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.

Earlier this month Sanofi, the world’s fourth largest pharmaceutical company by revenues, announced that it would go on a cost-cutting spree, trimming its expenditure by $US2.9billion annually and cutting many thousands of jobs in the process. Amidst the upheaval, Sanofi stated its key goal for 2012 onwards was ‘generating sustainable growth’ for shareholders (the complete presentation can be viewed here). One of the key targets for its cuts was R&D costs, both in terms of overall spend and employee headcount.

Sanofi isn’t alone in its belt-tightening operations. Along with many others, the three biggest pharmaceutical companies – Pfizer, Novartis and Merck – have all announced reductions, layoffs and restructures in the past 12 months. On each occasion, R&D departments have borne the brunt of the cutbacks, with the development of upcoming, in-house drugs coming to a standstill. Although this trend is not new to the pharmaceutical sector, the questions now are whether the US and EU can maintain their leading roles in medical development globally and who, if anyone, will win from cost-cutting?

There are several elements at play here, but the recent reductions have made one thing clear: drug development is evolving and it’s doing so rapidly. What’s less clear is whether the industry will continue to deliver innovative therapies to patients. After all, isn’t this the essence of pharmaceutical advancement?

For the ‘big pharma’ mentioned above, rationalisation and consolidation dictate the Board rooms. Driven by market conditions, initial spend and job cuts are a necessary element of an overall organisational change in strategy. Sanofi’s recent acquisition of orphan drug specialist Genzyme and Pfizer’s 2009 purchase of Wyeth saw both companies seek to minimise overlapping functions, streamline administrative or marketing divisions and reduce ‘waste’. While it is an unpleasant exercise for any organisation, these measures are necessary in order to facilitate the effective amalgamation of two organisations. Without preempting the outcome of any of these mergers, the success rate of M&A doesn’t hold much promise; perhaps success in this context needs redefining.

Beyond mergers and acquisitions, and often contributing to them, are several influential factors changing the playing field for drug developers. Featuring prominently in post-cutting analysis for many companies is a looming ‘patent cliff’. Here, a number of high-revenue, high profit-margin, large patient population drugs are coming to the end of their exclusive ‘life’ and big pharma lacks new products to fill the gaps.

Analysis by the Wall Street Journal reveals that nine patented drugs with total US sales of US$35bn will lose their exclusivity by the end of 2013; including Pfizer’s Lipitor, which generates annual sales of approximately $US7.5bn in the US alone. Increased competition by generic manufacturers who move in after patents lapse will quickly eat away at these markets, yet companies have few new drugs to replenish their pipelines; most of which aren’t expected to earn a fraction of these sales. In addition, we’ve recently seen the failure of several high profile Phase III studies, leading to the abandonment of prospective development programs and a subsequent narrowing of pharma pipelines.

Against this backdrop, and in the face of the recent global financial turmoil, insurance companies and health maintenance organisations that help patients meet drug expenses are similarly looking to reduce their costs. These payers are pressing for cheaper ‘branded’ drugs and are immediately switching to lower cost generics once they become available. For many industry watchers, we are nearing the end of an era when pharmaceutical companies had been able to produce drugs for mass markets and enjoy ‘blockbuster’ status (in excess of US$1bn annual sales).

The increased market pressure has forced companies to re-think their strategies, with resource allocation being one of the first areas to come under review when striving to sustain growth. As I’ve written before, the industry’s focus on rare indications is one such approach, but in the coming years it is likely that we’ll see a range of R&D tactics employed by big pharma to help grow its revenue and further its product reach. Unfortunately, this will see some drug programs slashed before their time, much to the detriment of patients.

On a more positive note, a scarcity of resources tends to fuel creativity, so, amid this pharma revolution, success will most likely originate from motivated teams who can maximise their proof of concept. Further ahead, innovative approaches, such as patient-driven partnerships and targeted therapies, may result in faster drug development, a greater number of drugs for specific groups and, ultimately, a better outcome for patients. Some also believe that the centre of the pharma industry may move to continents where the production costs are lower, resulting in a loss of global leadership for Europe and the US, but regional success elsewhere. Only time will tell how the pharma story will unfold, in the interim however, it is likely that innovative cost-cutting will remain the industry’s mantra.

Further reading & references

Merck To Cut Another 12,000 To 13,000 Jobs, Pharmalot, July 29, 2011

The Top 20 Pharmaceutical Companies, Contract Pharma, July 14, 2011

Pfizer Plans Deeper Cost Cuts, WSJ, June 8 2011

The XX Percent Solution: Pfizer To Cut More Jobs, Pharmalot, November 12, 2010

Image reference

‘IMG_1014’ uploaded to Flickr.com by Sue Waters on 22 November 2008, <http://www.flickr.com/photos/suewaters/3181424529/in/photostream/>

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.

When Andrew Pollack of the New York Times declared that the “world’s largest drug company is thinking small”, he wasn’t referring to reductions in sales force.

Rather, Pollack was reporting on a licensing deal between Pfizer and Israeli biotech company Protalix which built upon a growing global trend: big pharmaceutical companies were making a move into treatments for rare diseases, otherwise known as ‘orphan’ therapies.

In the months that followed Pollack’s December 2009 article, both Pfizer and GSK (two of the world’s largest pharmaceutical companies) launched specific business units focused on R&D for orphan drugs. In their announcements, both companies highlighted the significant unmet medical needs that exist in rare diseases and the potential of therapies that were in development.

Rare disease drug development, however, is nothing new and it could be argued that these two companies have come fairly late to the party with their specialized units. As I’ve blogged before, US legislation for orphan drugs was introduced in 1983 with the specific intention of grabbing the pharmaceutical development world’s attention and imagination to help patients who had been previously neglected for treatments. At the time, few companies took up the challenge, preferring to focus on so called mainstream ‘blockbuster’ drugs – those which would garner in excess of US$1billion in annual sales – but a select number saw this incentive program as a blessing and began to focus solely on orphan products.

Genzyme is arguably the best known of the orphan developers not only because of its commercial success – the company floated in 1986 raising US$27million and was just sold to pharmaceutical giant Sanofi-Aventis for US$20.1billion – but also for its utter dedication to the patient populations with which it worked. One needs only to look at the story of Myozyme’s development for Pompe disease to see the lengths to which Genzyme goes to complete its clinical program.

While such stories are truly exceptional from a viewpoint of corporate execution, Genzyme was – and, I expect, will continue to be under new ownership – a corporate entity with commercial goals. To fully appreciate the scope of orphan drugs, it pays to spend some time considering the corporate case of Genzyme and how it reached such a significant buyout value.

Cerezyme (imiglucerase) is arguably the best known of Genzyme’s products, not least because it accounts for a sizeable portion of Genzyme’s revenues, but also as it is a second generation orphan product, based on Genzyme’s first orphan drug Ceredase.

Both these products are aimed at correcting an imbalance in Gaucher’s disease, a rare genetic disorder affecting fewer than 10,000 individuals globally, which causes the accumulation of a lipid (glucocerebroside) in cells and the creation of ‘Gaucher’ cells in organs, particularly in the spleen, liver and bone marrow. Gaucher cells accumulate in the organs, causing them to enlarge and often impairing their function. Depending on the disease onset and location of accumulation, symptoms of Gaucher’s disease vary but can be severe and life threatening.
Cerezyme therapy mimics the natural process by which individuals without Gaucher’s disease process glucocerebroside, delivering an enzyme to break down this lipid inside the Gaucher cells and the body can then process the broken down lipid as normal.

The concept seems simple, yet the underlying technology (imiglucerase) was neither cheap to develop, nor is it easy to manufacture (the process involves growing and extracting Chinese hamster ovary cells in highly regulated laboratory conditions). The end result of this process is that annual Cerezyme treatment costs, on average, over US$200,000 per patient. There are, of course, issues with such a high price point for a drug, but many have explored this argument (with a particular focus on quality of life and dosage) and it is by working with the community and payors, such as governments and insurance companies, that such issues can be researched, discussed and resolved.

From a corporate standpoint, Cerezyme is a prime example of why so many large pharmaceutical companies are now focusing specifically on the orphan drug space. Genzyme netted Cerezyme total sales in excess of US$1.5billion over the past two calendar years with estimates that around 5,000 Gaucher’s disease patients are taking the drug, 10% of them without charge. (Those sales included a period in 2010 where Cerezyme manufacture was disrupted, delivering the company lower than expected sales for the drug in 2010 (US$719m).) It’s undeniable that this is a sound business model but the risk lies in exploring an approval system which was primarily intended to incentivise companies to pay attention to rare disorders.

More enticing for many therapeutic developers of late, however, is the potential for their orphan drug technology to be used in broader medical applications; so called ‘translational medicine’. Here, drugs which have multiple potential applications are investigated for indications with the greatest clinical need first (often orphan indications, where there are still so few therapies for more than 6,000 rare and often severe diseases) before being tested for more common indications within the community. This affords a developer (but also the regulator) comfort that it has a level of safety and efficacy data. This staged approach safeguards regulatory acknowledgement before addressing broader applications (which, in turn, could lead to reductions in drug costs due to economies of scale). Here, a translational medicine born out of orphan drug status can not only help a broader patient community, but also provide even greater returns for those who have invested time and money in a high-risk industry. It really is a win-win situation. However, patience is required from investors; they need to understand the long-term view and processes involved.

It is likely that we will see more orphan drug R&D announcements in the future as pharmaceutical companies expand their presence in the space. Hopefully the goals here will remain true to the orphan drug legislation and we can continue to provide new and better therapies to those patients who need them the most.

Links & further reading

• Andrew Pollack, Pfizer Deal Signals a Move Into Treating Rare Diseases, New York Times, December 2, 2009
• Robert Weisman, Pfizer adds focus on rare diseases, Boston.com, June 16, 2010
• Albertina Torsoli and Meg Tirrell, Sanofi-Genzyme deal worth $20.1 billion, Bloomberg, February 17, 2011
• Announcements on rare disease programs: GSK, Pfizer

Since our announcement last year that Clinuvel would commence a new program for SCENESSE® (afamelanotide) in nonsegmental vitiligo, the company has received vast interest in the application of the drug in this disease. Of the enquiries that best captured the essence of this program, one stood out: a US based analyst asked how the company intended to objectively measure the response to treatment, the repigmentation of vitiliginous lesions, in its trial.

Those acquainted with drug development will know this is the key question.

When evaluating a new therapy, one must be able to show the effects of that therapy first in isolation, then in comparison to the current standard of care (if it exists) and/or a placebo. The evaluation of the response to treatment must be objective and, importantly, should be done using a recognised method which allows third parties (initially regulators, but also the broader medical community) to compare the treatment to other therapies.

Vitiligo is a disorder where skin parts gradually lose pigment by the appearance of white lesions or ‘patches’. The pigment loss can be gradual or dramatic and can cease or recommence, spreading without warning. The medical community doesn’t quite yet know the reason for its onset. The goal of vitiligo therapy is to stop the spread of pigment loss and to return pigment to the lesions. One of the key issues in the evaluation of these therapies, however, has been how best to objectively measure the extent of repigmentation achieved and the time taken for the pigmentation to be restored.

Over the past decade, two methods of evaluation have been proposed and assessed in peer reviewed literature: the Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force (VETF) system. Importantly, the two methods are recognised by the regulatory agencies EMA and FDA.

The VASI is a validated quantitative scale developed  by a North American team (Hamzavi et al, see references below) with the goals of quantifying the total extent of depigmentation, allowing physicians to measure de/repigmentation over time and evaluating the effect of treatment on various body sites. Based on the Psoriasis Area Severity Index (PASI; a system for objectively measuring psoriasis), the VASI was initially developed to measure the response of vitiligo to narrowband ultraviolet-B (NB-UVB) treatment, but has since been used to evaluate various vitiligo therapies.

In the VASI assessment, the body is separated into five sites: hands, upper extremities, trunk, lower extremities and feet (subsequent studies have added a sixth site: the head/neck). Each site is clinically evaluated by visual assessment for the percentage of vitiligo involvement (depigmented skin) and the degree of skin depigmentation (using a visual scale of 0, 10, 25, 50, 75, 90 or 100%). The VASI score is then derived by multiplying the values assessed for the vitiligo involvement by the percentage of affected skin for each body site and summing the surface of the lesions of all body sites together.

Clinical evaluations of vitiligo therapies now use the VASI to assess initial levels of depigmentation then to monitor the levels of repigmentation achieved over a period of time and will often provide a percentage improvement of VASI seen (overall and/or at individual body sites). While criticisms have been leveled at the subjectivity of the VASI, it is generally accepted that the VASI allows for a more practical clinical workup than more time or resource intensive methods.

Based on SCORAD, a clinical evaluation system for atopic dermatitis, the VETF system has been developed over several years by a European group (see full list of the VETF team in Taïeb & Picardo reference below). The VETF evaluation system seeks to add more specific parameters to the quantitative measurement of depigmentation. Indeed, the VETF assesses the three dimensions of the disease (extent, staging and spreading/progression), and so provides three different values. Similar to the VASI assessment, the body is also separated into five different sites, specifically the head/neck, trunk, arms, legs and hands/feet.

Each site is clinically evaluated by visual and photographic assessment for the extent or percentage of vitiligo involvement (depigmented skin), the staging and the spreading of vitiligo. The staging and the spreading of vitiligo are assessed on the largest lesion within each specific body site. A specific UV light (a Wood’s lamp which allows the dermatologist to view pigment which is impossible to determine with the naked eye) is then used to illuminate the skin. Staging is assessed using grades from 0 (normal pigmentation) to 4 (complete hair whitening). Spreading is assessed using the following scores: 0 (stable disease), -1 (regressive disease) and +1 (progressive disease).

A clinical assessment form can also accompany the scoring in the VETF system to determine various factors within the given patient population, including the sex, age, duration of disease, age of onset, episodes of repigmentation, impact of vitiligo on quality of life, family history, additional medical conditions and the Fitzpatrick skin type of the patients involved. This allows for a greater clinical workup and for physicians to compare treatments based on reported factors beyond depigmentation; the downside being that this is a very labour intensive approach.

While the two systems differ in their approach and outcomes, both are widely recognised as validated standards for the comparative evaluation of vitiligo and vitiligo treatments under clinical conditions. Importantly, they also allow independent reviewers to objectively evaluate the efficacy of a treatment on an internationally recognised scale.

For more information on Clinuvel’s vitiligo program, go to www.clinuvel.com/vitiligo

References

Hamzavi I, et al (2004). “Parametric modeling of narrowband UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index.” Arch Dermatol. 140(6):677-83. Abstract online

Taïeb A, Picardo M & VETF Members (2007). “The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force.” Pigment Cell Res. 20(1):27-35. Abstract online

VETF, (2005). “Report on the 19^th IPCC Satellite Symposium on Vitiligo, Reston Virginia”. Online: http://www.espcr.org/docs/Report_VETF_IPCC2005.pdf.

Novel drug development is a business which is not well understood; perhaps one which is not well explained. To be able to launch a novel drug proposition, one needs tenacity, expertise and a talented team to succeed. Unlike a ‘follow-on’ product where an abundance of safety data on the molecule in one or other formulation or therapeutic application exists, those few companies working with new drugs must clear all the necessary stringent barriers from the outset.

This makes novel drug development a risky endeavour, amplified by a level of uncertainty even when it is believed that the necessary regulatory hurdles have been cleared and the drug development process seems complete. By looking at several new molecules being developed for obesity (Lorcaserin, Contrave and Qnexa particularly), one can see how uncertain the outcome remains, even when so much work and so many years have been invested; others have written extensively about these cases and I encourage avid readers to review the publications.

Adding to the volume of peer reviewed literature on drug approvals a piece from the Tufts Center for the Study of Drug Development has examined trends in the rate of new drug approvals over the past three decades (1980-2009), with a specific focus on 2000-09. The authors discovered that the rate of new drug approvals – referring specifically to new drug approvals (NDAs) and new biological approvals (BLAs) – increased from 1980 to the mid 1990’s but has since declined to its former levels. They temper that drug developers should not be alarmed because the peak in the 1990’s is likely to have been influenced by the introduction of the Prescription Drug Use Fee Act (PDUFA) of 1992, and thus indicates a change in the processing of drug approvals rather than a decrease in productivity within the sector.

The PDUFA, which permitted the FDA to collect an application fee from drug developers to assist with more timely assessment of new drug approvals, has effectively decreased the length of time required for the approval phase. A process which was taking, on average, nearly three years is now being completed in approximately half that time in the most recent decade.

More directly relevant to our work, the average approval time for products which have received orphan drug designations from 2000 to 2009 was less than for non-orphan drugs, as they tend to be given higher priority by the FDA (48 of the 60 orphan drugs approved by the FDA in this period were granted priority review status). During 2000-09 the average (mean) orphan product approval period was one year compared to 1.5 years for non-orphan products.

Conversely, orphan products approved in this period frequently took longer in the clinical phase* than non-orphans (7.1 years compared to 6.3). In the latter half of the decade (2005-09) both the clinical and approval phase times fell for orphan drugs to 5.9 and 0.8 years, respectively. Several factors could be identified in this data to both support and reject a thesis that drug approval times are falling, some of which I may explore at a further date, but the overall trend appears positive.

There is no precise formula for successful novel drug development, each molecule has its own pharmacological activity and addresses unique set of diseases. Indeed, the rate at which new drugs are approved suggests that each drug has its own formula for success, or that a combination of strategies is required to satisfy the regulatory requirements. In Clinuvel’s case with SCENESSE® (afamelanotide), we face our own specific development and regulatory challenges, but now that we have arrived at the final stages we try to learn from all cases around us how to optimise our chances of regulatory clearance in the first attempt.

* Editor’s note: the clinical phase as defined here is the time from first Investigational New Drug (IND) filing until the first NDA/BLA submission and thus doesn’t take into account clinical work which may have been completed in other jurisdictions prior to IND approval.

Reference

Kaitin, K I & DiMasi J A (2011). “Pharmaceutical Innovation in the 21st Century: New Drug Approvals in the First Decade, 2000–2009.” Clin Pharmacol Ther 89: 183-188. EPub December 29, 2010.

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/>

Effective communication is demanded more than ever in present-day drug development. I’ve blogged before about the role of patients in this process and the importance of acknowledging patient driven drug development. In a time of advanced technologies and communications it is my intention that Clinuvel be at the forefront of any developments in this area and that the company seeks new ways to discuss our program, online and off.

We also work in a highly regulated environment: very little of what the company does is without scrutiny from this perspective, either from our own regulatory team or from external organizations established for this purpose. Despite the hightened reviews, there remains a discord in the communications realm, with a lack of regulation surrounding tools referred to broadly as ‘social media’.

Dismissed by some as an early fad and embraced by others as a series of genuine outlets, ‘social media’ now plays an integral role in Clinuvel’s communications program, internally and externally. While I leave it others to debate exactly what constitutes ‘social media’, for Clinuvel we see these tools as anything which allows us to engage in a two-way conversation with the public.

Our team use social media outlets to communicate with patients, physicians, investors and other interested parties, for an array of purposes. We also encourage our staff to engage with each other over specific platforms. Whether discussing the objectives of our program, announcing changes to the structure or practices of the company, or addressing individual questions and concerns, social media allows for personal and immediate interaction. It also leaves us, as a company, open to certain liabilities. But foremost it enables us to speak to smaller groups in a more individualised manner.

When it comes to presenting information or marketing a drug, there are strict regulations for presentations in broadcast and written media, such as newspaper and magazines. However, since social media is a rapidly evolving medium with many outlets and formats, there are no obvious guidelines for its use by pharmaceutical and drug development companies. As a result, to date, the social media landscape has been largely unregulated (something I’ve explored in earlier posts, particularly in October 2009).

Two years ago several large pharmaceutical companies received warnings from the U.S Food and Drug Administration (FDA) regarding their use of social media to falsely promote products, having made claims that were “misleading” or did not fully explain the risks of certain medications. In order to avoid such issues in the future, the FDA set about detailing specific regulations and conventions regarding the use of this medium, yet we are still waiting more than 12 months after the initial FDA hearing, for further guidance.

The release of a guidance document for social media is now due at the end of the first quarter of 2011 and is expected to cover some of the following topics:

• Appropriate description of potential risks of a drug where there are restrictions on the length in social media
• Online dealings with external parties, such as manufacturers and distributors
• Inserting links in social media
• Amending false/misleading statements

We eagerly anticipate the formation of these policies, however we do not expect – nor do we wish – to significantly alter the way we use social media as a result of these regulations. To date, social media has been relatively successful in pharmaceuticals because of the application of common sense and attempted translation of other relevant laws by regulatory teams working in the space.

A decision to heavily regulating companies’ social media outlets, or a lack of flexibility in guidelines, will leave the pharmaceutical sector lagging behind digitally. Yet, we should acknowledge that social media must not become the pharmaceutical Wild West: a playground where other – often significant – responsibilities are flouted or ignored for the sake of a new medium.

Many industry pundits and ‘social media experts’ have had their say in recent months as to how the regulations will take shape. It is to hope that common sense will continue to prevail and social media can continue to allow for equitable conversation and the transmission of accurate information for the safety and benefit of all concerned. We’ll keep you posted on the outcome.

Links

Clinuvel’s Photoprotection Network on Facebook

Clinuvel’s Twitter account

Image reference

“it’s a series of tubes” uploaded to flickr.com on November 8 2007 by vanz <http://www.flickr.com/photos/vanz/2043629633/>