Pub Date : 2024-07-01Epub Date: 2024-07-05DOI: 10.1007/s40265-024-02060-1
Susan J Keam
Nogapendekin alfa inbakicept (ANKTIVA®; nogapendekin alfa inbakicept-pmln) is a recombinant interleukin-15 (IL-15) superagonist protein complex being developed by Altor BioScience, LLC, an indirect wholly owned subsidiary of ImmunityBio, Inc., for the treatment of solid and haematological cancers and HIV infection. In April 2024, nogapendekin alfa inbakicept was approved for use with Bacillus Calmette-Guérin (BCG) for the treatment of adult patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours in the USA. This article summarizes the milestones in the development of nogapendekin alfa inbakicept leading to this first approval for the treatment of cancer.
{"title":"Nogapendekin alfa Inbakicept: First Approval.","authors":"Susan J Keam","doi":"10.1007/s40265-024-02060-1","DOIUrl":"10.1007/s40265-024-02060-1","url":null,"abstract":"<p><p>Nogapendekin alfa inbakicept (ANKTIVA<sup>®</sup>; nogapendekin alfa inbakicept-pmln) is a recombinant interleukin-15 (IL-15) superagonist protein complex being developed by Altor BioScience, LLC, an indirect wholly owned subsidiary of ImmunityBio, Inc., for the treatment of solid and haematological cancers and HIV infection. In April 2024, nogapendekin alfa inbakicept was approved for use with Bacillus Calmette-Guérin (BCG) for the treatment of adult patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours in the USA. This article summarizes the milestones in the development of nogapendekin alfa inbakicept leading to this first approval for the treatment of cancer.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"867-874"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-21DOI: 10.1007/s40265-024-02047-y
Laurent Guilleminault, Stanislas Grassin-Delyle, Stuart B Mazzone
Refractory chronic cough is a disabling disease with very limited therapeutic options. A better understanding of cough pathophysiology has led to the development of emerging drugs targeting cough receptors. Recent strides have illuminated novel therapeutic avenues, notably centred on modulating transient receptor potential (TRP) channels, purinergic receptors, and neurokinin receptors. By modulating these receptors, the goal is to intervene in the sensory pathways that trigger cough reflexes, thereby providing relief without compromising vital protective mechanisms. These innovative pharmacotherapies hold promise for improvement of refractory chronic cough by offering improved efficacy and potentially mitigating adverse effects associated with current recommended treatments. A deeper comprehension of their precise mechanisms of action and clinical viability is imperative for optimising therapeutic interventions and elevating patient care standards in respiratory health. This review delineates the evolving landscape of drug development in this domain, emphasising the significance of these advancements in reshaping the paradigm of cough management.
{"title":"Drugs Targeting Cough Receptors: New Therapeutic Options in Refractory or Unexplained Chronic Cough.","authors":"Laurent Guilleminault, Stanislas Grassin-Delyle, Stuart B Mazzone","doi":"10.1007/s40265-024-02047-y","DOIUrl":"10.1007/s40265-024-02047-y","url":null,"abstract":"<p><p>Refractory chronic cough is a disabling disease with very limited therapeutic options. A better understanding of cough pathophysiology has led to the development of emerging drugs targeting cough receptors. Recent strides have illuminated novel therapeutic avenues, notably centred on modulating transient receptor potential (TRP) channels, purinergic receptors, and neurokinin receptors. By modulating these receptors, the goal is to intervene in the sensory pathways that trigger cough reflexes, thereby providing relief without compromising vital protective mechanisms. These innovative pharmacotherapies hold promise for improvement of refractory chronic cough by offering improved efficacy and potentially mitigating adverse effects associated with current recommended treatments. A deeper comprehension of their precise mechanisms of action and clinical viability is imperative for optimising therapeutic interventions and elevating patient care standards in respiratory health. This review delineates the evolving landscape of drug development in this domain, emphasising the significance of these advancements in reshaping the paradigm of cough management.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"763-777"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-20DOI: 10.1007/s40265-024-02048-x
Giancarlo De la Torre Canales, Mariana Barbosa Câmara-Souza, Malin Ernberg, Essam Ahmed Al-Moraissi, Anastasios Grigoriadis, Rodrigo Lorenzi Poluha, Maria Christidis, Hajer Jasim, Anna Lövgren, Nikolaos Christidis
Objective: Temporomandibular disorders (TMDs) encompass several conditions that cause pain and impair function of the masticatory muscles (M-TMDs) and temporomandibular joints. There is a large interest among clinicians and researchers in the use of botulinum toxin-A (BoNT-A) as a treatment for M-TMD. However, due to the lack of consistent evidence regarding the efficacy as well as adverse events of BoNT-A, clinical decision making is challenging. Therefore, this umbrella review aimed to systematically assess systematic reviews (SRs) evaluating BoNT-A treatment effects on pain intensity, mandibular movements, and adverse events in patients with M-TMDs.
Method: An electronic search was undertaken in the databases MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials (CENTRAL), Web of Science, Epistemonikos, ClinicalTrials.gov, and ICTRP to identify SRs investigating BoNT-A effects on M-TMDs, published from the inception of each database until 6 December 2023. The quality of evidence was rated according to the critical appraisal checklist developed by the umbrella review methodology working group. Only high-quality SRs were included.
Results: In total, 18 SRs were included. BoNT-A was shown to be more effective than placebo to reduce pain intensity, but not compared to standard treatments. Additionally, BoNT-A was not superior to placebo or standard treatments regarding improvement of mandibular movements. BoNT-A was considered to have a higher risk for adverse events on muscle and bony tissue compared with other treatments.
Conclusion: The synthesis in this umbrella review provides the highest level of evidence present. Taken together, there are indications of effectiveness of BoNT-A for treatment of M-TMDs, supported by moderate evidence. However, considering the risk of causing serious adverse events, treatment with BoNT-A is recommended to be the last treatment alternative.
{"title":"Botulinum Toxin-A for the Treatment of Myogenous Temporomandibular Disorders: An Umbrella Review of Systematic Reviews.","authors":"Giancarlo De la Torre Canales, Mariana Barbosa Câmara-Souza, Malin Ernberg, Essam Ahmed Al-Moraissi, Anastasios Grigoriadis, Rodrigo Lorenzi Poluha, Maria Christidis, Hajer Jasim, Anna Lövgren, Nikolaos Christidis","doi":"10.1007/s40265-024-02048-x","DOIUrl":"10.1007/s40265-024-02048-x","url":null,"abstract":"<p><strong>Objective: </strong>Temporomandibular disorders (TMDs) encompass several conditions that cause pain and impair function of the masticatory muscles (M-TMDs) and temporomandibular joints. There is a large interest among clinicians and researchers in the use of botulinum toxin-A (BoNT-A) as a treatment for M-TMD. However, due to the lack of consistent evidence regarding the efficacy as well as adverse events of BoNT-A, clinical decision making is challenging. Therefore, this umbrella review aimed to systematically assess systematic reviews (SRs) evaluating BoNT-A treatment effects on pain intensity, mandibular movements, and adverse events in patients with M-TMDs.</p><p><strong>Method: </strong>An electronic search was undertaken in the databases MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials (CENTRAL), Web of Science, Epistemonikos, ClinicalTrials.gov, and ICTRP to identify SRs investigating BoNT-A effects on M-TMDs, published from the inception of each database until 6 December 2023. The quality of evidence was rated according to the critical appraisal checklist developed by the umbrella review methodology working group. Only high-quality SRs were included.</p><p><strong>Results: </strong>In total, 18 SRs were included. BoNT-A was shown to be more effective than placebo to reduce pain intensity, but not compared to standard treatments. Additionally, BoNT-A was not superior to placebo or standard treatments regarding improvement of mandibular movements. BoNT-A was considered to have a higher risk for adverse events on muscle and bony tissue compared with other treatments.</p><p><strong>Conclusion: </strong>The synthesis in this umbrella review provides the highest level of evidence present. Taken together, there are indications of effectiveness of BoNT-A for treatment of M-TMDs, supported by moderate evidence. However, considering the risk of causing serious adverse events, treatment with BoNT-A is recommended to be the last treatment alternative.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"779-809"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-20DOI: 10.1007/s40265-024-02067-8
John A Hey, Susan Abushakra, Kaj Blennow, Eric M Reiman, Jakub Hort, Niels D Prins, Katerina Sheardova, Patrick Kesslak, Larry Shen, Xinyi Zhu, Adem Albayrak, Jijo Paul, Jean F Schaefer, Aidan Power, Martin Tolar
<p><strong>Introduction: </strong>ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.</p><p><strong>Methods: </strong>The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau<sub>181</sub>, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau<sub>181</sub> at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test.</p><p><strong>Results: </strong>The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau<sub>181</sub> reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks.</p><p><strong>Conclusions: </strong>The effect of ALZ-801 on reducing plasma p-tau<sub>181</sub> over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD.
{"title":"Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease.","authors":"John A Hey, Susan Abushakra, Kaj Blennow, Eric M Reiman, Jakub Hort, Niels D Prins, Katerina Sheardova, Patrick Kesslak, Larry Shen, Xinyi Zhu, Adem Albayrak, Jijo Paul, Jean F Schaefer, Aidan Power, Martin Tolar","doi":"10.1007/s40265-024-02067-8","DOIUrl":"10.1007/s40265-024-02067-8","url":null,"abstract":"<p><strong>Introduction: </strong>ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.</p><p><strong>Methods: </strong>The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau<sub>181</sub>, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau<sub>181</sub> at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test.</p><p><strong>Results: </strong>The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau<sub>181</sub> reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks.</p><p><strong>Conclusions: </strong>The effect of ALZ-801 on reducing plasma p-tau<sub>181</sub> over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD.","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"811-823"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-21DOI: 10.1007/s40265-024-02058-9
Connie Kang
Sotatercept (sotatercept-csrk; WINREVAIRTM) is an activin signalling inhibitor that is being developed by Merck and Co., Inc. (Rahway, NJ, USA) for the treatment of pulmonary arterial hypertension. Sotatercept recently received approval in the USA for the treatment of adults with pulmonary arterial hypertension [World Health Organisation (WHO) Group 1] to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. This article summarizes the milestones in the development of sotatercept leading to this first approval for pulmonary arterial hypertension.
Sotatercept（sotatercept-csrk；WINREVAIRTM）是一种激活素信号抑制剂，由默克公司（Rahway, NJ, USA）开发，用于治疗肺动脉高压。Sotatercept 最近在美国获得批准，用于治疗成人肺动脉高压患者（世界卫生组织（WHO）第 1 组），以提高运动能力、改善 WHO 功能分级并降低临床恶化事件的风险。本文总结了索泰特受体（sotatercept）开发过程中的里程碑事件，这些事件促成了索泰特受体（sotatercept）首次获准用于治疗肺动脉高压。
{"title":"Sotatercept: First Approval.","authors":"Connie Kang","doi":"10.1007/s40265-024-02058-9","DOIUrl":"10.1007/s40265-024-02058-9","url":null,"abstract":"<p><p>Sotatercept (sotatercept-csrk; WINREVAIR<sup>TM</sup>) is an activin signalling inhibitor that is being developed by Merck and Co., Inc. (Rahway, NJ, USA) for the treatment of pulmonary arterial hypertension. Sotatercept recently received approval in the USA for the treatment of adults with pulmonary arterial hypertension [World Health Organisation (WHO) Group 1] to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. This article summarizes the milestones in the development of sotatercept leading to this first approval for pulmonary arterial hypertension.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"857-862"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-04DOI: 10.1007/s40265-024-02053-0
Sohita Dhillon
Aprocitentan (TRYVIO™) is a once-daily oral dual endothelin A (ETA) and B (ETB) receptor antagonist developed by Idorsia Pharmaceuticals for the treatment of hypertension. The endothelin pathway has been implicated in hypertension. Aprocitentan inhibits the binding of endothelin-1 to ETA and ETB receptors, thereby preventing its deleterious effects and lowering blood pressure. In March 2024, aprocitentan received its first approval in the USA for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other drugs. This article summarizes the milestones in the development of aprocitentan leading to this first approval for hypertension not adequately controlled on other drugs.
{"title":"Aprocitentan: First Approval.","authors":"Sohita Dhillon","doi":"10.1007/s40265-024-02053-0","DOIUrl":"10.1007/s40265-024-02053-0","url":null,"abstract":"<p><p>Aprocitentan (TRYVIO™) is a once-daily oral dual endothelin A (ET<sub>A</sub>) and B (ET<sub>B</sub>) receptor antagonist developed by Idorsia Pharmaceuticals for the treatment of hypertension. The endothelin pathway has been implicated in hypertension. Aprocitentan inhibits the binding of endothelin-1 to ET<sub>A</sub> and ET<sub>B</sub> receptors, thereby preventing its deleterious effects and lowering blood pressure. In March 2024, aprocitentan received its first approval in the USA for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other drugs. This article summarizes the milestones in the development of aprocitentan leading to this first approval for hypertension not adequately controlled on other drugs.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"841-847"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-15DOI: 10.1007/s40265-024-02051-2
Sithara Ramdas, Maryam Oskoui, Laurent Servais
Spinal muscular atrophy (SMA) is a rare neurodegenerative neuromuscular disorder with a wide phenotypic spectrum of severity. SMA was previously life limiting for patients with the most severe phenotype and resulted in progressive disability for those with less severe phenotypes. This has changed dramatically in the past few years with the approvals of three disease-modifying treatments. We review the evidence supporting the use of currently approved SMA treatments (nusinersen, onasemnogene abeparvovec, and risdiplam), focusing on mechanisms of action, side effect profiles, published clinical trial data, health economics, and pending questions. Whilst there is robust data from clinical trials of efficacy and side effect profile for individual drugs in select SMA populations, there are no comparative head-to-head clinical trials. This presents a challenge for clinicians who need to make recommendations on the best treatment option for an individual patient and we hope to provide a pragmatic approach for clinicians across each SMA profile based on current evidence.
脊髓性肌萎缩症（SMA）是一种罕见的神经退行性神经肌肉疾病，其严重程度的表型范围很广。以前，表型最严重的脊髓性肌萎缩症患者会丧失生命，而表型较轻的患者则会逐渐致残。在过去几年中，随着三种改变病情的治疗方法获得批准，这种情况发生了巨大变化。我们回顾了支持使用目前已获批准的 SMA 治疗方法（nusinersen、onasemnogene abeparvovec 和 risdiplam）的证据，重点关注作用机制、副作用概况、已公布的临床试验数据、卫生经济学和待决问题。虽然在特定的 SMA 群体中，个别药物在疗效和副作用方面的临床试验数据十分可靠，但目前还没有头对头的比较性临床试验。这给临床医生带来了挑战，因为他们需要为个别患者推荐最佳治疗方案，而我们希望根据现有证据为临床医生提供一种实用的方法，适用于每种 SMA 特征。
{"title":"Treatment Options in Spinal Muscular Atrophy: A Pragmatic Approach for Clinicians.","authors":"Sithara Ramdas, Maryam Oskoui, Laurent Servais","doi":"10.1007/s40265-024-02051-2","DOIUrl":"10.1007/s40265-024-02051-2","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a rare neurodegenerative neuromuscular disorder with a wide phenotypic spectrum of severity. SMA was previously life limiting for patients with the most severe phenotype and resulted in progressive disability for those with less severe phenotypes. This has changed dramatically in the past few years with the approvals of three disease-modifying treatments. We review the evidence supporting the use of currently approved SMA treatments (nusinersen, onasemnogene abeparvovec, and risdiplam), focusing on mechanisms of action, side effect profiles, published clinical trial data, health economics, and pending questions. Whilst there is robust data from clinical trials of efficacy and side effect profile for individual drugs in select SMA populations, there are no comparative head-to-head clinical trials. This presents a challenge for clinicians who need to make recommendations on the best treatment option for an individual patient and we hope to provide a pragmatic approach for clinicians across each SMA profile based on current evidence.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"747-762"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-20DOI: 10.1007/s40265-024-02068-7
John A Hey, Jeremy Y Yu, Susan Abushakra, Jean F Schaefer, Aidan Power, Patrick Kesslak, Martin Tolar
<p><strong>Introduction: </strong>ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.</p><p><strong>Methods: </strong>The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ<sub>42</sub>/Aβ<sub>40</sub>) and tau pathology (p-tau<sub>181</sub>) were enrolled, with serial CSF and plasma levels of Aβ<sub>42</sub> and Aβ<sub>40</sub> measured over 104 weeks. Longitudinal changes of CSF Aβ<sub>42</sub>, plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex.</p><p><strong>Results: </strong>A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ<sub>42</sub> level and plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26).</p><p><strong>Conclusions: </strong>In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification poten
{"title":"Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model.","authors":"John A Hey, Jeremy Y Yu, Susan Abushakra, Jean F Schaefer, Aidan Power, Patrick Kesslak, Martin Tolar","doi":"10.1007/s40265-024-02068-7","DOIUrl":"10.1007/s40265-024-02068-7","url":null,"abstract":"<p><strong>Introduction: </strong>ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.</p><p><strong>Methods: </strong>The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ<sub>42</sub>/Aβ<sub>40</sub>) and tau pathology (p-tau<sub>181</sub>) were enrolled, with serial CSF and plasma levels of Aβ<sub>42</sub> and Aβ<sub>40</sub> measured over 104 weeks. Longitudinal changes of CSF Aβ<sub>42</sub>, plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex.</p><p><strong>Results: </strong>A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ<sub>42</sub> level and plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26).</p><p><strong>Conclusions: </strong>In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification poten","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"825-839"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-07-05DOI: 10.1007/s40265-024-02052-1
Yvette N Lamb
Givinostat (DUVYZAT™), an orally available histone deacetylase inhibitor, is being developed by Italfarmaco for the treatment of muscular dystrophy and polycythemia vera. Givinostat received its first approval on 21 March 2024, in the USA, for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. Approval was based on the results of the multinational phase III EPIDYS trial, in which givinostat recipients showed less decline than placebo recipients in the time taken to perform a functional task. Givinostat represents the first nonsteroidal treatment for DMD to be approved for use in patients irrespective of the specific genetic variant underlying their disease. Givinostat is available as an oral suspension to be administered twice daily with food. The recommended dosage is based on the body weight of the patient. In the EU, regulatory review of givinostat in DMD is currently underway. This article summarizes the milestones in the development of givinostat leading to this first approval for DMD.
{"title":"Givinostat: First Approval.","authors":"Yvette N Lamb","doi":"10.1007/s40265-024-02052-1","DOIUrl":"10.1007/s40265-024-02052-1","url":null,"abstract":"<p><p>Givinostat (DUVYZAT™), an orally available histone deacetylase inhibitor, is being developed by Italfarmaco for the treatment of muscular dystrophy and polycythemia vera. Givinostat received its first approval on 21 March 2024, in the USA, for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. Approval was based on the results of the multinational phase III EPIDYS trial, in which givinostat recipients showed less decline than placebo recipients in the time taken to perform a functional task. Givinostat represents the first nonsteroidal treatment for DMD to be approved for use in patients irrespective of the specific genetic variant underlying their disease. Givinostat is available as an oral suspension to be administered twice daily with food. The recommended dosage is based on the body weight of the patient. In the EU, regulatory review of givinostat in DMD is currently underway. This article summarizes the milestones in the development of givinostat leading to this first approval for DMD.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"849-856"},"PeriodicalIF":13.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-14DOI: 10.1007/s40265-024-02032-5
Sohita Dhillon
Crovalimab (®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH.
{"title":"Crovalimab: First Approval.","authors":"Sohita Dhillon","doi":"10.1007/s40265-024-02032-5","DOIUrl":"10.1007/s40265-024-02032-5","url":null,"abstract":"<p><p>Crovalimab (<sup>®;</sup> PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH.</p>","PeriodicalId":11482,"journal":{"name":"Drugs","volume":" ","pages":"707-716"},"PeriodicalIF":13.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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