Rare Disease Research – Why We Do What We Do

written by Richard Vesely, MD, VP, Regulatory Strategy Consulting

Systemic juvenile idiopathic arthritis – can we do better?

When I was a young pediatrician choosing my career path, I started flirting with the idea of pediatric rheumatology, and at the time, an older colleague told me:

“Definitely choose pediatric rheumatology! It has one great advantage; Whilst your patients will be chronically ill, no one will die, and one day you will pass them all on to adult care.”

Well, it was almost true. Sadly, there were still some patients dying, in particular those with a rare systemic juvenile idiopathic arthritis (sJIA).

I remember 3-year-old Rebecca coming to my clinic and immediately being admitted to the hospital. She had a fluctuating fever spiking over 40^oC, a mild pink rash, hepatomegaly, and an enlarged heart shadow on chest X-ray. Pericarditis. The only treatment that was able to bring the fever under control, at least temporarily, were corticosteroids, in doses that very quickly led to the development of iatrogenic Cushing syndrome. Within a few months, Rebecca had changed beyond recognition.  Other conditions Rebecca developed included – growth arrest, osteoporosis, progressing liver disease, recurrent pericarditis, interstitial lung disease, and arthritis. Immune suppression and infections.

NSAIDS, methotrexate, gold, sulphasalazine, and the remaining armamentarium available to the contemporary rheumatologist, were not working in stopping her disease. Becky was dismissed and again admitted to the hospital about every month with a flare. She had symptoms of what we know today as macrophage activation syndrome (MAS).

And then, on the brink of the third millennium, a new era in rheumatology started. In 1989, etanercept, the fusion protein competing with the natural receptor for tumor necrosis factor (TNF) developed by Bruce Beutler in Dallas, was given to the first patient. In 1998 it was approved for use in the US as the first biologic treatment in rheumatology (EMA approval followed in 2000). Infliximab and adalimumab, monoclonal anti-TNF antibodies, soon followed. Etanercept was then approved by the FDA in children with polyarticular JIA within six months after approval in adults, based on the results of the historical randomized withdrawal design trial with only 69 participants! Regulators at that time must have been really impressed by the effect of this new treatment.

And they were correct! Biological treatments have revolutionized the whole rheumatology world and changed the fate of many patients. Joint damage causing severe deformities and motility limitations has become increasingly rare in those with access to new medicines. The previously unheard-of disease remission has become realistic and the desired outcome.

When the first reports of etanercept success appeared, we approached the drug developers with a request to treat our most serious patient – Rebecca, but the production at that time was unable to cope with the stratospheric demand, and the new medicine was simply not available. We were only approached by a company representative a year after our initial request.

It was too late for Rebecca. She deteriorated quickly and died during one of the disease flares.

It appeared shortly after, however, that whilst effective in polyarticular JIA, etanercept and other anti-TNFs did not work well for patients with sJIA. Only drugs targeting interleukin 1 (IL-1) and 6 (IL-6) pathways developed later showed efficacy and became first-line treatments for this JIA category.

sJIA remains the most severe form of juvenile arthritis, and there are still patients refractory to any treatments currently available, resulting in children still dying from the disease to this day.  

Paradoxically, many of them do not develop significant arthritis or tend to develop it later in the course. Technically, until they do, they do not fulfill the current ILAR JIA classification criteria and often face exclusion from clinical trials, which are rare in this condition anyway. The disease is not economically attractive for developers, and regulatory requirements for pediatric plans have not been able to cover all the facets of this heterogeneous disease. In the absence of the JIA affliction occurring in adults (adult Still disease is even rarer) and the classification complexity (JIA has seven distinct categories), regulators have focused on requesting the development of new medicines for patients with more frequent JIA types. And these pediatric regulations worked perfectly. Children with polyarticular, psoriatic, and enthesitis-related categories of JIA are nowadays treated with the same medicines as adults with rheumatoid arthritis, spondylarthritis, or psoriatic arthritis. Even for “classic” sJIA, biologics have been tested and authorized. However, there remains a tragic unmet therapeutic need in the refractory population with MAS and lung involvement, who still face a fatality rate of up to 40%.

Looking back to my patient Becky, she would belong to this group. I remember her mother asking for help and support, but there was none at that time. Patient advocacy groups were, like everyone else, focusing on problems of more regular JIA forms.

In 2016 I was invited to represent the EMA for the first time at a meeting organized by Systemic JIA Foundation. There I met a group of enthusiastic parents of children with this refractory rare disease along with the founder of the foundation, Rashmi Sinha, an extremely successful IT entrepreneur who has dedicated her life and resources to create this foundation with the goal of helping to find a cure to this disease. Together with colleagues from the FDA and industry representatives, we listened to stories from parents and clinicians on how they have tried to save and improve the lives of these children impacted by the condition since early childhood. Researchers are trying hematopoietic stem cell transplantation, discovering new therapeutic targets like IL-18, interferon-gamma, and Janus kinase. But all face incredible obstacles in conducting proper clinical trials.

Since then, the sJIA Foundation (https://www.systemicjia.org/) has initiated a number of initiatives and achieved some remarkable milestones:

1. Brought together more than 50 families of patients with refractory sJIA with MAS and pulmonary involvement in the US and beyond, creating a pool of potential future trial patients
2. Raised awareness of the disease
3. Organized four NextGen Therapies conferences with leading clinicians, researchers, regulators, and industry representatives (the latest in February 2022)
4. Supported clinical trials in sJIA
5. Helped patients to access the most experienced centers
6. Helped in educating pediatric rheumatology centers
7. Launched an “Accelerate” project with the following objectives:
8. Study patients during flares & quiescent disease (from multiple centers)
9. Study organ biopsy tissue when available
10. Apply modern bioinformatics method to finding patterns
11. Build up a robust drug pipeline of new drugs
12. Identify “repurposed” drugs with established safety profile

Six years later, I am proud to continue my collaboration at Allucent with the Systemic JIA Foundation and their exceptional work in promoting new patient-centric models for patient–researcher collaboration.

As an interface between patients, industry, researchers, and regulators, we can not only increase awareness of this unmet need but also use our experience, contacts, and skills to provide regulatory advice, organize collaboration among stakeholders, and develop and conduct clinical trials using innovative designs, including a decentralized approach and data collection.

To learn more about our Rare Disease & Orphan Solutions, visit us at Rare Disease & Orphan CRO Services