Transforming childhood cancer treatment: A call for collective action towards child-first medicines

Why child-first and why now? 

Childhood cancer remains a major healthcare challenge. Around 45,000 children and adolescents in high income countries and another 90,000 in upper-middle-income countries are diagnosed with cancer each year [1]. Yet overall survival for children and young people with rare, relapsed, metastatic and/or refractory cancers remains low, with significant variance in outcomes remaining across indications and ethnicities, while survivors and their families are at risk of adverse health and quality of life outcomes [2], [3], [4].  

Until the last decade, drug development focused on enhancing untargeted chemotherapies and improved supportive care. However, recent advances in sequencing technologies have enabled the deep molecular characterisation of tumours at the DNA, RNA and epigenetic levels. These analyses have uncovered marked differences in the biology of cancers in children and young people compared to adults. Moreover, nearly 50% of paediatric tumours harbour a potentially druggable event, providing an untapped opportunity for a precision medicine approach [5]. The introduction of national initiatives of whole genome sequencing for children such as the Zero Childhood Cancer Program in Australia, 100,000 Genomes Project  and the Stratified Medicine Paediatrics (SMPaeds) in the UK as well as at other specialist centres in the USA and Europe mean that health systems are increasingly eager to use this wealth of information to optimise patient management [6], [7], [8], [9].  

With a few exceptions, almost all precision targeted therapies currently available to paediatric oncologists were first developed and commercialised for adult indications [10]. This means the availability of targeted drugs for children is largely opportunistic; it is not based upon mechanism of action of the therapeutic in children but instead the arbitrary availability of a complementary adult indication. While repurposing or label expansion of adult therapies is one route to impact, it is symptomatic of a wider systemic issue.  

‘Are we now researching drugs for paediatric targets, or have we just become more efficient at studying drugs [in children] developed for adult cancers?’ Moreno, et al [11] 

Consider the story of Abbe Panucci who at 10 years of age was diagnosed with stage 4 embryonal rhabdomyosarcoma. When she underwent care, the drugs that coursed through her veins over the 54 rounds of treatments were all developed before Abbe was born. In fact, the newest therapeutic she received was approved in 1996 and the oldest approved over 65 years ago. Thankfully for Abbe, her care led to remission, but the journey would take a toll. Abbe, like many who have survived childhood cancer, now faces increased risk of early menopause, infertility, osteoporosis, and neurological decline, even accelerated ageing, among other treatment-induced side effects [12]. While adults also face side effects from cancer treatment, children and young people are often still in the process of developing and have their entire lives ahead of them. As a result, the effects of treatment can have a profound cumulative impact over the lives of young survivors, underscoring the urgent need for treatments that are well-tolerated. Today, Abbe takes daily medication to combat the long-term effects of her treatment. 

We will soon reach the limit of what can be achieved using this adult-centred, untargeted approach, and for patients like Abbe, we are already too late. To unlock the next step-change in treating childhood cancers, we need to create a new paradigm which is centred around discovering, developing and commercialising tailored and well-tolerated therapeutics for children – child-first medicines.  

Market failure

The status quo isn’t working

While charities, foundations and government organisations have continued to support groundbreaking fundamental research into understanding and treating childhood cancer and supporting clinical trials, this has rarely been accompanied by subsequent private investment (whether that be pharma, biotech or venture capitalist) that is essential to sustainably take forward novel therapeutic concepts into medicines [13]. 

Pharmaceuticals are a particularly risky sector, not only because of the market risk – how well will health systems uptake the medicine, but also a heavily cascaded technical risk – how well do we understand the disease, target or medicine, all in a tightly regulated environment.  For the paediatric oncology market, there is a third fundamental constraint; is the market size large enough to make a return on investment? 

Where the costs in developing new medicines are so high and the absolute number of children with cancer are thankfully so small, there simply isn’t a sufficient financial incentive for investors to allocate their capital to develop these therapeutics, even when they could address a significant unmet need.  So where does this leave us? 

Market shaping

How mission-driven thinking and collective action could catalyse change

Non-profits have always been the driving vehicle advocating for change for children with cancer. Sidney Farber’s establishment of the Jimmy Fund in 1948, his pioneering research at the Dana-Farber Cancer Centre and his ability to rally major funding commitments from the US Congress, proved that major progress for childhood cancers require a clear vision, a directed effort and considerable resource [14].  

While there is a role for governments and regulators to ‘fix’ this market failure, non-profits can act as a significant pull incentive for future development (see Figure 1). However, the lack of co-ordination and shared consensus has hampered any significant progress in developing more effective, targeted medicines for children and young people with cancer. A market-shaping approach which orients international policy and action around new collective principles and embeds them in the design of collaboration, investment and innovation is key [15], [16]. The sector needs to come together to not only overcome this market failure, but to actively shape a new one.  

Our vision for C-Further is to establish a new model to advance innovative treatments for childhood cancer, through research, collaboration and co-funding. Creating a world where childhood cancers are treated effectively, with tailored and well-tolerated treatments is no small feat and we are aware of the significant challenge ahead. To do so, we must address four major hurdles: 

1 - Set the foundations

Over the last 50 years, Cancer Research UK has funded world-leading research to help children and young people live longer, better lives, free from the fear of cancer [17]. Although we don’t have all the answers, what’s clear is that we need to act now. Taking a therapeutic to market is a long process, so if we want to create the next step-change for children affected by cancer we need to start building upon these strong foundations and solve the future technical and financial challenges of developing child-first medicines as we go. Now is the right time to act, not only because of our collective knowledge has progressed to the point where we can meaningfully work together in lockstep to address this problem but also because of the momentum building around bold organisations going after major health challenges. Initiatives like the FNIH Rare Tumour Public-Private Partnership [18] and the AMR Action Fund [19] show that mission-driven thinking can bring together diverse groups from multiple sectors to crack hard problems.  

Cancer Research Horizons and LifeArc have built an experienced team and a platform to bring partners together under the banner of C-Further. By injecting $36m of capital into the system, we hope to galvanise the community and inspire others to pool their knowledge, infrastructure and funding together to create the critical mass of projects needed to create the next step-change in outcomes for children and young people with cancer. 

Our unique operating model will proactively source novel targeted therapeutics from leading international research institutes, the biopharmaceutical industry and paediatric hospitals. Through working in close collaboration with the originating researchers, underpinned by pooled drug discovery infrastructure, we will accelerate the development of these therapeutics along this cascade. By building a diversified pipeline across a wide range of indications, development stages and therapeutic modalities, we hope to build a unique international platform for the discovery of child-first medicines. 

2- Build momentum

When a mature, steady-state pipeline of discovery projects is established, we hope to become the ‘go-to’ organisation to develop child-first therapeutics, in partnership with the international cancer research community and guided by the patient voice. Once we have reached this critical milestone, the next stage will be identifying the optimal route to transition candidate therapeutics to first-in-child clinical trials.  

Clinical development may require a different organisational structure, with a highly specialist skill set and resourced by an order of magnitude more capital – we know that we cannot, nor should we be the only driver of this change. Notably, it is not clear that we can rely solely on market-rate capital even at the clinical stage where the incentives are still unbalanced with the costs and risks to develop further for some assets unpalatable [20].  

Financial structures which enable non-return seeking capital (e.g., philanthropy, charity, corporate social responsibility and government funding) to catalyse the investment of return seeking capital – so called ‘catalytic capital’ have gathered momentum in sectors addressing major contemporary global challenges such as climate change [21]. It is currently unclear whether such instruments are feasible in this relatively high-risk, low capital return setting. If validated in the biopharmaceutical sector, they could act as a capital multiplier to scale a broad portfolio of therapeutics, prioritising return on impact, rather than return on investment [22]. 

3 - Demonstrate impact

The ultimate measure of impact will be the creation of tailored and well-tolerated therapeutics that are approved by regulators and prescribed by paediatric oncologists to children and young people with cancer.  After successful clinical development, an end actor will always be required to sell the new therapeutic into the marketplace. For indications which are ultra-rare, it is unclear whether a commercialisation partner would have sufficient incentive to take on this role.  

Great Ormond St Hospital, Telethon Foundation, N-Lorem are recent examples of non-profits stepping into the shoes of commercial actors, taking a licence from regulators to provide access to medicines for ultra-rare disease patients [23], [24], [25]. As a community we must actively engage with such end actors, including the pharmaceutical industry, to ensure that we have full visibility of these late-stage challenges. Only then can we actively convene organisations, advocate for, and where necessary create the structures that will enable access for children with cancer. 

4 - Change the system

As well as solving the initial challenges of discovering, developing and commercialising child-first medicines, it will be vital to convene influential leaders across governments, regulators and industry to look at the problem holistically, identifying how the emergent child-first therapeutics that we are helping to create can be better adopted by the markets and be administered to patients in a co-ordinated fashion. This could include exploring regulatory reform, government-supported financial incentives or subscription/voucher-based pricing. In short, we need a suite of compelling ‘market pull’ incentives alongside the ‘push’ of a stack of new medicines lining up for approval – either alone will not be enough. Overall, we believe this could lead to a systemwide change in the market and a radically different operating environment for the discovery & development of such therapeutics, which could further accelerate the development of future therapeutics to treat the next generation of children with cancer.