Incentives for Innovation: the story of Gilenya by Novartis
With over 7,000 medicines in development, new treatments will continue to change patients’ lives, slowing disease progression, avoiding illness and reducing overall costs for healthcare systems. But developing a new medicine is a long, complex and risky process with no guarantees of success. Over the coming weeks, we look at a number of new medicines and the role that pharmaceutical incentives (or IP) have played in their development.
Multiple Sclerosis (MS) is the most common autoimmune disease of the central nervous system, affecting approximately 2.5 million people worldwide. It is a chronic disorder that disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss. MS manifests typically in the late 20s or early 30s of adult patients.
There are three types of MS: relapsing-remitting MS (RRMS); secondary progressive MS (SPMS); and primary progressive MS (PPMS). The evolution of MS results in an increasing loss of both physical and cognitive (e.g. memory) function. This has a substantial negative impact on the patients.
MS can affect many aspects of daily life. In advanced stages it can lead to a loss of independence e.g. the ability to walk without help. The course of MS is difficult to predict and varies from person to person. The most common subtype of MS is relapsing-remitting MS, in which a person experiences acute and unpredictable symptomatic attacks (relapses) interspersed with periods of decreased symptoms (remissions).
At present there is no cure for MS. A patient must manage their MS and its symptoms, which can worsen over time, for their entire life with medications in order to reduce the rate of relapses
How Gilenya changes patients’ lives by improving health outcomes
The approval of Gilenya® was a huge milestone development in the treatment of relapsing-remitting MS, as it was the first MS treatment with a new mechanism of action, targeting not only inflammation but also preventing degeneration of nerves and brain. It was also the first MS treatment to be administered as a pill which is much more convenient for patients compared to injections.
Gilenya impacts four key measures of MS activity. It: reduces acute and unpredictable symptomatic attacks; restricts damage to nerves and brain; limits brain volume loss; and slows down progression of the disease and of the resulting disability. Its effectiveness on all of these measures has been consistently shown in multiple controlled clinical studies and in the real-world setting.
The development of Gilenya and follow-on innovation
Gilenya was tested in a number of different indications since its patent was filed in 1993. Gilenya’s development journey included both successes and disappointing setbacks. What made the development of Gilenya particularly complex is the nature of MS. MS is characterised by both wide intra-patient and inter-patient variability in the disease. In addition, observing disease progression and relapses, the most meaningful measures of clinical efficacy in MS, is difficult as these events only occur at long and unpredictable intervals.
How incentives helped promote the development of Gilenya
The compound patent for fingolimod was foreign filed in October 1993, by Yoshitomo Pharmaceuticals Industries Ltd and Taito Co Ltd. Novartis in-licensed the compound in 1997 from Mitsubishi Tanabe Pharma Corporation.
The prospect of obtaining 10 years Regulatory Data Protection (RDP) and extending the protection provided by the basic patent by five years enabled Novartis to continue to invest in the extensive research and clinical trials required to bring the medicine to market, despite the failure of the drug in its first indication, the prevention of kidney rejection in renal transplant patients.
Between 2005 and 2011, a phase II trial was undertaken in patients with recurring MS and two Phase III studies in relapsing-remitting MS (RRMS). The pivotal phase III trials for Gilenya carried out in relapsing-remitting MS, lasted 2.5 and 3.5 years and led ultimately to approval in the EU. The clinical trial program was the largest in MS at the time, and included data from clinical studies showing significant efficacy in reducing relapses, the risk of disability progression, and the number of brain lesions detected by magnetic resonance imaging (MRI), a measure of disease activity, in people with relapsing forms of MS.
Gilenya was then recommended for approval by the European Medicines Agency in 2011, for adult patients with high disease activity despite treatment with at least one disease-modifying agent, or rapidly evolving MS with severe recurring attacks, the most common subtype (RRMS).
Gilenya was granted a Supplementary Protection Certificate (SPC), extending the term of the compound patent five years to October 2018, in order to compensate for the delay in approval that was due to significant time needed to conduct the complex clinical trials.
Novartis was also granted 10 years Regulatory Data Protection (RDP) until March 2021, which protect the data generated in the costly clinical trials from being used for the development of generic products.
In 2012, Novartis invested in research and development of a new, second-generation molecule, BAF312 (siponimod), for secondary progressive multiple sclerosis (SPMS), a late-stage, hard-to-treat form of MS. This marked the start of a Phase III study with siponimod, the largest randomised, controlled study in SPMS to date.
This was followed in 2013, by a Phase III study of Gilenya for the treatment of children with relapsing multiple sclerosis. The positive results have been presented at the 7th Joint European and Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) meeting on October 28, 2017 in Paris, France.
Gilenya may be granted extension of market exclusivity to March 2022 in Europe, for the treatment of children with relapsing MS, if clinical study results in the approval of a paediatric indication before March 2019.
 Multiple Sclerosis Trust, Prevalence and Incidence of Multiple Sclerosis; https://www.mstrust.org.uk/a-z/prevalence-and-incidence-multiple-sclerosis (Accessed 9th March 2017)
 PubMed Health. Multiple Sclerosis. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024311
 National Multiple Sclerosis Society. Ms Symptoms. http://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms
 Volker Brinkmann, Andreas Billich, Thomas Baumruker, Peter Heining, Robert Schmouder, Gordon Francis, Shreeram Aradhye and Pascale Burtin, Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nature Reviews Drug Discovery 2010; 9(11): 884