Lenacapavir: First Approval.

Lenacapavir (Sunlenca®) is a long-acting capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) being developed by Gilead Sciences Inc. It is available as an oral tablet and injectable solution, with the latter being a slow-release formulation to allow bi-annual subcutaneous administration. In August 2022, lenacapavir received its first approval in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen. This article summarizes the milestones in the development of lenacapavir leading to this first approval for the treatment of HIV-1 infection.

Ozanimod: A Review in Ulcerative Colitis.

Ozanimod (Zeposia®) is the first sphingosine-1-phosphate receptor (S1PR) modulator to be approved for the treatment of adults with moderately to severely active ulcerative colitis in the USA, and in adults with moderately to severely active ulcerative colitis who have had an inadequate or lost response to, or were intolerant of, either conventional therapy or a biologic in the EU. An oral agent, ozanimod is administered once daily as induction and maintenance therapy. In the randomized, double-blind, multinational phase 2 Touchstone and phase 3 True North clinical trials, ozanimod was effective in inducing clinical remission and maintaining remission relative to placebo in adults with moderately to severely active ulcerative colitis. Ozanimod was generally well tolerated in these studies, with manageable or transient adverse events (AEs). Current data from the Touchstone and True North open-label extensions are consistent with the primary studies with respect to therapeutic efficacy and tolerability, with no new safety signals observed. Although further data will be beneficial, ozanimod expands the treatment options for adults with moderately to severely active ulcerative colitis.

Ulcerative colitis is a chronic inflammatory bowel disease involving a dysregulated immune response in the intestinal mucosa. Conventional therapy options for moderate to severe ulcerative colitis are initially effective, but associated with increased risk of adverse events, resistance to treatment, or loss of response over time. Consequently, small molecule drugs have become of interest as alternative treatment options. Ozanimod (Zeposia^®) is an oral drug that targets and modulates the activity of sphingosine-1-phosphate receptors to reduce the movement of lymphocytes from the lymph nodes to sites of inflammation. Compared with placebo, ozanimod significantly improved rates of clinical remission and was generally well tolerated in adults with moderately to severely active ulcerative colitis. Findings from open-label extension studies suggest that ozanimod remains efficacious and generally well tolerated with long-term use. Although further data will be beneficial, ozanimod expands the treatment options for adults with moderately to severely active ulcerative colitis.

Dabigatran Etexilate: A Review in Pediatric Venous Thromboembolism.

Although rare in children, venous thromboembolism (VTE) is markedly more likely in hospitalized patients, particularly with the use of central venous access devices. Dabigatran etexilate (Pradaxa®) is one of the first direct non-vitamin K antagonist oral anticoagulants (DOAC) approved for use in pediatric patients. It is approved in the EU and USA for the treatment of VTE in patients who have been treated with a parenteral anticoagulant for ≥ 5 days, and for the prevention of recurrent VTE. In an open-label, phase 2b/3 clinical trial in pediatric patients with acute VTE treated for ≈ 3 months, dabigatran etexilate was non-inferior to standard of care (SOC) treatment for the primary composite endpoint of complete thrombus resolution, freedom from recurrent VTE and VTE-related death. In a single-arm phase 3 safety study, few patients experienced recurrent VTE with ≤ 12 months of anticoagulation with dabigatran etexilate. Dabigatran etexilate was generally well tolerated in both studies; bleeding events were mostly minor and, in the phase 2b/3 study, occurred at a similar incidence to SOC. Although further data will be useful, dabigatran etexilate is a valuable and convenient treatment option in pediatric VTE.

Venous thromboembolism (VTE) is rare in children, but its risk is markedly increased in hospitalized patients. Oral dabigatran etexilate (Pradaxa^®) is one of the first of its class to be approved to treat acute VTE and for the secondary prevention of VTE in pediatric patients. In clinical trials conducted in children (aged < 18 years), dabigatran etexilate had similar efficacy to standard of care treatments (other anticoagulants) in acute VTE, and prevented recurrent VTE with longer-term anticoagulation. Dabigatran etexilate was generally well tolerated; most bleeding events during treatment were minor. Although further data will be useful, dabigatran etexilate is a valuable and convenient treatment option in pediatric VTE.

Nivolumab Plus Relatlimab: First Approval.

Nivolumab plus relatlimab (nivolumab and relatlimab-rmbw; Opdualag™) is a fixed-dose, combination immunotherapy treatment being developed by Bristol Myers Squibb for the treatment of multiple types of advanced cancers. Both drugs are immunoglobulin G4 (IgG4) monoclonal antibodies developed to target immune checkpoints, with nivolumab targeting the programmed cell death protein 1 (PD-1) receptor and relatlimab being a newly developed, first-in-class drug targeting the lymphocyte-activation gene 3 (LAG-3) protein. In March 2022, nivolumab plus relatlimab received its first approval in the USA for the treatment of unresectable or metastatic melanoma in adult patients and paediatric patients aged ≥ 12 years who weigh ≥ 40 kg. This article summarizes the milestones in the development of this combination therapy leading to this first approval for unresectable or metastatic melanoma.

Risdiplam: A Review in Spinal Muscular Atrophy.

Risdiplam (Evrysdi®) is the first oral drug developed to treat spinal muscular atrophy (SMA) and is approved in multiple countries worldwide. It is approved for the treatment of SMA in patients aged ≥ 2 months in the USA and the EU, with this approval further specified in the EU for the treatment of 5q-autosomal recessive SMA with a clinical diagnosis of SMA types 1, 2, or 3 or with one to four survival motor neuron 2 (SMN2) copies. As an SMN2 pre-mRNA splicing modifier, risdiplam increases the production of full-length SMN protein, the lack of which drives the pathophysiology of SMA. In phase 2/3 clinical trials, risdiplam significantly improved motor function in infants with SMA type 1 and in patients aged 2-25 years with SMA types 2 or 3. These motor improvements were maintained with up to 2 years of treatment with risdiplam. Risdiplam was generally well tolerated, with a favourable benefit to risk balance. As an oral drug, risdiplam provides a convenient and useful treatment option across a broad range of patient ages and subtypes of SMA.

Patients with spinal muscular atrophy (SMA) have insufficient levels of survival motor neuron (SMN) protein due to a defect in the SMN1 gene. The SMN2 gene is also able to produce some SMN protein, but not to the amount required to maintain adequate muscle function and form. Risdiplam (Evrysdi^®) is a drug that targets SMN2 to improve the production of viable SMN protein and the first oral medication approved for the treatment of SMA. In the FIREFISH and SUNFISH clinical trials, risdiplam improved motor function in patients of all ages, with improvements maintained after 24 months of treatment. Risdiplam was generally well tolerated in these trials, with a favourable benefit to risk balance. As an orally administered treatment, risdiplam provides a convenient and useful treatment option across a broad range of patient ages and subtypes of SMA.

Teriflunomide: Pediatric First Approval.

Teriflunomide (Aubagio®), which was developed by Sanofi, is an oral immunomodulatory agent targeting the mitochondrial enzyme dihydroorotate dehydrogenase and available to adults to treat relapsing-remitting multiple sclerosis (MS). On 18 June 2021, teriflunomide received its first approval in this indication in pediatric patients aged ≥ 10 years in the EU. This article summarizes the milestones in the development of teriflunomide leading to this first pediatric approval for relapsing-remitting MS.

Olaparib: A Review as First-Line Maintenance Therapy in Advanced Ovarian Cancer.

Olaparib (Lynparza®) is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor approved for first-line maintenance treatment in adults with advanced ovarian cancer who are in complete or partial response to first-line, platinum-based chemotherapy. Originally approved as monotherapy, olaparib is also approved to be administered in combination with bevacizumab in patients whose cancer is associated with homologous recombination deficiency (HRD), defined by either a BRCA1/2 mutation and/or genomic instability. In phase III trials, olaparib monotherapy significantly improved progression-free survival (PFS) relative to placebo (SOLO-1), as did olaparib plus bevacizumab relative to placebo plus bevacizumab (PAOLA-1), in patients with advanced ovarian cancer who had responded to platinum-based chemotherapy. In PAOLA-1, improvements in PFS with olaparib plus bevacizumab were not seen in patients with HRD-negative tumours relative to placebo plus bevacizumab. Both olaparib monotherapy and olaparib in combination with bevacizumab had generally manageable tolerability profiles. Olaparib, alone or in combination with bevacizumab, is a useful option for the first-line maintenance treatment of adults with HRD-positive, advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line, platinum-based chemotherapy.

Oral olaparib (Lynparza^®) was originally approved as monotherapy for the first-line maintenance treatment of adults with advanced high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who responded to first-line, platinum-based chemotherapy. Olaparib is also approved to be used in combination with bevacizumab in patients whose cancer is associated with homologous recombination deficiency (HRD), which is characterized by BRCA1/2 mutations or genomic instability. Olaparib reduced the risk of disease progression or death in patients who had received platinum-based chemotherapy without bevacizumab (when olaparib was given as monotherapy) and with bevacizumab (when olaparib was given with bevacizumab). However, this reduction was not seen in patients with HRD-negative tumours who were treated with olaparib plus bevacizumab compared with placebo plus bevacizumab. Both olaparib monotherapy and olaparib in combination with bevacizumab had generally manageable tolerability profiles. Olaparib, alone or in combination with bevacizumab, is a useful option for the first-line maintenance treatment of adults with HRD-positive, advanced ovarian cancer who responded to first-line, platinum-based chemotherapy.

Olanzapine/Samidorphan: First Approval.

Samidorphan, which was developed by Alkermes, is an opioid receptor antagonist that has been co-formulated with olanzapine into a single-dose oral tablet to mitigate the risk of weight gain while providing the therapeutic effect of olanzapine. Olanzapine/samidorphan (LYBALVI™) was recently approved in the USA for the treatment of schizophrenia and bipolar I disorder. This article summarizes the milestones in the development of samidorphan leading to this first approval of olanzapine/samidorphan.

Diroximel Fumarate in Relapsing Forms of Multiple Sclerosis: A Profile of Its Use.

Diroximel fumarate (Vumerity®), an orally administered disease-modifying drug (DMD), expands the available treatment options for adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS (RRMS), and active secondary progressive MS. It demonstrates bioequivalence to dimethyl fumarate and was developed to provide similar clinical benefits, but with an improved gastrointestinal (GI) tolerability profile. In RRMS patients who are treatment-naïve or were previously treated with interferon-ß or glatiramer acetate, diroximel fumarate reduces annualized relapse rates, with most patients experiencing no relapses during treatment, and reduces the formation of new MS-associated brain lesions. Diroximel fumarate has an acceptable tolerability profile that is consistent with that of dimethyl fumarate, albeit with a significantly lower rate of GI adverse events.

Fostamatinib: A Review in Chronic Immune Thrombocytopenia.

Fostamatinib (Tavalisse®; Tavlesse®) is the first spleen tyrosine kinase (Syk) inhibitor approved for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who have had an insufficient response to previous treatment. By inhibiting Syk activation in macrophages, fostamatinib blocks autoantibody-mediated platelet phagocytosis. In the placebo-controlled phase III FIT1 and FIT2 trials, 24 weeks of oral fostamatinib therapy increased platelet count in previously treated adults with ITP. A significantly higher proportion of patients achieved stable response with fostamatinib than with placebo in FIT1, but not in FIT2; however, pooled analyses of the two studies showed that fostamatinib produced significantly higher stable and overall response rates than placebo. Interim findings from the ongoing FIT3 open-label extension study suggested that the efficacy of fostamatinib was maintained with long-term treatment (up to 62 months; median duration 6 months), including in patients receiving fostamatinib as second- or later-line treatment. Fostamatinib had a generally manageable tolerability profile in all three FIT studies, with no serious safety risks. Fostamatinib therefore provides an alternative treatment option for chronic ITP in adult patients with an insufficient response to previous treatment.

Sofpironium Bromide: First Approval.

Sofpironium bromide (ECCLOCK® in Japan) gel is a topical anticholinergic agent developed by Bodor Laboratories and licenced to Brickell Biotech for the treatment of hyperhidrosis. The drug is designed to reduce sweating by inhibiting M3 muscarinic receptors in eccrine glands at the application site. In September 2020, sofpironium bromide gel 5% received its first approval in Japan for the treatment of primary axillary hyperhidrosis (PAH). Clinical studies are currently ongoing in the USA to assess the safety and efficacy of sofpironium bromide gel 15% in PAH. This article summarizes the milestones in the development of sofpironium bromide gel leading to this first approval for the treatment of PAH.

Correction to: Romosozumab: A Review in Postmenopausal Osteoporosis.

Unfortunately the sections were published incorrectly in the original article.

Romosozumab: A Review in Postmenopausal Osteoporosis.

Romosozumab (Evenity®), a humanized monoclonal antibody, promotes bone formation and inhibits bone resorption by inhibiting sclerostin, a protein involved in the regulation of bone formation. Subcutaneous romosozumab is approved in several countries, including those of the EU for treating severe osteoporosis as well as in the USA for osteoporosis in postmenopausal women at high risk of fracture. In pivotal phase III trials (FRAME and ARCH), 12 months' once-monthly romosozumab 210 mg significantly reduced vertebral and clinical fracture risk versus placebo and oral alendronate in postmenopausal women with osteoporosis. After patients transitioned from romosozumab to 12-24 months of subcutaneous denosumab or oral alendronate, fracture risks were significantly improved versus placebo-to-denosumab and alendronate-only treatment. In these trials and a phase IIIb trial, romosozumab significantly increased bone mineral density (BMD) relative to placebo, alendronate and subcutaneous teriparatide at 12 months, with these benefits maintained 12-24 months after patients transitioned from romosozumab to alendronate or denosumab in pivotal trials. Romosozumab had a generally manageable tolerability profile. While further clinical experience is needed to more definitively establish its efficacy and safety, including its CV safety, romosozumab extends the treatment options in postmenopausal women with osteoporosis who have a high risk of fracture and in those who have failed or are intolerant to other available osteoporosis therapy.

Topical Minocycline Foam 4%: A Review in Acne Vulgaris.

Topical minocycline foam 4% (Amzeeq™) is approved in the USA for the treatment of inflammatory lesions of non-nodular, moderate to severe acne vulgaris (acne) in patients aged ≥ 9 years. It was developed to minimize systemic minocycline absorption and toxicity, and its high lipid content allows efficient drug movement through sebum and into affected sites. The favorable in vitro resistance profile of oral minocycline seen in Cutibacterium acnes (C. acnes) isolates was maintained with topical minocycline foam 4%. In 12-week, phase III clinical trials, once-daily topical minocycline foam 4% significantly improved both inflammatory and noninflammatory lesions relative to foam vehicle in patients aged ≥ 9 years with moderate to severe acne and was reported by most patients to be satisfactory or highly satisfactory to use. Extension trial data indicated that topical minocycline foam 4% continued to be effective for up to 52 weeks' therapy. Topical minocycline foam 4% was generally well tolerated in these patients, with most adverse events (AEs) and all serious AEs considered to be unrelated to treatment. Cutaneous AEs were uncommon, and findings from a dermal safety study showed that topical minocycline foam 4% did not have any effects related to phototoxicity, photoallergy, skin sensitization and skin irritation. Topical minocycline foam 4% is thus a useful addition to available treatment options for the management of inflammatory lesions of non-nodular, moderate to severe acne in adult and pediatric patients aged ≥ 9 years.

Levodopa Inhalation Powder: A Review in Parkinson's Disease.

Levodopa inhalation powder (Inbrija®) is approved for the intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with levodopa/dopa-decarboxylase inhibitor (LD-DCI) in the EU and specifically with carbidopa/levodopa in the USA. The approved dosage is 84 mg taken as needed up to five times a day. Administered via a breath-actuated inhaler, this formulation enables levodopa to bypass the gastrointestinal (GI) tract and, instead, rapidly enter the bloodstream through the pulmonary system. In the 12-week, double-blind, placebo-controlled, phase III SPAN-PD trial, as-needed levodopa inhalation powder 84 mg improved motor symptoms during OFF periods in PD patients (aged 30-86 years) treated with levodopa and carbidopa or benserazide. The likelihood of achieving an ON state 60 min postdose was significantly higher in the levodopa inhalation powder than the placebo group, with most patients in the levodopa inhalation powder group experiencing improvements in PD symptoms. Findings from longer-term, 52-week phase III studies were consistent with those from the SPAN-PD trial with regards to the treatment of OFF episodes. Levodopa inhalation powder was generally well tolerated and did not noticeably affect pulmonary function in PD patients. Providing a nonintrusive, convenient treatment method, levodopa inhalation powder is a promising option for the intermittent treatment of OFF episodes in patients with PD treated with a LD-DCI.

Correction to: Dapagliflozin: A Review in Type 1 Diabetes.

The article Dapagliflozin: A Review in Type 1 Diabetes, written by Julia Paik and Hannah A. Blair, was originally published Online First without Open Access.

Dapagliflozin: A Review in Type 1 Diabetes.

Oral dapagliflozin (Edistride®, Forxiga®) is approved in the EU at a dosage of 5 mg/day as an adjunct to insulin in adults with type 1 diabetes (T1D) and a body mass index (BMI) of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. As a highly selective SGLT2 inhibitor, dapagliflozin decreases plasma glucose levels independently of insulin action and enables glycaemic control improvement without increasing the risks associated with intensive insulin therapy. In the phase III DEPICT-1 and -2 trials, dapagliflozin 5 mg/day as an adjunct to insulin improved glycaemic control and reduced total daily insulin dose and bodyweight relative to placebo in adults with inadequately controlled T1D, including in patients with a BMI of ≥ 27 kg/m2, over 24 weeks of treatment. In extensions of these trials, these improvements were maintained up to 52 weeks. Dapagliflozin was generally well tolerated with a manageable safety profile and a hypoglycaemia profile generally similar to placebo. The incidence of diabetic ketoacidosis with dapagliflozin in patients with a BMI ≥ 27 kg/m2 was less than half that of the overall population who received dapagliflozin. Dapagliflozin is the first SGLT2 inhibitor to be approved for use in T1D and, while further clinical experience in T1D is required to more definitively establish its efficacy and safety profile, it provides a promising adjunctive treatment option for adults with T1D and a BMI of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.