By Andy Lewis, CRS Director-at-Large
Numerous circadian rhythms have been identified in humans that are controlled by the cyclical variation of various hormones. Far from simply concerning the sleep-wake cycle, an increasing number of physiological processes are known to follow such rhythms, including blood pressure, body temperature, drug metabolism, and pharmacokinetics to name but a few. Advances in controlled release drug delivery have opened up the possibility of developing formulations that exploit or mimic circadian rhythms to develop better treatments for patients. CRS Director-at-Large Andy Lewis interviewed Dr. Martin Whitaker (CEO of Diurnal Limited) on the concept of chronotherapeutics, the challenges faced in developing such products, and their clinical development.
Q What kind of physiological processes follow a circadian rhythm, and how are they relevant to disease treatments?
A There are a great many physiological processes that are rhythmic in nature. A number of these have been known about for a long time, hypothesized to be controlled by the central clock in our bodies but ultimately controlled by light. Sleep is perhaps the most recognisable diurnal rhythm that we have, and if we use this as an example, then it is well known that if we travel by air across several time zones then we become jet-lagged. It’s a prime paradigm of the consequences of when our diurnal rhythms are disrupted, leaving us feeling tired, fatigued, and lethargic. As we understand more and more about our body’s physiology, we are finding more specific rhythms that are relevant to certain diseases and our general well-being. This offers the exciting opportunity to develop specific chronotherapies and move closer to the goal of personalising medicines.
Q Diurnal has developed some modified release formulations that aim to mimic the endogenous rhythm of various hormones. Your lead product, Chronocort®, is currently in phase 2 clinical trials and has orphan drug designation. What requirements need to be met to obtain this, how do you apply, and what advantage does it bring?
A Chronocort® is a modified release therapy that delivers hydrocortisone (cortisol) in a manner that mimics the body’s normal circadian rhythm. This therapeutic approach has the potential to help patients suffering from two orphan diseases due to cortisol deficiency: congenital adrenal hyperplasia and adrenal insufficiency. Many countries worldwide now have orphan drug legislation that is aimed at encouraging drug development in diseases that are rare in the population that may not otherwise sustain commercial drug development. In Europe, the European Medicines Agency is responsible for administering orphan drug status, which affords 10 years market exclusivity from post marketing approval of the first drug to treat a disease that has a prevalence of less than 5 in 10,000. Such legislation has in the past been very attractive to small companies such as Diurnal to operate in these niche therapeutic areas, but it is now also of greater interest to larger pharmaceutical companies! We will have to watch this space carefully to see how this area develops.
Q What technology was used to develop the Chronocort® formulation, who led the team that developed it, and what were the key challenges to be overcome?
A Diurnal is not constrained by any one drug delivery technology. However, within the Diurnal team we have a number of individuals (Hiep Huatan, Development Director; Richard Ross, Chief Scientific Officer; and Martin Whitaker, CEO) that have a breadth of experience in controlled release, and indeed this is the rock on which the company was founded. The key ability of Diurnal is to work closely with clinicians in our chosen therapeutic area (endocrinology) so that we can recognise hormone circadian rhythms, understand how they work, and know what happens when they are altered or absent. By appreciating the physiology of these rhythms, we can identify the true unmet clinical needs of patients whose hormone rhythms are disrupted. Only then will we seek to match the drug delivery solution available to either correct or recreate the (natural) hormone rhythm.
Q Before it entered phase 2, how much work needed to be done to ensure it achieved the desired release profile?
A As with any drug development product, a significant amount of work was carried out prior to Chronocort® being administered to patients in our current phase 2 study. Diurnal had been developing Chronocort® since 2004, and the first attempts at making a tablet technology to recreate the daily rhythm of cortisol failed. However, these early setbacks provided the Diurnal team with invaluable knowledge and understanding of the disease conditions that we were aiming to treat (sometimes such knowledge is simply not available for rare diseases). This enabled us to develop an improved capsule formulation that has delivered the desired pharmacokinetic profile in human volunteers, and the hope is that it can now bring real clinical benefits to patients.
Q Have you managed to establish an in vitro–in vivo correlation? As gut motility follows a circadian rhythm, did you have to take it into account in developing the formulation? Are there differences between patients and healthy volunteers?
A This is an excellent question! Our key learnings from the Chronocort® preclinical development work were in understanding the physiology of the gut linked to the physicochemical properties of hydrocortisone. This enabled us to calculate an optimal “window of opportunity” for hydrocortisone absorption in humans, taking into account a number of complex parameters; from there we were able to put together a robust formulation using a unique combination of excipients to create a Chronocort® product that has the features of delayed and sustained release of hydrocortisone to provide the necessary amounts of drug that patients need throughout the day. The phase 1 studies in healthy volunteers were successful, and we have also recently received pharmacokinetic data from our phase 2 trial in patients, which has enabled us to continue the study and plan for phase 3.
Q Obtaining funding for a phase 2 clinical trial is a significant achievement. How did you approach this, and what advice would you give to other start-up companies facing a similar challenge?
A A reliable source of funding is perhaps the most significant challenge facing any small company. At Diurnal we are fortunate to have secured venture capital funding from Fusion IP plc—a U.K. AIM-listed investor—who specialises in creating early-stage companies and understands the complexity (and duration!) of what it takes to successfully develop a pharmaceutical product. Only by working effectively with our lead funder and other like-minded investors that Fusion IP put us in contact with were we able to secure phase 2 funding, and we are now looking forward to obtaining further investment to take our lead product, Chronocort®, through to the end of phase 3 trials and registration. I guess the moral of the story is choose your investment partners wisely and ensure that they remain committed to your long-term goals!
Q What advice would you give to young scientists starting out on their careers?
A The advice I would give is not to be constrained in one specialist area of controlled release science. Learn about the different aspects of drug delivery and pharmaceutical science. There are a great many exciting drug delivery technologies in development in addition to the ones currently in the marketplace. The key is to learn and understand about different technologies and then apply them to make new pharmaceutical products. Often a breakthrough can be made from applying knowledge from one area of expertise to solving a problem in another, so think broadly! There are many unsolved challenges that require drug delivery expertise. If we think about orphan diseases again, there have been approximately 7,000 rare diseases identified yet only about 300 treatments available in Europe for them, so there is a world of opportunity out there!
Q Are there any relevant articles or papers that you would recommend?
A Advanced Drug Delivery Reviews had a special edition on chronotherapy in July 2010, which is a good starting point for anyone wishing to find out more information about the area. Thereafter, individual rhythms and how chronotherapies are being developed to target these tend to be in specialised publications. For example, a number of interesting rhythms have been described recently in Parkinson’s disease, cancer, and kidney disease in addition to longer-understood rhythms involved in hypertension, inflammation, and cortisol metabolism.