Givinostat: First Approval.

Givinostat (DUVYZAT™), an orally available histone deacetylase inhibitor, is being developed by Italfarmaco for the treatment of muscular dystrophy and polycythemia vera. Givinostat received its first approval on 21 March 2024, in the USA, for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. Approval was based on the results of the multinational phase III EPIDYS trial, in which givinostat recipients showed less decline than placebo recipients in the time taken to perform a functional task. Givinostat represents the first nonsteroidal treatment for DMD to be approved for use in patients irrespective of the specific genetic variant underlying their disease. Givinostat is available as an oral suspension to be administered twice daily with food. The recommended dosage is based on the body weight of the patient. In the EU, regulatory review of givinostat in DMD is currently underway. This article summarizes the milestones in the development of givinostat leading to this first approval for DMD.

Eftrenonacog Alfa: A Review in Haemophilia B.

Eftrenonacog alfa (Alprolix®) is an extended half-life recombinant factor IX (rFIX)-Fc fusion protein (hereafter referred to as rFIXFc). Administered as an intravenous bolus, it is approved for prophylactic use and the treatment of bleeding in patients with haemophilia B in various countries worldwide, including those of the EU, as well as the USA. In multinational, phase III trials, rFIXFc was effective for the prophylaxis, perioperative management or on-demand treatment of bleeding in male patients with severe haemophilia B regardless of age and irrespective of whether or not they had been previously treated with FIX replacement products. Prophylactic efficacy was maintained over the longer term (up to 5 years) in previously treated patients. rFIXFc effectiveness in the real-world setting is supported by results of prospective studies, as well as the outcomes of several retrospective trials. rFIXFc was well tolerated in clinical trials in previously treated and untreated children, adolescents and/or adults with severe haemophilia B. Thus, rFIXFc continues to represent a useful treatment option among the haemophilia B patient population.

Haemophilia B is a rare inherited bleeding disorder caused by a deficiency in coagulation factor IX (FIX). Its management involves rectifying the deficiency in FIX by administering an FIX replacement product, thereby increasing FIX activity and reducing bleeding. FIX replacement therapy can be administered at the time of bleeding (i.e. as on-demand treatment) or prophylactically (as scheduled injections), as well as before surgery. Eftrenonacog alfa (also known as rFIXFc; Alprolix^®) is a replacement FIX therapy comprising FIX linked to a region of human immunoglobulin G to prolong the half-life of the product. It has been approved for the prevention and treatment of bleeding in patients with haemophilia B in various countries worldwide. Designed to require less frequent injections, rFIXFc was effective and well tolerated when used to prevent or treat bleeding, including before surgery, in individuals with haemophilia B regardless of age or whether they have been treated previously with an FIX replacement product. Thus, rFIXFc continues to represent a useful treatment option for individuals with haemophilia B.

Teprotumumab: A Review in Thyroid Eye Disease.

Teprotumumab (TEPEZZA®), a monoclonal antibody that inhibits the insulin-like growth factor 1 receptor (IGF-1R), is the first disease-modifying therapy approved for the treatment of thyroid eye disease (TED) in the USA. In phase II and III clinical trials in adults with active, moderate-to-severe TED, intravenous teprotumumab significantly improved proptosis response rate and a range of other TED outcomes, including overall response rate, Clinical Activity Score, diplopia and disease-specific quality of life. The clinical benefit of teprotumumab was maintained for up to 51 weeks post-treatment in the majority of patients. Teprotumumab was generally well tolerated; adverse events with the greatest risk difference compared with placebo were muscle spasms, hearing loss and hyperglycaemia. Early real-world experience suggests teprotumumab may also be beneficial in a more diverse TED population. Teprotumumab is the first approved treatment for TED and is effective at reducing symptoms which are often unamenable to historical pharmacological interventions. While further data are required, current evidence suggests teprotumumab represents an important advance in the treatment of TED.

Thyroid eye disease (TED) is an inflammatory disease that involves expansion of the soft tissue surrounding and behind the eye. It can lead to bulging of the eye(s), double vision, optic nerve compression and vision loss. Traditional treatments are often unsatisfactory. Insulin-like growth factor 1 receptor (IGF-1R) signalling is implicated in the progression of TED, leading to the development of teprotumumab (TEPEZZA^®). Teprotumumab, administered intravenously, is a first-in-class monoclonal antibody that inhibits IGF-1R. In clinical trials, teprotumumab was effective at improving bulging of the eye, inflammation, double vision and TED-related quality of life. Almost one year after the cessation of treatment, clinical benefits endured in most patients. Teprotumumab was generally well tolerated, with most adverse events being mild or moderate in severity. Adverse events included muscle spasms, hearing loss and hyperglycaemia. Teprotumumab is the first targeted therapy approved for TED and represents an important advance in the management of this condition.

Delafloxacin: A Review in Community-Acquired Pneumonia.

Delafloxacin (BAXDELA® in the USA; Quofenix® in the EU) is an anionic fluoroquinolone antibacterial that is approved for the treatment of community-acquired pneumonia (CAP) and acute bacterial skin and skin structure infections in adults. Delafloxacin demonstrated in vitro activity against Gram-positive and Gram-negative pathogens, including drug-resistant isolates. In a phase III trial in adults with CAP, delafloxacin was noninferior to moxifloxacin when assessed against FDA- and EMA-defined primary endpoints, with both fluoroquinolones achieving high treatment success rates. A prespecified subgroup analysis suggested that delafloxacin may be more efficacious than moxifloxacin in patients with a history of asthma or chronic obstructive pulmonary disease (COPD). Delafloxacin was generally well tolerated in patients with CAP, with most treatment-emergent adverse events graded as mild or moderate in severity. Fluoroquinolone-associated adverse events of special interest occurred infrequently, with no events of QT prolongation or phototoxicity reported with delafloxacin. Delafloxacin is an effective and generally well-tolerated treatment that increases the number of available treatments for CAP and, although further research is required, may be a useful option for patients with CAP and comorbid asthma or COPD.

Community-acquired pneumonia (CAP) can be caused by bacterial infection of the lungs, and is a common cause of infection-related deaths. As drug-resistant bacteria are becoming more common, new antibacterial drugs are needed. Delafloxacin (BAXDELA^® in the USA; Quofenix^® in the EU) is a fluoroquinolone antibacterial that inhibits bacterial enzymes required for DNA repair and replication. Delafloxacin kills a wide range of bacteria, including some drug-resistant variants. During a trial in adults with CAP, delafloxacin was as effective as moxifloxacin (also a fluoroquinolone antibacterial). Delafloxacin may be more effective than moxifloxacin in patients with a history of asthma or chronic obstructive pulmonary disease (COPD), although further research is needed. Most adverse events with delafloxacin were mild or moderate in severity, with diarrhoea being the most commonly occurring treatment-related adverse event (experienced by < 4% of recipients). Furthermore, the adverse effects of delafloxacin were generally consistent with those previously observed in patients with skin infections. Delafloxacin expands the range of treatments for CAP, and is potentially useful for patients with comorbid asthma or COPD.

Vericiguat: A Review in Chronic Heart Failure with Reduced Ejection Fraction.

Vericiguat (Verquvo®) is the first oral soluble guanylate cyclase (sGC) stimulator to be approved for the treatment of adults with symptomatic, chronic heart failure with reduced ejection fraction (HFrEF). In the phase III VICTORIA trial, vericiguat added to standard of care (SOC) was associated with a significantly lower risk of the primary composite endpoint of death from cardiovascular (CV) causes or first hospitalization from heart failure (HHF) than placebo added to SOC in adults with chronic HFrEF. The risk of all-cause mortality or first HHF (secondary composite endpoint) and the total number of HHF were also statistically significantly reduced by vericiguat therapy. Vericiguat showed no benefit with respect to the primary endpoint in a subgroup of patients with grossly elevated N-terminal pro-brain natriuretic peptide levels. Vericiguat was generally well tolerated; the most common treatment-related adverse event (AE) was hypotension. AEs of special interest included symptomatic hypotension and syncope, which occurred with low incidences that were similar between treatment groups. Thus, vericiguat is an effective and generally well-tolerated treatment option in patients with symptomatic, chronic HFrEF who have experienced a recent worsening event, expanding the options currently available for chronic HFrEF management.

Approximately half of patients with heart failure develop chronic heart failure with reduced ejection fraction (HFrEF). Despite using various standard treatments that are available, some patients with symptomatic, chronic HFrEF still develop worsening heart failure. Soluble guanylate cyclase (sGC) stimulators are an emerging treatment option for heart failure management. They work by stimulating sGC activity (which is reduced in patients with heart failure), with potential benefits for myocardial and vascular function. Vericiguat (Verquvo^®) is the first oral sGC stimulator to be approved for the treatment of adults with symptomatic, chronic HFrEF. When added to standard treatment(s) for chronic HFrEF, vericiguat reduced the combined risk of death from cardiovascular causes or first hospitalization for heart failure. This was primarily driven by a reduction in hospitalizations for heart failure (rather than in mortality). Vericiguat was generally well tolerated in these patients, and the incidences of adverse events of special interest such as symptomatic low blood pressure and fainting were low and similar between vericiguat and placebo recipients. Thus, vericiguat is an effective and well-tolerated treatment option in patients with symptomatic, chronic HFrEF who have experienced a recent worsening event.

Ganaxolone: First Approval.

Ganaxolone (ZTALMY®; Marinus Pharmaceuticals) is a synthetic neuroactive steroid that acts as a positive allosteric modulator of the gamma-aminobutyric acid (GABA)A receptor complex. Ganaxolone received its first approval in March 2022 in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older. Approval was based on the results of a multinational phase III trial, in which ganaxolone was effective in reducing seizure frequency in children and adolescents with CDD. In the EU, a Marketing Authorization Application has been filed for ganaxolone in the treatment of seizures associated with CDD and an opinion from the Committee for Medicinal Products for Human Use is expected later this year. Oral ganaxolone is also currently undergoing phase III evaluation in the treatment of tuberous sclerosis complex-related epilepsy, while an intravenous formulation of ganaxolone is being evaluated in refractory status epilepticus. This article summarizes the milestones in the development of ganaxolone leading to this first approval for seizures associated with CDD.

Pacritinib: First Approval.

Pacritinib (VONJO™) is an orally administered, small molecule kinase inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis and graft-versus-host disease. Pacritinib received its first approval in February 2022 in the USA for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. The accelerated approval was based on results from the randomized, active-controlled, phase III PERSIST-2 trial, in which spleen volume reduction was demonstrated in pacritinib recipients. This article summarizes the milestones in the development of pacritinib leading to this first approval for myelofibrosis.

Nirmatrelvir Plus Ritonavir: First Approval.

Nirmatrelvir plus ritonavir (Paxlovid™; Pfizer) is a co-packaged combination of nirmatrelvir and ritonavir tablets, intended for co-administration and developed for the treatment and post-exposure prophylaxis of coronavirus disease 2019 (COVID-19). Nirmatrelvir is a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, while ritonavir is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor and CYP3A inhibitor. Nirmatrelvir plus ritonavir received its first conditional authorization in December 2021 in the United Kingdom, for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19. In January 2022, nirmatrelvir plus ritonavir received authorization in the EU for use in the same indication. Nirmatrelvir plus ritonavir is authorized for emergency use in the USA. This article summarizes the milestones in the development of nirmatrelvir plus ritonavir leading to its first authorizations and approval for the treatment of COVID-19.

Ocrelizumab: A Review in Multiple Sclerosis.

Ocrelizumab (Ocrevus®) is an intravenously administered, humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The efficacy of ocrelizumab in reducing relapse rates and disease activity in patients with RMS was demonstrated in pivotal trials (versus interferon ß-1a) and supporting single-arm studies in specific subpopulations. In patients with PPMS, ocrelizumab reduced measures of clinical and MRI progression relative to placebo. Clinical benefits were maintained over ≥ 7.5 study years of treatment. Ocrelizumab was generally well tolerated and no new safety signals have emerged with long-term use. Extensive (albeit short-term) real-world data pertaining to ocrelizumab is consistent with that from clinical trials. Ocrelizumab provides the convenience of short, half-yearly infusions. Ocrelizumab continues to represent a generally well-tolerated, high-efficacy disease-modifying therapy (DMT) for RMS and is a valuable treatment for delaying disease progression in patients with PPMS (for whom there are currently no other approved DMTs).

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disease of the CNS. In most patients, it starts as relapsing-remitting MS (RRMS), which involves exacerbations of neurological symptoms (i.e. relapses) followed by periods of remission. In the less common primary progressive MS (PPMS), disability accrues steadily from disease onset. It is now understood that B cells play key roles in MS pathophysiology. Ocrelizumab (Ocrevus^®), a monoclonal antibody that selectively depletes CD20+ B cells, is approved for treating adults with RMS and PPMS in various countries worldwide. Ocrelizumab reduces relapse rates and indicators of disease activity in patients with RMS, and delays the worsening of disability in patients with RMS and PPMS. Of convenience to patients, ocrelizumab is intravenously administered every six months and can be infused rapidly (over ≈ 2 hours) without its safety being substantially altered. Ocrelizumab is a generally well-tolerated and highly effective treatment option for RMS and constitutes the first approved pharmacotherapy for PPMS.

Somatrogon: First Approval.

Somatrogon (NGENLA®), a long-acting human growth hormone based on C-terminal peptide technology, is in development by Pfizer and OPKO Health for the treatment of growth hormone deficiency in pediatric and adult patients. Administered as a once-weekly subcutaneous injection, somatrogon reduces treatment burden relative to once-daily human growth hormone therapy while providing non-inferior efficacy. Somatrogon received its first approval in October 2021 in Canada for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency). This article summarizes the milestones in the development of somatrogon leading to this first approval for the treatment of growth hormone deficiency.

Lonapegsomatropin: Pediatric First Approval.

Lonapegsomatropin (lonapegsomatropin-tcgd; SKYTROFA®), a long-acting prodrug of somatropin (human growth hormone), is in development by Ascendis Pharma as a treatment for growth hormone deficiency in pediatric and adult patients. Lonapegsomatropin received its first approval in August 2021 in the USA for the treatment of pediatric patients at least 1 year of age (and weighing ≥ 11.5 kg) with growth failure due to inadequate secretion of endogenous growth hormone. Lonapegsomatropin is administered as a once-weekly subcutaneous injection; the sustained release of somatropin from lonapegsomatropin eliminates the need for daily somatropin injections. This article summarizes the milestones in the development of lonapegsomatropin leading to this first pediatric approval for the treatment of growth hormone deficiency.

COVID-19: State of the Vaccination.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting coronavirus disease 2019 (COVID-19) pandemic has led to rapid vaccine development and emergency use (EU) rollout. Six vaccines, including two using novel mRNA technology, are EU-listed by the World Health Organisation, and promising published trial data are available for nine more. While efficacy is good, there are various barriers to their global use. Long-term safety and immunogenicity data are being collected along the way.

Osimertinib: A Review in Previously Untreated, EGFR Mutation-Positive, Advanced NSCLC.

Activating mutations in the epidermal growth factor receptor (EGFR) gene have been identified as key oncogenic drivers of non-small cell lung cancer (NSCLC). Osimertinib (Tagrisso®) is an orally administered, third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) that is widely approved for the first-line treatment of advanced NSCLC with activating EGFR mutations. In the pivotal phase III FLAURA trial, osimertinib significantly prolonged progression-free survival (PFS) and overall survival (OS) relative to first-generation EGFR-TKIs in patients with previously untreated, EGFR mutation-positive, advanced NSCLC. Osimertinib also significantly prolonged central nervous system (CNS) PFS in patients with CNS metastases at trial entry. Osimertinib had a generally manageable tolerability profile; the majority of adverse events considered to be possibly related to treatment were of mild to moderate severity. Osimertinib represents a valuable targeted therapeutic for use in adults with previously untreated, EGFR mutation-positive, advanced NSCLC.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with a poor prognosis. In about 17% of Caucasian patients and 39% of Asian patients with NSCLC, mutations in the epidermal growth factor receptor (EGFR) gene drive tumour growth. EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve clinical outcomes in patients with NSCLC harbouring EGFR mutations. Osimertinib (Tagrisso^®) is the first approved third-generation EGFR-TKI. When given to patients with previously untreated, EGFR mutation-positive, advanced NSCLC, osimertinib delayed disease progression or death by ≈ 9 months and extended overall survival by ≈ 7 months relative to first-generation EGFR-TKIs. Overall, the tolerability of osimertinib was similar to that of the first-generation EGFR-TKIs. Osimertinib is an effective, valuable treatment for patients with previously untreated, EGFR mutation-positive, advanced NSCLC.

Imeglimin Hydrochloride: First Approval.

Imeglimin hydrochloride (TWYMEEG®; hereafter referred to as imeglimin) is an orally administered, first-in-class glimin being developed by Poxel and, in several Asian countries, Sumitomo Dainippon Pharma for the treatment of type 2 diabetes (T2D). The glimins are a novel class of glucose-lowering agents that target multiple components of diabetes-associated pathology. In June 2021, imeglimin received its first approval for use in T2D in Japan. The Japanese approval was based on extensive preclinical and clinical data, including positive results from the pivotal phase III TIMES programme. This article summarizes the milestones in the development of imeglimin leading to this first approval for T2D.