Orphan Drug Research Articles

Three Pillars of Support for Orphan Drug Programs: Individual Valuations, Societal Valuations, and Anonymous Altruism

ObjectivesTo identify and describe potential societal and individual sources of support for orphan drug programs. MethodsThe Generalized Risk-Adjusted Cost-Effectiveness method shows that acute illness and disability severity increase individuals’ willingness to pay for health gains. We develop a social welfare function (SWF) that incorporates individuals’ own values, combined with politically or ethically determined weights. We introduce the concept of horizontal equity—that individuals in similar situations should be treated similarly—into the SWF. Finally, we introduce anonymous altruism into individuals’ utility functions—the desire to help others, without knowing their identity. ResultsCombined with the empirical link between disease severity and rarity, the Generalized Risk-Adjusted Cost-Effectiveness method demonstrates heightened willingness to pay for health gains for people with rare diseases, leading rational individuals to support orphan drug programs, our first pillar of support. Adding horizontal equity to the SWF further increases societal support for orphan drug programs. Anonymous altruism, focusing most strongly on those in the most-dire circumstances, leads to altruistic support for those with severe disorders. Because innovators’ economic incentives lead them to focus on larger markets, anonymous altruistic individuals will increasingly prefer public investments into rare diseases over time, as private markets systematically produce gains for common diseases. ConclusionsWe identified 3 supporting pillars for orphan drug programs: (1) individuals’ propensity to prefer treatments for severe diseases; (2) the preference for horizontal equity in our social welfare; (3) anonymous altruism, the desire to help strangers, coupled with market incentives that underserve strangers with rare diseases.

Unraveling the interaction mechanism between orphan drug Nitisinone and bovine serum albumin through spectroscopic and in silico approaches

The interaction between Nitisinone (NTBC) and bovine serum albumin (BSA) as the transport protein in a circulating system was investigated for the first time utilizing various analytical (UV–Vis spectrophotometry, fluorescence spectroscopy, dynamic light scattering, and differential scanning calorimetry) and computational (molecular docking and molecular dynamics simulations) methods. The BSA fluorescence intensity was quenched upon interaction with NTBC, and the quenching mechanism was observed as static. The interaction between NTBC and BSA was examined at 288 K, 298 K, and 308 K where the binding constants were found to be 1.44 × 105 ± 0.22 M−1, 5.18 × 104 ± 0.20 M−1, and 3.02 × 104 ± 0.22 M−1 respectively, suggesting an intermediate binding affinity between NTBC and BSA. Changes in the microenvironment surrounding tryptophan and tyrosine residues of BSA were elucidated using 3-D fluorescence spectroscopy. Thermodynamic studies revealed the calculated values of ΔH = − 54.34 ± 5 kJ/mol and ΔS = − 0.0908 ± 0.24 kJ/mol K−1, indicating the involvement of van der Waals forces and hydrogen bonds in the interaction between NTBC and BSA. Moreover, the interaction’s spontaneous nature was evidenced by negative ΔG values across all temperatures. Using dynamic light scattering, it was observed that higher NTBC concentrations led to a gradual rise in hydrodynamic diameter and notable aggregation of the NTBC-BSA complex. Moreover, changing signal values and shifted peaks of BSA, NTBC, and complex in differential scanning calorimetry curves, meant there were molecular interactions between the NTBC and BSA. In silico approaches also elucidated how NTBC binds to active sites on BSA, further supporting other findings. Moreover, molecular docking studies offer a more profound insight into the changing dynamics of hydrophobic, hydrogen, and halogen bonding involved in stabilizing the NTBC-BSA complex.

Teaching an old drug new tricks: Regulatory insights for the repurposing of hemin in cardiovascular disease.

Drug repurposing has gained significant interest in recent years due to the high costs associated with de novo drug development; however, comprehensive pharmacological information is needed for the translation of pre-existing drugs across clinical applications. In the present study, we explore the current pharmacological understanding of the orphan drug, hemin, and identify remaining knowledge gaps with regard to hemin repurposing for the treatment of cardiovascular disease. Originally approved by the United States Food and Drug Administration in 1983 for the treatment of porphyria, hemin has attracted significant interest for therapeutic repurposing across a variety of pathophysiological conditions. Yet, the clinical translation of hemin remains limited to porphyria. Understanding hemin's pharmacological profile in health and disease strengthens our ability to treat patients effectively, identify therapeutic opportunities or limitations, and predict and prevent adverse side effects. However, requirements for the pre-clinical and clinical characterization of biologics approved under the U.S. FDA's Orphan Drug Act in 1983 (such as hemin) differed significantly from current standards, presenting fundamental gaps in our collective understanding of hemin pharmacology as well as knowledge barriers to clinical translation for future applications. Using information extracted from the primary and regulatory literature (including documents submitted to Health Canada in support of hemin's approval for the Canadian market in 2018), we present a comprehensive case study of current knowledge related to hemin's biopharmaceutical properties, pre-clinical/clinical pharmacokinetics, pharmacodynamics, dosing, and safety, focusing specifically on the drug's effects on heme regulation and in the context of acute myocardial infarction.

Adverse events associated with eteplirsen: A disproportionality analysis using the 2016–2023 FAERS data

BackgroundEteplirsen (Exondys 51) is an orphan drug approved for the treatment of Duchenne muscular dystrophy (DMD), having received accelerated approval from the U.S. Food and Drug Administration (FDA) in 2016. The primary aim of this study is to closely monitor adverse events (AEs) associated with eteplirsen and to identify emerging signals to better characterize their safety profile. MethodsAEs due to eteplirsen usage reported from the third quarter (Q3) of 2016 to the fourth quarter (Q4) of 2023 were collected from the FDA Adverse Event Reporting System (FAERS). The role_code of AEs mainly includes primary suspect (PS), secondary suspect (SS), concomitant (C), and interaction (I). This study targeted reports with a role_cod of ‘PS.’ According to the FDA deduplication rule, the latest FDA_DT is selected when the CASEID is the same, and the higher PRIMARYID is selected when the CASEID and FDA_DT are the same. Disproportionality analyses, encompassing four algorithms for reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian configuration promotion neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were utilized to quantify the signals of AEs associated with eteplirsen. ResultsFrom the FAERS database, a total of 13,205,369 reports were amassed throughout the study duration. Following the eradication of duplicates, the number of reports with eteplirsen designated as the PS amounted to 1480 encompassed 25 organ systems. Among these, “general disorders and administration site conditions,” “injury, poisoning, and procedural complications,” “respiratory, thoracic, and mediastinal disorders,” “infections and infestations,” “vascular disorders,” and “product issues” met at least one of the four computational criteria. Additionally, 55 Preferred Terms (PTs) aligned with the prescribed algorithms. The median time to AEs in these patients was 903 days with an interquartile range (IQR) of 269–1575 days. Moreover, 70.04 % of AEs manifested one year or more after the initiation of treatment. ConclusionAs an orphan drug granted accelerated approval, our study has confirmed well-known adverse drug reactions and identified potential safety issues associated with eteplirsen treatment. This has contributed to a deeper understanding of the complex interrelations between adverse reactions and the use of eteplirsen. The findings underscore the critical importance of ongoing monitoring and sustained observation to promptly detect and effectively manage AEs, thereby enhancing the overall safety and well-being of patients treated with eteplirsen for DMD.

HTA28 Comparative Analysis of Orphan Drug HTA Assessment: Perspectives from HAS and SMC

HTA28 Comparative Analysis of Orphan Drug HTA Assessment: Perspectives from HAS and SMC

EE525 Comparative Analysis of Launch Prices for Orphan Drugs in the US and EU4

EE525 Comparative Analysis of Launch Prices for Orphan Drugs in the US and EU4

HTA79 Navigating the Clinical Effectiveness Challenges for Orphan Drug Assessments: A NCPE Review

HTA79 Navigating the Clinical Effectiveness Challenges for Orphan Drug Assessments: A NCPE Review

HPR4 What Makes an Orphan Medicine? Determining Characteristics of Non-Oncology Orphan Approvals from 2015-2022

HPR4 What Makes an Orphan Medicine? Determining Characteristics of Non-Oncology Orphan Approvals from 2015-2022

International comparison of availability for orphan drugs: focused on approved orphan drugs in South Korea

International comparison of availability for orphan drugs: focused on approved orphan drugs in South Korea

Pricing, Procurement and Reimbursement Policies for Incentivizing Market Entry of Novel Antibiotics and Diagnostics: Learnings from 10 Countries Globally.

Fostering market entry of novel antibiotics and enhanced use of diagnostics to improve the quality of antibiotic prescribing are avenues to tackle antimicrobial resistance (AMR), which is a major public health threat. Pricing, procurement and reimbursement policies may work as AMR 'pull incentives' to support these objectives. This paper studies pull incentives in pricing, procurement and reimbursement policies (e.g., additions to, modifications of, and exemptions from standard policies) for novel antibiotics, diagnostics and health products with a similar profile in 10 study countries. It also explores whether incentives for non-AMR health products could be transferred to AMR health products. This research included a review of policies in 10 G20 countries based on literature and unpublished documents, and the production of country fact sheets that were validated by country experts. Initial research was conducted in 2020 and updated in 2023. Identified pull incentives in pricing policies include free pricing, higher prices at launch and price increases over time, managed-entry agreements, and waiving or reducing mandatory discounts. Incentives in procurement comprise value-based procurement, pooled procurement and models that delink prices from volumes (subscription-based schemes), whereas incentives in reimbursement include lower evidence requirements for inclusion in the reimbursement scheme, accelerated reimbursement processes, separate budgets that offer add-on funding, and adapted prescribing conditions. While a few pull incentives have been piloted or implemented for antibiotics in recent years, these mechanisms have been mainly used to incentivize launch of certain non-AMR health products, such as orphan medicines. Given similarities in their product characteristics, transferability of some of these pull incentives appears to be possible; however, it would be essential to conduct impact assessments of these incentives. Trade-offs between incentives to foster market entry and thus potentially improve access and the financial sustainability for payers need to be addressed.

How Has the Treatment of Polish Children with Dravet Syndrome Changed? Future Perspectives.

This report focuses on the treatment histories of 21 patients diagnosed with Dravet syndrome (DRVT) under the care of the Mother and Child Institute in Warsaw. This paper aims to present typical treatment schemes for patients with drug-resistant epilepsy, as well as to highlight the influence of genetic diagnosis on pharmacotherapeutic management and to present an economic analysis of hospitalization costs. This paper will also summarize the effectiveness of the latest drugs used in DRVT. Clinical data were collected retrospectively from available medical records. The effectiveness of anticonvulsant treatment was assessed based on epileptic seizure diaries and observations by caregivers and pediatric neurologists. The study group (n = 21) consisted of patients aged 3-26 years. Orphan drugs dedicated to Dravet syndrome were introduced in all patients due to the genetic diagnosis, which significantly improved the patients' clinical conditions. The breakthrough drugs were stiripentol (in 16/21) and fenfluramine (in 3/21). In recent years, molecular genetics has rapidly developed in Poland, along with a steady increase in knowledge of Dravet syndrome among the medical profession. Early and precise diagnosis provides the opportunity to target treatment with drugs dedicated to Dravet syndrome with high efficacy.

Framework for developing cost-effectiveness analysis threshold: the case of Egypt

BackgroundCost-effectiveness analyses rarely offer useful insights to policy decisions unless their results are compared against a benchmark threshold. The cost-effectiveness threshold (CET) represents the maximum acceptable monetary value for achieving a unit of health gain. This study aimed to identify CET values on a global scale, provide an overview of using multiple CETs, and propose a country-specific CET framework specifically tailored for Egypt. The proposed framework aims to consider the globally identified CETs, analyze global trends, and consider the local structure of Egypt’s healthcare system.MethodsWe conducted a literature review to identify CET values, with a particular focus on understanding the basis of differentiation when multiple thresholds are present. CETs of different countries were reviewed from secondary sources. Additionally, we assembled an expert panel to develop a national CET framework in Egypt and propose an initial design. This was followed by a multistakeholder workshop, bringing together representatives of different governmental bodies to vote on the threshold value and finalize the recommended framework.ResultsThe average CET, expressed as a percentage of the gross domestic product (GDP) per capita across all countries, was 135%, with a range of 21 to 300%. Interestingly, while the absolute value of CET increased with a country’s income level, the average CET/GDP per capita showed an inverse relationship. Some countries applied multiple thresholds based on disease severity or rarity. In the case of Egypt, the consensus workshop recommended a threshold ranging from one to three times the GDP per capita, taking into account the incremental relative quality-adjusted life years (QALY) gain. For orphan medicines, a CET multiplier between 1.5 and 3.0, based on the disease rarity, was recommended. A two-times multiplier was proposed for the private reimbursement threshold compared to the public threshold.ConclusionThe CET values in most countries appear to be closely related to the GDP per capita. Higher-income countries tend to use a lower threshold as a percentage of their GDP per capita, contrasted with lower-income countries. In Egypt, experts opted for a multiple CET framework to assess the value of health technologies in terms of reimbursement and pricing.

Associations between prognosis and primary endpoint selection in phase III oncology trials in the United States.

e23022 Background: Overall survival (OS) is commonly used as a primary endpoint in phase III oncology trials in the United States, serving as direct evidence of clinical benefit and as an objective outcome measure. Other endpoints such as progression-free survival (PFS) and objective response rate (ORR) are also utilized. Factors such as a cancer type and treatment line are considered important for primary endpoint selection, however, the fundamental factor influencing primary endpoint selection across various cancer types or treatment lines remains unclear. I hypothesize that the prognosis of the target patient population is one of the key fundamental factors across any groups in primary endpoint selection. This study aims to investigate the associations between the prognosis and the type of primary endpoint. Methods: All phase 3 clinical trials conducted in the US, focusing on drug therapies for cancer, between January 1, 2015 and Dec 31, 2022 were included. Multinomial logistic regression was utilized to assess the relationships between prognosis, indicated by the median overall survival of the control arm, and the type primary endpoint among OS, non-OS time-to-event endpoints (Other TTE), and response or remission rate (RR). Models were adjusted for cancer type, treatment line, the primary endpoint of the previous clinical study for the same target patient population, monotherapy, mechanism of action (MOA), biomarker for the drug, orphan drug designation (ODD), and accelerated approval (AA) before regulatory approval. Results: Out of 5,877 phase 3 clinical trials, 151 studies and 167 evaluation sets were included in the analysis. When the prognosis and the type of primary endpoint were tested, this factor demonstrated a statistically significant difference with a positive coefficient for Other TTE, RR, and a co-primary endpoint of OS and Other TTE compared to OS. The prognosis, the median OS of the control arm, was 10.5 months (95% CI 5.00-16.6) for OS, 18.5 months (95% CI 7.50-34.3) for Other TTE, 32.9 months for RR, and 13.6 months (95% CI 8.7-46.6) for the co-primary endpoint of OS and Other TTE respectively. No effect modification was observed for Other TTE and the co-primary endpoint of OS and Other TTE. Conclusions: A better prognosis is associated with the selection of surrogate endpoints in phase 3 oncology trials among many factors. The associations between the prognosis and the type of primary endpoint were observed for Other TTE and a co-primary endpoint of OS and Other TTE. These findings elucidate one of the fundamental factors for primary endpoint selection and emphasize the importance of prognosis in selecting a primary endpoint in phase 3 clinical trial in oncology in the US. However, further study is required to comprehensively understand the impact of RR on primary endpoint selection, as this analysis was limited by the lack of median OS data for RR.

Pharmacological Profile of Novel Anti-cancer Drugs Approved by USFDA in 2022: A Review.

For any drug molecule, it is mandatory to pass the drug approval process of the concerned regulatory authority, before being marketed. The Food and Drug Administration (FDA), throughout the year, approves several new drugs for safety and efficacy. In addition to new drug approvals, FDA also works on improving access to generic drugs, aimed to lower the cost of drugs for patients and improve access to treatments. In the year 2022 twelve new drug therapies were approved for managing varying cancers. This manuscript is focused to describe the pharmacological aspects including therapeutic uses, mechanisms of actions, pharmacokinetics, adverse effects, doses, indication for special cases, contraindications, etc., of novel FDA-approved anticancer drug therapies in the year 2022. FDA has approved about 29% (11 out of 37) novel drug therapies for varying types of cancers such as lung cancer, breast cancer, prostate cancer, melanoma, leukemia, etc. The Center for Drug Evaluation and Research CDER has reported that 90% of these anticancer drugs (e.g. Adagrasib, Futibatinib, Mirvetuximabsoravtansinegynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Olutasidenib, Pacritinib, Tebentafusp-tebn, Teclistamab-cqyv, and Tremelimumab-actl) as orphan drugs and recommended to treat rare or uncommon cancers such as non-small cell lung cancer, metastatic intrahepatic cholangio-carcinoma, epithelial ovarian cancer, follicular lymphoma, metastatic melanoma, metastatic uveal melanoma, etc. CDER has identified six anticancer drugs (e.g. Lutetium (177Lu)vipivotidetetraxetan, Mirvetuximabsoravtansine- gynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Tebentafusp-tebn, Teclistamab-cqyv) as first-in-class drugs i.e. drugs having different mechanisms of action from the already existing ones. The newly approved anticancer drugs shall provide more efficient treatment options for cancer patients. Three FDA-approved anticancer drugs in the year 2023 are also briefly described in the manuscript. This manuscript, describing the pharmacological aspects of eleven anticancer novel drug therapies approved by the FDA, shall serve as a helpful document for cancer patients, concerned academicians, researchers, and clinicians, especially oncologists.

Challenges and Proposed Reforms for NHI Coverage of Rare Diseases and Orphan Drugs in Taiwan

Challenges and Proposed Reforms for NHI Coverage of Rare Diseases and Orphan Drugs in Taiwan

Leptin replacement therapy in the management of lipodystrophy syndromes

Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.

Partial lipodystrophy: Clinical presentation and treatment

Lipodystrophic syndromes are acquired or genetic rare diseases, characterized by a generalized or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They are probably underdiagnosed, especially for partial forms. They are characterized by a lack of adipose tissue or a lack of adipose development leading to metabolic disorders associated with often severe insulin resistance, hypertriglyceridemia and hepatic steatosis. In partial forms of lipodystrophy, these mechanisms are aggravated by excess visceral adipose tissue and/or subcutaneous adipose tissue in the upper part of the body. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counseling. Early lifestyle and dietary measures focusing on regular physical activity, and balanced diet avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndromes.

Navigating Intellectual Property Rights: Patentability and Market Exclusivity for Orphan Drugs in The Evolving Landscape

Intellectual property is an intangible property created with the endeavor of human intellect. This concept is formulated for the recognition and value for the inventions, creation of mind, literary or artistic work, designs, and traditional knowledge can be given recognition by providing Intellectual Property Rights. Intellectual property is necessary for the progress and well-being of the humanity so that new inventions and creations, further innovations are encouraged. Patent gives exclusive rights for product and process whereby without the permission of the patent owner invention cannot be commercialized. Patent Law is developed as per the standards prescribed in the TRIPS agreement globally. Patent rights are also granted for drugs as pharmaceutical research is expensive and unpredictable. Pharmaceutical sector protects their inventions by product or process patent rights. Nowadays rare diseases or orphan’s diseases caused by genetic alterations have become a threat for human life. It has become a necessity to develop new drugs or orphan drugs to treat these rare disorders even though it is fewer in numbers. In US and EU once a drug receives the status of orphan is attained the protection is limited to 10 to 12 years of protection from commercialization. In such scenario the companies who have spent millions for their Research and Development will not be in a situation to take back the investment. High revenue or capital investment is hindering the development of orphan drugs. Orphan drug exclusivity with the patent protection will definitely help in encouraging more inventions for rare diseases thereby generating a world without disease. This paper surmises upon the importance of patent to orphan drugs and exclusivity to the manufactures which can be achieved only by appropriate policy decisions and regulatory framework.

Non-Invasive Spinal Cord Stimulation for Motor Rehabilitation of Patients with Spinal Muscular Atrophy Treated with Orphan Drugs.

Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several other drugs have been approved for the treatment of this disease. Transcutaneous spinal cord stimulation (tSCS) modulates spinal neuronal networks, resulting in changes in locomotion and posture in patients with severe spinal cord injury and stroke. We hypothesize that tSCS can activate motor neurons that are intact and restored by medication, slow the decline in motor activity, and contribute to the development of motor skills in SMA patients. Thirty-seven children and adults with SMA types 2 and 3 participated in this study. The median duration of drug treatment was over 20 months. The application of tSCS was performed during physical therapy for 20-40 min per day for ~12 days. Outcome measures were specific SMA motor scales, goniometry of contractured joints, and forced vital capacity. Significant increases in motor function, improved respiratory function, and decreased contracture were observed in both type 2 and 3 SMA participants. The magnitude of functional changes was not associated with participant age. Further studies are needed to elucidate the reasons for the beneficial effects of spinal cord electrical stimulation on SMA.

Determining value in the treatment of activated PI3Kδ syndrome in Spain: a multicriteria decision analysis from the perspective of key stakeholders

Introduction: Activated phosphoinositide 3-kinase (PI3K)δ syndrome (APDS) is an ultra-rare inborn error of immunity (IEI) combining immunodeficiency and immune dysregulation. This study determined what represents value in APDS in Spain from a multidisciplinary perspective applying multicriteria decision analysis (MCDA) methodology. Methods: A multidisciplinary committee of nine experts scored the evidence matrix. A specific framework for orphan drug evaluation in Spain and the weights assigned by a panel of 98 evaluators and decision-makers was used. Re-evaluation of scores was performed. Results: APDS is considered a very severe disease with important unmet needs, including misdiagnosis and diagnostic delay. Current management is limited to treatment of symptoms with off-label use of therapies supported by limited evidence. Therapeutic benefit is partial, resulting in limited disease control. Haematopoietic stem cell transplantation (HSCT), the only potential curative alternative, is restricted to a reduced patient population and without evidence of long-term efficacy or safety. All options present a limited safety profile. Data on patients’ quality of life are lacking. APDS is associated with high pharmacological, medical and indirect costs. Conclusions: APDS is considered a severe disease, with limited understanding by key stakeholders of how treatment success is assessed in clinical practice, the serious impact that has on patients and the associated high economic burden. This study brings to light how MCDA methodology could represent a useful tool to complement current clinical and decision-making methods used by APDS experts and evaluators.