Failing the most vulnerable

In Europe, every year almost 35,000 children and young adults are diagnosed with cancer. Of these around 6,000 young cancer patients die of the consequences of their disease. This makes cancer the biggest disease related cause of death in children in Europe.

Now, while it’s true the prognosis and survival statistics have improved over the years – in the 1960s, the average 5-year survival for children diagnosed with cancer was only 20-30%; today this number is more than 80% – around 20% of patients still succumb to the consequences of their disease in the first 5 years after diagnosis.

For the survivors, they will have relied on invasive treatments, often combining surgery, intense radiation therapy, and aggressive chemotherapy. As children undergo these treatments at the peak of their mental and physical development, the side-effects can, unsurprisingly, be huge.

More than two thirds of surviving paediatric patients are estimated to suffer from one or more chronic issues related to their treatment. The potential side-effects are diverse, including dysfunctions in reproductive, cardiovascular, renal, pulmonary, ocular and auditory organs. They can also include functional and activity limitations, and even the development of secondary tumours. These side effects can become severe, disabling, life-threatening or fatal. Additionally, surviving patients suffer from the psychological impact of their disease, the treatment, the side-effects and the uncertainty related to their health situation.

The direct suffering of the children confronted with cancer is unjust and unacceptable. The direct and indirect societal burden of cancer in children is large and should be avoided. Most people would agree with these statements. Yet, innovation in paediatric cancer has been limited – indeed between 2007 and 2022, only two drugs developed specifically for childhood cancers were approved by the EMA and five by the FDA.

What is stopping us from bringing better options to the front line of paediatric cancer care? To get to the answer, we need to first look at the diseases themselves.

Complex and varied

Cancer in children and young adults is not a single disease, but comprises a diverse set of illnesses. There are, in fact, 12 main groups which are further split in 47 subgroups, each subgroup further broken down into multiple subdivisions.

The survival statistics differ materially between the different types and sub-types. As a consequence, the average 5-year survival statistic of 80% is the product of widely varying underlying expected outcomes.

This diversity in underlying diseases within paediatric oncology and their drivers has far reaching consequences. Each individual malignancy is a rare or even ultra-rare disease and so the number of patients with a specific disease is low. This rarity reduces the pace at which scientific understanding of a disease is built.

Given the differences in biology, each malignancy – and its underlying pathways – needs to be understood in its own right.

It’s also very clear that cancer in children is different from cancer in adults in many critical ways – the appearance of the tumour, speed of development and organ of origin are often very distinct from cancers in adults. The underlying cause for the disease also differs. Cancers in adults typically result from the accumulation of mutations in an adult cell which cause the cell to show uncontrolled behaviour. Cancer in children typically is caused by a much more limited set of defining mutations or alterations in the cell, which have a direct impact on the cell’s cancerous behaviour. There is a higher prevalence of germline mutations driving the disease, but the defining mutations can also develop somatically.

The combination of malignancy specific defining mutations, but low overall mutational burden, make prevention impossible. This leaves adequate diagnosis and treatment as the only option for this vulnerable patient population.

Economic hurdles

Beyond the scientific challenges, the specific traits of paediatric cancer create a set of economic hurdles for paediatric specific therapeutic development.

Given the fact the biology of cancer in children is different from adults, spill-over effects from adult developments or options for repurposing adult drugs are often restricted. They can be successful if they address a relevant pathway, but often paediatric specific developments are required.

However, it is this specificity which can introduce issues. When developing a paediatric specific therapeutic, the clinical effect is often confined to a single or, at the most, a limited number of malignancies. The rarity of these limits the number of patients that will require the treatment, and thus the market potential is limited. Paediatric specific therapeutics therefore tend to each be low volume markets.

The costs to maintain a supply of the therapeutic is high and fixed costs for keeping a drug on the market – including regulatory compliance – are also high and must be spread over the smaller number of patients. Consequently, the small patient population leads to limited revenue and subsequently a low profit market.

Independent of the low market potential, the costs to develop a therapeutic in the first place are also high. Lower scientific knowledge of the paediatric targets and pathways can mean additional pre-clinical work. On top of the conventional costs (data management, product availability, trial coordination etc) the clinical stages are complicated by paediatric specific needs. Dosing, formulation, administration, patient follow-up – they all need to be tailored to the young person’s situation and their developing metabolisms.

Additionally, the small patient population may slow down trial recruitment, and extend the time-to-market of the therapeutic.

The risk of failure is inherently attached to the development of therapeutics. Failure can of course be linked to the lack of effectiveness, but just as likely it could be secondary reasons such as unexpected toxicity making the candidate drug unsuitable as therapeutic. Childhood metabolism is less well studied, and metabolic models of adults cannot necessarily be extrapolated to children. This results in uncertainty in drug development and potential failures of otherwise promising pathways and concepts.

So, the potential for profit in the paediatric cancer market is constrained by the small number of patients each individual therapeutic might serve. Developing a therapeutic already involves high costs, lengthy development times and a significant risk of failure, and so the traditional pharmaceutical industry – where the business model requires markets with a higher profit potential – shows limited interest in paediatric oncology which offers an unfavourable risk-return balance. As a result, paediatric oncology is unable to attract the capital required to finance developments.

An end-to-end solution

The economic hurdles of – and associated underinvestment in – paediatric oncology are widely recognised and multiple incentives have been designed in an attempt to address them, including Priority Review Vouchers in the US, and (extended) market exclusivity in the EU.

Although well intended, these incentives alone have historically been insufficient to fuel a wave of innovation. A more structural and systemic perspective is incredibly valuable in addressing the issues behind this.

Along the therapeutic development chain – from scientific understanding, drug discovery, clinical development and commercialisation – the solution will need to be tailored to the needs of paediatric patients.

And, thankfully, many participants are developing infrastructure, knowledge and networks to bridge the gaps in this journey. Earlier this year, the CRUK and NIH coordinated Cancer Grand Challenges released funding for not just one but two teams, earmarking a total of £40 million for developing our scientific understanding of solid paediatric tumours.

And now LifeArc and CRUK have launched C-Further, a CYP therapeutic discovery consortium aiming to transform promising science into real drug candidates. The initiative is dedicating funding and resources to developing new medicines exclusively for children’s and young people’s cancers. It’s an international consortium bringing together researchers, clinicians, investors and other partners to address the market failure in delivering new drugs for paediatric cancer.

I am hopeful that as the pipeline of drug candidates develops, also the clinical and commercialisation stages will see initiatives being launched to take these candidates through the clinical stages, so we can make real therapeutics available to children and young people with cancer.