Ensitrelvir Fumaric Acid: First Approval.

Ensitrelvir fumaric acid (Xocova®) is an oral SARS-CoV-2 main protease inhibitor developed by Shionogi for the treatment of SARS-CoV-2 infection. It is the first single-entity, nonpeptidic, noncovalent, small molecule antiviral of its kind. Following emergency regulatory approval in Japan in November 2022, ensitrelvir received standard approval in Japan on 5 March 2024 for the treatment of SARS-CoV-2 infection. This article summarizes the milestones in the development of ensitrelvir leading to this first standard approval for SARS-CoV-2 infection.

Dimdazenil: First Approval.

Dimdazenil (Junoenil®) is a small-molecule, oral, partial positive allosteric modulator of the gamma-aminobutyric acid (GABA)A receptor that is being developed by Zhejiang Jingxin Pharmaceutical in collaboration with Evotec for the treatment of insomnia. Dimdazenil is designed to overcome issues associated with full GABAA receptor agonists, such as tolerance, withdrawal symptoms and associated adverse effects. On 29 November 2023, dimdazenil oral capsules received approval in China for the short-term treatment of insomnia. This article summarizes the milestones in the development of dimdazenil leading to this first approval for insomnia.

Iptacopan: First Approval.

Iptacopan (FABHALTA®) is an oral complement Factor B inhibitor developed by Novartis Pharmaceuticals for the treatment of complement-mediated diseases. Acting upstream of complement 5 in the alternative pathway, iptacopan inhibits both terminal complement-mediated intravascular haemolysis and complement 3-mediated extravascular haemolysis. On 5 December 2023, iptacopan received approval in the USA for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH). This article summarizes the milestones in the development of iptacopan leading to this first approval for PNH.

Perfluorohexyloctane Ophthalmic Solution: A Review in Dry Eye Disease.

Perfluorohexyloctane ophthalmic solution (Miebo®) is a single-entity, water-, steroid- and preservative-free, first-in-class semifluorinated alkane that is approved in the USA for the treatment of the signs and symptoms of dry eye disease (DED). DED is often linked with meibomian gland dysfunction (MGD), which causes an excessive evaporation of tears. Perfluorohexyloctane ophthalmic solution stabilizes the lipid layer of the tear film and inhibits tear evaporation by forming a monolayer at the air-liquid interface. In the phase III GOBI and MOJAVE trials in adults with DED associated with MGD, one drop of perfluorohexyloctane ophthalmic solution instilled in each eye four times daily over 8 weeks resulted in statistically significant and clinically meaningful improvements in the signs and symptoms of DED compared with hypotonic saline (0.6%). The agent was generally well tolerated, with most ocular adverse events being mild or moderate in severity. The efficacy and tolerability of perfluorohexyloctane ophthalmic solution was sustained for up to 52 weeks in an extension study (KALAHARI). As the first and currently the only prescription treatment approved in the USA directly addressing the pathophysiology of excessive tear evaporation, perfluorohexyloctane ophthalmic solution is a valuable emerging option for the management of DED.

Dry eye disease (DED) is a common eye disorder caused by many factors. In most cases, DED is linked with meibomian gland dysfunction (MGD), which causes an excessive evaporation of tears. Perfluorohexyloctane ophthalmic solution (Miebo^®), a single-entity, water-, steroid- and preservative-free, first-in-class semifluorinated alkane, is approved in the USA for the treatment of the signs and symptoms of DED. The agent stabilizes the lipid layer of the tear film and prevents the evaporation of tears by forming a layer on the surface of the tear film. In two phase III clinical trials in adults with MGD-associated DED, one drop of perfluorohexyloctane ophthalmic solution instilled in each eye four times daily over 8 weeks led to significant improvements in the signs and symptoms of DED when compared with hypotonic saline (0.6%). Perfluorohexyloctane ophthalmic solution was generally well tolerated, with most ocular adverse events being mild or moderate in severity. Thus, as the first and currently the only prescription treatment approved in the USA directly addressing excessive tear evaporation, perfluorohexyloctane ophthalmic solution is a valuable emerging option for the management of DED.

Tirzepatide: A Review in Type 2 Diabetes.

Tirzepatide (Mounjaro®), a first-in-class dual incretin agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, is approved for use as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM) in the USA, EU, Japan and other countries. It comes as single-dose prefilled pens and single-dose vials. In phase III SURPASS trials, once-weekly subcutaneous tirzepatide, as monotherapy or add-on-therapy to oral glucose-lowering medications and insulin, was superior to the GLP-1 receptor agonists (RAs) dulaglutide 0.75 mg and semaglutide 1 mg as well as basal and prandial insulin for glycaemic control and weight loss in adults with inadequately controlled T2DM. Tirzepatide was generally well tolerated, with a safety profile consistent with that of GLP-1 RAs. Tirzepatide was associated with a low risk of clinically significant or severe hypoglycaemia and no increased risk of major adverse cardiovascular events. Adverse events were mostly mild to moderate in severity, with the most common being gastrointestinal events including nausea, diarrhoea, decreased appetite and vomiting. In conclusion, tirzepatide is a valuable addition to the treatment options for T2DM.

Many people with type 2 diabetes mellitus (T2DM) do not achieve and maintain glycaemic and weight management goals using currently available treatments. Tirzepatide (Mounjaro^®) is the first incretin-based glucose-lowering medication to be approved as an add-on to diet and exercise in adults with T2DM that targets both the glucose-dependent insulinotropic polypeptide receptor (GIP) and the glucagon-like peptide-1 (GLP-1) receptor. In patients with inadequately controlled T2DM, tirzepatide improved glycaemic control and body weight more so than dulaglutide 0.75 mg, semaglutide 1 mg and insulin when used on its own or in combination with other medications. Tirzepatide was generally well tolerated and had a low risk of hypoglycaemia. The most common adverse events were usually short-lived gastrointestinal-related events, which were generally mild to moderate in nature, including nausea, diarrhoea, decreased appetite and vomiting. Tirzepatide is a valuable addition to the treatment options for people with inadequately controlled T2DM.

Nedosiran: First Approval.

Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for the treatment of primary hyperoxaluria (PH). It reduces oxalate overproduction by inhibiting the expression of the hepatic lactate dehydrogenase (LDH) enzyme. Nedosiran received its first approval on 29 September 2023 in the USA to lower urinary oxalate levels in children aged ≥ 9 years and adults with PH type 1 (PH1) and relatively preserved kidney function [e.g. estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2]. This article summarizes the milestones in the development of nedosiran leading to this first approval for PH1.

Durvalumab: A Review in Advanced Biliary Tract Cancer.

Durvalumab (Imfinzi®), a therapeutic human monoclonal antibody which binds to and blocks the activity of the immunosuppressive programmed death-ligand 1 (PD-L1) protein, is approved in the USA, EU, Japan and other countries in combination with gemcitabine and cisplatin for adults with advanced biliary tract cancer. In the pivotal phase 3 TOPAZ-1 trial, durvalumab plus gemcitabine and cisplatin significantly prolonged overall survival and progression-free survival compared with placebo plus gemcitabine and cisplatin in adults with advanced biliary tract cancer. Benefit from durvalumab was seen irrespective of primary tumour location, disease status at diagnosis (unresectable or recurrent), or initial levels of PD-L1 expression. The tolerability of durvalumab plus gemcitabine and cisplatin was manageable. Overall, the addition of durvalumab to gemcitabine and cisplatin is a valuable new treatment option for adults with advanced biliary tract cancer.

Biliary tract cancers are a diverse group of cancers that develop in the bile ducts or the gallbladder. Patients with these cancers typically have poor survival. Chemotherapy (gemcitabine plus cisplatin) has been the first-line treatment for biliary tract cancer for over a decade, with no new treatments further improving on its overall survival benefit until recently. Durvalumab (Imfinzi^®) belongs to a class of drugs known as checkpoint inhibitors; these drugs activate the immune system to help fight cancer. In the phase 3 TOPAZ-1 trial, the addition of durvalumab to first-line chemotherapy prolonged the overall survival compared with placebo plus chemotherapy in adults with advanced biliary tract cancer. The tolerability of durvalumab in combination with chemotherapy was manageable. Thus, durvalumab plus gemcitabine and cisplatin is a valuable new treatment option for adults with advanced biliary tract cancer.

Respiratory Syncytial Virus Prefusion F Subunit Vaccine: First Approval of a Maternal Vaccine to Protect Infants.

Pfizer is developing a bivalent respiratory syncytial virus (RSV) prefusion F subunit vaccine (RSVpreF; ABRYSVO™) for preventing RSV illness in infants and individuals aged ≥ 60 years. RSVpreF received approval for vaccination of pregnant individuals to help protect infants against RSV illness on 21 August 2023 in the USA. RSVpreF is also approved in the USA (31 May 2023) for active immunization of individuals aged ≥ 60 years for the prevention of lower respiratory tract disease (LRTD) caused by RSV. In the EU, RSVpreF has received approval for both indications, and it has been submitted for regulatory approval in Canada (both indications) and in Japan (maternal immunization to protect infants). This article summarizes the milestones in the development of RSVpreF leading to the approval for use in pregnant individuals to prevent LRTD in infants.

Lotilaner Ophthalmic Solution 0.25%: First Approval.

Lotilaner ophthalmic solution 0.25% (XDEMVY™), a gamma-aminobutyric acid-gated chloride channel (GABA-Cl) inhibitor selective for mites, is being developed by Tarsus Pharmaceuticals for the treatment of Demodex blepharitis and meibomian gland dysfunction in patients with Demodex lid infestation (Demodex-induced meibomianitis). On 24 July 2023, lotilaner ophthalmic solution 0.25% received its first approval in the USA for the treatment of Demodex blepharitis. The agent is also currently in phase 3 development for Demodex blepharitis in China and phase 2 development for Demodex-induced meibomianitis in the USA. This article summarizes the milestones in the development of lotilaner ophthalmic solution 0.25% leading to this first approval for the treatment of Demodex blepharitis in the USA.

Olipudase Alfa in Non-CNS Manifestations of Acid Sphingomyelinase Deficiency: A Profile of Its Use.

Olipudase alfa (Xenpozyme™) is an intravenously administered acid sphingomyelinase enzyme replacement therapy indicated to treat non-CNS manifestations of acid sphingomyelinase deficiency (ASMD) in adult and paediatric patients. It is the first and currently the only disease-modifying treatment for ASMD. Olipudase alfa treatment improves hepatosplenomegaly, lung function and platelet counts, along with multiple other pathological features of ASMD in adult and paediatric patients with ASMD. These benefits are sustained through at least 24 months of treatment. Olipudase alfa is generally well tolerated; infusion-associated reactions (mostly mild) were the most common treatment-related adverse events. Other warnings and precautions associated with its use include risks of hypersensitivity reactions (including anaphylaxis) and elevated transaminase levels seen in clinical trials, and foetal malformation based on animal studies. All these risks are generally manageable. A gradual dose escalation of olipudase alfa, followed by a maintenance phase, is required to reduce the risks of toxic sphingomyelin catabolites build up, infusion-associated reactions and transient transaminase elevations.

Sphingomyelin, a fatty substance found in mammalian cell membranes, is broken down by the enzyme acid sphingomyelinase in healthy individuals. Acid sphingomyelinase deficiency (ASMD) is a rare inherited genetic disorder, in which the patient's body does not produce enough of the acid sphingomyelinase enzyme, leading to accumulation of sphingomyelin in major organs such as lungs, liver and spleen. ASMD types A and A/B (but not type B) also involve brain cells. Olipudase alfa (Xenpozyme™) is an enzyme replacement therapy indicated to treat non-CNS manifestations of ASMD in adult and paediatric patients. By reducing sphingomyelin accumulation, olipudase alfa improves lung function, reduces liver and spleen volume, and increases platelet counts, while also correcting other ASMD-related dysfunctions. These benefits are sustained through at least 24 months of treatment. Olipudase alfa is generally well tolerated. It is the first and currently the only disease-modifying treatment for ASMD.

Rezafungin: First Approval.

Rezafungin (Rezzayo™), an intravenous once-weekly echinocandin that inhibits 1,3-ß-D-glucan synthase, is being developed by Cidara Therapeutics. In March 2023, rezafungin received approval in the USA for the treatment of candidaemia and invasive candidiasis in patients aged ≥ 18 years who have limited or no alternative treatment options. Rezafungin is also being developed for the prevention of invasive fungal diseases in blood and marrow transplant recipients. This article summarizes the milestones in the development of rezafungin leading to the first approval for the treatment of candidaemia and invasive candidiasis.

Sparsentan: First Approval.

Sparsentan (FILSPARI™) is an oral, dual endothelin angiotensin receptor antagonist that is being developed by Travere Therapeutics for the treatment of immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis (FSGS). In February 2023, sparsentan received accelerated approval in the USA for reducing proteinuria in adults with primary IgA nephropathy who are at risk of rapid disease progression. This article summarizes the milestones in the development of sparsentan leading to this first approval for IgA nephropathy.

Selinexor-Bortezomib-Dexamethasone: A Review in Previously Treated Multiple Myeloma.

Selinexor [Nexpovio® (EU); Xpovio® (USA)] is a first-in-class, selective exportin-1 inhibitor. Oral selinexor once weekly in combination with subcutaneous bortezomib once weekly and oral dexamethasone twice weekly (selinexor-bortezomib-dexamethasone) is approved in the EU and USA for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. In the open-label, randomized, phase 3 BOSTON trial, this regimen significantly prolonged progression-free survival (PFS) compared with the standard bortezomib-dexamethasone regimen in patients with previously treated multiple myeloma. Selinexor-bortezomib-dexamethasone had a generally manageable tolerability profile and an acceptable safety profile in BOSTON, with a lower incidence of peripheral neuropathy (a bortezomib-induced toxicity) compared with bortezomib-dexamethasone. The triplet regimen uses less bortezomib and dexamethasone during the first 24 weeks of treatment. The efficacy and safety profiles of selinexor-bortezomib-dexamethasone, combined with its once-weekly administration of selinexor and bortezomib, make it a useful additional triplet therapy option for previously treated multiple myeloma.

Despite the availability of several drug classes, relapse and refractoriness is common in multiple myeloma. Selinexor [Nexpovio^® (EU); Xpovio^® (USA)] is an oral drug that selectively inhibits exportin-1, a nuclear exporter protein overexpressed in many cancer cells. Selinexor-bortezomib-dexamethasone is approved in the EU and USA for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. In the pivotal BOSTON trial, the triplet regimen significantly prolonged PFS compared with standard bortezomib-dexamethasone regimen in patients with previously treated multiple myeloma, with a generally manageable tolerability profile and an acceptable safety profile. Selinexor-bortezomib-dexamethasone uses less bortezomib and dexamethasone versus standard bortezomib-dexamethasone regimen. Therefore, selinexor-bortezomib-dexamethasone is a useful additional triple treatment option for previously treated multiple myeloma.

Selpercatinib: A Review in Advanced RET Fusion-Positive NSCLC.

Selpercatinib (Retevmo®/Retsevmo®) is an orally-administered, selective inhibitor of rearranged during transfection (RET) kinase approved for the treatment of advanced RET fusion-positive non-small cell lung cancer (NSCLC). In a pivotal phase 1/2 clinical trial in this population, selpercatinib treatment was associated with robust and durable responses, including intracranial responses, in patients previously treated with platinum-based chemotherapy, as well as in treatment-naïve patients. Selpercatinib had a manageable tolerability profile and an acceptable safety profile; adverse events could generally be managed with dose reductions and only a small proportion of patients discontinued selpercatinib due to treatment-related adverse events. The most common treatment-related adverse events that were grade 3-4 in severity were hypertension, elevated alanine aminotransferase and elevated aspartate aminotransferase. Thus, currently available evidence suggests that selpercatinib is a promising new RET-targeted therapy option for patients with advanced RET fusion-positive NSCLC.

Targeted therapy against the oncogenic driver in tumours carrying such mutations offers the potential for greater anti-tumour efficacy and limited off-target toxicity. Fusion of the rearranged during transfection (RET) gene with another gene is one such driver in a small subset of patients with non-small cell lung cancer (NSCLC). Selpercatinib (Retevmo^®/Retsevmo^®) is a selective RET kinase inhibitor that is taken orally for the treatment of advanced NSCLC with an RET gene fusion. In the pivotal clinical trial in these patients, selpercatinib demonstrated durable responses both in patients previously treated with platinum-based chemotherapy and patients with no prior treatment. Selpercatinib also demonstrated anti-tumour activity against brain metastases associated with NSCLC. Adverse events with selpercatinib were generally manageable with dose reductions and few patients discontinued selpercatinib due to adverse effects. Thus, current data suggest that selpercatinib is a promising new RET-targeted treatment option for advanced RET fusion-positive NSCLC.

Relugolix/Estradiol/Norethisterone (Norethindrone) Acetate: A Review in Symptomatic Uterine Fibroids.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate (Ryeqo®; Myfembree®) has been approved for the management of heavy menstrual bleeding associated with uterine fibroids in the USA and management of moderate to severe symptoms of uterine fibroids in the EU. Relugolix is a gonadotropin releasing hormone (GnRH) receptor antagonist that decreases serum estradiol and progesterone concentrations to postmenopausal levels. The addition of estradiol/norethisterone acetate to relugolix ameliorates relugolix-induced bone loss and hot flush. In the two phase 3 LIBERTY trials, relugolix + estradiol/norethisterone substantially decreased menstrual bleeding and improved a range of other uterine fibroid symptoms in women with uterine fibroids-associated heavy menstrual bleeding. The combination was generally well tolerated, with vasomotor symptoms being the most common adverse reaction. Treatment with this combination for over up to 2 years did not induce a clinically meaningful bone loss in the majority of women. Relugolix/estradiol/norethisterone acetate, with its convenient once-daily administration, is a useful addition to current pharmacological treatment options for premenopausal women with symptomatic uterine fibroids.

Uterine fibroids are a common type of noncancerous tumours that grow in the uterus. In some women, these tumours cause debilitating symptoms, such as heavy menstrual bleeding, pelvic pain and passing of blood clots. Hysterectomy is the only definitive treatment for this condition, but is associated with some disadvantages. Less invasive procedures and medical treatments are now available to treat these symptoms. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone acetate (Ryeqo^®; Myfembree^®) has been approved to treat symptoms of uterine fibroids. This combination works by suppressing ovarian hormone levels. In clinical trials, relugolix + estradiol/norethisterone substantially reduced menstrual bleeding and improved several other symptoms in women with uterine fibroids-associated heavy menstrual bleeding. The combination was generally well tolerated and had a minimal impact on bone loss, a known adverse effect of such therapies. With its convenient once-daily administration, relugolix/estradiol/norethisterone acetate is a useful addition to current medical treatment options for premenopausal women with symptomatic uterine fibroids.