Drug development is extremely challenging no matter the condition – nine in ten drugs fail in clinical trials. However, this worrying situation is even more dire for patients with rare diseases; only around 5% of as many as 7,000 rare diseases have treatments, and clinical trial failures are very common.

For instance, earlier this year, Newron Pharmaceuticals announced its drug sarizotan had failed to meet its primary or secondary endpoints in a Phase II/III study in patients with Rett syndrome. As a result, Newron terminated its development programme for this rare condition, which is a severe neurodevelopmental disorder associated with the loss of acquired fine and gross motor skills, as well as the development of neurological, cognitive and autonomic dysfunction. There are no approved treatments for Rett syndrome, complications of which can be life-threatening.

However, it is not all doom and gloom for rare disease patients. There is beginning to be a paradigm shift in attitudes towards rare disease development.

“Make no mistake, we have a long way to go, and the challenge of developing a drug for any disease remains difficult,” notes Aurora Research Institute rare disease-focused research scientist Dr Sheldon Garrison. “[But]if conversations between patients, clinicians, academic researchers, companies, and others can happen early and often, and financial support continues to grow, we will be successful in bringing treatments forward for the rare disease patients who so desperately need them.”

There are multiple challenges involved with rare disease drug development. With experience working with the US National Organization for Rare Disorders (NORD) and directly in rare disease research, Garrison sees the main challenges being at pre-clinical stages.

In pre-clinical stages, Garrison notes that the difficulty of modelling rare diseases is a major barrier.

“An appropriate model that represents the disease is often essential to test a library or portfolio of potential agents,” he says. “For many rare diseases, the simple genetic mutation model is insufficient to mirror the conditions in humans, making translation to clinical features difficult. Should the wrong model be selected, drugs may go on a trajectory that will never meet the needs of the patient and later fail in clinical trials.”

Issues with translating animal modelling into human trials posed a challenge to Newron’s Rett syndrome drug.

More issues emerge when the drug advances into clinical trials. There are challenges recruiting and retaining from such small pools of patients. This situation is not helped by the fact that “many rare disease conditions affect paediatric populations, and paediatric clinical trials carry with them additional needs to properly do these studies,” explains Garrison.

This, in turn, creates challenges around trial design and clinical outcomes. Regulators traditionally look for large, placebo-controlled trials, which is not always possible with small patient populations that are spread across various countries. In addition, because there are often few previous trials in these diseases, there is a lack of established clinical endpoints that will be accepted by regulators.

A final challenge Garrison notes is around funding. “Broadly, there is interest from the National Institutes of Health (NIH), and foundations have been supportive,” he notes. “But there’s a huge gap between where we are and where we need to be in terms of funding.

"Many foundations have grants that range from $50,000 to $100,000 to pilot projects, which can be critical to launching a program, but that does not get you far in drug development.” On average, bringing a drug to market costs around $1bn.

Over the past few years, a shift in attitudes towards rare disease drug development has begun, bringing hope to at-need patients.

Garrison attributes this primarily to “changes in the way different stakeholders interact with each other”. He adds: “Never before have different stakeholder groups been so engaged. Pharmaceutical companies, clinicians, researchers, regulatory bodies and others are listening to the patient voice as they race towards developing first-in-class treatments for those who need them.”

As such, funding for rare disease research studies is improving, according to Garrison, and regulators are becoming even more engaged in fostering rare disease research. They have become more accepting of more flexible trial designs that take advantage of new and emerging technologies, including data analytics, real-world data, artificial intelligence, as well as virtual clinical tools.

There has also been some improvement in pre-clinical modelling. “Academic researchers, pharmaceutical companies, and patient groups are investing more than ever in developing suitable rodent and cellular models of the disease,” says Garrison. “As a result, exciting gene therapies and drugs are being developed that may lead to a cure for the otherwise most challenging diseases.”

This has created a situation where, despite the Covid-19 pandemic and its wide-ranging impact on drug development and commercialisation, the US Food and Drug Administration (FDA) has managed to approve numerous rare disease drugs this year.

Three noteworthy examples are Novartis’s Ilaris, the first treatment for adult-onset Still’s disease (AOSD), the first treatment for long-chain fatty acid oxidation disorders (LC-FAODs) in the form of Ultragenyx’s Dojolvi, as well as Zogenix’s Fintepla to treat Dravet syndrome-associated seizures.

Named after the British doctor, Sir George Frederic Still, who first described the condition in the late 1800s, AOSD is a rare, inflammatory disease that affects the whole body. It is associated with episodes of high fever, a pink-coloured rash, joint and muscle pain and a sore throat.

For some patients, these symptoms develop randomly and disappear following localised, symptom-focused treatment, while others experience chronic symptoms that can lead to serious, long-term, disabling complications. This is particularly the case with the joint pain, which, if the AOSD is left untreated, can lead to destruction of affected joints.

Until now, with the FDA approval of Novartis’s Ilaris (canakinumab), AOSD patients have had no approved treatments beyond those that treat the individual symptoms. These patients rely on nonsteroidal anti-inflammatory drugs and corticosteroids to manage their fever and joint paint, as well as immunosuppressive drug Otrexup.

Although AOSD is idiopathic, the disorder seems to act as an autoinflammatory syndrome linked with the interleukin-1 (IL-1) cytokine. As it’s an IL-1 inhibitor, Ilaris successfully suppresses the inflammation in patients with AOSD.

As Ilaris was initially improved for a similar condition, systemic juvenile idiopathic arthritis (SIJA), in 2013, this helped Novartis in its clinical development programme for AOSD. An FDA release explains that the outcomes in the trial were established by comparing Ilaris’s efficacy in SJIA patients.

FAODs are a group of rare, genetic conditions that lead to metabolic problems and energy production deficiencies. There are many different types that present themselves in different ways; long-chain FAODs (LC-FAODs) are caused by a defect in at least one enzyme used to break down long-chain fatty acids for energy.

This disease presents itself early in childhood and has multiple symptoms, including muscle weakness, disease of the heart muscle and low blood sugar. Sometimes LC-FOAD can lead to serious, life-threatening medical complications, including premature death and frequent hospitalisations.

Management of LC-FAOD is primarily through a modified low-fat, high-carbohydrate diet, and avoiding long gaps between eating.

1. Vomiting
2. Seizures
3. Muscle weakness
4. Disease of the heart muscle
5. Low blood sugar.

At the end of June, rare-disease focused Ultragenyx’s Dojolvi (triheptanoin) became the first and only FDA-approved treatment for patients with these disorders. Dojolvi acts as a metabolite replacement for people with LC-FAOD as it is purified, synthetic, 7-carbon fatty acid triglyceride designed to provide medium-chain, odd-carbon fatty acids.

“With today’s FDA approval, patients living with this serious, unpredictable, and often catastrophic disease now have an approved therapy,” said Ultragenyx chief medical officer Camille Bedrosian. “Many patients with long-chain fatty acid oxidation disorders have difficult lives with frequent hospitalisations and major medical events despite the best current care. Now these patients have an approved treatment as an option to help manage their disease.”

Within a month of Dojolvi’s approval, Ultragenyx launched an UltraCare programme to support patient access to this treatment, no matter their insurance status.

Dravet syndrome is a form of childhood-onset epilepsy characterised by frequent and severe seizures, many of which require hospitalisation, cause long-term motor impairments and may lead to sudden and unexpected death.

Although there are some anti-seizure medications used for Dravet syndrome, many patients still experience these debilitating seizures. This creates worries for families and patients because they “never know when the next seizure is going to occur, whether they will end up in the emergency room, or what the consequences might be following the seizure”, noted Dravet Syndrome Foundation executive director Mary Anne Meskis. Therefore, there is an enduring unmet need for new treatments for patients with drug resistant Dravet syndrome.

1. Seizures
2. Movement and balance issues
3. Delayed language and speech issues
4. Growth and nutritional issues
5. Sleeping difficulty
6. Sensory integration disorders
7. Unsteady walking, crouched gait
8. Disruptions of the autonomic nervous system

Zogenix’s Fintepla (fenfluramine) showed in two clinical trials it could profoundly reduce the frequency of convulsive seizures when added to existing treatment regimens. The patient group studied in the trials were those whose seizures were inadequately controlled with at least one anti-epileptic drug. This is central to Fintepla’s approval by the FDA in late June.

Zogenix CEO and president Stephen J. Farr noted: “The approval of Fintepla by the FDA is a significant milestone we are proud to celebrate with the patients and families living with Dravet syndrome.

“We began this global development program nearly six years ago after researchers in Belgium recognised the potential of fenfluramine, a drug with distinct pharmacology from all other anticonvulsant agents, to treat intractable seizures in Dravet syndrome.”