Earlier today we announced that two health insurers in Switzerland had agreed to reimburse SCENESSE® (afamelanotide) for the rare disease erythropoietic protoporphyria (EPP). While this is an encouraging step forward for the program and for Swiss patients, I felt it appropriate to take a moment to discuss the important role that Switzerland has played, and continues to play, in our EPP program.

In 2006 Clinuvel announced that it would commence a new clinical trial program focused on an unknown disease in a small open label study. At the time I noted that our aim was to “provide a prophylactic treatment for [a] debilitating and incurable skin disorder”.

The theory behind the use of the drug in EPP was quite simple. EPP is a metabolic disorder which causes the accumulation of a phototoxic chemical compound, known as protoporphyrin IX or PPIX, in the skin. When PPIX is exposed to specific wavelengths of light within the visible spectrum, it causes a phototoxic reaction underneath the surface of the skin which most patients describe as progressive, painful, debilitating and, unusually, invisible – there are no physical signs on the skin that a reaction is taking place. To prevent reactions, patients need to protect their skin from these wavelengths of light which, for most, means leading a life sheltered from light sources and hiding in the dark.

It was widely known that melanin, the pigment in skin, acts as a barrier between skin cells and light, preventing light from penetrating the upper layer of the skin and providing protection. This process was well understood with invisible ultraviolet light, where those with darker skin types have much lower rates of skin cancer compared to those with fairer skin. With the commencement of our EPP program, however, we were about to confirm that melanin, activated by our drug SCENESSE®, also protects skin from visible light.

The first EPP patients received the drug under a Phase II protocol at Zurich’s Triemli Hospital. This open label study, using a 20mg slow release formulation, showed promising results early on. Clinical measurements and patient reports suggested that the drug increased melanin density and improved patients’ tolerance to artificial and natural (sun) light. (For those interested, this study, CUV010, and its results have been published in the New England Journal of Medicine and Photochemistry and Photobiology). Perhaps more importantly, however, we received the first of many reports that the drug was having a positive impact upon patients’ lives, enabling them to do things they never could before because they could expose their skin to sunlight.

Encouraged by the Phase II reports, we worked to map out a broader EPP program which would help fully determine whether the drug could provide a safe and effective prophylactic therapy for these patients. A 12 month placebo controlled multi-centre European and Australian Phase III study protocol with the 16mg SCENESSE® implant (CUV017) was agreed and the first regulatory approval – received from Switzerland’s Swissmedic – saw the trial commence ahead of schedule, with the first patients enrolled at the Triemli Hospital. Mid way through this study Swissmedic granted SCENESSE® an orphan drug designation for EPP, recognising the drug’s potential to assist these patients for whom there is no other therapy.

Having completed the CUV017 study early, an interim efficacy analysis was conducted on 14 Swiss patients, showing that – even in a small sample size – the drug was having an impact, reducing the maximum and total severity scores for phototoxic reactions when compared to placebo. The results also provided the first longer term data on the safety profile of the drug in EPP, with no serious adverse effects or safety concerns identified amongst the patients.

For our team, however, the most encouraging ‘result’ lay beyond the study: all 14 patients had taken the unique step of requesting ongoing use of the active drug for the following 12 months, a treatment made possible under so-called ‘compassionate use’ laws. Many of these patients have since been granted ongoing access to the drug under these laws, providing them with a greatly improved quality of life and providing the program with important data on the long term use of the drug. Indeed, some Swiss EPP patients have received more than six years of almost continuous treatment with SCENESSE®. The feedback is very positive on both its use and effect.

We look forward to being able to continue ongoing treatment of the Swiss EPP community and expanding access of the drug to those who may not have been eligible for compassionate use. This week’s news provides the team with great encouragement as to the safety and efficacy of the drug, but also with great satisfaction that we are finally reaching our goal of delivering a therapy for patients who need it most.

Image reference:

“brienzen rothorn” uploaded to flickr.com by Martin Abegglen (twicepix) on August 26, 2010 <http://www.flickr.com/photos/twicepix/5244209675/in/photostream/>

Those who have taken an interest in Clinuvel will have learned with joy that, on Monday February 6^th, the company announced its first official filing for SCENESSE® (afamelanotide) with the European Medicines Agency. It has taken our teams around six years to arrive at this point. Benchmarked against peer companies, it is a relatively swift development path for a first-in-class drug; we first publicly announced our erythropoietic protoporphyria (EPP) program in September 2006. It is an opportune moment to reflect briefly on how we reached this milestone and then discuss the steps that must be taken from here.

Clinuvel announced its first encouraging results from the EPP program in February 2007, following the completion of an open-label Phase II study (CUV010) of five patients in Switzerland. These results, published in the New England Journal of Medicine and Photochemistry and Photobiology, confirmed what had already been reported to the physicians involved throughout the study: afamelanotide enabled patients to expose parts of their skin to sunlight and monochromatic light – for the first time – without incurring phototoxic reactions. These reactions can range from swelling and burns to long lasting lesions, accompanied by intense pain for which no analgesic seems to work. These patients have been literally scarred for life.

These first results gave reason for optimism for the second larger trial, CUV017. In this multicenter trial, conducted in Europe and Australia, the physicians in charge learned that patients received a clinical benefit from the drug enabling them to lead an unrestricted outdoor life during the spring and summer. This was the first breakthrough in EPP we had seen under conditions of use. The drug’s reported safety profile was excellent, and with dialogue and guidance from the EMA, two new trials were initiated. The challenge for these studies was to capture data relevant to quality of life and outdoors exposure. In November and December 2011, we reported the positive outcomes of these studies – Phase II US (CUV030) and Phase III EU (CUV029) – which formed the final elements of the EMA submission. Being aware that regulatory agencies wish to see mid and long term safety data and clinically meaningful results, the other indications for which SCENESSE® was tested by Clinuvel have been included in our submission, providing essential supporting data from approximately 650 patients treated with SCENESSE®. Foremost, the results of all four EPP studies demonstrated SCENSSE® was a viable prophylactic treatment for EPP, and one which was well tolerated by those patients during the clinical program.

Running parallel to the clinical program, afamelanotide obtained orphan drug designations from the FDA, EMA and Swissmedic in 2008, and Australia’s TGA in 2010 for the treatment of EPP. This formal regulatory status entitles the company to certain incentives for its program. More than 20 individual regulatory approvals and consent from ethics committees for each trial site helped us to better understand the regulatory needs and ensured we conformed to the expected international standards. I expect there are many who follow the company and who don’t quite understand and appreciate the effort required to secure these approvals, but each one was a significant step toward our final goal and cause for confidence and celebration for our teams.

In May 2010 we received one of the biggest boosts to the program’s standing and further proof that we were on track to deliver this drug for patients for whom there is no therapy. At the completion of our first European Phase III study, the Italian regulatory authorities made SCENESSE® available for prescription prior to its formal EU approval, resulting in the company obtaining its first reimbursement for drug supply, known formally as an AIFA 648/96 listing. While maintaining our focus and yet with reasonable modesty, it indicated an important positive review in Europe. To our knowledge this special dispensation had never been given for a novel medical therapy in dermatology. Today, the Italian patients continue to benefit from SCENESSE®; their anecdotes of life on drug are most gratifying and make us realise how difficult life must be for those condemned to an indoors existence.

Over the course of the EPP program we collected more than half a million data points from patients, recording their experiences which differentiated between active and placebo treatment. More than a million physician report forms were written up and reviewed by the clinical study investigators and their teams. Without the dedication of the academic centers and their willingness to participate in the trials, we would not have reached our first filing. From this position, I thank both physicians and patients for their continued effort, time and belief in the drug and our teams.

Moving forward from the positive news and landmark event of submitting a first dossier to the EMA, new challenges lie ahead. The regulatory review period is an active process which will require more work and time from our teams over the coming months. The EMA’s task is to challenge our dossier and pose questions on all aspects of the drug’s development. Those who are familiar with drug development know that this process will take time, but we are confident that we have optimised the European dossier in anticipation of a rigorous review. Audits, inspections and reviews have been conducted and passed, but undoubtedly more will follow. Although the EMA review process is confidential, we hope to be able to give updates when appropriate. Looking further afield, we now await feedback from the FDA on the direction of our US program; another step which is entirely dictated by the FDA review and timelines and which will likely set new challenges for Clinuvel’s EPP program in 2012.

If there is one learning that I take away from the past six years, it’s that the CUV team embraces the numerous challenges along the journey and will continue to meet them. Health, persistence from our teams and safety of SCENESSE® are the requisites for further success.

A protoporphyrin IX molecule

Over recent months I have written several times of the need for Clinuvel to prove clinical relevance in our trials with the use of SCENESSE® (afamelanotide) in erythropoietic protoporphyria (EPP). In orphan populations the need to demonstrate how a novel drug assists in their daily activities and improve their lives is at the forefront of the regulators’ minds. And so it should be, after all the objective of the pharmaceutical industry is to develop drugs which address either disease or symptoms adequately and safely. The results the company released yesterday from our Phase II US study of the drug in EPP (CUV030) have given us important data towards demonstrating clinically relevant improvement of patients’ lives.

In EPP we identified a patient population who are absolute intolerant of light and UV. Since childhood they have come to accept the causality between minimal amounts of light exposure and the price to pay for this. Once EPP patients expose themselves, they start feeling strange and subtle sensations of their skin, tingling, tickling and persistent stimulation. If they do not heed to these pre-warning signs, they literally burn their skin within minutes with irreversible damage. The pain described by the many patients suffering from this genetic disease is hardly describable, the scars are not only on their skin, they are literally condemned to an indoors and isolated life.

Each patient we have spoken to has vivid memories of burns and skin reactions – being forced into an isolated life at school, missing out on social occasions, having to wear protective clothing, having to explain their ‘invisble’ disease to family and friends and partners, most of all missing out on their children’s outdoors lives.

I see it as Clinuvel’s task to offer these patients a ‘normal’ existence: an ability to go outdoors and live with the anxiety of the consequences of light exposure. If the administration of SCENESSE® would enable these patients to lead a normal life during spring and summer, free of anxiety and to actively seek outdoors exposure, we would have succeeded in our mission.

The challenge has always been and continue to be for patients to overcome their lifelong anxiety, trust in the drug and slowly alter their behavior. In analysing the data of the latest trial (CUV030) we have identified how the patients on drug were seeking minutes and hours outdoors without suffering the painful episodes typically reported when suffering from this disease.

In the pharmaceutical sector, we all become aware of the scarcity of resources and need to demonstrate efficacy in life-threatening diseases, improvement of symptoms in severe diseases and better quality of life for patients. Mankind is entitled to an improved quality of life; efforts to better one’s existence should be the principal motive in developing drugs. This task has been quite challenging for Clinuvel’s teams over the years, but we have now witnessed and learned from US patients who received SCENESSE® how the treatment changed their spring and summer existence.

The many letters we received from the broader EPP community have been appreciated and at times have been endearing. The impact and degree of suffering EPP patients (and their families) have gone through is only realised when reading these letters. An existence in the dark for the majority of one’s life is hard to imagine.

I empathise with all of the porphyria community and express the hope that we can continue to assist all these patients who have endured their ordeal. It is a privilege to serve you.

Since 2006 Clinuvel has trialed SCENESSE® in a truly unique group of individuals: patients living with erythropoietic protoporphyria (EPP), a rare genetic blood disorder which causes an absolute intolerance to light.

EPP prevents patients from leading ‘normal’ lives, especially outdoors. It is one of the few diseases that manifest clinically with initially invisible symptoms which cause severe dermal pain for several days. This not only presents a challenge for diagnosis and treatment, but also for generating meaningful clinical trial results – those which are measurable numerically and are used by regulatory authorities to evaluate the efficacy of a drug in a patient population. Here, real life patient experiences during a trial can play an important role in providing clinical relevance and analysing hard data.

I had never seen a case of EPP clinically prior to the commencement of our program with SCENESSE® (this is, I expect, the case for the majority of physicians, and even dermatologists). Yet, I’ve since spent many hours talking to EPP patients and their physicians, reading their correspondence and discussing this contact with the Clinuvel team to try to better understand EPP and how we may measure and evaluate the effects of our drug clinically and in a ‘lived’ experience.

Understanding EPP in practical terms is difficult for someone who has never had this first-hand experience. An EPP burn, patients tell us, is not like sunburn or a scald. The pain is an intense deep burning sensation without relief, yet is largely invisible (at least for the initial reaction).In the following days skin can be painful and swollen or develop into blisters, a rash, scabs or crusts. During this period, many EPP patients report an inability to focus on anything other than their reaction, seeking the dark and relying on high-dose pain killers or sleeping medication for distraction. A 1987 patient survey conducted by E Rufener of the Brain Research Institute at the University of Zürich – one of the first to recognise the social and psychological distress EPP causes – suggested that personality changes and suicidal thoughts were common following a reaction.

Seemingly trivial day-to-day tasks can cause a reaction or must simply be avoided due to the anxiety of provoking an EPP reaction. To provide context, most EPP patients will incur one or two ‘severe’ reactions to sunlight (i.e. those requiring hospitalisation and prolonged use of analgesics) in their lifetime; following this experience there is a – well justified – fear of incurring such burns and pain again and so subsequent exposure is avoided. Work and other activities are left to the twilight hours or are endured with an extreme risk of severe pain or the serious discomfort of bulky ‘sun gear’ (and the unwanted attention it can bring). Thus, following diagnosis of EPP, the standard advice given to patients to date is that they should avoid sun and light exposure and hence avoid the pain it can cause.

Yet, to suggest someone should simply ‘avoid sun’ fails to account for the practical realities of such an endeavor or the devastating effect it can have on work life, social interaction (particularly during the crucial development years of childhood) and physical and mental well-being. Many of these individuals are forced to live a nocturnal life or with the constant fear of sunlight exposure, knowing that even accidental exposure may cause debilitating pain and force them indoors for several days. It is unsurprising that EPP patients report much higher levels of mental illness and unemployment compared to the general populace.

Adults with EPP are forced to learn their limits. They change their whole way of life and adopt behaviours to avoid reactions and the consequential pain. In childhood, however, a lack of diagnosis (the ‘average’ age of diagnosis is 8 years old) and understanding of EPP can lead to horrific, painful reactions. Many children with EPP, desperate not to appear different to their peers, will participate in outdoor activities and endure the pain of an EPP reaction until it reaches a critical, intolerable level and they recieve severe burns. Hospitalisation and/or heavy sedation at this point are not uncommon. This is a burden no child or their parent should have to endure at these times.

It is Clinuvel’s goal to make a therapy available to this patient group – initially as adults, but with a longer term view to all with EPP – to reduce the mental and physical burden of EPP and help patients live a daily routine with exposure to light, something that many of us take for granted. The questions the team is seeking to answer now (with clinical results from two late stage EPP studies) are intended to help us reach this goal. In short, we need to know how the treatment of EPP with SCENESSE® can be evaluated statistically and, just as importantly, with an understanding of the impact of EPP on their daily lives (i.e. clinical relevance).

More than 250 individuals with EPP have been involved in our clinical program to date across three continents. Following the completion of our studies a large percentage of these have corresponded with the company – either directly or through their treating physician – to provide feedback or support for the program. Here, real-life feedback from patients who are returning to work, taking part in social activities outdoors for the first time or being able to conduct daily tasks without pain or fear of a reaction, all make for powerful ‘data’, particularly when contextualised with the severe physical and social impact of EPP prior to therapy.

The personal nature of this correspondence and willingness to share has struck me and continues to be a humbling experience. Yet, what many of these individuals probably haven’t realised is the true impact of their words on helping to further our EPP program. Over the years patient correspondence has not only helped reinforce the value of the program to the team but provided us with invaluable insight well beyond what we see in statistics or numbers. As we now approach the release of final analysis from our two studies, personal reminders that the therapy has dramatically altered an individual’s life for the better and allowed him or her to ‘live normally’, means we appear to be achieving the goals we have for our patients. In terms of how we review results, approach numbers and conduct our discussions with physicians, these powerful patient experiences are never far from our minds.

Reference

Rufener, EA 1987, ‘Erythropoietic protoporphyria: a study of its psychosocial aspects’, British Journal of Dermatology, 116:703-708.

Development of novel drugs is truly like no other business: one attempts to address questions that may have never been previously posed – let alone answered – in the pursuit of improving the lives and quality of life of patients. As I eluded to in my recent letter to shareholders, the team is now well into the analysis of results from our erythropoietic protoporphyria (EPP) program; two studies from the US and Europe. This is a complex and time consuming task that requires one to collate and make sense of thousands of data points to answer a seemingly straight forward question: does this trial show that the drug is safe and effective?

Obtaining an answer needs to be understood from the concept of clinical relevance. Put simply, results don’t just need to show that a treatment or intervention has an effect on a disease. Rather, they need to indicate that that effect is relevant to the current clinical understanding, treatment and care for the disease or indication. They need to show that the drug’s effect is having a positive, meaningful impact upon a patient’s prognosis and care. This is a crucial point to consider in the development of protocols and in the careful analysis of results, as it is how regulators will review the results.

Later this year, pending clinical results, we intend to file SCENESSE® (afamelanotide) with the European Medicines Agency (EMA) for marketing authorisation approval (MAA). If successful, this will allow us to make the drug available across Europe. The team’s current work is focused on building a dossier of information which will allow the EMA to objectively review all data on the drug’s safety and efficacy as a prophylactic treatment for EPP.

In analysis, however, numbers are only half the work. One must employ lateral thinking to determine the relevant outcome of a study, followed by a discussion with the relevant medical community to challenge and validate the study results.

Rare diseases are often poorly understood, even in the medical community, and very seldom seen outside of specialist centres. Here clinical relevance is of even greater value as traditional study endpoints are generally of little value and unique, disease specific, endpoints must be developed, quantified and employed. Looking back at when we commenced our EPP program in 2006, we had to first work with the community of patients, physicians and regulators to develop and validate these endpoints before embarking on an expanded clinical program.

In short, the quantitative objective of our EPP studies is to determine whether the drug can prevent or reduce the incidence and severity of reactions in EPP, caused predominantly by light around 408nm in wavelength (blue spectrum). From a clinical relevance perspective, however, we also aim to be able to show whether the drug improves the patients’ quality of life, allows them to expose their skin to sunlight for extended periods of time or alters the UV/light avoidance behaviour ingrained in them since childhood (including so-called ‘shadow jumping’). The addition of objective clinical measurements – such as phototesting – provides further numerical support.

These factors will form the basis of our understanding of whether SCENESSE® provides a benefit to our patients and has a positive and measurable impact on their lives. In the coming weeks we will learn the results from this program and ideally be able to confirm the clinical relevance of the first prophylactic treatment in EPP.

Held biennially, the Porphyrins & Porphyrias conference (P&P) is the world’s largest gathering on the porphyrias – a group of metabolic disorders causing biochemical disruptions in the pathway of the body which synthesizes haem (heme).

As a result of each of these disruptions, the body presents with unique symptoms ranging from skin symptoms and phototoxicity – as those seen in erythropoietic protoporphyria and congenital erythropoietic porphyria – through to acute attacks of abdominal pain, seen most commonly in acute intermittent porphyria. In short, no two porphyrias are clinically identical yet they are discussed as a single group of disorders with a similar cause. As a matter of fact, there are eight variations of porphyrias, each with a specific clinical manifestation of disease.

P&P is a unique conference, reflecting the current scientific thinking on the diseases. The attending experts represent the challenges presented by the porphyrias from both a research and clinical perspective. There are specialists from diverse backgrounds – dermatologists, haematologists, gastroenterologists, photobiologists, metabolic specialists, geneticists and transplant experts, amongst others – attending the conference and tackling both basic research and clinical care for porphyrias. This diversity is clearly reflected in the conference’s program, where a dermatological case study may sit parallel to theoretical discussions of gene therapy.

Fortunately, great progress has been made in recent years to better integrate clinical care for patients with porphyria, and the results of some of these programs were presented or discussed throughout the conference, including the EPNET project and the British and Irish Porphyria Network (BIPNET). The ongoing success and funding of such programs provides physicians with better integrated access to research, while ensuring patients are delivered the highest possible quality of care. A similar initiative has been established in the USA, which has been active in clinical research as well as highlighting the importance of clinical care in the porphyrias.

Although a number of interesting presentations were given across the porphyrias, given our clinical focus it is cutaneous porphyrias, specifically erythropoietic protoporphyria (EPP), which we’ll discuss further.

Prof Dr Jean-Charles Deybach delivered the plenary lecture on EPP, which included highlighting the newly understood X-linked dominant erythropoietic protoporphyria (XLDPP). Despite being clinically similar in that they both cause phototoxicity, rather than being caused by a deficiency like EPP, XLDPP is caused by an activation of a gene leading to overproduction and accumulation of the phototoxic enzyme protoporphyrin IX (PPIX) in the blood. Prof Dr Deybach discussed the possibility of patients with EPP developing gallstones, as well as the rate at which EPP patients suffer liver failure requiring transplant; it is believed that 2-5% of EPP patients incur this failure, but it is impossible to predict in which patients this will occur. This highlighted the need for regular liver tests in EPP, and encouraging patients to be aware of the risk to their liver.

A prevalence study from Denmark showed that the European nation had a relatively high incidence of EPP compared to the rest of Europe with a 2010 prevalence of 1:103,774 individuals (based on a Danish population of 5.5 million). Working from the basis that EPP and XLDPP both cause disturbances in the metabolism of iron, a team from Switzerland showed that the availability of iron in the blood may have an effect on the function of ferrochelatase, the enzyme which is deficient in EPP. Meanwhile a UK based team suggested that mRNA analysis could assist in unraveling some of the still-unknown links in genetic variations in EPP. Both these studies admit that follow up work is required to confirm their theses.

Following the release of a large body of work on EPP from Sweden last year, the same team presented research on liver transplantation in EPP patients across Europe. Following a literature and transplant registry search, the team uncovered 31 patients who had undergone 35 transplants following EPP-induced liver failure across Europe between 1983 and 2008. This study in particular highlighted the risk of EPP patients to phototoxic injury during surgery; that is patients could have an EPP reaction caused by surgical lighting, something seen in 25% of those patients who didn’t have filters fitted to their surgical lights.

A key presentation for Clinuvel was data from our first European and Australian Phase III study of SCENESSE® (afamelanotide) in EPP (CUV017) along with clinical anecdotes from our Phase II study and ongoing compassionate use programs. At the previous P&P conference Phase II results (CUV010) had been presented, so results from this larger study attracted good interest and discussion. Prof Dr Elisabeth Minder presented an overview of EPP before discussing how, numerically, patients responded to treatment. Prof Minder highlighted the seasonality of the drug’s effect in this study and the changes in melanin density in EPP patients throughout the study. Data were also presented on changes to quality of health and quality of life throughout the study where a clear trend, but no statistical significance, could be seen in patients receiving the drug compared to placebo. Questions from the audience focused on the drug’s safety profile, including its longer term use (Prof Dr Minder highlighted that her team had been treating several patients under study and compassionate use protocols for more than 30 months and additional long term use information would come from Italy).

In addition to the main conference, the British Porphyria Association hosted an international patient day, giving patients the opportunity to learn much of the progress from the conference and various patient associations, as well as ask questions directly to experts about their condition. It is always interesting to hear direct discussion between a patient and an expert as everybody learns from such discussions.

Questions and suggested answers on EPP were as follows*:

What can be done to relieve phototoxicity in EPP?

The panel admitted this was difficult and the discussion was quickly assumed amongst the patient group present. It was generally agreed that cooling the sensitive area was important, although one individual suggested that very warm water can provide relief. Both aloe vera and tea tree oil were suggested as possible coolants.

What is the link between EPP and gallstones?

Unlike the ordinary gallstone, which is often full of cholesterol, gallstones in EPP are dark purple and full of protoporphyrin. While it is unlikely that gallstones will cause health problems, it is best that they be removed. Further, there is unfortunately little that can be done to prevent the development of gallstones.

Is there a link between EPP and fatigue?

One of the panel highlighted that the key thing to remember about fatigue is that it is incredibly difficult to explain medically and may not always be linked to EPP (or other porphyrias). The panel agreed that there is a link between EPP and fatigue, but that this may be coincidental, rather than causal.

General discussion

Two other key points were raised during general discussion. The first, a theoretical, discussed the links between EPP and cholesterol levels where more research should be focused to better understand whether EPP may lead to higher cholesterol and the best way to deal with this clinically.

The second discussion focused on clinical care, with a member of the panel emphasising that not all symptoms seen in patients should be directly attributed to porphyria; ‘you’re not immune from other disorders within the population’. In essence, this panel member was encouraging patients to knock out other possible ailments or conditions as causing symptoms before attributing them to porphyria, as this could ultimately lead to better clinical workups and thus better clinical care.

It is always fascinating to attend a conference of this nature and of significant value to those who attend. Clinuvel was proud to be able to provide sponsorship and ongoing support of porphyrias research and understanding. For those who are unaware, we’re in the middle of National Porphyria Awareness Week in the USA and will be highlighting more events on Twitter throughout the week. If you have any questions, feel free to post a comment below or drop us an email to mail@clinuvel.com.

Finally, our thanks to all involved in the P&P conference; we look forward to Porphyrins & Porphyrias 2013 in Luzern, Switzerland!

* Disclaimer: Information presented is designed for educational and informational purposes only. Third parties listed on this sheet have not explicitly endorsed this information. The information provided is not a substitute for professional, medical and health advice. Do not interpret or use this information to diagnose or treat a health problem or disease without consulting a professionally qualified health care provider. Please consult a relevant health care provider if you have any questions or concerns or if you wish to determine the information you are relying on is appropriate for your medical condition/s. Clinuvel Pharmaceuticals Ltd (‘Clinuvel’) does not endorse or attest to the validity or accuracy of any treatments or medications mentioned. Clinuvel makes no representations concerning the efficacy or suitability of any treatments, medications mentioned. Clinuvel has made every effort to ensure the accuracy of information and welcomes your feedback on any information.

Image reference

‘Cardiff April 2010 063′ uploaded to Flickr.com by shining.darkness on April 8, 2010 <http://www.flickr.com/photos/33124746@N04/4529993211/>

As part of an ongoing series, Clinuvel has released its third video featuring Mikey, an Australian man with erythropoietic protoporphyria (EPP). EPP is a rare disorder in which a chemical, called protoporphyrin IX, accumulates in the skin. When exposed to UV and visible light, the protoporphyrin IX molecules in the skin undergo a chemical reaction which results in swelling scarring and can leave those with EPP in considerable pain.

Mikey recalls a conversation between his physician and his mother at the time of his diagnosis. When beta carotene treatment failed to provide any benefit, they were told there was nothing more that could be done. As a forecast of the future health complications the doctor expected Mikey to face, he remarked to his mother, “…don’t plan any 30th birthday because he probably won’t be alive”.
Mikey discusses some of the professional challenges he has faced, including one instance he has described on the blog: working on an airport flight line. Despite sheltering beneath the airplane’s vast wing, Mikey was bombarded with reflected sunlight from the concrete tarmac which damaged his skin and caused excruciating pain. One also gets the sense of the awkwardness of circumstances where his health was at stake and yet his colleagues could not understand the urgency of the situation.

The other videos in Mikey’s EPP series are also available: Part 1 and Part 2. Alternatively, you can read Mikey’s blog posts.

You can learn more about Clinuvel’s EPP program here.

As the Northern Hemisphere approaches the end of winter, we are beginning to see more mentions of ‘sun allergies’ in popular press, online and in social media.

Most people are not actually ‘allergic’ to the sun, but rather are suffering the first symptoms of seasonal or light-induced skin disorders, known medically as photodermatoses. Photodermatoses cause a person’s skin to react to even the briefest sunlight exposure by burning, swelling or developing a rash. Most distressingly, these diseases can have sudden onset where people, who may have never experienced them before, see symptoms following their first day in the spring sun.

The most common disease referred to as a ‘sun allergy’ is polymorphous light eruption (PLE or PMLE), a condition which affects up to 20% of fair skinned individuals.  PLE is a delayed, recurrent, abnormal reaction to sunlight (or artificial ultraviolet radiation) which mostly affects areas of the skin not normally exposed, such as the upper arms, cleavage and trunk. Non-scarring, itchy or burning lesions appear on sun-exposed skin 30 minutes to several hours following sunlight exposure. The exact cause of PLE is not known, however it is believed to be a delayed hypersensitivity reaction to an allergen produced in the body following sunlight exposure.

Another sun ‘allergy’ is actually a form of atopic dermatitis, or eczema, which is aggravated by sunlight exposure. Rather than the traditional allergic reaction, photoaggravated or photosensitive atopic dermatitis sees the onset or exacerbation of a rash and/or inflammation of the skin following sunlight or UV exposure. As with PLE, the exact cause of photoaggravated atopic dermatitis is unknown.

One final common condition referred to as a ‘sun allergy’ is actually the result of drug or chemical-induced photosensitivity. A number of drugs and chemicals – including antibiotics, non-steroidal anti-inflammatory drugs, psoralens and frangrances – can cause skin rashes following light exposure. These are often the first form of photosensitivity a physician or dermatologist will try to eliminate during diagnosis.

Several less common sun ‘allergies’, which tend to be more severe in both their onset and severity, are the porphyrias. Porphyrias, including erythropoietic protoporphyria (EPP), are metabolic disorders which can cause varying levels of photosensitivity or phototoxicity (so not really ‘allergies’ at all). EPP involves the accumulation in the skin of a chemical known as protoporphyrin IX which causes intolerance to light. When the skin is exposed to the sun, these molecules undergo a chemical reaction that results in swelling, excruciating pain and scarring. As it is a genetic disorder, the symptoms of EPP are lifelong and are normally first experienced during a child’s first summer.

Hydroa vacciniforme is a photodermatosis which predominantly affects children. Inflamed bumps and fluid-filled blisters (vesicles) erupt on the skin – particularly the face, ears and hands – following exposure to sunlight. Ultraviolet A (UVA) radiation (320-400nm) is the main wavelength of light which has been demonstrated to induce these symptoms. The vast majority of hydroa vacciniforme cases resolve spontaneously in adolescence or early adulthood, although rare cases have been reported to continue throughout later life.

Finally, there is a true sun ‘allergy’ called solar urticaria (SU). SU is an allergic reaction induced by sunlight or UV exposure which causes raised red skin welts (wheals) very soon after, or during, exposure. In severe cases of SU, prolonged or intense light exposure may cause anaphylaxis; severe, potentially life-threatening allergic reactions. Although rare, SU can occur at any age, making it an extremely unpredictable disorder.

Many ‘sun allergies’ go undiagnosed or misdiagnosed due to their rarity or the difficulties of identifying UV and light as underlying causes. However, diagnostic tools such as phototesting and blood testing (particularly for porphyrias) can help in the correct identification or elimination of a sun allergy diagnosis.

Editor’s note: we recognise that many of these conditions are not true allergies, but this are often how individuals can best describe them to the world. If we’ve missed one you think may be relevant, leave us a comment below.

Image reference

‘autumn leaves between sun halos and flashlight’ uploaded to flickr.com by ‘oedipusphinx — — — — theJWDban’ on October 13 2009 <http://www.flickr.com/photos/oedipusphinx/4008724345/>.

As part of our ongoing focus on erythropoietic protoporphyria (EPP), we’ve invited Victoria to share her experiences with EPP as a guest blogger. You can read Victoria’s first post here.

When I was first diagnosed with EPP there was a huge sense of relief: someone had actually listened to me and believed that something wasn’t quite right.

That said, I am not overjoyed at having the condition as it restricts my life so much. When Spring starts to approach I get anxious as I dread having a reaction; my freedom to go out feels more restricted.

How would I explain EPP in my own words?

EPP is a controlling disease; it is a disease that I would not even wish on my worst enemy.

When I have a reaction I feel that my body goes into this strange shock. The pain is so intense, I never know what to do. Even doing simple things like holding a knife and fork, having a shower, even speaking (when my face reacts) is hard.

I feel isolated and alone, I just want to be by myself as I feel that others cannot understand my pain. I get very frustrated and upset. I can’t sleep. I can’t control it.

Because EPP causes my iron levels and Vitamin D levels to be low, I am constantly tired, I actually long for a day that I don’t feel tired. I wish I had more energy.

EPP to me is like a time bomb. When the weather is warm you never know when it will go off but, when it does boy do I know about it.

I feel isolated when I can’t go on camping trips or days out that involve being outside all day, I’m so scared of having a reaction and when I do I feel embarrassed and upset.

When I try and explain my condition to others, the reactions vary.

I have some friends who I feel really do try to understand and that means a lot to me, I once gave a talk on EPP at my Church and their continued support is amazing! One woman came to me after the service and asked how to spell Erythropoietic Protoporphyria so she could look it up, which touched me a little.

There are other, responses, however, that frustrate me. Some people think they know all about EPP when in reality they have no idea or understanding; that’s when I feel on my own with this lonely disease. After all, how can I expect people to know all about something they will never experience?.

My faith keeps me going especially through those times, sometimes I ask ‘God why?’ But then I think ‘well maybe I can help and encourage others with this condition’.

I found other sufferers through Facebook which really helps as when I am having a bad time with EPP I can just speak to them, as they understand.

Writing these blogs will not only help me, but I hope other sufferers will be able to relate and share their own experiences.

Photo – Victoria in her sun protective clothing, courtesy of Mansfield Chad

We were delighted this week to be able to announce the successful completion of our first Phase II study conducted in the US, a placebo controlled, randomised trial of SCENESSE® (afamelanotide) for patients diagnosed with erythropoietic protoporphyria (EPP) (CUV030).

Completion of clinical visits for CUV030 is an important milestone in our US development program. Equally important for the global program, however, is the feedback we’ve already received on the study: no drug related serious adverse events identified to date and a high patient retention with 70 of the 77 enrolled patients completing the entire study.

Throughout drug development programs in our industry, patient retention remains a significant issue. While it is expected that some patients fail ‘screening’ – early study visits to assess their suitability for and ability to commit to a study – those who do pass this initial hurdle may still choose – or be forced – to discontinue due to family commitments, illness, inability to comply with stringent study visit dates or a host of other reasons.

Consistent industry wide figures vary, but there are suggestions that between 30-52% of patients will drop out of clinical trials, a trend which is on the rise. Not only does failure to retain patients impact upon the quality of data which is eventually produced from a study, it can also increase the length of time required to conduct a study and data analysis at its conclusion.

Low retention rates may also signify deeper concerns – perceived or real – about the undesirable side effects, safety or efficacy of a drug throughout a study compared to a placebo or the other treatment (usually the standard of care) being used.

Our team works hard to keep  patients in the trials and we recognise that early recognition of the risk of dropping out is vital to eventual success. I believe that patients completing a trial  is a result of good study design, careful planning and precise execution as seen in  our last two reported EPP studies (CUV030 and the Phase III CUV017), which have both enjoyed approximately 90% patient retention.

Finally, we are privileged that members of the EPP community with whom we work have taken it upon themselves to continue supporting the company and our trials. I see this as one of the most satisfying indicators of support for the program thus far and I thank all those involved for their commitment.

Our focus is now on the analysis of data from CUV030 and the completion of Clinuvel’s confirmatory Phase III EPP study being conducted across Europe (CUV029). I look forward to being able to discuss these, and other, milestones in our program in the coming months.

References

Elvridge, S, (2010). “The Importance Of Patient-Retention Strategies”. Life Science Leader. Available online at http://www.lifescienceleader.com/index.php?option=com_jambozine&layout=article&view=page&aid=4009.

Kaitin, KI, (2008). “Impact Report: Growing Protocol Design Complexity Stresses Investigators, Volunteers.” Tufts Center for the Study of Drug Development.

Image reference

‘Edward Everett Square Flag – 1’ uploaded to Flickr.com by Adam Pieniazek on June 29, 2007 <http://www.flickr.com/photos/adampieniazek/677580548/>