Leap of faith – PharmaTimes

In 2024, Rare Disease Day falls on an appropriately rare calendar date: 29 February, a leap year.

This international awareness campaign provides the perfect opportunity to highlight the world’s lesser-known medical conditions — and to discuss the latest challenges within the rare disease research landscape.

While these conditions might be individually uncommon, the cumulative number of people suffering from a rare or orphan disease sits at over 300 million around the world — with each patient facing unique and often life-limiting obstacles during their day-to-day lives due to their disorder.

So, how can clinical research investment help specialists navigate rare diseases — and improve the lives of those living with them?

The landscape

According to the UK Rare Diseases Framework, one in 17 people is affected by a rare disease during their lifetime. That could include several people you see on your daily commute or even someone within your extended family.

What’s more, the National Institute for Health and Care Research (NIHR) says at least 75% of rare diseases are caused by genetic factors, which primarily affect children — over 30% of whom die before their fifth birthday. And yet, the vast majority of these conditions have no therapeutic treatments. Why?

Typically, the low incidence of rare diseases creates significant challenges in the design and execution of clinical trials for new therapeutics. 

Each orphan disease impacts very few patients (think one in a million versus one in 2,000), presenting significant research obstacles because trial patients are few and often geographically widespread.

As a result, 95% of the 7,000+ rare conditions we know of lack effective treatment, leaving countless patients without a solution to their suffering.

That’s not to say there hasn’t been any positive progress in these areas. The NIHR Rare Diseases Research Landscape Project Report (September 2023) found that between 2016 and 2021, the UK government, the Medical Research Council (MRC) and the NIHR had funded 698 rare disease awards with a cumulative value of over £627 million.

Still, those 698 awards only made up 7% of the total awards given by MRC and NIHR during this timeframe.

The following diseases received the largest proportion of funding from the 698 awards:

• Motor neurone disease (8%).
•  Huntington’s disease (5%).
• Cystic fibrosis (4%).
• Frontotemporal dementia (4%).
• Idiopathic pulmonary fibrosis (3%).

That equates to almost a quarter of funding spent on just five of the 7,000+ diseases in desperate need. Yet, there are many other rare and orphan conditions that need more support from the drug research industry.

To name a few…

1.     Fibrodysplasia ossificans progressiva (FOP)

Affecting around one in two million people, this condition — also called ‘stoneman syndrome’ — slowly turns connective tissues, such as tendons, muscles and ligaments into bone.

It’s a genetic disorder often noticeable in early childhood, starting in the neck and shoulders before moving down the body to cause progressive loss of mobility, malnutrition and breathing problems.

2.      Alkaptonuria

Also known as ‘black urine disease’, this extremely rare genetic metabolic disorder (affecting only 1 in 100,000–250,000) prevents the body from breaking down tyrosine and phenylalanine.

The disease may cause dark urine or urine that turns black when exposed to the air. Affected individuals can develop discolouration of the skin covering cartilage within the body, and alkaptonuria has also been known to contribute to progressive arthritis of the spine and large joints.

3.     Stargardt disease

Stargardt disease affects the eye and leads to vision loss in children and young adults. It’s caused by a genetic change that affects how the body uses vitamin A and leads to a build-up of fatty material on the small part of the retina needed for sharp central vision.

It’s estimated to impact one in 8,000–10,000 people, with symptoms including light sensitivity, colour blindness and grey, black or hazy spots in the central (and sometimes peripheral) visual field. Currently, no specific treatment for Stargardt disease exists, though some are in development.

4.     Ocular melanoma

A rare eye cancer, ocular melanoma has an incidence of only 5 in a million adults. Nonetheless, it’s the most common primary eye cancer in adults.

Symptoms of this malignant eye tumour include a dark spot on the iris, blurred or distorted vision, a change in pupil shape or the sensation of flashing lights. Patients may require the surgical removal of the eye to prevent the cancer from spreading.

5.     Cutaneous T-cell lymphoma (CTCL)

T-cell skin lymphomas come in many different types, but CTCL is very rare — with only 350 people diagnosed with it in the UK each year and only around 3,000 new cases reported annually in the US.

This condition typically affects people over 60 and is seen more in men than women. Early symptoms can include flat, red, rash-like patches that can be itchy and sometimes painful.

The causes of CTCL aren’t known, and there isn’t a cure. However, doctors can prescribe various internal and external treatments to manage the disease.

Romidepsin — a histone deacetylase (HDAC) inhibitor — was approved for CTCL patients in the USA in 2009. However, this drug isn’t yet approved for use in the EU or the UK because authorities are reluctant to support its submission to the European Medicines Agency — highlighting geographical inequalities in the development cycle for rare disease therapeutics.

A promising future for rare disease trials

When you’re living with a rare condition, every small improvement makes a big difference.

To improve the lives of patients with rare disease research worldwide, the international medical research community must collaborate with pharmaceutical and biotech partners to bring the right expertise and resources together.

Not only can these projects change patients’ lives, but rare disease research can also bring many wider benefits — from unexpected scientific breakthroughs to developments in precision medicine approaches.

Fortunately, we’ve seen increasing attention to under-represented conditions in recent years — with several new policies designed to tackle investment barriers.

In July 2023, the UK Rare Disease Research Platform was established by the MRC and the NIHR with a £14 million investment over five years. The platform’s launch followed the announcement of the Rare Disease Action Plan for England in 2023, which includes financial support to drive progress and collaboration across a range of rare conditions.

Success stories have emerged amongst the disorders receiving funding, including promising treatment options for cystic fibrosis sufferers. 

For example, the introduction of small-molecule, mutation-specific drugs capable of restoring the function of defective cystic fibrosis transmembrane conductance regulator (CFTR) proteins has been transformative for some people who suffer from this genetic disorder.

As is the case with many rare disease treatments, however, these therapeutics aren’t currently available in all parts of the world — widening existing health inequalities and presenting new challenges for medical professionals, pharmaceutical companies and patients alike.

As such, although we’re heading in the right direction, researchers must continue championing a broad range of rare and orphan diseases to secure future investment and make life-saving progress in these largely neglected areas.

Julie Matthews is CEO of TMC Pharma