Pub Date : 2022-10-10DOI: 10.1080/21678707.2022.2134776
Ann Mercurio, Ashray B Maniar, A. Wei, R. Carvajal
ABSTRACT Introduction Mucosal melanomas are rare and aggressive forms of cancer that have consistently eluded meaningful recovery with various anticancer therapies. Patients with unresectable mucosal melanomas have benefited from prolonged survival with the use of systemic drugs, including immune checkpoint inhibitors, but prognosis for mucosal malignancies remains inferior compared to cutaneous melanomas. FDA breakthrough and orphan drug designations for novel IL-2 formulations bempegaldesleukin and nemvaleukin highlight the potential for restoring cytokine-based therapy as a viable option in treating mucosal melanomas. Areas covered In this review, we discuss the biological and clinical features of mucosal melanomas, the current therapies available to this patient population including anti-PD1 and targeted therapies, and the potential for integrating novel IL-2 formulations into the existing armamentarium. Recently published clinical trial outcomes evaluating IL-2-based drugs are critically evaluated within the context of the existing treatment landscape for mucosal melanomas. Expert Opinion We conclude that clinical trials are a key priority for eligible patients who may stand to benefit from IL-2 therapy. For patients with unresectable and advanced disease who are unable to participate in trials, anti-PD1 and targeted therapies may still be considered as front- and next-line treatments on a case-by-case basis.
{"title":"Targeting the IL-2 pathway for the treatment of mucosal melanoma","authors":"Ann Mercurio, Ashray B Maniar, A. Wei, R. Carvajal","doi":"10.1080/21678707.2022.2134776","DOIUrl":"https://doi.org/10.1080/21678707.2022.2134776","url":null,"abstract":"ABSTRACT Introduction Mucosal melanomas are rare and aggressive forms of cancer that have consistently eluded meaningful recovery with various anticancer therapies. Patients with unresectable mucosal melanomas have benefited from prolonged survival with the use of systemic drugs, including immune checkpoint inhibitors, but prognosis for mucosal malignancies remains inferior compared to cutaneous melanomas. FDA breakthrough and orphan drug designations for novel IL-2 formulations bempegaldesleukin and nemvaleukin highlight the potential for restoring cytokine-based therapy as a viable option in treating mucosal melanomas. Areas covered In this review, we discuss the biological and clinical features of mucosal melanomas, the current therapies available to this patient population including anti-PD1 and targeted therapies, and the potential for integrating novel IL-2 formulations into the existing armamentarium. Recently published clinical trial outcomes evaluating IL-2-based drugs are critically evaluated within the context of the existing treatment landscape for mucosal melanomas. Expert Opinion We conclude that clinical trials are a key priority for eligible patients who may stand to benefit from IL-2 therapy. For patients with unresectable and advanced disease who are unable to participate in trials, anti-PD1 and targeted therapies may still be considered as front- and next-line treatments on a case-by-case basis.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"10 1","pages":"34 - 47"},"PeriodicalIF":0.8,"publicationDate":"2022-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46362141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-08DOI: 10.1080/21678707.2022.2134007
Jong Hyuk Lee, Seung-Lai Yoo
ABSTRACT Background This study aims to analyze the policy and its effects as they apply to new orphan drug (OD) and the budget impact after reimbursement listing in South Korean National Health Insurance (NHI). Methods We analyzed 198 new drugs listed by South Korea’s NHI from July 2007 to March 2017. A comparison of the time to listing for ODs and non-orphan drugs (NODs) was conducted via the Mann–Whitney U test. The budget impact of ODs was analyzed by the NHI claim data from the listing date of new drugs until 31 December 2018. Results An analysis of the time shows that the period (median) for NOD (13.2 months) was shorter than for OD (17.4 months) (Mann–Whitney U test: p = 0.018). The annualized budget impact of OD was 4,967,049 US$/year and that of NOD was 7,800,924 US$/year. Additionally, the percentage of oncology orphan drugs in the total pharmaceutical expenditure was 1.1%; as such, the percentage of non-oncology orphan drug was only 0.9%. Conclusions There has been no significant evidence for patient accessibility improvement regarding new ODs. The proportion of ODs in South Korea’s NHI total pharmaceutical expenditure is not high and the proportion of ODs among new drugs is even lower.
{"title":"Pricing and reimbursement policy for new orphan drugs in South Korea: focused on patient accessibility and budget impact","authors":"Jong Hyuk Lee, Seung-Lai Yoo","doi":"10.1080/21678707.2022.2134007","DOIUrl":"https://doi.org/10.1080/21678707.2022.2134007","url":null,"abstract":"ABSTRACT Background This study aims to analyze the policy and its effects as they apply to new orphan drug (OD) and the budget impact after reimbursement listing in South Korean National Health Insurance (NHI). Methods We analyzed 198 new drugs listed by South Korea’s NHI from July 2007 to March 2017. A comparison of the time to listing for ODs and non-orphan drugs (NODs) was conducted via the Mann–Whitney U test. The budget impact of ODs was analyzed by the NHI claim data from the listing date of new drugs until 31 December 2018. Results An analysis of the time shows that the period (median) for NOD (13.2 months) was shorter than for OD (17.4 months) (Mann–Whitney U test: p = 0.018). The annualized budget impact of OD was 4,967,049 US$/year and that of NOD was 7,800,924 US$/year. Additionally, the percentage of oncology orphan drugs in the total pharmaceutical expenditure was 1.1%; as such, the percentage of non-oncology orphan drug was only 0.9%. Conclusions There has been no significant evidence for patient accessibility improvement regarding new ODs. The proportion of ODs in South Korea’s NHI total pharmaceutical expenditure is not high and the proportion of ODs among new drugs is even lower.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"10 1","pages":"22 - 27"},"PeriodicalIF":0.8,"publicationDate":"2022-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45788605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-07DOI: 10.1080/21678707.2022.2134008
Cássia Cunico, S. Leite
In Brazil, the Federal Constitution establishes that health is a social right and a duty of the governments of the Union, the States, and the Municipalities [1]. Public institutions and agencies constitute the public health system – Unified Health System (SUS) [2]. The organization and functioning of the SUS are based on principles that provide, among others, open access, free of charge and comprehensive healthcare [2]. Many advances in the structuring of public health policies have allowed greater access to services and medicines at SUS, however, there is a need for continuous progress when considering some population niches such as those with rare health conditions. The National Policy for Comprehensive Care for People with Rare Diseases (PNAIPDR) was published in 2014 [3] and implemented in 2015 [4]. At that time, a Panel of Experts established diseases or a group of diseases that were initially considered a priority within the scope of PNAIPDR [4]. According to this policy, the definition of a rare disease is given by the prevalence threshold, which establishes that rare disease affects up to 65 people per 100,000 inhabitants [3]. However, there is no notification system in the country that considers the registration of rare diseases, and only some diseases are of compulsory notification [5]. Consequently, there is no registry system with epidemiological information that can provide prevalence data to establish the rarity of a given health condition and create a list based on population prevalence. So, despite being a widely used term, one can ask: what are, in fact, the rare diseases treated, in some way, in the Brazilian public health system? At the international level, the Orphanet report provides a list of diseases considered rare in Europe (prevalence of up to 50/100,000 inhabitants) and the European Commission advocates the creation of the European Rare Disease Registry Platform that would act as a focal point for the registries of rare diseases in the European Union [6]. Furthermore, in the United States, which was the first country to establish national orphan drug legislation, in 1983, and is now one of the leaders in the treatment of rare diseases in the world, the estimated prevalence, added to the data source and basis consulted is a required evidence for the FDA to provide orphan designation to a medicine [7,8]. In Brazil, the PNAIPDR aims to qualify and guarantee people with rare diseases, in a timely manner, access to diagnostic and therapeutic means available according to their needs [3]. To this end, it provides for the organization and availability of dedicated services prepared to meet this population’s demands. However, state and municipal health managers are often faced with doubts about the classification of a given disease as rare or not, which generates conflicts with patients and associations, in addition to organizational difficulties in prioritizing and planning such services to meet the requirements of the publishe
{"title":"Rare diseases: proposition of a list based on the Brazilian Health System","authors":"Cássia Cunico, S. Leite","doi":"10.1080/21678707.2022.2134008","DOIUrl":"https://doi.org/10.1080/21678707.2022.2134008","url":null,"abstract":"In Brazil, the Federal Constitution establishes that health is a social right and a duty of the governments of the Union, the States, and the Municipalities [1]. Public institutions and agencies constitute the public health system – Unified Health System (SUS) [2]. The organization and functioning of the SUS are based on principles that provide, among others, open access, free of charge and comprehensive healthcare [2]. Many advances in the structuring of public health policies have allowed greater access to services and medicines at SUS, however, there is a need for continuous progress when considering some population niches such as those with rare health conditions. The National Policy for Comprehensive Care for People with Rare Diseases (PNAIPDR) was published in 2014 [3] and implemented in 2015 [4]. At that time, a Panel of Experts established diseases or a group of diseases that were initially considered a priority within the scope of PNAIPDR [4]. According to this policy, the definition of a rare disease is given by the prevalence threshold, which establishes that rare disease affects up to 65 people per 100,000 inhabitants [3]. However, there is no notification system in the country that considers the registration of rare diseases, and only some diseases are of compulsory notification [5]. Consequently, there is no registry system with epidemiological information that can provide prevalence data to establish the rarity of a given health condition and create a list based on population prevalence. So, despite being a widely used term, one can ask: what are, in fact, the rare diseases treated, in some way, in the Brazilian public health system? At the international level, the Orphanet report provides a list of diseases considered rare in Europe (prevalence of up to 50/100,000 inhabitants) and the European Commission advocates the creation of the European Rare Disease Registry Platform that would act as a focal point for the registries of rare diseases in the European Union [6]. Furthermore, in the United States, which was the first country to establish national orphan drug legislation, in 1983, and is now one of the leaders in the treatment of rare diseases in the world, the estimated prevalence, added to the data source and basis consulted is a required evidence for the FDA to provide orphan designation to a medicine [7,8]. In Brazil, the PNAIPDR aims to qualify and guarantee people with rare diseases, in a timely manner, access to diagnostic and therapeutic means available according to their needs [3]. To this end, it provides for the organization and availability of dedicated services prepared to meet this population’s demands. However, state and municipal health managers are often faced with doubts about the classification of a given disease as rare or not, which generates conflicts with patients and associations, in addition to organizational difficulties in prioritizing and planning such services to meet the requirements of the publishe","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"10 1","pages":"28 - 33"},"PeriodicalIF":0.8,"publicationDate":"2022-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49537278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-01DOI: 10.1080/21678707.2022.2131393
P. Giraldo, L. López de Frutos, J. J. Cebolla
ABSTRACT Introduction Lysosomal acid lipase deficiency disease (LALD; MIM#278000) is an ultrarare lysosomal storage disease with a wide range of phenotypic variability. It is caused by the deficient activity of lysosomal acid lipase (LAL) enzyme, encoded by LIPA. Consequently, it leads to the buildup of cholesterol esters and triglycerides within the lysosomes, in the liver, spleen, adrenal glands, intestinal wall, and vascular tree. Early diagnosis is important to avoid progressive impaired liver function and an elevated risk of cardiovascular complications. Areas covered A systematic review has been carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) guidelines. All original articles and review articles published up to December 2021 about the diagnosis and follow-up of lysosomal acid lipase deficiency, Wolman disease, acid cholesterol ester hydrolase deficiency, and cholesterol ester hydrolase deficiency storage disease were reviewed by three independent researchers. A total of 169 articles were included. Expert opinion The identification of LALD by activity determination techniques using a dry blood spot has facilitated rapid and accurate diagnosis in screening programs. It is important to reduce the mortality associated with severe phenotypes and morbi-mortality in mild phenotypes, since safe and effective enzyme replacement therapy is available.
{"title":"Recommendations for overcoming challenges in the diagnosis of lysosomal acid lipase deficiency","authors":"P. Giraldo, L. López de Frutos, J. J. Cebolla","doi":"10.1080/21678707.2022.2131393","DOIUrl":"https://doi.org/10.1080/21678707.2022.2131393","url":null,"abstract":"ABSTRACT Introduction Lysosomal acid lipase deficiency disease (LALD; MIM#278000) is an ultrarare lysosomal storage disease with a wide range of phenotypic variability. It is caused by the deficient activity of lysosomal acid lipase (LAL) enzyme, encoded by LIPA. Consequently, it leads to the buildup of cholesterol esters and triglycerides within the lysosomes, in the liver, spleen, adrenal glands, intestinal wall, and vascular tree. Early diagnosis is important to avoid progressive impaired liver function and an elevated risk of cardiovascular complications. Areas covered A systematic review has been carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) guidelines. All original articles and review articles published up to December 2021 about the diagnosis and follow-up of lysosomal acid lipase deficiency, Wolman disease, acid cholesterol ester hydrolase deficiency, and cholesterol ester hydrolase deficiency storage disease were reviewed by three independent researchers. A total of 169 articles were included. Expert opinion The identification of LALD by activity determination techniques using a dry blood spot has facilitated rapid and accurate diagnosis in screening programs. It is important to reduce the mortality associated with severe phenotypes and morbi-mortality in mild phenotypes, since safe and effective enzyme replacement therapy is available.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"10 1","pages":"11 - 21"},"PeriodicalIF":0.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45324373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-18DOI: 10.1080/21678707.2022.2066996
V. Ravarotto, G. Bertoldi, L. F. Stefanelli, Laura Gobbi, L. Calò
ABSTRACT Introduction Gitelman’s syndrome (GS) is a rare inherited tubulopathy characterized by hypokalemia, hypomagnesemia, and metabolic alkalosis due to inactivating mutations of the distal convoluted tubule sodium chloride cotransporter. This entails reduced extracellular volume and consequent activation of counterbalancing systems such as the renin–angiotensin–aldosterone system. Although with high levels of angiotensin II, Gitelman’s patients do not display hypertension or its cardiovascular and renal remodeling complications related to overactivation of those systems. Areas covered The present review will explore the available experimental evidence on angiotensin II signaling in GS. The understanding of these mechanisms might be useful to track the rationale for novel treatments of Gitelman’s syndrome. Expert opinion These peculiar characteristics make GS a human model to investigate the angiotensin II signaling in humans to give deeper insights into the pathophysiology of hypertension. Current treatment for GS includes potassium and magnesium supplements with additional tailored treatments for concomitant chondrocalcinosis or prolonged QT interval; however, additional nutritional approaches could be considered that might minimize possible supplements’ side effects.
{"title":"Molecular aspects of the altered Angiotensin II signaling in Gitelman’s syndrome","authors":"V. Ravarotto, G. Bertoldi, L. F. Stefanelli, Laura Gobbi, L. Calò","doi":"10.1080/21678707.2022.2066996","DOIUrl":"https://doi.org/10.1080/21678707.2022.2066996","url":null,"abstract":"ABSTRACT Introduction Gitelman’s syndrome (GS) is a rare inherited tubulopathy characterized by hypokalemia, hypomagnesemia, and metabolic alkalosis due to inactivating mutations of the distal convoluted tubule sodium chloride cotransporter. This entails reduced extracellular volume and consequent activation of counterbalancing systems such as the renin–angiotensin–aldosterone system. Although with high levels of angiotensin II, Gitelman’s patients do not display hypertension or its cardiovascular and renal remodeling complications related to overactivation of those systems. Areas covered The present review will explore the available experimental evidence on angiotensin II signaling in GS. The understanding of these mechanisms might be useful to track the rationale for novel treatments of Gitelman’s syndrome. Expert opinion These peculiar characteristics make GS a human model to investigate the angiotensin II signaling in humans to give deeper insights into the pathophysiology of hypertension. Current treatment for GS includes potassium and magnesium supplements with additional tailored treatments for concomitant chondrocalcinosis or prolonged QT interval; however, additional nutritional approaches could be considered that might minimize possible supplements’ side effects.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"10 1","pages":"1 - 10"},"PeriodicalIF":0.8,"publicationDate":"2022-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44171181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-02DOI: 10.1080/21678707.2021.2050368
R. Siddiqui, Mohamed Yehia Abouleish, Mustafa I. Khamis, T. Ibrahim, N. Khan
Given the opportunity and access to susceptible hosts, freeliving amoebae (Naegleria fowleri, Acanthamoeba spp., Balamuthia mandrillaris) can produce fatal diseases involving the brain[1]. It is disturbing that the rate of mortality has remained over 90%, despite decades of research in drug discovery and major breakthroughs taking place in chemotherapy and supportive care. For example, N. fowleri, the causative agent of primary amoebic meningoencephalitis was first described in 1965, while granulomatous amoebic meningoencephalitis due to Acanthamoeba and B. mandrillaris were reported in 1978 and 1990, respectively. Yet, the treatment using a combination of drugs (often antifungals such as amphotericin B and azoles) remains a hit-and-miss approach [2]. Even with treatment, reported cases with successful prognosis have been few and far between, requiring high suspicion together with early diagnosis, and a favorable outcome is mostly seen in the cases reported in the USA. The very high mortality rate is attributed to (i) inefficacy of drugs to penetrate the otherwise highly restrictive blood–brain barrier to target the parasites residing within the central nervous system, and (ii) the lack of available parasite-specific drugs. At present, the management of brain-eating amoebae infection involves a combination of drugs including, amidines, neomycin, biguanides, ergosterol inhibitors such as azoles/amphotericin B, sulfadiazine, milfetosine, etc.[2]. Several compounds may not be effective in reaching the infection site (limited blood–brain barrier permeability), exhibit inadequate amoebicidal properties in vivo at physiologically relevant concentrations, and/or show high host cell cytotoxicity. Given the rarity of the disease, it is not surprising that the pharmaceutical industry has shown no interest in the development and/or modulation of compounds that are blood–brain barrier permeable with potential to target the brain-eating amoebae effectively at the infection site, without harming human cells. The reuse of medicines is a valid avenue to expedite our advances in the development of effective treatment options against neglected brain-eating amoebae infections. Herein, we discuss clinically used drugs for neuropathological conditions that are blood–brain barrier permeable, as well as parasitespecific compounds developed against related protozoa, as potential avenues to design chemotherapeutics against orphan infections due to pathogenic free-living amoebae (Figure 1). In this regard, there are three avenues to be explored;
{"title":"Current medicines hold promise in the treatment of orphan infections due to brain-eating amoebae","authors":"R. Siddiqui, Mohamed Yehia Abouleish, Mustafa I. Khamis, T. Ibrahim, N. Khan","doi":"10.1080/21678707.2021.2050368","DOIUrl":"https://doi.org/10.1080/21678707.2021.2050368","url":null,"abstract":"Given the opportunity and access to susceptible hosts, freeliving amoebae (Naegleria fowleri, Acanthamoeba spp., Balamuthia mandrillaris) can produce fatal diseases involving the brain[1]. It is disturbing that the rate of mortality has remained over 90%, despite decades of research in drug discovery and major breakthroughs taking place in chemotherapy and supportive care. For example, N. fowleri, the causative agent of primary amoebic meningoencephalitis was first described in 1965, while granulomatous amoebic meningoencephalitis due to Acanthamoeba and B. mandrillaris were reported in 1978 and 1990, respectively. Yet, the treatment using a combination of drugs (often antifungals such as amphotericin B and azoles) remains a hit-and-miss approach [2]. Even with treatment, reported cases with successful prognosis have been few and far between, requiring high suspicion together with early diagnosis, and a favorable outcome is mostly seen in the cases reported in the USA. The very high mortality rate is attributed to (i) inefficacy of drugs to penetrate the otherwise highly restrictive blood–brain barrier to target the parasites residing within the central nervous system, and (ii) the lack of available parasite-specific drugs. At present, the management of brain-eating amoebae infection involves a combination of drugs including, amidines, neomycin, biguanides, ergosterol inhibitors such as azoles/amphotericin B, sulfadiazine, milfetosine, etc.[2]. Several compounds may not be effective in reaching the infection site (limited blood–brain barrier permeability), exhibit inadequate amoebicidal properties in vivo at physiologically relevant concentrations, and/or show high host cell cytotoxicity. Given the rarity of the disease, it is not surprising that the pharmaceutical industry has shown no interest in the development and/or modulation of compounds that are blood–brain barrier permeable with potential to target the brain-eating amoebae effectively at the infection site, without harming human cells. The reuse of medicines is a valid avenue to expedite our advances in the development of effective treatment options against neglected brain-eating amoebae infections. Herein, we discuss clinically used drugs for neuropathological conditions that are blood–brain barrier permeable, as well as parasitespecific compounds developed against related protozoa, as potential avenues to design chemotherapeutics against orphan infections due to pathogenic free-living amoebae (Figure 1). In this regard, there are three avenues to be explored;","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"227 - 235"},"PeriodicalIF":0.8,"publicationDate":"2021-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49312919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-02DOI: 10.1080/21678707.2021.2050367
T. Tarrant, S. Kelly, M. Hershfield
ABSTRACT Introduction Humans have two adenosine deaminase isozymes, ADA1 and ADA2, which differ in affinity for their substrates, adenosine (Ado) and 2ʹdeoxyadenosine (dAdo), and their localization. Inherited deficiencies of ADA1 and ADA2 compromise different aspects of immune and hematological function. The metabolic consequences of ADA1 deficiency show that its enzymatic (ADA) activity is central to its biological function. By contrast, the function of ADA2 is uncertain and no direct metabolic consequences of the deficiency of ADA2 (DADA2) have yet been identified. Several potential pathogenetic mechanisms related to, or independent of, ADA2 enzymatic activity have been proposed. Areas covered We will review the discovery of ADA2 and DADA2, and two principal hypotheses: that ADA2 regulates the concentration of extracellular Ado and/or that it is a growth factor. We will consider two newer proposals that involve the effects of ADA2 products rather than its substrates, one of which postulates a pathogenic role for elevated levels of ADA2. Expert opinion Some currently proposed mechanisms of DADA2 pathogenesis are controversial or contradictory, and supportive evidence is inadequate. Progress in several areas may clarify the function of ADA2 and facilitate the development of new therapies for DADA2 based on elucidation of its pathogenesis.
{"title":"Elucidating the pathogenesis of adenosine deaminase 2 deficiency: current status and unmet needs","authors":"T. Tarrant, S. Kelly, M. Hershfield","doi":"10.1080/21678707.2021.2050367","DOIUrl":"https://doi.org/10.1080/21678707.2021.2050367","url":null,"abstract":"ABSTRACT Introduction Humans have two adenosine deaminase isozymes, ADA1 and ADA2, which differ in affinity for their substrates, adenosine (Ado) and 2ʹdeoxyadenosine (dAdo), and their localization. Inherited deficiencies of ADA1 and ADA2 compromise different aspects of immune and hematological function. The metabolic consequences of ADA1 deficiency show that its enzymatic (ADA) activity is central to its biological function. By contrast, the function of ADA2 is uncertain and no direct metabolic consequences of the deficiency of ADA2 (DADA2) have yet been identified. Several potential pathogenetic mechanisms related to, or independent of, ADA2 enzymatic activity have been proposed. Areas covered We will review the discovery of ADA2 and DADA2, and two principal hypotheses: that ADA2 regulates the concentration of extracellular Ado and/or that it is a growth factor. We will consider two newer proposals that involve the effects of ADA2 products rather than its substrates, one of which postulates a pathogenic role for elevated levels of ADA2. Expert opinion Some currently proposed mechanisms of DADA2 pathogenesis are controversial or contradictory, and supportive evidence is inadequate. Progress in several areas may clarify the function of ADA2 and facilitate the development of new therapies for DADA2 based on elucidation of its pathogenesis.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"257 - 264"},"PeriodicalIF":0.8,"publicationDate":"2021-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60429150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-02DOI: 10.1080/21678707.2021.2022472
G. Meskill, U. Kallweit, Donna Zarycranski, C. Caussé, O. Finance, X. Ligneau, C. Davis
ABSTRACT Introduction Narcolepsy is a chronic neurological disorder of sleep-wake instability that typically requires lifelong pharmacotherapy. Narcolepsy medications target the cardinal symptoms of excessive daytime sleepiness (EDS), cataplexy (the sudden loss of muscle tone often triggered by strong emotion), or both. Areas covered A comprehensive review of the clinical trial data evaluating the efficacy of pitolisant (Wakix) for the treatment of cataplexy is provided. Expert opinion There remains an important need to improve the recognition and assessment of cataplexy. Treatment effectiveness should be evaluated with a patient-specific approach that takes into account not only a reduction in the frequency and severity of cataplexy attacks, but also fewer limitations imposed by cataplexy and enhancements in quality of life. Pitolisant, a histamine H3-receptor antagonist/inverse agonist, has demonstrated efficacy for the reduction of both cataplexy and EDS in patients with narcolepsy, including patients who experience frequent cataplexy attacks. Histamine plays an important role in the regulation of sleep and wakefulness, and pitolisant is thought to act directly via the histamine system and indirectly via other neurotransmitter systems. Based on the favorable efficacy and safety profile demonstrated in clinical trials, pitolisant should be considered as first-line treatment for patients with narcolepsy.
{"title":"Pitolisant for the treatment of cataplexy in adults with narcolepsy","authors":"G. Meskill, U. Kallweit, Donna Zarycranski, C. Caussé, O. Finance, X. Ligneau, C. Davis","doi":"10.1080/21678707.2021.2022472","DOIUrl":"https://doi.org/10.1080/21678707.2021.2022472","url":null,"abstract":"ABSTRACT Introduction Narcolepsy is a chronic neurological disorder of sleep-wake instability that typically requires lifelong pharmacotherapy. Narcolepsy medications target the cardinal symptoms of excessive daytime sleepiness (EDS), cataplexy (the sudden loss of muscle tone often triggered by strong emotion), or both. Areas covered A comprehensive review of the clinical trial data evaluating the efficacy of pitolisant (Wakix) for the treatment of cataplexy is provided. Expert opinion There remains an important need to improve the recognition and assessment of cataplexy. Treatment effectiveness should be evaluated with a patient-specific approach that takes into account not only a reduction in the frequency and severity of cataplexy attacks, but also fewer limitations imposed by cataplexy and enhancements in quality of life. Pitolisant, a histamine H3-receptor antagonist/inverse agonist, has demonstrated efficacy for the reduction of both cataplexy and EDS in patients with narcolepsy, including patients who experience frequent cataplexy attacks. Histamine plays an important role in the regulation of sleep and wakefulness, and pitolisant is thought to act directly via the histamine system and indirectly via other neurotransmitter systems. Based on the favorable efficacy and safety profile demonstrated in clinical trials, pitolisant should be considered as first-line treatment for patients with narcolepsy.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"237 - 246"},"PeriodicalIF":0.8,"publicationDate":"2021-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41413344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-02DOI: 10.1080/21678707.2021.2047021
K. L. Miller, Selma Kraft, A. Ipe, Lewis J. Fermaglich
ABSTRACT Background The Orphan Drug Act was created to stimulate the development of drugs and biologics for rare diseases. Investigating products that have received orphan drug designation provide a greater understanding of rare disease drug development, as well as the repositioning business models of developers. Research design and methods We used a dataset containing all orphan drug designations between 1983 and 2019. To analyze the orphan products, we constructed a variable, ‘unique product,’ that allowed for the standardization of generic names of drugs and biologics. Additional analysis was performed on the most frequently designated unique products and their repositioning strategies. Results We found 5,099 orphan drug designations representing 3,269 unique products, of which 508 had an orphan-designated approval from FDA. Unique products with only a single designation represented 2,448 (75%) of the total products and 26 (1%) products had 10 or more designations. Over 60% of these unique products with 10 or more designations were antineoplastics or immunomodulators. Conclusions The most designated unique products revealed a continuum of repositioning strategies, from the repurposing of approved drugs to parallel indication development programs for recently developed drugs. The fact that over 3,000 unique products have been studied for rare diseases indicates that future repositioning opportunities may become increasingly available.
{"title":"Drugs and biologics receiving FDA orphan drug designation: an analysis of the most frequently designated products and their repositioning strategies","authors":"K. L. Miller, Selma Kraft, A. Ipe, Lewis J. Fermaglich","doi":"10.1080/21678707.2021.2047021","DOIUrl":"https://doi.org/10.1080/21678707.2021.2047021","url":null,"abstract":"ABSTRACT Background The Orphan Drug Act was created to stimulate the development of drugs and biologics for rare diseases. Investigating products that have received orphan drug designation provide a greater understanding of rare disease drug development, as well as the repositioning business models of developers. Research design and methods We used a dataset containing all orphan drug designations between 1983 and 2019. To analyze the orphan products, we constructed a variable, ‘unique product,’ that allowed for the standardization of generic names of drugs and biologics. Additional analysis was performed on the most frequently designated unique products and their repositioning strategies. Results We found 5,099 orphan drug designations representing 3,269 unique products, of which 508 had an orphan-designated approval from FDA. Unique products with only a single designation represented 2,448 (75%) of the total products and 26 (1%) products had 10 or more designations. Over 60% of these unique products with 10 or more designations were antineoplastics or immunomodulators. Conclusions The most designated unique products revealed a continuum of repositioning strategies, from the repurposing of approved drugs to parallel indication development programs for recently developed drugs. The fact that over 3,000 unique products have been studied for rare diseases indicates that future repositioning opportunities may become increasingly available.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"265 - 272"},"PeriodicalIF":0.8,"publicationDate":"2021-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44379600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-02DOI: 10.1080/21678707.2021.2049755
A. Ogasawara, Daisuke Shintatni, Sho Sato, K. Hasegawa
ABSTRACT Introduction Uterine carcinosarcoma (UCS) is a highly aggressive disease, and had been traditionally recognized as a uterine sarcoma. In recent years, it has been categorized as a subtype of high-grade endometrial cancer. Its prognosis is extremely poor, and approximately half of the patients with early-stage disease will recure and eventually die. Due to its high relapse rate, an effective adjuvant therapy is needed. As UCS has a high incidence of distant recurrence, systemic chemotherapy may be beneficial as an adjuvant therapy even in completely resected early-stage cases. A search of PubMed database was performed for research articles published between January 1981 and January 2022. Areas covered We have summarized the current evidence of adjuvant chemotherapy in patients with UCS. Expert opinion There have been only a limited number of prospective randomized trials which enrolled solely carcinosarcoma, particularly with only adjuvant chemotherapy. Several trials have suggested that adjuvant chemotherapy is effective for both early and advance stage. Regarding the chemotherapy regimens, combination chemotherapies including either platinum or ifosfamide are all effective as an adjuvant chemotherapy. Among these, currently paclitaxel plus carboplatin is considered the most preferred regimen in terms of efficacy and toxicity profile.
{"title":"Adjuvant chemotherapy in patients with uterine carcinosarcoma: a review of clinical outcomes and considerations","authors":"A. Ogasawara, Daisuke Shintatni, Sho Sato, K. Hasegawa","doi":"10.1080/21678707.2021.2049755","DOIUrl":"https://doi.org/10.1080/21678707.2021.2049755","url":null,"abstract":"ABSTRACT Introduction Uterine carcinosarcoma (UCS) is a highly aggressive disease, and had been traditionally recognized as a uterine sarcoma. In recent years, it has been categorized as a subtype of high-grade endometrial cancer. Its prognosis is extremely poor, and approximately half of the patients with early-stage disease will recure and eventually die. Due to its high relapse rate, an effective adjuvant therapy is needed. As UCS has a high incidence of distant recurrence, systemic chemotherapy may be beneficial as an adjuvant therapy even in completely resected early-stage cases. A search of PubMed database was performed for research articles published between January 1981 and January 2022. Areas covered We have summarized the current evidence of adjuvant chemotherapy in patients with UCS. Expert opinion There have been only a limited number of prospective randomized trials which enrolled solely carcinosarcoma, particularly with only adjuvant chemotherapy. Several trials have suggested that adjuvant chemotherapy is effective for both early and advance stage. Regarding the chemotherapy regimens, combination chemotherapies including either platinum or ifosfamide are all effective as an adjuvant chemotherapy. Among these, currently paclitaxel plus carboplatin is considered the most preferred regimen in terms of efficacy and toxicity profile.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"247 - 255"},"PeriodicalIF":0.8,"publicationDate":"2021-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43397694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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