Drugs

Keramatian, Kamyar; Chakrabarty, Trisha; DuBow, Anais; Saraf, Gayatri; Yatham, Lakshmi N.

doi: 10.1007/s40265-023-01872-xpmid: 37227597

Depression is the most commonly experienced mood state over the life span in individuals with bipolar disorder (BD) and is the primary driver of functional impairment and suicidality in BD. Despite this, there are few effective treatments for BD depression, with only a handful of atypical anti-psychotics and inconsistent evidence for traditional mood stabilizing agents. There have been few major ‘breakthroughs’ in the treatment of BD depression, and until recently, few agents that work via novel mechanisms of action to exert therapeutic effects. Here, we review treatments for BD depression which are emergent or on the horizon. Included are new atypical anti-psychotics, glutamate modulators (ketamine and cycloserine/lurasidone), neurosteroid modulators (zuranolone), anti-inflammatories and mitochondrial modulators, cannabidiol (CBD) and psilocybin. New atypical anti-psychotics lumateperone and cariprazine have demonstrated efficacy in large-scale, placebo-controlled, double-blind randomized controlled trials (RCT) in treatment of BD depression. Non-racemic amisulpride showed potential therapeutic benefit in one RCT which requires replication. Three small RCTs examined the efficacy of intravenous ketamine in BD depression and showed rapid antidepressant and anti-suicidal effects after a single infusion. Anti-inflammatory and mitochondrial modulators show inconsistent evidence for efficacy. There are currently no adequately powered RCTs of zuranolone, psilocybin or CBD in BD depression to support their use. While there are potentially efficacious, mechanistically novel agents on the horizon, they require further study and validation. Further investigation on how these agents may impact specific subgroups of patients will also advance the field.

Mercadante, Sebastiano

doi: 10.1007/s40265-023-01876-7pmid: 37308798

Intravenous methadone may be useful in acute and chronic pain management compared with other opioids because of its pharmacokinetic and pharmacodynamic characteristics, including the long duration of effect and ability to modulate both pain stimuli propagation and analgesic descending pathways. However, methadone is underused in pain medicine because of several misperceptions. A review of studies was performed to assess data regarding the use of methadone in perioperative pain and chronic cancer pain. The majority of studies have shown that intravenous methadone produces an effective postoperative analgesia and lowers opioid consumption in the postoperative period, without more adverse effects in comparison with other opioid analgesics, and has an interesting potential to prevent persistent postoperative pain. A minority of studies investigated the use of intravenous methadone for cancer pain management. These studies were mostly case series that showed promising activities of intravenous methadone for difficult pain conditions. There is sufficient evidence suggesting that intravenous methadone is effective in perioperative pain, while more studies are needed in patients with cancer pain.

Vuyyuru, Sudheer K.; Shackelton, Lisa M.; Hanzel, Jurij; Ma, Christopher; Jairath, Vipul; Feagan, Brian G.

doi: 10.1007/s40265-023-01882-9pmid: 37266801

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, comprises multiple complex immune-mediated disorders. Early diagnosis and prompt disease control may prevent long-term complications and hospitalization. The therapeutic options have expanded in the last two decades, with the development of biologics and small molecules targeting specific pathways implicated in inflammatory bowel disease pathogenesis. The interleukin (IL)-23/Th-17 axis is one such example. Targeting IL-12/23 is effective for the treatment of both moderate-to-severe Crohn’s disease and ulcerative colitis, and ustekinumab (an IL-12/23p40 antagonist) is approved for both indications. In patients with psoriasis, improved clinical outcomes were observed with agents that more selectively targeted IL-23 (IL-23p19 antagonists) compared with those that target both IL-12 and IL-23. Many specific IL-23p19 antagonists are currently being investigated in Crohn’s disease and ulcerative colitis, and risankizumab has been recently approved for moderate-to-severely active Crohn’s disease. In this review, we summarize the mechanisms of action and the evidence from clinical trials supporting the efficacy and safety of IL-23p19 antagonists for the treatment of inflammatory bowel disease.

Patel, Dilan A.; Crain, Mallory; Pusic, Iskra; Schroeder, Mark A.

doi: 10.1007/s40265-023-01889-2pmid: 37247105

Acute graft-versus-host disease (GVHD) occurs in approximately 50% of patients and remains a primary driver of non-relapse and transplant-related mortality. The best treatment remains prevention with either in vivo or ex vivo T-cell depletion, with multiple strategies used worldwide based on factors such as institution preference, ability to perform graft manipulation, and ongoing clinical trials. Predicting patients at high risk for developing severe acute GVHD based on clinical and biomarker-based criteria allows for escalation or potential de-escalation of therapy. Modern therapies for treatment of the disease include JAK/STAT pathway inhibitors, which are standard of care in the second-line setting and are being investigated for upfront management of non-severe risk based on biomarkers. Salvage therapies beyond the second-line remain suboptimal. In this review, we will focus on the most clinically used GVHD prevention and treatment strategies, including the accumulating data on JAK inhibitors in both settings.

Skjellerudsveen, Berit Mære; Skoie, Inger Marie; Dalen, Ingvild; Grimstad, Tore; Omdal, Roald

doi: 10.1007/s40265-023-01888-3pmid: 37219801

BackgroundFatigue is a frequent complaint in patients with inflammatory bowel disease. Biological drugs have demonstrated beneficial effects on some extraintestinal manifestations, but the effect on fatigue is not clear.ObjectiveThis study investigated the effects of biological and small molecule drugs approved for inflammatory bowel disease on fatigue.MethodsWe performed a systematic review and meta-analysis of randomized, placebo-controlled trials reporting Federal Drug Agency (FDA)-approved biological and small molecule drugs for use in ulcerative colitis and Crohn’s disease in which measures of fatigue were recorded before and after treatment. Only induction studies were included. Maintenance studies were excluded. We searched Embase (Ovid), Medline (Ovid), PsycINFO (Ovid), Cinahl (EBSCOhost), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov in May 2022. Risk of bias was analyzed using the Cochrane risk-of-bias tool. Standardized mean difference was used to measure the treatment effect.ResultsA total of seven randomized controlled trials composed of 3835 patients were included in the meta-analysis. All of the studies included patients with moderately to severely active ulcerative colitis or Crohn’s disease. The studies used three different generic fatigue instruments: the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form 36 Health Survey Vitality Subscale versions 1 and 2. Overall treatment with biological or small molecule agents showed a beneficial effect compared with placebo, with a standardized mean difference of 0.25 (95% confidence interval 0.15–0.34, p < 0.001). The effect was independent of type of drug or subtype of inflammatory bowel disease.DiscussionThe risk of bias was considered to be low for all domains except for missing outcome data. Even though the included studies were of high methodological quality, the review is limited by the small number of studies included and that the available studies were not designed to evaluate fatigue specifically.ConclusionBiological and small molecule drugs used in inflammatory bowel disease have a consistent, though small, beneficial effect on fatigue.

Frampton, James E.

doi: 10.1007/s40265-023-01881-wpmid: 37316680

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Shirley, Matt

doi: 10.1007/s40265-023-01894-5pmid: 37285013

Glofitamab (Columvi®) is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody being developed by Roche for the treatment of B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL). Glofitamab received its first approval (with conditions) on 25 March 2023, in Canada, for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, DLBCL arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR T-cell therapy or have previously received CAR T-cell therapy. Glofitamab is also under regulatory review for relapsed or refractory DLBCL in the EU and USA and in April 2023 received a positive opinion recommending the granting of a conditional marketing authorization in the EU. Clinical development of glofitamab, as a monotherapy and in combination with other agents for the treatment of non-Hodgkin lymphomas, is continuing worldwide. This article summarizes the milestones in the development of glofitamab leading to this first approval for relapsed or refractory DLBCL.

Duggan, Sean; Al-Salama, Zaina T.

doi: 10.1007/s40265-023-01895-4pmid: 37256490

Leniolisib (JOENJA®) is an oral selective phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor being developed by Pharming Group NV in-licensed from Novartis for the treatment of immunodeficiency disorders. In March 2023, leniolisib received its first approval for the treatment of activated PI3Kδ syndrome (APDS) in adult and paediatric patients 12 years of age and older. Leniolisib is also under regulatory review in European Union for the treatment of APDS. Development of leniolisib for the treatment of Sjögren’s syndrome has been discontinued. This article summarizes the milestones in the development of leniolisib leading to this first approval for APDS.

Heo, Young-A.

doi: 10.1007/s40265-023-01898-1pmid: 37261622

Lee, Arnold

doi: 10.1007/s40265-023-01902-8pmid: 37269456