Talicabtagene Autoleucel: First Approval.

Talicabtagene autoleucel (NexCAR19™) is a chimeric antigen receptor (CAR) T-cell therapy being developed by the Indian Institute of Technology, Bombay (IIT-B) and Immunoadoptive Cell Therapy (ImmunoACT) for the treatment of relapsed/refractory B-cell malignancies. Talicabtagene autoleucel contains autologous T cells from the patient, which have been modified to express a humanized anti-CD19 CAR that targets B cells. A single intravenous dose of talicabtagene autoleucel was associated with high response rates in pooled results from a phase I and phase II trial in patients with relapsed/refractory B-cell malignancies. Talicabtagene autoleucel was approved in India for the treatment of relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia on 13 October 2023. This article summarizes the milestones in the development of talicabtagene autoleucel leading to this first approval for relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia.

Bimekizumab: A Review in Psoriatic Arthritis.

Although several biological disease-modifying antirheumatic drugs (bDMARDs), including interleukin (IL)-17A inhibitors, are approved for psoriatic arthritis, the treatment of this disease remains suboptimal. Bimekizumab (Bimzelx®), a dual IL-17A and IL-17F inhibitor, is approved in the EU, Great Britain and Japan for the treatment of psoriatic arthritis. In pivotal phase 3 clinical trials in patients who were bDMARD-naïve or previously had an inadequate response or intolerance to tumour necrosis factor (TNF) α inhibitors, bimekizumab improved the signs and symptoms of psoriatic arthritis across a range of joint, skin, radiographic and patient-reported outcomes compared with placebo, including the proportion of patients achieving a ≥ 50% response in the American College of Rheumatology criteria. Phase 2 clinical trial data have shown that responses are maintained up to 3 years. Bimekizumab was generally well tolerated in patients with psoriatic arthritis, with a safety profile consistent with that in other approved indications. The most common adverse events included nasopharyngitis, upper respiratory tract infection, oral candidiasis, headache and diarrhoea. In conclusion, bimekizumab extends the treatment options available to patients with psoriatic arthritis.

Psoriatic arthritis is a chronic, painful, inflammatory condition that can involve peripheral and axial joints, skin and nails, and can lead to structural joint damage. Several disease-modifying antirheumatic drugs (DMARDs), including biologicals (bDMARDs) that target various inflammatory cytokines, are approved for psoriatic arthritis. However, many patients do not respond or lose response to these treatments. Bimekizumab (Bimzelx^®), an inhibitor of both interleukin (IL)-17A and IL-17F, is approved for the treatment of psoriatic arthritis in the EU, Great Britain and Japan. In clinical trials, bimekizumab improved the signs and symptoms of psoriatic arthritis across key disease domains compared with placebo, including the proportion of patients achieving ≥ 50% response in the American College of Rheumatology criteria. Bimekizumab was efficacious whether patients were naïve to bDMARDs or previously had an inadequate response to or did not tolerate tumour necrosis factor (TNF) α inhibitors. Clinical responses were sustained long-term (up to 3 years). Bimekizumab was generally well tolerated, with the most common adverse events being infections (such as nasopharyngitis, upper respiratory tract infection and oral candidiasis), headache and diarrhoea. In conclusion, bimekizumab extends the treatment options available to patients with psoriatic arthritis.

Eplontersen: First Approval.

Eplontersen (Wainua™) is a ligand-conjugated antisense oligonucleotide directed to TTR, which is being developed by Ionis Pharmaceuticals and AstraZeneca for the treatment of TTR-mediated amyloidosis (ATTR). Eplontersen, which is targeted to the liver by a ligand containing three N-acetyl galactosamine residues, binds to wild-type and variant TTR mRNA, thus reducing the levels of circulating TTR protein and amyloid deposition. Subcutaneous eplontersen reduced serum TTR levels, inhibited neuropathy progression and improved health-related quality of life in patients with polyneuropathy of hereditary ATTR (ATTRv-PN; v for variant) in a phase III trial. Based on these results, eplontersen was approved in the USA for the treatment of ATTRv-PN on 21 December 2023 and is currently undergoing regulatory review for a similar indication in the EU, the UK, Switzerland and Canada. Eplontersen is also undergoing phase III development for ATTR cardiomyopathy. This article summarizes the milestones in the development of eplontersen leading to this first approval for ATTRv-PN.

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.

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer.

Trastuzumab deruxtecan (Enhertu®) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate approved in several countries, including the USA and those of the EU, for adults with unresectable or metastatic HER2-positive breast cancer who have previously received at least one prior anti-HER2-based regimen. In a pivotal phase 3 trial in this setting, intravenous trastuzumab deruxtecan demonstrated prolonged progression-free survival compared with trastuzumab emtansine (previously the recommended second-line therapy in this indication). Trastuzumab deruxtecan had a generally manageable safety and tolerability profile. Common treatment-related adverse events included haematological and gastrointestinal disorders. Interstitial lung disease (ILD)/pneumonitis is associated with a regulatory warning and requires careful monitoring. In conclusion, trastuzumab deruxtecan is a valuable new treatment option for HER2-positive breast cancer, having been shown to be effective with a generally manageable safety and tolerability profile in adults with unresectable or metastatic disease who have received one or more prior anti-HER2-based regimens.

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have improved HER2-positive breast cancer outcomes in recent years. Despite this, almost all patients will eventually experience disease progression (cancer growth or spread). Trastuzumab deruxtecan (Enhertu^®) is an intravenously administered treatment that combines a drug that is toxic to cells and an antibody that targets it to HER2-expressing cells. It has been approved in several countries for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have previously received one or more anti-HER2-based therapies. In a pivotal clinical trial, trastuzumab deruxtecan showed longer survival without disease progression than trastuzumab emtansine (the previously recommended treatment after first disease progression). Trastuzumab deruxtecan had a generally manageable safety and tolerability profile. The most common classes of adverse events were blood and gastrointestinal disorders. Fatal events of interstitial lung disease (ILD)/pneumonitis have occurred with trastuzumab deruxtecan and patient monitoring is required. Trastuzumab deruxtecan is a valuable new option for patients with unresectable or metastatic HER2-positive breast cancer who have received at least one prior anti-HER2-based regimen.

Daridorexant in Insomnia Disorder: A Profile of Its Use.

Daridorexant (Quviviq™) is a useful option for the treatment of insomnia disorder, which has shown efficacy in younger and older adults. It antagonises the orexin receptors, thereby reducing the wake drive. Daridorexant is the first dual orexin receptor antagonist to be approved for the treatment of chronic insomnia in the EU and has been approved for insomnia in the USA. In phase 3 clinical trials, daridorexant dose-dependently improved objective latency to persistent sleep, objective wake time after sleep onset, subjective total sleep time and, at the 50 mg dose, subjective daytime functioning compared with placebo. Daridorexant was generally well tolerated. Adverse events (AEs) commonly associated with insomnia drugs, such as somnolence, fatigue and dizziness, occurred at a similar or slightly greater frequency with daridorexant than with placebo. Falls occurred at a similar or lower frequency with daridorexant than with placebo. Most AEs were mild in severity and the incidence was not dose-dependent. The efficacy of daridorexant was maintained during a 12-month extension trial, with no new safety or tolerability concerns.

Insomnia disorder is characterized by persistent difficulty falling asleep and/or maintaining sleep and impaired daytime functioning. Dual orexin receptor antagonists suppress wakefulness and are generally considered to have a favourable safety profile compared with older classes of insomnia drugs, including less risk of tolerance, dependence, abuse and withdrawal effects. Daridorexant (Quviviq™) is the first dual orexin receptor antagonist approved for the treatment of chronic insomnia in the EU and has been approved for insomnia in the USA. In clinical trials, daridorexant improved objective sleep onset, objective sleep maintenance and self-reported total sleep time, and self-reported daytime functioning at a 50 mg dose. Daridorexant was generally well tolerated, with a low incidence of adverse events such as sleepiness, fatigue, dizziness and falls, most of which were similar to that with placebo. The efficacy and tolerability of daridorexant were sustained for 12 months. With a favourable safety profile compared to other classes of insomnia drugs, minimal residual next-morning effects and improvements in daytime functioning, daridorexant is a useful option for the treatment of insomnia disorder.

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.

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.

Inebilizumab: A Review in Neuromyelitis Optica Spectrum Disorder.

Inebilizumab (Uplizna®) is a recently approved monoclonal antibody for use in adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody seropositive. Inebilizumab targets the B cell antigen CD19 and effectively depletes circulating B cells, thus suppressing inflammatory NMOSD attacks that are potentially disabling or life-threatening. It is approved as an intravenous infusion in several countries. In the pivotal phase 2/3 N-MOmentum trial, inebilizumab reduced the risk of NMOSD attacks compared with placebo, including in AQP4-antibody seropositive patients. Inebilizumab also significantly reduced the risk of disability score worsening, the number of NMOSD-related hospitalisations and MRI lesion count, but had no significant effect on low-contrast binocular vision. The treatment effect on relapse risk and disability scores was sustained in inebilizumab-treated patients for ≥ 4 years during the open-label extension. Inebilizumab was generally well tolerated, with the most common adverse events being urinary tract infection and arthralgia. Thus, inebilizumab is an effective treatment option for adults with AQP4-antibody seropositive NMOSD.

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic condition denoted by relapsing autoimmune attacks affecting the central nervous system, which may lead to accruing disability or death. It is frequently associated with anti-aquaporin-4 (AQP4) autoantibodies. In recent years, three new monoclonal antibody therapies have gained regulatory approval for the treatment of NMOSD. Inebilizumab (Uplizna®), a monoclonal antibody that targets B cells, is approved for use in AQP4-antibody seropositive adults as an intravenous infusion. Inebilizumab was effective at preventing NMOSD relapse compared with placebo in a pivotal phase 2/3 trial. It also prevented worsening of disability scores, and decreased the number of NMOSD-related hospitalisations and MRI lesions, but did not significantly improve low-contrast binocular vision. The clinical benefit of inebilizumab was maintained long-term (≥ 4 years in the open-label extension). Inebilizumab was generally well tolerated, with most adverse events being mild to moderate in severity. The most common adverse events were urinary tract infection and joint pain. Inebilizumab provides an effective option for preventing NMOSD attacks in adults who are AQP4-antibody seropositive.

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review.

Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet ß-cells and may thus cause ß-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of ß-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are ß-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.

Altered metabolic gene expression in the brain of a triprolyl-human amylin transgenic mouse model of type 2 diabetes.

Type 2 diabetes mellitus is a major health concern worldwide; however, the molecular mechanism underlying its development is poorly understood. The hormone amylin is postulated to be involved, as human amylin forms amyloid in the pancreases of diabetic patients, and oligomers have been shown to be cytotoxic to ß-cells. As rodent amylin is non-amyloidogenic, mice expressing human amylin have been developed to investigate this hypothesis. However, it is not possible to differentiate the effects of amylin overexpression from ß-cell loss in these models. We have developed transgenic mice that overexpress [25, 28, 29 triprolyl]human amylin, a non-amyloidogenic variant of amylin, designated the Line 44 model. This model allows us to investigate the effects of chronic overexpression of non-cytotoxic amylin. We characterised this model and found it developed obesity, hyperglycaemia and hyperinsulinaemia. This phenotype was associated with alterations in the expression of genes involved in the amylin, insulin and leptin signalling pathways within the brain. This included genes such as c-Fos (a marker of amylin activation); Socs3 (a leptin inhibitor); and Cart, Pomc and Npy (neuropeptides that control appetite). We also examined Socs3 protein expression and phosphorylated Stat3 to determine if changes at the mRNA level would be reflected at the protein level.