A rare opportunity

The challenges of developing products in rare diseases are many - but no obstacle for Novartis Development teams.

Tuberous sclerosis. Cystic fibrosis. Muckle-Wells syndrome. Cushing's disease. These conditions may not be as common, nor as well known, as diseases such as hypertension, lung cancer or rheumatoid arthritis. But these "rare diseases" still have a devastating impact on patients, their families, and society as a whole. That's why on February 28, organizations around the world will be participating in Rare Disease Day 2009. Their goal is to raise awareness with policy makers and the public of rare diseases and of their impact on patients' lives.

Novartis recognizes the significant unmet medical need in this area, and is committed to developing innovative treatments for diseases with no or limited treatment options. But if the benefits are clear, there are serious challenges. "Clinical trials in rare diseases require a tremendous amount of resources, due to their often complex design and implementation requirements," says Karin Blumer, Director Public Policy R&D in Global Public Affairs. "They require persistence and innovation - there is no standard plan for how to proceed." The rewards of successful completion are many: but to get there, Novartis development teams often have had to work and adapt to achieve their goals.

Finding the patients for SOM230

For the SOM230 team, it was more about raising awareness and getting patients to the sites, according to Ulrike Schoenherr, Clinical Trial Head, SOM230. "In a rare disease, there are only so many centers, and the patients are not always nearby or known to the study investigators. How do you get information about this study out to the patients? And once patients are aware of the trial, how do you get the patients to the sites when they live hundreds of kilometers away and have to bring with them several liters of urine that they collect at home as part of the study assessments? That was our biggest challenge."

“Half to three-quarters of all rare diseases occur in children, often already manifesting in early childhood. That’s why Novartis is focusing so much effort in this area to address the medical needs of children.”

Thomas Severin, External Affairs Head Pediatrics

SOM230 is a novel somatostatin analogue being investigated for the treatment of Cushing's disease, agromegaly and carcinoid tumors. Cushing's disease is a rare condition with incidence ranges from 1-3 patients per million per year, but there was a well-established physician community. In addition, our long history in endocrinology meant that setting up sites was not the problem. The biggest challenge was patient awareness.

The team went for an all-out approach. "We worked with patient groups in the countries," says Ulrike. "We created flyers for physicians to share with other physicians. And we and our key opinion leaders went to all global and local endocrine conferences and talked to everyone." In the end, the SOM230 team managed to enroll 150 patients across 80 centers in 22 countries for their study in Cushing's disease. "To our knowledge, this is the largest trial ever performed in Cushing's disease. It took a tremendous effort from the global and local teams at Novartis and the sites to get this far and to keep the study running smoothly. We now hope that our efforts will pay off and that the study results will show evidence that patients are benefiting from this treatment."

No blueprint - the ACZ885 experience

ACZ885, submitted to regulatory authorities in the US and EU at the end of 2008 for the treatment of Muckle-Wells syndrome, started with a first study in one small cohort of only four patients, reports Thomas Jung, Global Program Head for ACZ885. Expanding our clinical trial program beyond this posed a big challenge - Muckle-Wells syndrome is a very rare, ultra-orphan disease, with an incidence of only one in a million. There were no patient organizations, and the disease was not well known by most physicians - and was a well-specialized disease even among rheumatologists.

With no blueprint to work from, Thomas and his team did it the old fashioned way - they hit the books. "We went back to the literature, looking for anyone who has written anything about interleukin 1ß - one form of the interleukin-1 protein that causes the body to attack itself in autoinflammatory diseases - or Muckle-Wells syndrome from the 1970s to today. We found a total of 50 papers, and contacted all of the authors, where possible. This was the most efficient way to get patients on board - and it paid off."

The outreach from Novartis caused a snowball effect - many physicians knew another who had a Muckle-Wells patient. Within a few weeks, about 50 patients were on board. "The only way we managed to do this was through a peer-to-peer, physician-to-physician dialogue. But it took real commitment and perseverance from the team and a strong support from the company for such a rare disease program."

Rare disease in children

Sadly, much of the impact of rare diseases is among children. "Half to three-quarters of all rare diseases occur in children, often already manifesting in early childhood. Chronic and progressive suffering impacts quality of life and shortens life expectancy," says Thomas Severin, External Affairs Head Pediatrics. "That's why Novartis is focusing so much effort in this area to address the medical needs of children, for example in Cystic Fibrosis, Systemic Onset Juvenile Idiopathic Arthritis, Muckle-Wells, Osteogenesis imperfecta, and Tuberous Sclerosis. At the same time, rare diseases are addressed in pediatric oncology and by providing novel vaccines for children."

The challenge of finding treatments for rare disease in children is even more complicated. "We have the usual challenges of small patient numbers and difficulty in recruitment," says Christina Bucci-Rechtweg, interim Global Brand Medical Director for zoledronic acid. "But in addition, we are faced with extra challenges in, for example, protocol design. Often, there is no approved standard of care nor established guidelines for management of adequate well-controlled comparator trials, thus relegating studies to either historical controls or placebo-control, which is rarely acceptable in children with significant symptomatology."

Overcoming these challenges often requires a partner-and working with them early and often. "The importance of specialized networks such as PRINTO Network for Pediatric Rheumatology, POG (pediatric oncology group) or STOPP (Canadian osteoporosis network) cannot be underestimated," says Christine. "They are essential to establishing a patient base from which to find patients." In addition, early collaboration with specialists helps to ensure that study end points are of clinical utility, and early collaboration with the network of Novartis country organizations helps ensure buy-in for resourcing to small, specialty studies. "Novartis is actively reaching out to established and evolving pediatric clinical research networks to collaborate with the experts in the field and facilitate pediatric clinical trials," says Thomas.

Easing the path to approval

"There is much more that can and needs to be done on a political level to ease clinical development in this field, including "globalization" of knowledge and expertise on rare diseases," says Karin. "We are working hard now with regulators around the world to help facilitate and encourage trials in these rare diseases."

“To these patients, it's not a rare disease, it's their disease.”

Karin Blumer, Director Public Policy R&D in Global Public Affairs

Events like the Rare Disease Day 2009 are also key. Rare Disease Day is an annual, awareness-raising event coordinated by EURORDIS, the European Organization for Rare Diseases, at an international level and National Alliances at a national level. "The day is open to the general public, patient organizations, NGOs and the rare disease community at large," says Karin. "And the goal is really to help make sure the voice of these patients is heard."

Sadly, this is often not the case. But regardless of the challenges, both groups like EURORDIS and Novartis are committed to getting these patients the care and treatment their deserve. "To these patients, it's not a rare disease, it's their disease," says Karin. "Just because it's not common doesn't mean it doesn't have a profound impact on their lives, and that of their families. We have to continue to do all we can to help find treatments for all diseases - rare or common."