regardless of antibody status and in preregistration stage in the EU. Several clinical studies of intravenous and subcutaneous formulation of efgartigimod are also being investigated for other autoimmune diseases including bullous pemphigoid, chronic inflammatory demyelinating polyradiculoneuropathy, immune thrombocytopenia, autoimmune myositis and pemphigus. This article summarizes the milestones in the development of efgartigimod leading to this first approval for generalized myasthenia gravis.

Budesonide/Glycopyrronium/Formoterol: A Review in COPD.

Budesonide/glycopyrronium/formoterol (BREZTRI AEROSPHERE™; TRIXEO AEROSPHERE™) is an inhaled fixed-dose combination of the inhaled corticosteroid (ICS) budesonide, the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide and the long-acting ß2-agonist (LABA) formoterol fumarate approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). It is delivered via a pressurized metered-dose Aerosphere inhaler and is formulated using co-suspension delivery technology. In two pivotal phase III trials of 24-52 weeks' duration, budesonide/glycopyrronium/formoterol reduced the rates of moderate/severe COPD exacerbations and improved lung function to a greater extent than budesonide/formoterol and/or glycopyrronium/formoterol. Budesonide/glycopyrronium/formoterol also demonstrated beneficial effects on dyspnoea, rescue medication requirements and health-related quality of life (HR-QOL), and reduced the risk of all-cause mortality. Budesonide/glycopyrronium/formoterol was generally well tolerated, with the tolerability profile being generally similar to that of the individual components. Budesonide/glycopyrronium/formoterol provides a useful and convenient option for the maintenance treatment of COPD, including for patients whose disease is inadequately controlled with dual ICS/LABA or LAMA/LABA therapy.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease that is characterized by chronic airflow limitation and persistent respiratory symptoms. A step-up treatment approach combining an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA) and a long-acting ß₂-agonist (LABA) may provide clinical benefits in patients with COPD whose disease is inadequately controlled by dual therapies (ICS/LABA or LAMA/LABA). Budesonide/glycopyrronium/formoterol (BREZTRI AEROSPHERE™; TRIXEO AEROSPHERE™) is a fixed-dose ICS/LAMA/LABA combination approved for the maintenance treatment of COPD. It is administered twice daily via a single pressurized metered-dose Aerosphere inhaler. Patients with moderate to very severe COPD receiving budesonide/glycopyrronium/formoterol had fewer moderate or severe COPD exacerbations and improved lung function, respiratory symptoms and quality of life compared with patients receiving ICS/LABA or LAMA/LABA therapy. The risk of death was reduced compared with that of patients receiving LAMA/LABA therapy. Budesonide/glycopyrronium/formoterol was generally well tolerated, with similar rates of adverse events to dual therapy. Budesonide/glycopyrronium/formoterol is a useful and convenient option for the maintenance treatment of COPD.