Drugs

Paul, Barry; Rodriguez, Cesar; Usmani, Saad Z.

doi: 10.1007/s40265-022-01697-0pmid: 35412114

With recent advances in myeloma therapy, patients can achieve long-term remissions, but eventually relapses will occur. Triple-class refractory myeloma (disease that is refractory to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) and penta-refractory myeloma (disease that is refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) are associated with a particularly poor prognosis, and novel treatments are desperately needed for these patients. Targeting B cell maturation antigen (BCMA), which is ubiquitously expressed on plasma cells, has emerged as a well-tolerated and highly efficacious strategy in patients with relapsed and refractory myeloma. Several mechanisms of targeting BCMA are currently under investigation, including antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T cells and natural killer (NK) cells, all with unique side effect profiles. Early phase clinical trials showed unprecedented response rates in highly refractory myeloma patients, leading to the recent approvals of some of these agents. Still, many questions remain with regard to this target, including how best to target it, how to treat patients who have progressed on a BCMA-targeting therapy, and whether response rates will deepen if these agents are used in earlier lines of therapy. In this review, we examine the rationale for targeting BCMA and summarize the data for several agents across multiple classes of BCMA-targeting therapeutics, paying special attention to the diverse mechanisms and unique challenges of each therapeutic class.

Schifano, Fabrizio; Catalani, Valeria; Sharif, Safia; Napoletano, Flavia; Corkery, John Martin; Arillotta, Davide; Fergus, Suzanne; Vento, Alessandro; Guirguis, Amira

doi: 10.1007/s40265-022-01701-7pmid: 35366192

‘Smart drugs’ (also known as ‘nootropics’ and ‘cognitive enhancers’ [CEs]) are being used by healthy subjects (i.e. students and workers) typically to improve memory, attention, learning, executive functions and vigilance, hence the reference to a ‘pharmaceutical cognitive doping behaviour’. While the efficacy of known CEs in individuals with memory or learning deficits is well known, their effect on non-impaired brains is still to be fully assessed. This paper aims to provide an overview on the prevalence of use; putative neuroenhancement benefits and possible harms relating to the intake of the most popular CEs (e.g. amphetamine-type stimulants, methylphenidate, donepezil, selegiline, modafinil, piracetam, benzodiazepine inverse agonists, and unifiram analogues) in healthy individuals. CEs are generally perceived by the users as effective, with related enthusiastic anecdotal reports; however, their efficacy in healthy individuals is uncertain and any reported improvement temporary. Conversely, since most CEs are stimulants, the related modulation of central noradrenaline, glutamate, and dopamine levels may lead to cardiovascular, neurological and psychopathological complications. Furthermore, use of CEs can be associated with paradoxical short- and long-term cognitive decline; decreased potential for plastic learning; and addictive behaviour. Finally, the non-medical use of any potent psychotropic raises serious ethical and legal issues, with nootropics having the potential to become a major public health concern. Further studies investigating CE-associated social, psychological, and biological outcomes are urgently needed to allow firm conclusions to be drawn on the appropriateness of CE use in healthy individuals.

Shah, Manan P.; Neal, Joel W.

doi: 10.1007/s40265-022-01698-zpmid: 35412115

Over the past 2 decades, rapid advances in molecular profiling and the development of targeted therapies have dramatically improved the clinical course of advanced non-small-cell lung cancer (NSCLC). Mutations in the epidermal growth factor receptor (EGFR) gene are found in about a third of patients with advanced NSCLC, and the approval of first-generation EGFR targeted kinase inhibitors significantly improved survival when compared with platinum-based doublet chemotherapy (PBC), the previous standard of care. Inevitably, selective pressure from first-generation EGFR inhibitors led to acquired resistance mechanisms, such as the T790M mutation. The advent of third-generation EGFR inhibitors (e.g., osimertinib) successfully overcame the T790M resistance mechanism, and osimertinib subsequently became the first-line therapy for EGFR mutant NSCLC. Currently, research in EGFR mutant NSCLC is primarily focused on targeting resistance mechanisms to osimertinib. Over the past several years, many important acquired and intrinsic mechanisms of resistance to osimertinib have been identified. Acquired resistance mechanisms include C797X, mesenchymal epithelial transition factor (MET) amplification, HER2/HER3 amplification, phosphoinositide 3-kinase (PI3K) pathway mutations, RAS/mitogen-activated protein kinase (MAPK) pathway mutations, cell–cycle gene alterations, oncogenic fusions, and histologic transformations. An important intrinsic resistance mechanism to osimertinib is the EGFR exon 20 insertion mutation, which is sensitive to the newly Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor mobocertinib and the EGFR/MET bispecific antibody amivantamab. This review article aims to (1) summarize the advances in the treatment of EGFR mutant NSCLC, (2) delineate known resistance mechanisms to the current first-line therapy, osimertinib, and (3) describe the development of targeted drugs that aim to overcome these resistance mechanisms.

Landgren, Valdemar; Savard, Josephine; Dhejne, Cecilia; Jokinen, Jussi; Arver, Stefan; Seto, Michael C.; Rahm, Christoffer

doi: 10.1007/s40265-022-01696-1pmid: 35414050

Guidelines for the pharmacological treatment of paraphilic disorders have historically been based on data from forensic settings and on risk levels for sexual crime. However, emerging treatment options are being evaluated for individuals experiencing distress because of their sexual urges and preferences, targeting both paraphilic disorders such as pedophilic disorder (PeD) and the new diagnosis of compulsive sexual behavior disorder (CSBD) included in the International Classification of Diseases, 11th Revision (ICD-11). As in other mental disorders, this may enable individualized pharmacological treatment plans, taking into account components of sexuality (e.g. high libido, compulsivity, anxiety-driven/sex as coping), medical and psychiatric comorbidity, adverse effects and patient preferences. In order to expand on previous reviews, we conducted a literature search focusing on randomized controlled trials of pharmacological treatment for persons likely to have PeD or CSBD. Our search was not restricted to studies involving forensic or criminal samples. Twelve studies conducted between 1974 and 2021 were identified regardless of setting (outpatient or inpatient), with only one study conducted during the last decade. Of a total of 213 participants included in these studies, 122 (57%) were likely to have PeD, 34 (16%) were likely to have a CSBD, and the remainder had unspecified paraphilias (40, 21%) or sexual offense (17, 8%) as the treatment indication. The diagnostic procedure for PeD and/or CSBD, as well as comorbid psychiatric symptoms, has been described in seven studies. The studies provide some empirical evidence that testosterone-lowering drugs reduce sexual activity for patients with PeD or CSBD, but the body of evidence is meager. There is a need for studies using larger samples, specific criteria for inclusion, longer follow-up periods, and standardized outcome measures with adherence to international reporting guidelines.

Blair, Hannah A.

doi: 10.1007/s40265-022-01705-3pmid: 35416593

Subcutaneous daratumumab (DARZALEX®) co-formulated with recombinant human hyaluronidase (DARZALEX FASPRO®) is approved in several countries, including the USA and those of the EU, for use in combination with bortezomib, cyclophosphamide and dexamethasone for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. Daratumumab is a CD38-targeting, human IgG1κ monoclonal antibody. In the pivotal phase III ANDROMEDA trial in adults with newly diagnosed systemic AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone significantly increased the proportion of patients achieving a haematological complete response relative to bortezomib, cyclophosphamide and dexamethasone alone (primary endpoint). Daratumumab combination therapy produced rapid and deep haematological responses which were associated with improved major organ deterioration progression-free survival (PFS). The addition of daratumumab also led to higher cardiac and renal response rates at 6 and 12 months. Daratumumab had an acceptable tolerability profile when used as combination therapy. Therefore, daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone represents an important emerging first-line treatment option for patients with systemic AL amyloidosis.

Markham, Anthony

doi: 10.1007/s40265-022-01700-8pmid: 35347635

Gefapixant (Lyfnua®; Merck & Co.) is a first-in-class, non-narcotic, selective P2X3 receptor antagonist being developed for the treatment of refractory chronic cough or unexplained chronic cough. Marketing approval for gefapixant is being sought in the EU and USA, and the drug was recently approved for marketing in Japan as treatment for refractory or unexplained chronic cough. This article summarizes the milestones in the development of gefapixant leading to this first approval.

Lee, Arnold

doi: 10.1007/s40265-022-01708-0pmid: 35362854

Clazosentan (PIVLAZ™) is a small molecule, endothelin (ET) A receptor-selective antagonist being developed by Idorsia Pharmaceuticals. ETA receptor inhibition by clazosentan decreases ET-related cerebral vasospasm, which may occur after an aneurysmal subarachnoid haemorrhage. Clazosentan has been approved in Japan for use in the prevention of cerebral vasospasm, vasospasm-related cerebral infarction and cerebral ischaemic symptoms after aneurysmal subarachnoid haemorrhage, following the results from the JapicCTI163369 and JapicCTI163368 phase III trials. This article summarises the milestones in the development of clazosentan leading to this first approval in this indication.

Dhillon, Sohita

doi: 10.1007/s40265-022-01704-4pmid: 35364798

Tebentafusp (tebentafusp-tebn; Kimmtrak®) is a first-in-class, bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor (TCR) CD3 T cell engager being developed by Immunocore for the treatment of uveal melanoma and malignant melanoma. The TCR arm of tebentafusp binds to HLA-A*02:01-positive uveal melanoma cells and activates polyclonal T cells, through CD3, to release inflammatory cytokines and cytolytic proteins, resulting in the direct lysis of tumour cells. In January 2022, tebentafusp received its first approval in the USA for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma, and in February 2022 received a Positive Opinion from the EU Committee for Medicinal Products for Human Use for the treatment of uveal melanoma. Tebentafusp is under regulatory review for the treatment of metastatic uveal melanoma in the UK, Australia and Canada. Clinical studies of tebentafusp are underway for uveal melanoma and cutaneous melanoma in several countries worldwide. This article summarizes the milestones in the development of tebentafusp leading to this first approval for unresectable or metastatic uveal melanoma.

Hoy, Sheridan M.

doi: 10.1007/s40265-022-01709-zpmid: 35384641

Palovarotene (Sohonos™) is an orally bioavailable selective retinoic acid receptor (RAR)γ agonist being developed by Ipsen for the reduction of heterotopic ossification (HO) formation in patients with fibrodysplasia ossificans progressiva (FOP). By binding to RARγ, palovarotene inhibits bone morphogenetic protein and SMAD 1/5/8 signalling: interfering with these pathways prevents chondrogenesis and ultimately HO by permitting normal muscle tissue repair or regeneration to occur. Palovarotene received its first approval on 21 January 2022 to reduce the formation of HO in adults and children aged 8 years and above for females and 10 years and above for males with FOP in Canada. This article summarizes the milestones in the development of palovarotene leading to this first approval.

Barbier, Liese; Vulto, Arnold G.

doi: 10.1007/s40265-022-01714-2pmid: 35389202