Optimus-Era Dose Finding for Rare Cancers.

SUMMARY: Advances in cancer biology and diagnostics have led to the recognition of a multitude of rare cancer subtypes, emphasizing the pressing need for strategies to accelerate drug development for patients with these cancers. This paper addresses the unique challenges of dose finding in trials that accrue small numbers of patients with rare cancers; strategies for dose optimization are proposed, in line with evolving approaches to dose determination in the age of the US Food and Drug Administration's Project Optimus.

Drug development blossoms for rare, fatal bone disease.

Five drugs are now approved or in trials for genetic condition that triggers misplaced bone growth.

HTA criteria adopted in different models of public healthcare systems for orphan drugs: A scoping review.

Access to drugs for rare diseases constitutes a challenge to healthcare systems, especially those with public funding. This study aimed to map and summarize the criteria used by HTA agencies in different healthcare systems to evaluate reimbursement recommendations for orphan drugs. A comprehensive literature search was performed on the databases PubMed, LILACS, Scopus, and Embase and the gray literature (Google Scholar and websites of HTA agencies). Publications addressing the criteria used by HTA agencies in countries with public healthcare systems when evaluating reimbursement recommendations for orphan drugs were included. This scoping review included 23 studies published between 2014 and 2023, mostly consisting of reviews of HTA reports, guidance documents, and original articles. The criteria were mapped from 19 countries and ranked within three models of healthcare systems (National Health System, National Health Insurance, and Social Health Insurance). All models shared concerns about unmet needs and disease nature. In addition, NHS countries (e.g., United Kingdom, Sweden, and Italy) prioritized innovation and system-level impact, while SHI countries (e.g., Germany, France, the Netherlands) usually valued budget impact and employed expedited evaluation processes. This review provides a comprehensive understanding of the general tendencies of each healthcare system model in establishing differentiated criteria to address the challenges posed by the limited evidence and investment in the field of rare diseases.

Trends from two decades of orphan designations in paediatric rare neuromuscular diseases.

Rare diseases are characterized by substantial unmet need mostly because the majority have limited, or no treatment options and a large number also affect children. Since the inception of EU orphan regulation in 2000 the European Medicines Agency Committee for Orphan Medicinal Products has received several applications for paediatric rare neuromuscular diseases (PERAN) however treatment options remain limited. Here we discuss the results form an observational, retrospective, cross-sectional study to characterize the currently authorised orphan medicinal products (OMP) and orphan designations (OD) given to products for PERAN in the last two decades. In the EU about half of PERAN diseases have at least one active OD approved since 2000, and about half of these are for Duchenne muscular dystrophy (DMD). The large majority of PERAN diseases do not have an authorised medicine with only 6 OMP currently authorised for Spinal muscular atrophy (3); DMD (1) and Myasthenia gravis (2). One in five products have inactive or discontinued regulatory development but clinical trials are ongoing for the vast majority of PERAN diseases, and more than half are in the final stage of clinical research with significantly more products with medical plausibility based in clinical data reaching advanced stages in clinical development.

The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs.

Rare diseases (RD) affect a small number of people compared to the general population and are mostly genetic in origin. The first clinical signs often appear at birth or in childhood, and patients endure high levels of pain and progressive loss of autonomy frequently associated with short life expectancy. Until recently, the low prevalence of RD and the gatekeeping delay in their diagnosis have long hampered research. The era of nucleic acid (NA)-based therapies has revolutionized the landscape of RD treatment and new hopes arise with the perspectives of disease-modifying drugs development as some NA-based therapies are now entering the clinical stage. Herein, we review NA-based drugs that were approved and are currently under investigation for the treatment of RD. We also discuss the recent structural improvements of NA-based therapeutics and delivery system, which overcome the main limitations in their market expansion and the current approaches that are developed to address the endosomal escape issue. We finally open the discussion on the ethical and societal issues that raise this new technology in terms of regulatory approval and sustainability of production.

Issues, Challenges and Opportunities for Economic Evaluations of Orphan Drugs in Rare Diseases: An Umbrella Review.

BACKGROUND AND OBJECTIVES: There are significant challenges when obtaining clinical and economic evidence for health technology assessments of rare diseases. Many of them have been highlighted in previous systematic reviews but they have not been summarised in a comprehensive manner. For all stakeholders working with rare diseases, it is important to be aware and understand these issues. The objective of this review is to identify the main challenges for the economic evaluation of orphan drugs in rare diseases. METHODS: An umbrella review of systematic reviews of economic studies concerned with orphan and ultra-orphan drugs was conducted. Studies that were not systematic reviews, or on advanced therapeutic medicinal products, personalised medicines or other interventions that were not considered orphan drugs were excluded. The database searches included publications from 2010 to 2023, and were conducted in MEDLINE, EMBASE and the Cochrane library using filters for systematic reviews, and economic evaluations and models. These filters were combined with search terms for rare diseases and orphan drugs. A hand search supplemented the literature searches. The findings were reported by a compliant Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. RESULTS: Two hundred and eighty-two records were identified from the literature searches, of which 64 were duplicates, whereas five reviews were identified from the hand search. A total of 36 reviews were included after screening against inclusion/exclusion criteria, 35 from literature searches and one from hand searching. Of those studies 1, 27 and 8 were low, moderate and high quality, respectively. The reviews highlight the scarcity of evidence for health economic parameters, for example, clinical effectiveness, costs, quality of life and the natural history of disease. Health economic evaluations such as cost-effectiveness and budget-impact analyses were scarce, and generally low-to-moderate quality. The causes were limited health economic parameters, together with publications bias, especially for cost-effectiveness analyses. CONCLUSIONS: The results highlighted issues around a considerable paucity of evidence for economic evaluations and few cost-effectiveness analyses, supporting the notion that a paucity of evidence makes economic evaluations of rare diseases more challenging compared with more prevalent diseases. Furthermore, we provide recommendations for more sustainable approaches in economic evaluations of rare diseases.

Paediatric clinical study of 3D printed personalised medicines for rare metabolic disorders.

Rare diseases are infrequent, but together they affect up to 6-10 % of the world's population, mainly children. Patients require precise doses and strict adherence to avoid metabolic or cardiac failure in some cases, which cannot be addressed in a reliable way using pharmaceutical compounding. 3D printing (3DP) is a disruptive technology that allows the real-time personalization of the dose and the modulation of the dosage form to adapt the medicine to the therapeutic needs of each patient. 3D printed chewable medicines containing amino acids (citrulline, isoleucine, valine, and isoleucine and valine combinations) were prepared in a hospital setting, and the efficacy and acceptability were evaluated in comparison to conventional compounded medicines in six children. The inclusion of new flavours (lemon, vanilla and peach) to obtain more information on patient preferences and the implementation of a mobile app to obtain patient feedback in real-time was also used. The 3D printed medicines controlled amino acid levels within target levels as well as the conventional medicines. The deviation of citrulline levels was narrower and closer within the target concentration with the chewable formulations. According to participants' responses, the chewable formulations were well accepted and can improve adherence and quality of life. For the first time, 3DP enabled two actives to be combined in the same formulation, reducing the number of administrations. This study demonstrated the benefits of preparing 3D printed personalized treatments for children diagnosed with rare metabolic disorders using a novel technology in real clinical practice.

Institutional Priority-Setting for Novel Drugs and Therapeutics: A Qualitative Systematic Review.

BACKGROUND: There is a lack of guidance on approaches to formulary management and funding for high-cost drugs and therapeutics by individual healthcare institutions. The objective of this review was to assess institutional approaches to resource allocation for such therapeutics, with a particular focus on paediatric and rare disease populations. METHODS: A search of Embase and MEDLINE was conducted for studies relevant to decision-making for off-formulary, high-cost drugs and therapeutics. Abstracts were evaluated for inclusion based on the Simple Multiple-Attribute Rating Techniques (SMART) criteria. A framework of 30 topics across 4 categories was used to guide data extraction and was based on findings from the initial abstract review and previous health technology assessment (HTA) publications. Reflexive thematic analysis was conducted using QSR NVivo 12 software. RESULTS: A total of 168 studies were included for analysis. Only 4 (2%) focused on paediatrics, while 21 (12%) centred on adults and the remainder (85%) did not specify. Thirty-two (19%) studies discussed the importance of high-cost therapeutics and 34 (23%) focused on rare/orphan drugs. Five themes were identified as being relevant to institutional decision-making for high-cost therapeutics: institutional strategy, substantive criteria, procedural considerations, guiding principles and frameworks, and operational activities. Each of these themes encompassed several sub-themes and was complemented by a sixth category specific to paediatrics and rare diseases. CONCLUSION: The rising cost of novel drugs and therapeutics underscores the need for robust, evidence-based, and ethically defensible decision-making processes for health technology funding, particularly at the hospital level. Our study highlights practices and themes to aid decision-makers in thinking critically about institutional, substantive, procedural, and operational considerations in support of legitimate decisions about institutional funding of high-cost drugs and therapeutics, as well as opportunities and challenges that exist for paediatric and rare disease populations.

The Role of Pharmacogenomics in Rare Diseases.

Rare diseases have become an increasingly important public health priority due to their collective prevalence and often life-threatening nature. Incentive programs, such as the Orphan Drug Act have been introduced to increase the development of rare disease therapeutics. While the approval of these therapeutics requires supportive data from stringent pre-market studies, these data lack the ability to describe the causes of treatment response heterogeneity, leading to medications often being more harmful or less effective than predicted. If a Goal Line were to be used to describe the multifactorial continuum of phenotypic variations occurring in response to a medication, the 'Goal Posts', or the two defining points of this continuum, would be (1) Super-Response, or an extraordinary therapeutic effect; and (2) Serious Harm. Investigation of the pharmacogenomics behind these two extreme phenotypes can potentially lead to the development of new therapeutics, help inform rational use criteria in drug policy, and improve the understanding of underlying disease pathophysiology. In the context of rare diseases where cohort sizes are smaller than ideal, 'small data' and 'big data' approaches to data collection and analysis should be combined to produce the most robust results. This paper presents the importance of studying drug response in parallel to other research initiatives in rare diseases, as well as the need for international collaboration in the area of rare disease pharmacogenomics.

Rare diseases and pyruvate kinase M2: a promising therapeutic connection.

Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that regulates proliferating cell metabolism. The role of PKM2 in common diseases has been well established, but its role in rare diseases (RDs) is less understood. Over the past few years, PKM2 has emerged as a crucial player in RDs, including, neoplastic, respiratory, metabolic, and neurological disorders. Herein, we summarize recent findings and developments highlighting PKM2 as an emerging key player in RDs. We also discuss the current status of PKM2 modulation in RDs with particular emphasis on preclinical and clinical studies in addition to current challenges in the field.

Sensory neuropathy as a manifestation of multiple acyl-coenzyme A dehydrogenase deficiency.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder which typically manifests with muscle weakness. However, despite late-onset MADD being treatable, it is often misdiagnosed, due in part to the heterogeneity of presentations. We report a case of late-onset MADD manifesting first as a sensory neuropathy before progressing to myopathic symptoms and acute metabolic decompensation. Early diagnostic workup with acylcarnitine profiling and organic acid analysis was critical in patient outcome; metabolic decompensation and myopathic symptoms were completely reversed with riboflavin supplementation and dietary modification, although sensory neuropathy persisted. Clinical consideration of MADD as part of the differential diagnosis of neuropathy with myopathy is crucial for a timely diagnosis and treatment of MADD.

Identification of barriers to implementation of precision oncology in patients with rare cancers.

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice.

Analysis of caregiver perspectives on patients with mucopolysaccharidosis II treated with pabinafusp alfa: results of qualitative interviews in Japan.

BACKGROUND: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked metabolic disorder predominantly affecting males. Pabinafusp alfa, an iduronate-2-sulfatase enzyme designed to cross the blood-brain barrier, was approved in Japan in 2021 as the first enzyme replacement therapy targeting both the neuropathic and somatic signs and symptoms of MPS II. This study reports caregivers' experiences of MPS II patients receiving pabinafusp alfa through qualitative interviews. METHODS: Semi-structured, qualitative interviews were conducted with caregivers at seven clinical sites in Japan using a semi-structured moderation guide (Voice of the Caregiver guide). Thematic analysis was applied to the interview transcripts to identify symptoms and health-related quality of life impacts at baseline, changes during treatment, and overall treatment experience. RESULTS: Seven caregivers from 16 trial sites participated, representing seven children aged 8-18 years who had received pabinafusp alfa for 3.3-3.5 years at the time of the interviews. Data suggest a general trend toward improvement in multiple aspects, although not all caregivers observed discernible changes. Reported cognitive improvements included language skills, concentration, self-control, eye contact, mental clarity, concept understanding, following instructions, and expressing personal needs. Further changes were reported that included musculoskeletal improvements and such somatic changes as motor function, mobility, organ involvement, joint mobility, sleep patterns, and fatigue. Four caregivers reported improvements in family quality of life, five expressed treatment satisfaction, and all seven indicated a strong willingness to continue treatment of their children with pabinafusp alfa. CONCLUSION: Caregivers' perspectives in this study demonstrate treatment satisfaction and improvement in various aspects of quality of life following therapy with pabinafusp alfa. These findings enhance understanding of pabinafusp alfa's potential benefits in treating MPS II and contribute to defining MPS II-specific outcome measures for future clinical trials.

Analysis of the first ten years of FDA's rare pediatric disease priority review voucher program: designations, diseases, and drug development.

BACKGROUND: The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program. RESULTS: We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data. CONCLUSIONS: The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development-from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.

Potential of Artificial Intelligence to Accelerate Drug Development for Rare Diseases.

The growth in breadth and depth of artificial intelligence (AI) applications has been fast, running hand in hand with the increasing amount of digital data available. Here, we comment on the application of AI in the field of drug development, with a strong focus on the specific achievements and challenges posed by rare diseases. Data paucity and high costs make drug development for rare diseases especially hard. AI can enable otherwise inaccessible approaches based on the large-scale integration of heterogeneous datasets and knowledge bases, guided by expert biological understanding. Obstacles still exist for the routine use of AI in the usually conservative pharmaceutical domain, which can easily become disillusioned. It is crucial to acknowledge that AI is a powerful, supportive tool that can assist but not replace human expertise in the various phases and aspects of drug discovery and development.

Orphan drug development: Challenges, regulation, and success stories.

Rare diseases, also known as orphan diseases, are diseases with low occurrence in the population. Developing orphan drugs is challenging because of inadequate financial and scientific resources and insufficient subjects to run clinical trials. With advances in genome sequencing technologies, emergence of cell and gene therapies, and the latest developments in regulatory pathways, some orphan drugs that have curative potential have been approved. In India, due to its large population and resource crunch, developing orphan drugs is phenomenally challenging. After adopting the Orphan Drug Act, the US-FDA has continuously made advances in regulatory pathways for orphan drugs. Particularly, n-of-one clinical trials have been successful in some cases. India has recently adopted policies that have impacted the long-neglected rare-disease ecosystem; however, there is no clear regulatory path for orphan drug development in India. We have proposed a multi-pronged approach involving close collaboration between the government, regulatory bodies, industries, and patient advocacy groups to boost orphan drug development in India. We believe that rapidly evolving technologies and business models can enable better and faster development of novel orphan drugs in India and other resource-constrained countries.

Non-viral delivery of nucleic acid for treatment of rare diseases of the muscle.

Rare muscular disorders (RMDs) are disorders that affect a small percentage of the population. The disorders which are attributed to genetic mutations often manifest in the form of progressive weakness and atrophy of skeletal and heart muscles. RMDs includes disorders such as Duchenne muscular dystrophy (DMD), GNE myopathy, spinal muscular atrophy (SMA), limb girdle muscular dystrophy, and so on. Due to the infrequent occurrence of these disorders, development of therapeutic approaches elicits less attention compared with other more prevalent diseases. However, in recent times, improved understanding of pathogenesis has led to greater advances in developing therapeutic options to treat such diseases. Exon skipping, gene augmentation, and gene editing have taken the spotlight in drug development for rare neuromuscular disorders. The recent innovation in targeting and repairing mutations with the advent of CRISPR technology has in fact opened new possibilities in the development of gene therapy approaches for these disorders. Although these treatments show satisfactory therapeutic effects, the susceptibility to degradation, instability, and toxicity limits their application. So, an appropriate delivery vector is required for the delivery of these cargoes. Viral vectors are considered potential delivery systems for gene therapy; however, the associated concurrent immunogenic response and other limitations have paved the way for the applications of other non-viral systems like lipids, polymers, cellpenetrating peptides (CPPs), and other organic and inorganic materials. This review will focus on non-viral vectors for the delivery of therapeutic cargoes in order to treat muscular dystrophies.