Today, February 28, marks Rare Disease Day: an annual event to help highlight the effects of rare diseases on individuals, families and the community, and to raise awareness in the hope of finding treatments, or even cures. As a snapshot, a rare disease is defined in Europe as one which affects less than 1 in 200,000 people. Some 6,000-8,000 rare diseases have been identified to date, and it’s estimated that up to 30 million people across the European Union and another 30 million across the US are affected by a rare disease.

Clinuvel takes an active stance on patients’ rights – we’re working hard to get SCENESSE® approved for the rare light intolerance erythropoietic protoporphyria (EPP). This year’s theme Rare Diseases Without Borders resonates with us particularly, as it recognises the global challenges that rare disease patients, and those working with them, face. Cultural and linguistic challenges aside, to get a new drug to rare disease patients one must find those patients then tackle myriad national, regional and local laws and regulations every step of the way. In short, a more cohesive, multinational approach is needed to better address the needs of rare disease patients.

Let me give a brief example from our own work. We believe that EPP affects around 10,000 individuals globally. As a genetic disease, prevalence is higher in certain regions and is centered on populations with fairer skin types (Fitzpatrick I-II). This inevitably leads to Europe and the US, each home to roughly 4,000 EPP patients, many of whom remain undiagnosed.

Our goal with SCENESSE® (afamelanotide) has been to prove that the drug could safely protect the skin of EPP patients by activating dermal melanin and thereby reducing the number and severity of intolerable phototoxic reactions. To prove the safety and efficacy of a drug requires a critical mass of patients. Without this, it is difficult to find sufficient study subjects who fit the inclusion criteria and are willing to undergo the rigours of a clinical study to provide statistical evidence (p values) on the effect of the drug. In common diseases this often means recruiting thousands of patients from a population of millions, but in EPP we knew that a large number of study sites with only a few patients would be needed. This necessitated running multicenter studies across a large number of countries in order to obtain an acceptable number of study participants as well as running other trials evaluating the drug in multiple diseases. However, the lack of cohesion in the process across these countries makes running such a study a logistical feat.

Each country – and indeed in certain countries each region – has a unique regulatory and ethical process which must be followed before patients can be enrolled. These processes will often be influenced by past study experiences (both good and bad) as well as local laws and medical best practices. While a protocol – the master document outlining how a study will be conducted – may be acceptable to Country A, Country B may reject it or request sweeping changes that necessitate resubmission to the authorities in County A, who may or may not agree with the changes. As the goal is to treat all patients under an identical protocol and ensure compliance, this regulatory ballet can often add significantly to the time and resources required to commence a study, already a significant burden in the rare disease space.

Recognising such challenges across borders is a positive step for rare disease advocates. While initiatives such as orphan drug legislation are positive steps in overcoming international barriers, there is clearly more that could be done. In the example given above, a centralised or uniform process for EU regulatory submissions – perhaps one based on the EMA’s approvals process – could be a positive step in expediting drug trials for rare disease patients while continuing to ensure public safety. Across the broader drug development industry, initiatives such as early access schemes, uniform pricing and reimbursement, and greater cross-cultural recognition of clinical relevance would all assist in achieving our goal: delivering therapies to those who need them most.

All the best for Rare Disease Day 2013

- Lachlan

On a separate note, Yann Le Cam, the head of the European rare disease patient group EURORDIS, has discussed at some length many of the other bureaucratic barriers that exist and solutions being considered over at the rare diseases blog; well worth reviewing.

Image reference

Border Zone uploaded to Flickr.com by NH53, June 9, 2012. < http://www.flickr.com/photos/nh53/7365575062/>

We’ve just released the first results from our vitiligo program which you can view online here. Following their release, we expect a number of questions from the vitiligo community, some of which we hope to address below. If you have any other questions, feel free to contact us via Facebook or email.

What was the CUV102 study?

CUV102 was an open-label Phase IIa study conducted in three US expert centres (The Vitiligo & Pigmentation Institute of Southern California in Los Angeles, The Henry Ford Hospital in Detroit and Mount Sinai Hospital in New York). The trial was designed as a ‘proof-of-concept’: to explore the potential of SCENESSE® to repigment depigmented skin in vitiligo. In total, 54 patients enrolled in the study and 41 completed the full treatment course. All of these patients were of Fitzpatrick skin types III-VI, generally darker skin types.

All patients received narrowband UVB (NB-UVB) light therapy 2-3 times a week over a course of six months. Half of the patients (‘Group A’) in the study were also given four doses of SCENESSE®, one each at the start of months 2-5. The other half (‘Group B’) received only NB-UVB. Patients had their vitiligo monitored throughout the study using the VASI and VETF techniques, clinical measuring tools which have been developed specifically for vitiligo.

Results from these patients were then evaluated, comparing the results from Group A to Group B, to determine what effect, if any, the drug had on repigmentation. Specifically we wanted to know the effect of the drug on the speed of repigmentation after administration and depth (degree) of repigmentation achieved. Safety is a key issue in any drug trial, and was considered another key evaluation point. Finally, the overall stability of pigmentation is being assessed by following the patients up for six months and monitoring if their vitiligo returns to repigmented or new areas of their skin.

What are the results from the CUV102 study?

A full copy of the company’s results announcement can be found on our website: SCENESSE® successful in Phase IIa vitiligo study

We’ve also released a presentation, providing an overview of our program and results: Presentation: Clinical Study Results – US Phase IIa Vitiligo Study CUV102

Clinical trial results are based on the concept of statistical significance – how probable is it that the results are true or the result of chance? For those unfamiliar with reading trial results, we suggest first reviewing this post on our blog: Understanding clinical trial results – P values.

Using both the VASI and VETF methods, the study showed that patients from Group A (who had received SCENESSE® alongside NB-UVB) had favourable treatment outcomes compared to those in Group B (NB-UVB alone) at the completion of six months of treatment. These results were statistically significant for both the VASI – (p=0.025) which expresses total depigmentation – and VETF – (p=0.023) which expresses the extent of depigmentation – systems.

VASI can also be used to measure the time taken to see the first repigmentation in a clinical trial. Based on analysis of VASI scores in CUV102, those patients who had received the combination therapy achieved earlier repigmentation than those on monotherapy (a median time of 43 days versus 68 days p=0.086).

Analysis of a subset of darker skinned patients showed that patients in Group A showed significantly better, more complete and deeper repigmentation than those in Group B (p=0.046).

As an overview, based on results seen to date, we believe that SCENESSE® as an adjunctive therapy with NB-UVB phototherapy speeds up and assists the repigmentation process initiated by phototherapy, thus reducing the required dose of NB-UVB radiation. The extent and speed of this repigmentation varied, however, between patients and only a relatively small number of patients were involved in this study. Because of this, further studies are required in a larger number of patients to fully determine whether SCENESSE® is a safe and effective treatment for vitiligo.

Will Clinuvel run further trials in vitiligo? When will SCENESSE® be approved for use in vitiligo?

Based on the results of the CUV102 study, Clinuvel does expect to expand its vitiligo program in 2013, however the company is yet to announce when and where these studies will take place.

If there are more trials how can I participate? Can I register with Clinuvel?

Every clinical trial has inclusion and exclusion criteria which dictate which individuals can participate in a clinical trial. These criteria are determined by the company and/or physicians running the trial and approved by regulatory and ethical authorities.

Clinuvel does not recruit trial participants directly, as to do so may jeopardise the integrity of data generated in clinical trials. The company cannot respond to individual requests to be involved in the studies of SCENESSE® in vitiligo.

Clinuvel advises individuals with vitiligo to talk to their treating physician as they are best positioned to discuss the different treatment options for vitiligo, including clinical trials.

Is SCENESSE® available for purchase anywhere in the world?

Currently SCENESSE® is only available by a physician’s prescription in Italy and Switzerland under specific special access schemes. These schemes allow physicians to prescribe SCENESSE® to Italian or Swiss residents diagnosed with erythropoietic protoporphyria (EPP) but not for vitiligo. For more information on this scheme, see Clinuvel’s website.

SCENESSE® cannot be obtained outside of Clinuvel’s clinical trials anywhere else in the world.

When will SCENESSE® be available for vitiligo anywhere in the world?

This is a difficult question to answer at present as there are many variables involved in drug development. A ‘best case’ scenario would be 2-3 years, however this relies on future studies proving the drug to be safe and effective in a large number of vitiligo patients. The best way to stay abreast of updates is through our website, http://www.clinuvel.com.

How can I find out more about Clinuvel’s program for vitiligo with SCENESSE®?

Log onto http://www.clinuvel.com/en/vitiligo

Following much hype and fanfare at the Olympics, news reports have begun to trickle out on the costs of the Games and the longer term impact they might have on the British economy. While not immune to Europe’s economic spluttering across the Channel, many of the issues facing Britain’s bottom line are unique, and they may have broader implications for drug development, more specifically for drug pricing and reimbursement.

The British government provides healthcare to residents through the National Health Service (NHS). (Similar, but not identical, services exist across the broader UK for Wales, Scotland and Northern Ireland). This includes covering the costs of general doctors’ consultations, emergency medicine, surgeries, some dental and ophthalmological services, and, to a certain extent, medical devices and drugs. Although funded centrally, the NHS is run at local levels, with specific administrations overseeing much of the organisation’s work. Healthcare is one of the largest line items on the British budget each year, expected to cost around £130bn in 2012/2013, around 5% of the UK’s GDP.

Part of this cost is due to the fact that the NHS covers the cost of medical therapies when it’s believed cost effective to do so. An independent NHS body – the National Institute for Clinical Excellence, or NICE – is charged with making evaluations and recommendations as to the most appropriate technologies to address health issues, based on their clinical effectiveness and cost-effectiveness, using a specific technology appraisals system.

The appraisal system, although seemingly convoluted, tries to take into account a large number of stakeholder views in order to appraise technologies, including patients, treating physicians, experts in the relevant field(s) of medicine and manufacturers of the technology (either a drug development company or a medical devices company). Following the review, a final appraisal is published and used by the NHS at a local level to determine which technologies to fund. A positive NICE recommendation means a technology must be reimbursed by the NHS. An unfavourable review means locals NHS bodies may still reimburse a technology, but are not obligated (and thus far less likely) to do so. Of equal significance is that NICE’s technology appraisals have become a watermark for other countries’ reimbursement bodies, meaning decisions have a flow on effect, particularly in Europe.

For new medical technologies, an additional body exists to help NICE prior to its formal review: the NIHR Horizon Scanning Centre (NHSC).  The NHSC conducts formal reviews of emerging medical technologies with the goal of providing briefings to relevant NHS bodies (including NICE) on the technology and its impact (both in terms of treating patients and in terms of potential economic costs). This information can then be fed into technology appraisals, where relevant, and may assist in expediting a review. (The Scottish Medicines Consortium, a separate entity which advises the Scottish NHS, actually conducts this review in house as part of a technology assessment, approaching manufacturers directly during the pre-approval phase).

Technology appraisals take a number of factors into account, but the key measurement is a unit known as a Quality Adjusted Life Year (QALY). In essence, QALYs are a universally recognised method of determining a health outcome, such as the effect of a treatment, on a patient’s Quality of Life (QoL) and the length of their life. The addition of a full year of perfect health equals a QALY of 1.0. It enables a (relatively) objective method of comparing the effectiveness of two treatments; a particularly important factor when considering both the pricing of a new treatment and its effectiveness against the agreed ‘gold standard’ of therapy. For most drugs, NICE has a cap of £30,000 (approx A$45,000) per QALY, at which point it will no longer consider a therapy cost effective. (Although the cap was recently increased for terminal cancer drugs to £50,000).

QALYs are not without their drawbacks, however, and in recent years NICE has come under fire from both the industry and patient groups for rejecting treatments which could improve and save lives. This has been particularly acute as many of the highest profile negative opinions from NICE have been for new generation cancer treatments; expensive drugs, but ones which have often been hailed as breakthroughs in modern medicine.

Two cases of particular note are Britsol-Myers Squibb’s drug Yervoy (ipilimumab) and Roche’s Zelboraf (vemurafenib); therapies designed to treat late stage malignant melanoma. Yervoy was approved by the European Medicines Agency (EMA) in May 2011 after a late stage trial showed metastatic melanoma patients lived for a median of 10 months with the treatment versus 6.4 months with placebo, with 20 percent of the Yervoy patients living for more than 2 years. Zelboraf is a targeted melanoma therapy, designed to treat patients with a specific genetic mutation known as V600e. Late stage Zelboraf data showed the drug improved “progression-free” survival of patients with V600e mutations by 3.7 months, and overall survival by 3 months, compared to patients treated with dacarbazine, a chemotherapy drug approved for melanoma.

Despite the encouraging stats, both drugs have thus far been rejected by NICE for failing to conform to the QALY guidelines. A course of treatment with Yervoy is reported to cost £80,000 per patient (an average of four doses at £20,000 per dose), while Zelboraf, a weekly treatment, costs £1,750 per dose, excluding consultation fees and diagnostics, or around £52,000 for the average treatment course of seven months. NICE knocked back Yervoy in October 2011, noting that the primary data submitted did not provide comparative treatment statistics despite showing that there was great long-term benefit for 10% of patients treated and improved survival for around 30%. Zelboraf has been rebuffed twice – once in June as it breached the QALY threshold and again in August, with NICE requesting additional information. (At time of writing, however, it looks likely that Roche might try a third submission with NICE.)

Cogent arguments for and against NICE’s actions, as well as some scolding of both companies for their pricing strategies have played out in the press, and will likely do so for some time to come. It’s easy to see why patients and their treating physicians would want access to treatments which may improve and prolong their lives, regardless of cost. It’s equally understandable the bottom lines must be met by both government agencies who fund new medical technologies and the companies who develop and market them.

Some strategies are, however, helping to end the deadlock and achieve that final goal of drug development: delivering new therapies to patients. In the past 12 months Takeda Pharmaceuticals and Novartis have both had NICE rejections reversed, enabling countrywide access to two new oncology drugs – Takeda’s Mepact (mifamurtide), a pediatric bone cancer drug costing about £50,000 per QALY, and Novartis’ Tasigna (nilotinib), a second-line therapy for chronic myeloid leukemia which costs around £30,000 annually. In both instances NICE was initially concerned at the overall cost of treatment (as the drugs are for long term use) as well as weaker clinical evidence, but issued positive cost effectiveness guidance after the companies offered to establish patient access schemes (PAS’s) to reduce overall costs. Here, the companies offer reduced pricing or patient specific reimbursement – or a combination thereof – to facilitate lower overall costs and thus lower prices per QALY.

Beyond cancer drugs, orphan drugs – drugs for rare diseases affecting less than 5 per 10,000 people in EU countries – have been subject to different procedures under NICE, with ‘ultra-orphan’ drugs – those which affect less than 1:50,000, or around 1,200 Britons – subject to review by a specific Advisory Group For National Specialised Services (AGNSS). The AGNSS system allows for specific review of a technology by a smaller group of specialists within a given field, with advice going directly to the Secretary of State for Health. This provides a more targeted review for diseases or conditions which few doctors will ever see, and even fewer will correctly diagnose. It also provides greater discretion for the NHS when dealing with diseases which may only affect a few hundred people in the country, thus providing minimal impact for the country. The AGNSS system is currently undergoing review and will probably be rolled into the NICE system, but it is unlikely before the 2013/14 financial year. Thus, it is the likely system under which SCENESSE® will be evaluated, should it receive an approval under from the European Medicines Agency.

Looking beyond the specifics, a broader review of NICE’s methodology is underway to ensure its guidelines are the most appropriate way to evaluate technologies. A review of the appeals process for drug companies is also in progress. It will be of interestto see what recommendations arise from these reviews and whether any amends, if implemented, will help improve the overall access for patients to new, effective technologies in the long term. Time will tell.

References:

Adams, Ben, “NICE: Bristol-Myers Squibb’s Yervoy too costly” InPharm, October 14, 2011. <http://www.inpharm.com/news/169173/nice-bristol-myers-squibbs-yervoy-too-costly>

Adams, Ben, “Roche’s melanoma pill launched in UK”, InPharm, March 14, 2012. <http://www.inpharm.com/news/171766/roche-s-melanoma-pill-launched-uk>

Adams, Ben, “Roche’s Zelboraf rejected by NICE”, InPharm, June 15, 2012. <http://www.inpharm.com/news/173023/roche-s-zelboraf-rejected-nice>

Borland, Sophie, “New cancer drugs held up by the NHS for nine years as rationing body accused of letting down patients”, Daily Mail, May 15, 2012. <http://www.dailymail.co.uk/news/article-2144957/New-cancer-drugs-held-NHS-years-rationing-body-accused-letting-patients.html>

Dickson, Neil, “Rare diseases part 2: orphan drugs – a paradigm shift for marketing”, PharmaPhorum, August 8, 2012. <http://www.pharmaphorum.com/2012/08/08/rare-diseases-part-2-orphan-drugs-paradigm-shift-marketing/>

First World Plus, “NICE requests more information on Roche’s Zelboraf”, August 12, 2012. <http://www.firstwordplus.com/Fws.do?articleid=2AF8065A2F734CFEAC2C0A47C1A274D5&src=corp_site>

Gaffney, Alexander, “NICE to Assume Review of High-cost Orphan Drug Products”, Regulatory Focus, July 23, 2012. < http://www.raps.org/focus-online/news/news-article-view/article/1957/nice-to-assume-review-of-high-cost-orphan-drug-products.aspx>

HIS Healthcare and Pharma Blog, “AGNSS — Is There Really a Need For a NICE of Rare Disorders?”, February 6, 2012. <http://healthcare.blogs.ihs.com/2012/02/06/agnss-is-there-really-a-need-for-a-nice-of-rare-disorders/>

Hirschler, Ben, Reuters, “UK cost agency rejects Roche’s new melanoma pill”, June 14, 2012. <http://uk.reuters.com/article/2012/06/14/us-roche-britain-idUKBRE85D1RJ20120614>

HM Treasury, “Budget 2012 Documents”, March 21, 2012. <http://www.hm-treasury.gov.uk/budget2012_documents.htm>

NHS, August 8, 2011. <http://www.nhs.uk/news/2011/08August/Pages/new-skincancer-drug-yervoy-ipilimumab.aspx>

Reuters, “UK cost body seeks more info on Roche cancer pill”, August 9, 2012. <http://in.reuters.com/article/2012/08/09/roche-britain-idINL6E8J985J20120809>

Stanton, Tracy, “U.K. to revamp NICE appeals after industry complaints”, FiercePharma, August 21, 2012. <http://www.fiercepharma.com/story/uk-revamp-nice-appeals-after-industry-complaints/2012-08-21?utm_medium=nl&utm_source=internal>

Image reference: ‘mind the gap’ posted to Flickr.com by robzand, August 23, 2012 <http://www.flickr.com/photos/robzand/7872085160/>

A new article was published last week looking at a small pilot study of SCENESSE® (afamelanotide) in acne vulgaris. Before discussing this piece specifically, I think it is relevant to briefly review melanocortins and their receptors.

The active ingredient in SCENESSE®, afamelanotide, has been the focus of over 80 peer reviewed journals (as well as being mentioned in at least 100 more) since the initial formulatory work with the drug began in the 1980s. In the last two years alone the drug and its actual or theoretical application in the clinic have been presented at least 20 times at various global scientific forums. This growing library of resources reflects the enthusiasm of the medical community to put a new compound through its paces, both in vitro and in vivo.

While much of this activity has focused on trial results or observations – such as those presented at the American Academy of Dermatology meeting earlier this year – others have chosen to focus on the potential of the drug to address various disorders or diseases, chiefly in dermatology, but also in other medical fields.

Afamelanotide is from a family of molecules known as melanocortins, based on the naturally occurring hormone alpha-Melanocyte Stimulating Hormone, or alpha-MSH. Afamelanotide binds with a particular receptor – melanocortin 1 or MC1R – on the walls of melanocytes – pigment producing skin cells – which in turn stimulates melanin in the skin.

Research into the properties of natural alpha-MSH has shown it to have a range of functions beyond pigmentation, with the natural hormone binding to further melanocortin receptors (numbered 1-5) present on various cells across the human body. Taking a step further, the activation (with an agonist such as alpha-MSH) or blocking (with an antagonist) of melanocortin receptors across the body could unlock a vast array of therapeutic potential.

Closer to our work, melanin also plays a number of roles in human skin. At Clinuvel we focus on two of its primary and best understood functions: photoprotection and pigmentation.

With a basic understanding of the role that melanocortins and alpha-MSH play in the functioning of human skin, it’s easy to see why there has been so much academic focus on melanocortins – these receptors and their agonists and antagonists present a range of possibilities for modern medicine, much of which we’re yet to fully understand.

This brings us back to the undertaken pilot acne study.

Acne vulgaris (just acne to most of us) is one of the most common dermatological disorders, affecting nearly the entire population at some stage of their life, but most commonly during adolescence. Acne is largely caused by a blocking of pores in the skin, the accumulation of sebum and subsequent inflammation resulting in comedones, pimples. For most people, acne is a moderate nuisance, destined to ruin high school photos and first dates. For up to 14% of people, however, acne becomes a distressing battle with the skin which continues well into adulthood. For these patients, a range of over the counter and prescription medications exist, with oral steroids currently used as the golden standard to reduce severe acne.

According to a range of non-clinical studies, natural alpha-MSH is widely understood to have an anti-inflammatory and anti-oxidative effect when it binds with certain melanocortin receptors, including MC1R in skin. Thus, the scientific question was posed: would afamelanotide, an alpha-MSH analogue, exhibit the same properties as the natural hormone when given to patients with acne?

After administering the drug to three adult male patients and observing the progress of their acne over eight weeks the jury is still out, but the authors of the piece – a team from the University of Muenster in Germany – conclude that the drug warrants further investigation for this common disease.

For the moment, though, it makes little sense for Clinuvel to pursue an acne program. The reasons are numerous, but many are covered in my piece last week on effective drug development. The opportunity may arise to return to a larger study for acne with a melanocortin drug and, if so, it is certain that this early stage clinical work will have played a pivotal role in advancing dermatological therapies.

- Lachlan

Reference

Bohm M, Ehrchen J, Luger TA, (2012). “Beneficial effects of the melanocortin analogue Nle4-d-Phe7-α-MSH in acne vulgaris.” JEADV. ePub 27 July 2012.

Image reference

A cross section of skin with acne from http://www.clinuvel.com/en/skin-science/skin-conditions/common-skin-conditions/acne-vulgaris

Take ten years, half a billion dollars and countless man hours from some of the most highly trained, intelligent individuals on the globe. You still stand a 90% chance of failure, some of which is totally out of your control. This is the apparent reality of modern drug development.

With the odds so stacked against it, it’s little wonder that the drug development sector is one requiring constant evolution in rethinking how to survive. In addition to the ‘regular’ risks of drug development, turmoil in global markets since 2007 has seen risk adverse investors shun drug development and biotechnology stocks for blue chip companies which are perceived as safer. The pressure to perform has increased for those companies who continue to work in the space.

In short, it’s forced even greater creativity to ensure survival and prosperity.

Like many peer companies who have reached a late stage of drug development, Clinuvel’s path was unique and hardly comparable to other pharma companies. (Each company has its own challenges and they are seldom comparable to others within the same sector.) By 2006 SCENESSE® (afamelanotide), our lead drug, had captured the public’s imagination, but was only in its infancy from a regulatory perspective.

To reach the market, a new drug must be proven safe and effective in a specific medical ‘indication’ (you can read more about this process on the clinical trials section of our website). The drug product must also be manufactured to a certain standard, known in the industry as cGMP, or current Good Manufacturing Practice. These three criteria (safety, efficacy and quality) should be constantly under review by any development company in the knowledge that they are the yardsticks by which regulators will measure a program and, ultimately, determine whether a drug can be marketed.

For Clinuvel it became obvious that the mechanism of action of afamelanotide – activating melanin in skin – would best be suited for a number of specialities, dermatology, gastro-enterology and haematology. Less obvious in 2006 was whether the drug would prove safe and effective as a prophylactic or symptomatic treatment for the chosen indications.

Melanin has numerous properties within the skin, but one of our key understandings – and now fundamental to Clinuvel’s program – is its ability to protect skin from various wavelengths of light. Here, melanin acts as an umbrella over skin, reflecting and absorbing photons of light across the electromagnetic spectrum and preventing them from penetrating into the layers of skin where they can cause the most damage.

In all skin types, the penetration of invisible ultraviolet light (UV, particularly wavelengths of 280-400 nanometers) over time can cause damage. For fair skinned individuals in particular, excessive exposure of skin to UV over a period of time will lead to skin cancer.

It made sense for Clinuvel to pursue the potential for our drug to prevent skin cancer, but we needed to narrow the playing field to make drug development realistic and feasible for patients who needed the drug most. In ‘healthy’ individuals, skin cancer takes decades to develop. A trial program here would also take decades to develop (a Phase IIb alone would likely be 1,000s of patients over 10 years), so we focused on a subset of patients who we knew were more likely to incur skin cancer in a shorter period of time – immunosuppressed organ transplant recipient (OTR) patients. Even here, a multi-year chronic Phase II study is being conducted, so proving the drug may help safely prevent skin cancer is still some way off.

Delving deeper, the company learnt more about less common disorders which are caused when sun/light impacts upon skin. Many of these – known broadly as photodermatoses – are acute diseases: symptoms occur within seconds or minutes of sunlight exposure. Consulting and in dialogue with experts who lead the field of photodermatology, we identified a small number of these diseases and set about the rigorous task of clinical evaluation of the drug’s safety and efficacy.

Since 2006 it has become clear that one indication is the most promising for SCENESSE®: erythropoietic protoporphyria or EPP. Here, melanin is blocking visible wavelengths of light (particularly blue light), preventing them from penetrating the skin and causing the painful phototoxic reactions which are characteristic of EPP. In practical terms, we are seeing that the drug is safely enabling EPP’ers to venture outside in sunlight for the first time. For many it is literally life changing.

Regulatory support for the EPP program in the form of orphan drug designations, along with encouraging patient and clinical evidence of the drug’s effect, compelled the team to accelerate this program. It was evident from our conversations with external parties, and clinical trial results, that EPP was the indication with the best opportunity to prove SCENESSE® was a safe and effective treatment. More recent support from payors in Italy and Switzerland suggests that there is now a broader recognition of this opportunity to deliver a drug for EPP patients.

Our task is not over and there are still significant hurdles for the company to overcome. While now recognised in Europe, US and Japan, EPP has a lower profile on other parts of the world and the company is working to expand the understanding of this severe disorder. Vitiligo presents a new challenge – our first program dedicated to pigmentary disorders where the drug may be able to assist millions of patients is still in its infancy and will require further trials and fine tuning. The aforementioned OTR skin cancer program will also complete its first study this year, and may present us with a further avenue of development. It’s a fascinating time for us.

Drug development is full of uncertainty. One thing, however, is certain – the Clinuvel team will continue to evolve our program to maximise our chances of getting SCENESSE® to the patients who need it most.

- Lachlan

Image reference
“Medicine” posted to Flickr.com by Kevin (KB35) on October 19, 2007 <http://www.flickr.com/photos/kb35/1644550531/>

Several recent stories have caught the industry’s attention and set media imaginations alight, but none moreso than last week’s record-breaking US$3B marketing settlement between pharma giant GlaxoSmithKline and the US government. In short, GSK plead guilty to withholding safety data and illegal marketing practices related to three drugs and agreed to pay US$1B in criminal fines and US$2B to resolve civil complaints with the federal and several state governments.

The Financial Times responded to the GSK news by branding the industry as ‘unethical’ and called for greater transparency and scrutiny; particularly of industry-doctor relationships (you can read the piece with a subscription here). For some time we’ve been publicly discussing the role of illegal marketing, highlighting around 12 months ago the then record US$2.3B settlement Pfizer paid for activities similar to GSK’s. The practice has continued to grab the media spotlight as companies scramble to respond to the drying up of product pipelines and the ongoing demands of shareholders for increasing returns in difficult markets.

It has been clear that dramatic reforms were needed in our sector, and that the marketing and distribution of drugs required novel eyes, a different approach. Within Clinuvel this topic has been one of much debate in recent years, and a review of the pharmaceutical axis – company, insurers, prescribing physicians, and patients – has taken place in the context of the specific therapeutic area in which our teams operate. In summary, the driving factors for successful development of SCENESSE® have been the patients first, and physicians second. Due to our specific fields of focus, namely dermatology and gastro-enterology (with regards erythropoietic protoporphyria, or EPP), and due to the nature of the disorder the demand for treatment has been very much driven by patients’ experiences following drug administration.

Since 2006 Clinuvel has been working with the EPP community, a unique group of individuals (Recently I discussed the development of this program and I encourage you to read this piece, if you haven’t already). Having met EPP patients around the world it has become obvious to me that this disorder poses a severe burden on the existence of these patients and their families.

In the world of unlimited communication and social media, it became apparent in 2007 that patients’ perceived benefits of SCENESSE® as a newly introduced treatment, as well as possible side effects, would be best reported by patients themselves. Therefore, the company openly took the position that patients’ demand would largely determine the company’s decision to continue clinical trials and distribution, or to discontinue the development. In our case a remarkable shift in the pharmaceutical axis took place from physicians to patients, whereby positive clinical experiences became widely known through media channels, social media and Twitter and became key to our clinical program. Responding to patients’ experiences, we altered clinical trial protocols, discussed the patients’ needs and tailored the therapy regimen to the future use of the product: year round photoprotection.

By working closely with insurers, patients and absorbing the physicians views on ‘medical need’ and best clinical utility, Clinuvel secured early on a dialogue whereby the patient ultimately – in the case of porphyria – strongly made their experiences known to us, sponsor of the clinical trials.

In this particular program, we needed to return to the core value of delivering drugs and new solutions for patients. It’s complex, time consuming, costly and – at times – an incredibly frustrating endeavor. Yet, if successful, it can also be a journey of great satisfaction for all involved.

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/>

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.