Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic ApproachMelville, Andrew R.; Kearsley-Fleet, Lianne; Buch, Maya H.; Hyrich, Kimme L.
doi: 10.1007/s40265-020-01309-9pmid: 32361822
Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled disease. Whilst most patients are adequately treated on methotrexate and other first-line disease-modifying anti-rheumatic drugs (DMARDs), a proportion requires biologic (b) and targeted synthetic (ts) DMARDs, with a further subsection failing multiple agents. Recent observational studies have adopted working definitions of refractory RA based on number of failed DMARDs, with prevalence estimates of 6–21% depending on threshold and study population. Risk factors include treatment delay, baseline disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defining refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassification risk of co-existent non-inflammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defining refractory disease; registry studies show that growing treatment options have resulted in rapid b/tsDMARD cycling and earlier refractory status, and refractory RA is itself a dynamic concept, evolving with each new therapeutic class. Whilst the biology underpinning refractory RA remains largely unknown, a general overview of biomarker studies and clinical trials old and new offers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufficient to personalise or meaningfully sequence b/tsDMARDs. Therefore, avoidance of a refractory course is best achieved by following proven management paradigms (e.g. early diagnosis and treat-to-target), addressing modifiable risk factors, and considering enrolment in novel trials.
Novel Approaches Towards a Functional Cure of HIV/AIDSBailon, Lucia; Mothe, Beatriz; Berman, Lance; Brander, Christian
doi: 10.1007/s40265-020-01322-ypmid: 32436069
Therapeutic approaches towards a functional cure or eradication of HIV have gained renewed momentum upon encouraging data emerging from studies in SIV monkey models and recent results from human clinical studies. However, a multitude of questions remain to be addressed, including how to deal with the latent viral reservoir, how to boost the host immune response to the virus and what the hurdles are to reach relevant viral compartments in the body. Advances have been made especially with regard to identifying agents that can reactivate the latent virus in vivo and boost the cellular and humoral immunity, but it remains largely unclear whether any of these strategies can awaken a sufficiently large fraction of the viral reservoir and whether the boosted immunity can prevent rapid viral replication once antiretroviral treatments are stopped.
Treatment of Antipsychotic-Induced Akathisia: Role of Serotonin 5-HT2a Receptor AntagonistsPoyurovsky, Michael; Weizman, Abraham
doi: 10.1007/s40265-020-01312-0pmid: 32385739
Akathisia is one of the most prevalent and distressing adverse effects associated with antipsychotic drug treatment. Propranolol, a non-selective beta-adrenergic receptor antagonist, is currently considered a first-line treatment for antipsychotic-induced akathisia (AIA). Surprisingly, the evidence for its anti-akathisia effect is modest. Propranolol’s side effects (e.g. orthostatic hypotension, bradycardia), contraindications (e.g. asthma) and increased complexity in titration schedules limit its use in some patients. Anticholinergic agents and benzodiazepines merely provide symptomatic relief in patients with AIA. Effective and well-tolerated treatment remains a major unmet need in akathisia and warrants a search for new anti-akathisia agents. Accumulating evidence during the last two decades indicates that agents with marked postsynaptic serotonin 5-HT2a receptor antagonism (ritanserin, cyproheptadine, trazodone, mianserin, mirtazapine) may represent a new class of potential anti-akathisia remedies. Among these agents, low-dose mirtazapine (7.5 mg or 15 mg once daily) has demonstrated the most compelling evidence for therapeutic efficacy. In this narrative review we highlight the clinical significance of AIA, outline major approaches for its management and propose a practical algorithm for its treatment.
Immune Checkpoint Blockade in Oncogene-Driven Non-Small-Cell Lung CancerSomasundaram, Ashwin; Socinski, Mark A.; Villaruz, Liza C.
doi: 10.1007/s40265-020-01320-0pmid: 32436070
Patients with oncogene-driven lung cancer have limited therapeutic options after progressing on their targeted tyrosine kinase inhibitor (TKI) therapy. Given the growing role of immune checkpoint inhibitor (ICI) therapy in the treatment of lung cancer, oncogene-driven cancer has warranted further evaluation regarding ICI therapy. However, initial ICI studies have suggested that ICI monotherapy is not only lacking in efficacy, but that it may be less tolerable in oncogene-driven non-small-cell lung cancer (NSCLC). We performed a detailed review of the literature using Pubmed, and present the current and impactful findings here. Studies evaluating the use of concurrent ICI therapy and TKI therapy have also suggested increased toxicity and lack of increased activity in these patients. Larger studies have suggested that the sequence of ICI therapy and TKI, such as utilizing ICI therapy after TKI as opposed to before TKI, may play a role in reducing toxicity (hepatotoxicity, pneumonitis); however, these studies are limited in number. Novel methods of patient selection, including low tumor mutational burden, inflamed phenotyping, and high CD8 + tumor infiltrating lymphocytes, may aid in determining ideal patients to give ICI therapy. Novel therapeutic combinations including the addition of anti-VEGF (vascular endothelial growth factor) therapy or radiotherapy show promising findings for these patients. Given the growing unmet need for therapeutic options in patients with oncogene-driven NSCLC who have failed TKI therapy, further research is warranted.
Galcanezumab: A Review in the Prevention of Migraine and Treatment of Episodic Cluster HeadacheScott, Lesley J.
doi: 10.1007/s40265-020-01329-5pmid: 32504377
Galcanezumab (Emgality®) is a humanized monoclonal antibody targeting the calcitonin gene-related peptide (CGRP), thereby inhibiting its physiological activity, with CGRP playing a key role in the pathophysiology of migraine and headache disorders. In pivotal phase 3 trials, recommended dosages of subcutaneous galcanezumab once monthly were significantly more effective than placebo as preventive therapy in adults with episodic (EVOLVE-1 and -2; over 6 months) or chronic (REGAIN; over 3 months) migraine (± aura), including in patients who had failed several prior preventive migraine drugs (CONQUER; over 3 months). The beneficial effects of galcanezumab preventive treatment in reducing the number of monthly migraine headache days (MHDs) and improving health-related quality of life (HR-QOL) were sustained during up to 1 year of treatment. In adults with episodic cluster headache, galcanezumab treatment was associated with a significant reduction in the weekly frequency of cluster headache attacks across weeks 1–3 compared with placebo (primary endpoint), albeit during weeks 4–8, there was a convergence of results between these treatment groups. Although further evidence from the clinical setting is required to determine its long-term safety profile, given its convenient administration regimen, efficacy and short-term tolerability profile, monthly galcanezumab represents an important emerging option for the prevention of episodic and chronic migraine (± aura) and the treatment of episodic cluster headache.
Isatuximab: First ApprovalDhillon, Sohita
doi: 10.1007/s40265-020-01311-1pmid: 32347476
Isatuximab (isatuximab-irfc; Sarclisa®) is an IgG1 monoclonal antibody that binds to the glycoprotein CD38 expressed on the surface of haematopoietic and tumour cells. It is being developed by Sanofi, under a license from Immunogen, for the treatment of haematological malignancies. In March 2020, intravenous isatuximab (in combination with pomalidomide and dexamethasone) was approved in the USA for the treatment of adult patients with multiple myeloma who have received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor. Isatuximab has also received a positive opinion in the EU for the treatment of relapsed and refractory multiple myeloma. This article summarizes the milestones in the development of isatuximab leading to the first approval in the USA.
Cabotegravir Plus Rilpivirine: First ApprovalMarkham, A.
doi: 10.1007/s40265-020-01326-8pmid: 32495274
A regimen comprising extended release injectable suspensions of cabotegravir and rilpivirine for concurrent administration (CABENUVA™) is being developed by ViiV Healthcare and Janssen Pharmaceutica (Janssen) as a complete regimen for HIV infection. Based on the results of the ATLAS and FLAIR trials, the regimen was recently approved in Canada for the treatment of HIV-1 infection in adults to replace current antiretroviral therapy in patients who are virologically stable and suppressed. This article summarizes the milestones in the development of co-packaged cabotegravir and rilpivirine leading to this first approval.
Pemigatinib: First ApprovalHoy, Sheridan M.
doi: 10.1007/s40265-020-01330-ypmid: 32472305
Pemigatinib (PEMAZYRE™), a small molecule inhibitor of fibroblast growth factor receptor (FGFR) 1, FGFR2 and FGFR3, received accelerated approval in April 2020 in the USA for the treatment of adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma and a FGFR2 fusion or other rearrangement, as detected by a US FDA-approved test. Developed by Incyte Corporation, it is the first targeted treatment for cholangiocarcinoma in the USA. The recommended dosage of pemigatinib is 13.5 mg once daily, administered orally with or without food, on days 1–14 of a 21-day cycle until disease progression or unacceptable toxicity. Pemigatinib received orphan designation for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2 in August 2019 in the USA. A regulatory assessment for pemigatinib as a treatment for adults with locally advanced or metastatic cholangiocarcinoma and a FGFR2 fusion or rearrangement that is relapsed or refractory after ≥ 1 line of systemic therapy is underway in the EU. Pemigatinib is also undergoing clinical development in various countries worldwide for use in several other FGFR-driven malignancies (e.g. solid tumour, urothelial carcinoma). This article summarizes the milestones in the development of pemigatinib leading to this first approval for the treatment of adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma and a FGFR2 fusion or other rearrangement, as detected by a US FDA-approved test.