RARE DISEASES

Such conditions may be sex-linked, for example Hunter disease appears almost exclusively in males.2When it comes to rare diseases, one size does not fit all. They vary between countries and regions, and may be clustered in geographical communities, such as commonly inherited conditions like acute intermittent porphyria (which presents in Dutch descendants in South Africans), and Gaucher disease. 3The timing of diagnosis of each condition varies from knowing there is a genetic probability before conception (which is common in intermarrying communities), during foetal development (detected by amniocentesis), to discovering the disease as part of an infant screening programme (for example, maple syrup urine disease). 4The early predictions can make these conditions easier to manage. 5 However, even in countries where healthcare is sophisticated, it could take several years to get a confirmation, for example with lysosomal storage disease.

During this extended period, the disease process is ongoing and interfering with childhood development, often irreversibly.5

Rare diseases can have life-changing effects for the patients and families concerned, but the level of impact on individuals varies.2It ranges from debilitating, with potentially fatal outcomes, to a manageable disease burden that 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. 5In 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.

Diagnostic innovations have been a key driver of this change. The global biotech industry has developed increasingly sophisticated diagnostic capabilities for rare diseases.8This 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 diseases.8Based on a sound scientific understanding, the options for novel therapeutics have increased. 8For 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 that accumulate in all tissues, sequestered into lysosomes. 8It 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.8Therapeutic 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

One of the biotech industry’s great contributions has been the making of the human recombinant ‘missing’ enzyme, 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.2The one limitation of ERT is that the recombinant enzyme does not cross the blood-brain barrier. 2Thus, 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, it is subject to a situation in which the body stabilises, but the cognitive function continues to deteriorate as metabolic products accumulate. 2This failure of ERT to address the cognitive deficit has led to new approaches to get the missing enzymes across the blood-brain barrier. 2There 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 piggybacked 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 neuro-dysfunction. 2

Clinical trials for rare diseases are particularly challenging. These medicines are intended for children, the younger the better, so 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.10The 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. 10This 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

In treating lysosomal storage disease, demonstrating the biochemical efficacy in patients is making a significant contribution.2This shows the primary mechanism of action working in patients and that treatment decreases the accumulated by-products (heparan sulphate for Hunter disease) in cerebrospinal fluid and would demonstrate that 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 governments.10However, 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. 10Increasingly, 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 combined ‘forces’ of advocacy and education on government and policy makers have helped both industry and healthcare providers to become more effective and have 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 AI 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 that 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 US Food and Drug Administration, the National Institutes of Health, European Medicines Agency, 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 diseases.13 There is momentum and motivation to 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 diseases and treatment solutions the recognition they deserve.