Inside Clinuvel: Porphyrins & Porphyrias 2013
The biennial Porphyrins & Porphyrias conference is the only international meeting of global key opinion leaders on the group of diseases known as porphyrias. Convening last week (15-19 May) in Lucerne, Switzerland, P&P has become an important fixture on Clinuvel’s calendar, providing an opportunity to review updates from across the globe and discuss our program with international experts.
Our specific interest in the porphyrias lies with erythropoietic protoporphyria (EPP), one of the rarer forms of the disease grouping and the lead indication for our drug SCENESSE® (afamelanotide 16mg implant). Indeed there were a number of presentations reviewing updates in thinking on EPP, including presentation of results from Clinuvel’s program. I’ll return to those shortly, however, as there have been significant advances in another form of porphyria and it would be remiss not to at least mention these here.
Porphyrins and pathways
Porphyrias are diseases which arise due to genetic defects. If the specific genetic material is passed from both parents, a child will be born with a porphyria. In some instances, porphyrias can also be acquired due to chemical exposure or secondary diseases leading to similar genetic malfunctions. What is common to all porphyrias, however, is the accumulation of molecules in the body known as porphyrins or porphyrin precursors due to a malfunction in the pathway by which the body produces haem (heme). The accumulation of these molecules can then lead to acute and chronic symptoms in porphyrias, often onset by a ‘trigger’.
In EPP, for example, the phototoxic molecule protoporphyrin IX (PPIX) is accumulated in the skin which, when triggered by exposure to visible light, causes unbearable, untreatable attacks of dermal pain which can last for several days.
Advances in genetic therapy for acute porphyrias
In acute porphyria, the accumulation of other porphyrins and/or their precursors can lead to acute attacks on other organs, often presenting as nausea, vomiting and severe abdominal pain for which narcotics are often the recommended therapy. While a therapy exists – a haem arginate product is often used in these patients as a preventative and responsive therapy – acute porphyrias have long been considered as viable candidates for gene therapies which would better help manage their disease and eliminate or reduce the need for other therapies. At the 2011 P&P conference in Cardiff the gene therapies were discussed in depth, however this year preliminary observations from two teams were reported for the first time. The first is already in human clinical trials with a small cohort of patients being treated across Europe, while the second reported successful results in animal models with the plan to commence human studies in the coming year. Both teams reported encouraging data and/or anecdotes from their work. While many steps will need to be taken before conclusive evidence of the safety and efficacy of genetic therapy is at hand, it is indeed exciting to view these important advances for rare disease patients.
In addition to the buildup of the phototoxic molecule PPIX in the skin in EPP, PPIX can also accumulate in the liver, leading to liver failure in a small number of patients (you can view one EPP patient discussing her experiences with liver transplantation following liver failure on our YouTube channel here). Traditionally quoted as “1-4%” or “about 5%” of patients, the reality is that the chances of liver failure in EPP are not really understood, nor is it possible to predict which patients may suffer from liver failure. Presenting this in some depth, Dr Staffan Wahlin from the Karolinska Institute highlighted that there is still much to learn about liver toxicity in EPP and that patients needed to be closely monitored, perhaps every 6-12 months, as well as counseled on the traditional risk factors for liver failure.
Data from Clinuvel’s European Phase III confirmatory study (CUV029) of SCENESSE® in EPP were presented in an oral abstract by Dr. Janneke Langendonk of the Erasmus MC University Hospital, Rotterdam, representing the eight study centers which took part. After closely reviewing the study’s setup and objectives, Dr Langendonk gave a review of both the statistical results and the reports from her patients, acknowledging both indicated a positive efficacy profile for the drug. Dr Langendonk also reviewed the safety profile of afamelanotide in EPP from her experiences, suggesting that the adverse events seen in the studies which were drug related were not serious.
A collaborative response
For the second time in the P&P conference’s history, the final day of presentations was devoted to an international porphyria patient day – encouraging interaction between both physicians and patients to gain a better understanding of the porphyrias. In all, more than a dozen nations were represented in the room, with presentations on all forms of porphyrias simultaneously translated from English to German.
For me, this international delegation gave the best indication yet that the community surrounding porphyria research – clinicians, patients and industry – has dramatically improved its ability to collaborate across borders with the goal of finding therapies for porphyria patients. Initiatives such as EPNET, the American Porphyrias Consortium and the Protect Our Future program have gained traction in recent years and are better integrating to achieve common goals. This kind of approach is vital in rare diseases which are difficult to diagnose, lack effective treatments and are generally poorly understood by those outside the immediate field. We’ll be working hard to assess the role of Clinuvel’s drug as an effective therapy for patients who need it most.
Remember Research is the key to your cure!
Remember Research is the key to your cure!