Published by Pharmafile. Autumn edition 2022
A Complex Disease Area
In recent years, rare diseases have increasingly received mainstream recognition. There are more than 300 million people with a ‘rare disease’ representing well over 7,000 different inherited, spontaneous, and complex genetic conditions that cause biochemical defects leading to a unique disease(1). While rare diseases, by their nature, affect relatively small numbers they have a big impact on patients’ lives. By definition, each disease represents fewer than 1 in 2,000 people(1); some are common household names such as Down’s Syndrome, Cystic Fibrosis and Tay-Sachs disease, others are less well known(1). Some may be classified as an ultra-rare disease; for example, mucopolysaccharidosis II (also known as Hunter disease) occurs at a rate of <0.3 per 100,000 live births in Scandinavia, and globally only one case of ribose-5 phosphate isomerase deficiency has ever been reported(1).
Such conditions may be sex-linked, for example Hunter disease appears almost exclusively in males(2). When it comes to rare diseases one size does not fit all. They vary between countries and regionally, and may be clustered in geographical communities, such as the commonly inherited conditions like acute intermittent porphyria (which presents in Dutch descendants in South Africans), and Gaucher disease(3) .
The timing of diagnosis of each condition varies from knowing there is a genetic probability before conception (which is common in intermarrying communities), or during foetal development (detected by amniocentesis), to discovering the disease as part of an infant screening programme (for example maple syrup urine disease)(4). These early predictions can make these conditions easier to manage(5). However, even for those in countries where healthcare is sophisticated, it could take several years to get a confirmation; for example Lysosomal Storage Disease. During this extended period the disease process is ongoing and interfering with childhood development, often irreversibly(5).
Overlooked Importance
Rare diseases can have life changing effects for the patients and families concerned, but the level of impact on individuals varies(2). It ranges from debilitating, and potentially fatal outcomes, to a manageable disease burden which persists to maturity, especially when the individual is part of a well-developed healthcare system. In either situation, for the parents and carers of a sick child, the burden is an agony(5). In the case of a more severe rare disease, where the defect is present from birth and may progress until death, the growing disease severity and inevitable outcome can be financially and emotionally devastating(5).
Historically the relatively low numbers of rare disease patients discouraged industry investment in developing new therapies, making it a Cinderella disease area that was often overlooked by pharmaceutical companies. However, the landscape has changed: awareness, patient advocacy and very significant incentives from the major national regulatory agencies have shone the spotlight on rare diseases(6,7). There is increasing collaboration between patient groups, scientists, healthcare systems and regulatory agencies to share knowledge and work towards creating the best support for the rare disease landscape.
Innovation As A Catalyst For Change
Diagnostic innovations have been a key driver of this change. The global biotech industry has developed increasingly sophisticated diagnostic capabilities for rare diseases(8). This has progressed to the DIY collection of stabilised specimens (urine, saliva or blood spots) and returning these to the laboratory for processing and scrutiny via growing and helpful informatic platforms, which guide clinicians and patient’s carers towards further action(8). This technological revolution has been a game changer for those working in the field of rare diseass(8). Based on a sound scientific understanding the options for novel therapeutics have increased(8).
For instance, a significant number of rare diseases are defined as lysosomal storage diseases. In these conditions the absence of one or more enzymes leads to unmetabolised by-products which accumulate in all tissues, sequestered into lysosomes(8). It is this accumulation that disrupts normal tissue biology and leads to organ dysfunction, lack of growth, malformed joints and many other tissue defects(8). The process of accumulation also takes place in the brain and can cause neuro-dysfunction, ranging from disruptive behaviour to dementia(8). Therapeutic intervention to break the cycle of accumulating waste should result in restoration of a more normal physiology and clinical stabilisation. If started early enough, there is the potential to limit the intensity of the condition(2).
Breaking Down the Brain Blood Barrier
One of the biotech industry’s great contributions has been the making of the human recombinant ‘missing’ enzyme, and in demonstrating that this could be administered intravenously and is safe and efficacious. This is enzyme replacement therapy (ERT), which has been developed into life-changing treatments for multiple conditions(2). The one limitation of ERT is that the recombinant enzyme does not cross the blood-brain barrier(2). Thus, whereas all somatic tissues benefit from ERT therapy, the CNS does not. This is seen clearly in Hunter disease where conventional ERT has contributed to major quality of life improvements and extended survival, but is subject to a situation in which the body stabilises, but the cognitive function continues to deteriorate as metabolic products accumulate(2). This failure of ERT to address the cognitive deficit has led to new approaches to get the missing enzymes across the blood-brain barrier(2). There has been significant success in constructing a fusion protein where the missing enzyme is linked to either a monoclonal antibody or antibody fragment that binds selectively to one of the blood-brain transport systems. The fusion protein, with enzyme activity, joins the transport system and is piggy-backed into the brain(2). In the case of Hunter disease, companies are using either the ferritin transport system or the insulin transport system to move the missing enzyme into the brain to digest accumulated waste products and stabilise or reverse neurodysfunction(2).
The Challenges of Clinical Trials
Clinical trials for rare diseases are particularly challenging. As these medicines are intended for children, the younger the better, safety is of paramount concern. Normal child development is complex, but in a child with a rare disease, even more so. Assessing treatment options through clinical trials is problematic: children with rare conditions are of different ages and at different disease stages for diseases that may be highly variable. The nature of the condition means that it is patient specific, and standardisation isn’t necessarily possible. In the case of Hunter disease, assessing boys going through puberty adds an extra level of unpredictability and variability, and treatment-related cognitive improvements are difficult to show(9) Most importantly, these are rare diseases, so there are limited numbers of patients from whom to collect data.
Increasingly, there has been a willingness of regulatory agencies to evaluate a multi-domain responder index (MDRI), which better assesses complex and heterogeneous disease by evaluating a broad array of different endpoints(10). The MDRI assesses changes of clinically relevant thresholds for each domain in each individual patient to measure clinically meaningful change before and during treatment for that individual. Effective therapy would be expected to stabilise or improve more different endpoints, but there are no constraints on which endpoint(10). This allows the impact of a treatment to be assessed in a wider range of patients with the rare disease. In addition, the input of carers is being accepted as very relevant to therapeutic outcome, as they are closest to the patient, have experienced their ’good-days’ and ’bad-days’, and will see and record trends(10).
Demonstrating the biochemical efficacy in patients is making a significant contribution to treating Lysosomal Storage Disease(2) Showing the primary mechanism of action is working in patients and that treatment decreases the accumulated by-products (for Hunter disease Heparan Sulphate) in cerebrospinal fluid would demonstrate the fusion protein had crossed the blood-brain barrier and that the enzyme was functioning effectively(10).
Child health policies vary around the world. Whereas the USA is identifying rare disease as early as possible, the infrastructure supporting rare disease in other countries may be more limited. This creates health inequality, now being addressed by the actions of advocacy groups and government(10). However, this is not always implemented and in India the High Court has expressed displeasure over government failure to treat children suffering from Duchenne muscular dystrophy. The High Court has ruled treatment should start immediately under the National Policy for Rare Diseases, implemented in 2021, and patient groups will continue to encourage the Government to meet its obligations(10).
Increasingly, drugmakers have begun to explore value-based drug costing, and ensuring efficacy before there is a cost (or providing rebates if treatment cannot continue) could make Payers more willing to reimburse for rare disease treatment(11).
The changing landscape
The combined ‘forces’ of advocacy and education on government and policy makers has helped both industry and healthcare providers to become more effective and has harnessed significant progress for multiple rare diseases. However, there does need to be better candidate selection to shorten development times and to establish clinical outcomes (or surrogates) that help prove efficacy. The potential application of machine-learning is enormous: including (a) helping screen patient data to help identify trial subjects, (b) applying artificial intelligence to the vast bioinformatic understanding and (c) identifying new druggable pathways for specific diseases and putative molecules(12). Clinical trials now include increasing contributions from carers on how their individual patient responds to therapy and using biomarker surrogates (products accumulated in cerebrospinal fluid for the lysosomal diseases) to demonstrate changes should translate into therapeutic effects.
The Biotech-Advocacy-Government community has already delivered major developments with high impacts. The C-Path Institute, a consortium of U.S. Food and Drug Administration and the National Institutes of Health, European Medicines Agency and Japan’s Pharmaceuticals and Medical Devices Agency, and industry and advocacy groups, has recently embarked on a programme to develop better diagnostic and treatment infrastructures for the patients of rare disease(13). There is momentum and motivation to make this happen and deliver lasting change in the field of rare diseases and improve patient’s lives globally. We’ve come a long way in recent years, but we still have further to go to give rare disease the recognition and treatment solutions centre stage, they deserve it!
References
1. National Center for Advancing Translational Sciences. Genetic and Rare Disease Information Centre. https://rarediseases.info.nih.gov/ Accessed September 2022.
2. D’Avanzo F, Rigon L, Zanetti A, Tomanin R. Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment. Int J Mol Sci. 2020 Feb 13;21(4):1258. doi: 10.3390/ijms21041258.
3. Gaucher Disease. The 5 Most Common Ashkenazi Genetic Diseases https://www.gaucherdisease.org/blog/5-common-ashkenazi-genetic-diseases/. Accessed September 2022.
4. Genomics of Rare Diseases: Understanding Disease Genetics Using Genomic Approaches. A volume in Translational and Applied Genomics. 2021; Edited by: Claudia Gonzaga-Jauregui and James R. Lupski. ISBN 978-0-12-820140-4, DOI – https://doi.org/10.1016/C2019-0-01157-0. Elsevier Inc. Academic Press.
5. Joseph R, DiCesare EB, Miller A. Hunter Syndrome: Is It Time to Make It Part of Newborn Screening? Adv Neonatal Care. 2018 Dec;18(6):480-487. doi: 10.1097/ANC.0000000000000569. PMID: 30499826.
6. FDA. Office of Orphan Products Development. https://www.fda.gov/about-fda/office-clinical-policy-and-programs/office-orphan-products-development. Accessed September 2022.
7. FDA. Office of Orphan Products Development. https://www.fda.gov/about-fda/office-clinical-policy-and-programs/office-orphan-products-development. Accessed September 2022
8. Tandon, P.K., Kakkis, E.D. The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J Rare Dis 16, 183 (2021). https://doi.org/10.1186/s13023-021-01805-5.
9. van der Lee JH, Morton J, Adams HR, Clarke L, Ebbink BJ, Escolar ML, Giugliani R, Harmatz P, Hogan M, Jones S, Kearney S, Muenzer J, Rust S, Semrud-Clikeman M, Wijburg FA, Yu ZF, Janzen D, Shapiro E. Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure. Mol Genet Metab. 2017 Jun;121(2):70-79. doi: 10.1016/j.ymgme.2017.05.004. Epub 2017 May 6. PMID: 28501294.
10. Black N, Martineau F, Manacorda T. (2015) Diagnostic odyssey for rare diseases: exploration of potential indicators. London: Policy Innovation Research Unit, LSHTM. Live Law. Treatment Of Children With Rare Diseases Cannot Be Deferred Due To Unavailability Of Long Term Clinical Trial Studies: Delhi High Court https://www.livelaw.in/news-updates/treatment-children-rare-diseases-delhi-high-court-201258https://www.livelaw.in/news-updates/treatment-children-rare-diseases-delhi-high-court-201258. Accessed September 2022.
11. Fantini, B., & Vaccaro, C. M. (2019). Value based healthcare for rare diseases: efficiency, efficacy, equity. Annali dell’Istituto Superiore Di Sanità, 55(3), 251-257].
12. Hirsch MC, Ronicke S, Krusche M, et al. Rare diseases 2030: how augmented AI will support diagnosis and treatment of rare diseases in the future. Annals of the Rheumatic Diseases 2020;79:740-743.
13. Critical Path Institute. Programs. https://c-path.org/programs/. Accessed September 2022.
