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Current Pain and Headache Reports Sep 2023Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their favorable side effect profile and versatility in treating... (Review)
Review
PURPOSE OF REVIEW
Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their favorable side effect profile and versatility in treating headaches acutely and preventively, gepants are preferred over triptans. We will cover the indications for the four FDA-approved gepants in adults: rimegepant, atogepant, ubrogepant, and zavegepant. This review will illustrate how gepants will continue to revolutionize the acute and preventive treatment of headaches.
RECENT FINDINGS
Gepants are now available in oral tablet, dissolving tablet, and intra-nasal spray formulations. Recent studies have shown promising utility in treating the pre-headache or prodromal phase. They have favorable tolerability, no evidence for association with medication overuse, and remain a safer alternative in those who have cerebrovascular risk factors. Additional research is needed to explore occurrence of Raynaud's phenomenon in participants treated with gepants, as it has been associated with CGRP monoclonal antibodies, but are not extensively studied in gepants. Gepants are expected to play a significant role in the next generation of migraine treatments.
Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Pyridines; Pyrroles; Migraine Disorders; Raynaud Disease
PubMed: 37531032
DOI: 10.1007/s11916-023-01142-1 -
The New England Journal of Medicine Nov 2023Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced -mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced -mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear.
METHODS
We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety.
RESULTS
A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively.
CONCLUSIONS
Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with -mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).
Topics: Humans; Disease Progression; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms; Antineoplastic Agents
PubMed: 37870969
DOI: 10.1056/NEJMoa2309719 -
Blood Advances Aug 2023The discovery of isocitrate dehydrogenase 1 (IDH1) mutations in acute myeloid leukemia (AML) and the resounding success of molecularly targeted therapies in related... (Review)
Review
The discovery of isocitrate dehydrogenase 1 (IDH1) mutations in acute myeloid leukemia (AML) and the resounding success of molecularly targeted therapies in related myeloid malignancies swiftly prompted the development of IDH1mut inhibitors. Olutasidenib (formerly known as FT-2102) is an orally administered novel IDH1mut inhibitor that entered clinical development in 2016, proceeded briskly through the developmental process, and was granted regular approval to treat patients with R/R IDH1mut AML on 1 December 2022. Single agent olutasidenib, a potent and selective IDH1mut inhibitor, demonstrated highly durable remission rates along with meaningful outcomes, such as transfusion independence, in patients with R/R IDH1mut AML. This review will examine the preclinical and clinical development and the positioning of olutasidenib in the IDH1mut AML treatment landscape.
Topics: Humans; Isocitrate Dehydrogenase; Pyridines; Quinolines; Leukemia, Myeloid, Acute
PubMed: 37196640
DOI: 10.1182/bloodadvances.2023009854 -
Platelets Dec 2023Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune... (Review)
Review
Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors.
Topics: Humans; Aminopyridines; COVID-19; Oxazines; Protein Kinase Inhibitors; Purpura, Thrombocytopenic, Idiopathic; Pyridines; Syk Kinase
PubMed: 36331249
DOI: 10.1080/09537104.2022.2131751 -
Expert Opinion on Pharmacotherapy 2023Traditional treatment strategies for acute myeloid leukemia (AML) have primarily relied on standard chemotherapy regimens for four decades. Indeed, the landscape of AML... (Review)
Review
INTRODUCTION
Traditional treatment strategies for acute myeloid leukemia (AML) have primarily relied on standard chemotherapy regimens for four decades. Indeed, the landscape of AML therapy has evolved substantially in recent years, mainly due to the introduction of hypomethylating agents and small molecules.Bcl2 inhibitor venetoclax, Fms-like tyrosine kinase 3 (FLT3) inhibitors such as midostaurin and gilteritinib, and isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) inhibitors ivosidenib and enasidenib, as well as hedgehog (HH) pathway inhibitor glasdegib represented a significant step forward in AML therapeutic armamentarium. Smoothened (SMO) inhibitor in combination with low-dose cytarabine marks a recent milestone.
AREAS COVERED
Ivosidenib, the first-in-class, selective, allosteric IDH1R132 inhibitor, showed the capability to induce differentiation of primary mIDH1 AML blasts. Clinical data highlighted its exceptional safety profile, as a standalone therapy and in combination strategy. Additionally, comprehensive studies consistently demonstrated its effectiveness, both in monotherapy and in association with chemotherapy.
EXPERT OPINION
The identified ivosidenib's strengths, including its remarkable safety record and ability to yield positive therapeutic outcomes, position it as an ideal partner for both classic chemotherapy and biological treatments, i.e. hypometilant agents and/or venetoclax. Further studies are warranted to explore strategies for overcoming the occurrence of ivosidenib resistance.
Topics: Humans; Hedgehog Proteins; Leukemia, Myeloid, Acute; Pyridines; Antineoplastic Agents; Mutation
PubMed: 37874005
DOI: 10.1080/14656566.2023.2272659 -
American Journal of Health-system... Jul 2023
Topics: Humans; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Phosphates
PubMed: 37257154
DOI: 10.1093/ajhp/zxad095 -
Lancet (London, England) Dec 2023Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a migraine attack and is characterised by non-aura symptoms that precede headache onset. The aim of this trial was to evaluate the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome.
METHODS
This PRODROME trial was a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial of ubrogepant 100 mg conducted at 75 research centres and headache clinics in the USA. Eligible participants were adults aged 18-75 years who had at least a 1-year history of migraine with or without aura and a history of two to eight migraine attacks per month with moderate to severe headache in each of the 3 months before screening. Eligible participants were randomly assigned (1:1) to either receive placebo to treat the first qualifying prodrome event and ubrogepant 100 mg to treat the second qualifying prodrome event or to receive ubrogepant 100 mg to treat the first qualifying prodrome event and placebo to treat the second qualifying prodrome event. An automated interactive web-response system used permuted blocks of four to manage randomisation. All people giving interventions and assessing outcomes were masked to group assignment during the study. People doing data analysis, which occurred after study completion, were not masked to group assignment. During the double-blind treatment period, each participant was instructed to orally take two tablets of the study drug at the onset of each qualifying prodrome event. The primary endpoint was absence of moderate or severe intensity headache within 24 h after study-drug dose; efficacy analyses were conducted with the modified intention-to-treat (mITT) population, defined as all randomly assigned participants with at least one headache assessment within 24 h after taking the study drug during the treatment period. The safety population included all treated participants who took at least one administration of study drug. The trial is registered with ClinicalTrials.gov (NCT04492020).
FINDINGS
Between Aug 21, 2020, and April 19, 2022, 518 participants were randomly assigned to double-blind crossover treatment. The safety population included 480 participants and the mITT population included 477 participants; 421 (88%) of 480 participants were female and 59 (12%) were male. Absence of moderate or severe headache within 24 h after a dose occurred after 190 (46%) of 418 qualifying prodrome events that had been treated with ubrogepant and after 121 (29%) of 423 qualifying prodrome events that had been treated with placebo (odds ratio 2·09, 95% CI 1·63-2·69; p<0·0001). Adverse events that occurred within 48 h after study-drug administration were reported after 77 (17%) of 456 qualifying prodrome events that had been treated with ubrogepant and after 55 (12%) of 462 events that had been treated with placebo.
INTERPRETATION
Ubrogepant was effective and well tolerated for the treatment of migraine attacks when taken during the prodrome.
FUNDING
AbbVie.
Topics: Adult; Humans; Male; Female; Cross-Over Studies; Migraine Disorders; Pyridines; Double-Blind Method; Headache; Treatment Outcome
PubMed: 37979595
DOI: 10.1016/S0140-6736(23)01683-5 -
Drugs Jul 2023Leniolisib (JOENJA) is an oral selective phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor being developed by Pharming Group NV in-licensed from Novartis for the... (Review)
Review
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.
Topics: Adult; Humans; Child; Phosphatidylinositol 3-Kinases; Class I Phosphatidylinositol 3-Kinases; Immunologic Deficiency Syndromes; Pyridines
PubMed: 37256490
DOI: 10.1007/s40265-023-01895-4 -
Handbook of Clinical Neurology 20245-Hydroxytryptamine (HT)/serotonin receptor agonism has been a long-recognized property of triptan medications, and more recently, the study and development of... (Review)
Review
5-Hydroxytryptamine (HT)/serotonin receptor agonism has been a long-recognized property of triptan medications, and more recently, the study and development of medications with selective binding to the 1F receptor subtype have been explored. While the exact mechanism contributing to decreased symptoms of an acute migraine attack remains unclear, selective 5-HT1F agonists have demonstrated clinical efficacy with lasmiditan as the only approved medication from this class to date. Lasmiditan lacks vasoconstrictive properties, giving it utility in specific patient populations in whom triptans should be avoided. Availability, central nervous system (CNS) side effects, and 8-hour driving restriction may affect its clinical use.
Topics: Humans; Benzamides; Piperidines; Pyridines; Receptors, Serotonin; Tryptamines; Serotonin 5-HT1 Receptor Agonists
PubMed: 38307661
DOI: 10.1016/B978-0-12-823357-3.00032-X -
MMW Fortschritte Der Medizin Mar 2024
Topics: Humans; Pyridines; Biofilms; Imines
PubMed: 38514576
DOI: 10.1007/s15006-024-3764-z