The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein

The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer’s disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the ’amyloidogenic’ proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the ’non-amyloidogenic’ pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β–secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer’s disease.

Postmarketing safety of orphan drugs: a longitudinal analysis of the US Food and Drug Administration database between 1999 and 2018

Background Information about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors. Methods This retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events. Results Amongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings [Incidence rate ratio (IRR): 1.95 (1.02–3.73)] and approved for long-term use [IRR: 2.76 (1.52–5.00)]. Conclusions and Relevance In this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.

Orphan Medicine Incentives: How to Address the Unmet Needs of Rare Disease Patients by Optimizing the European Orphan Medicinal Product Landscape Guiding Principles and Policy Proposals by the European Expert Group for Orphan Drug Incentives (OD Expert Group)

Today policy makers face the challenge to devise a policy framework that improves orphan medicinal product (OMP) development by creating incentives to deliver treatments where there are none and to authorize innovative and transformative treatments where treatments already exist. The European Expert Group on Orphan Drug Incentives (hereafter, OD Expert Group) came together in 2020 to develop policy proposals to facilitate EU policy makers to meet this challenge. The group brings together representatives of the broad rare disease community, including researchers, academia, patient representatives, members of the investor community, rare disease companies and trade associations. The group’s work builds on the recognition that only an ambitious policy agenda developed in a multi-stakeholder setting can bring about the quantum leap needed to address unmet needs of rare disease patients today. Along the OMP development path, the OD Expert Group has identified four main needs that a policy revision should address: 1) Need to improve the R&D ecosystem for basic research and company take-up of development. 2) Need to improve the system of financial incentives and rewards. 3) Need to improve the flexibility, predictability and speed of the regulatory pathway. 4) Need to improve the coherence and predictability of demand and pricing for OMPs. This article presents the results of the OD Expert Group work as a set of guiding principles that the revision of the policy framework should follow and a set of 14 policy proposals that address the main needs of OMP development in Europe today.

Should rare diseases get special treatment?

Orphan drug policy often gives ‘special treatment’ to rare diseases, by giving additional priority or making exceptions to specific drugs, based on the rarity of the conditions they aim to treat. This essay argues that the goal of orphan drug policy should be to make prevalence irrelevant to funding decisions. It aims to demonstrate that it is severity, not prevalence, which drives our judgments that important claims are being overlooked when treatments for severe rare diseases are not funded. It shows that prioritising severity avoids problems caused by prioritising rarity, and that it is compatible with a range of normative frameworks. The implications of a severity-based view for drug development are then derived. The severity-based view also accounts for what is wrong with how the current system of drug development unfairly neglects common diseases that burden the developing world. Lastly, the implications of a severity-based view for current orphan drug policies are discussed.

Assessment of Regulatory Strategies for Orphan Drug Development and Approval Process in USA & EU

Orphan medicines are pharmaceutical drugs or vaccines supposed to deal with, preventing or diagnose of a rare disease (viz., ailment, Huntington's disease, syndrome, etc.). The meaning of rare sicknesses varies throughout some jurisdictions, however, generally contemplates the ailment of occurrence, severity, and life of alternate healing options. An uncommon ailment isn't worldwide and depends on the rules and guidelines officially adopted and approved via each region or U.S.A. The Orphan Drug Act, 1983 (ODA) has been recognized and adopted in numerous nations, international (United States of America (USA) and European Union (EU).) in the preceding 35 years, and has effectively advanced R and D ventures to widen new pharmaceuticals for the remedy of rare sickness. The rate of occurrences of such diseases were outpaced at an extra pace than the speed with which medicines are researched and developed to treat rare diseases. One of the main reasons is that the pharmaceutical industry is not interested in researching the enhancement of orphan medicines since they no longer have a significant large market. Despite the multiple incentives provided by the orphan drug act, this is the current reality. However, in this article, we've tried to concentrate on the current regulatory framework, current concepts of rare disease, regulatory challenges for rare disease drug development, and orphan drug approval in the United States & the European Union.

Orphan Drugs, Compounded Medication and Pharmaceutical Commons

Regulatory agencies installed orphan drug regulations to stimulate research and development of new innovative treatments for life-threatening diseases with a low prevalence (rare diseases). We established a list of well-known food-related ingredients with clinical evidence for rare diseases in the open medical literature that obtained marketing authorization as an expensive “orphan drug”, protected by intellectual property (IP) rights. We show that these ingredients are part of an established practice of medicinal compounding—a form of point of care manufacturing. We argue that these ingredients should be considered as “pharmaceutical commons”, and that regulatory incentives for private companies and market protection mechanisms such as IP rights are not justified in this case.

COST-EFFECTIVENESS OF ORPHAN DRUGS FOR LEUKEMIA TREATMENT: A SYSTEMATIC REVIEW

Introduction: Leukemia is a rare disease related to hematologic cancer stemming from the bone marrow. The Vietnam Ministry of Health (MOH) promulgated the Orphan Drugs List, in which there were 37 orphan drugs indicated for leukemia. This study aimed to systematically review all studies on the cost-effectiveness analysis (CEA) of these orphan drugs in leukemia treatment. Materials and methods: This study conducted a systematic review on all studies published till August 2021 on the National Center for Biotechnology Information (NCBI), SpringerLink, and Biomed Central. 23 studies were selected in this systematic review, which were studies that had available full-texts, were written in English, aimed to analyze the cost-effectiveness of leukemia drugs listed on the Vietnam MOH’s Orphan Drugs List. The results were presented by describing CEA findings by five different leukemia types, with a focus on the incremental cost-effectiveness ratio (ICER) of each orphan drug and the comparison to the willingness-to-pay (WTP) threshold. All the cost currency values were converted to USD in 2021 to make comparison. Results: Of 37 drugs on the Vietnam MOH’s orphan drug list, 24 drugs were cost-effectiveness analyzed with available full-texts. Of 23 selected studies in the review, there were 10 studies regarding lymphocytic leukemia (43.5%) and 13 studies regarding myeloid leukemia (56.5%). 60.9% studied on relapsed/refractory patients, 39.1% conducted cost-analyses with a social perspective, and 47.7% used overall survival combined with progression-free survival (OS-PFS) as a clinical endpoint. Quality-adjusted life year (QALY) was used as an effectiveness measurement unit in 65.2% of the total selected studies. 15 studies made a conclusion that their studied orphan drugs were cost-effective. 100% of the studies regarding acute lymphoblastic leukemia showed the orphan drugs of interest were cost-effective (ICER < WTP threshold); while about 50% of the studies regarding other leukemia types showed the orphan drugs of interest were not cost-effective (ICER > WTP threshold) and thus required suitable financial aid. Conclusion: This study provided information on the cost-effectiveness of 24 out of 37 orphan drugs for leukemia treatment listed on the Vietnam MOH's Orphan Drugs List. These orphan drugs could be considered as a financial burden for leukemia patients and other potential payers such as the Vietnam Social Security due to their considerably high cost.