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/>

I find vitiligo to be a fascinating, yet devastating disorder: almost overnight, patients see their skin colour erode and their identity change. Vitiligo has a serious impact on individuals and their family and professional relationships, something I’ve discussed before when looking at treatment challenges.

Because of this impact, we’ve been very careful of the way in which we discuss vitiligo publicly to ensure that, rather than adding to the distress of those affected, we can have a positive impact on disease awareness while we execute our clinical program. I’ve had the privilege to speak with individuals from a broad range of backgrounds living with, and treating, this disorder, with conversations ranging from disease impact, to treatments, to prevalence. During these discussions I also try to seek feedback on how we present the program: what we are doing and how we can do it better. This feedback has, in turn, led to changes, large and small, in our communications (and hopefully will continue to do so).

Yet, one story is often at the forefront when discussing vitiligo with investors, journalists and the broader public which we haven’t discussed until today: the case of Michael Jackson’s very public battle with vitiligo and pigment change. Often these conversations boil down quickly to the “Michael Jackson skin disease”.

Jackson was first diagnosed with vitiligo in 1986. He admitted to having the disease when he appeared on the Oprah Winfrey show in 1993 (see below) and his diagnosis was subsequently confirmed by a number of medical professionals. Despite this there was speculation and doubt for a number of years about his gradual change in skin pigment. One need only look at his pigment change in photographs over the course of his life to understand how he likely relied heavily on make-ups (‘camouflage’) to even out his skin tone and eventually totally depigmented the skin that was most often seen, his face and hands. (It is also a commonly held view that Jackson’s famous glove was likewise an attempt to conceal pigmentary loss on his hands.)

Jackson’s case holds a special, yet polarising, place in the vitiligo community. While he gave some visibility to the disease, there are some who would rather Jackson wasn’t associated with it, and others who wished he’d done more to emphasise the impact of vitiligo while he was still alive. There is a strong movement to have June 25, the anniversary of Jackson’s death, recognised as World Vitiligo Day, but there is also a pushback to avoid the association due to controversies surrounding Jackson’s life and his unwillingness to associate with his vitiligo. It is difficult territory, to say the least.

What I will say is this: vitiligo is a disease which affects people from all backgrounds, races and creeds. While probably one of the most recognised people in the world, Jackson is not the only person to live with vitiligo in the public eye, and there are at least 45 million others around the globe with it today. Vitiligo’s impact on each of these individuals varies as they witness changes in their pigmentation. Their response to this impact also varies, with many choosing not to discuss it in any form. In trying to raise the profile of vitiligo, I expect we will continue to have discussions of Jackson and his public depigmentation, but the goal here will be to broaden the understanding of vitiligo and its impact, rather than encompass the disease in one man’s very visible struggle.

- Lachlan

Image reference

‘Michael Jackson mural’ posted to Flickr.com by Franco Folini on October 28, 2012 < http://www.flickr.com/photos/livenature/8133298859/>

External links

Oprah discussing Michael Jackson’s vitiligo

The June 25 World Vitiligo Day initiative

Last week I gave a snapshot of the formal process undertaken by the European Medicines Agency (EMA) to review a Marketing Authorisation Application (MAA) dossier under the Centralised Procedure. While this provides some context, looking at historical review timelines provides some sense of how long a future application may take. This is far from an exact science, but given the queries we have received of late on approvals timelines, I felt it appropriate to provide some internal perspective.

The EMA’s timelines are confidential, with only set time points at which companies are allowed to publish information (CHMP meetings in particular). Once a drug has been approved by the EMA, however, the Agency issues a summary of the entire review process, known as an EPAR, or European Public Assessment Report. This document outlines the timeframes required by the EMA to perform the review, along with the names of the co-rapporteurs and a summary of the product in some depth, much of which likely reflects the dossier submitted, albeit in an abbreviated version. (The EPARs are published online by the EMA and are free to download.)

At present, there are 65 approved orphan drugs represented with EPARs on the EMA’s website. These exclude at least one recent approval (Novartis’ Jakavi), but represent approvals dating back to 2001. The numbers tell an interesting story.

For all orphan approvals, the mean procedure time from submission of an application to European Commission ratification was 502 days, with a median time of 471 days. For those drugs approved from 2007 until today (36 drugs), those numbers drop to 500 and 460. If one excludes those orphan drugs which have had negative CHMP opinions issued and then been approved on appeal (Gilead’s Cayston, Epicept’s Ceplene and Pharmaxis’ Bronchitol), the 2007 until today mean is 481 days and the median is 453 days.

This seems like quite a process, but probably of greater relevance is the time taken from the EMA’s acceptance of a MAA dossier until the announcement of a CHMP opinion; which is widely considered the EMA’s review process. Here, the average review time for all 65 EPARs is 387 days, with a median of 358 days. These numbers don’t change significantly for the 2007-present period, unless you exclude the three negative opinions, producing a mean of 377 days and a median of 365 days.

The fastest review was Novartis’ Glivec (Gleevec in the US), which took just 121 days from dossier acceptance to CHMP opinion, with the 20 fastest reviews of orphan drugs taking, on average, 248 days from dossier acceptance to CHMP opinion.

The slowest review was Pharmaxis’ Bronchitol, which took 841 days (after suffering a negative opinion setback), with the 20 slowest reviews taking, on average, 555 days. (Bronchitol was, however, not the slowest drug to go from submission to EC approval; that was seen by Shire’s Xagrid, approved in 966 days in 2004 under Exceptional circumstances, and taking 110 days from CHMP opinion-EC ratification).

In reality, the figures can tell only part of the story. Each orphan drug’s path to market is unique, relying on years of work by dedicated teams to ensure a product can be proven safe and effective as a treatment for patients who have often had little or no previous therapy. Despite this, I will try to add context to the EPAR data after it has been released by the EMA and will update some of the numbers above, should anything relevant arise. Looking further, I also hope to be able to publish relevant news on the EMA’s review of Clinuvel’s SCENESSE® (afamelanotide) as and when the Agency allows us.

- Lachlan

Image reference:

‘Map of New Europe’ posted to Flickr.com by Cea. <http://www.flickr.com/photos/centralasian/6713923007/> (See site for license details).

For many years we’ve taken an active interest in the time required by regulatory authorities globally to approve orphan drugs. Clearly this kind of activity is required for forecasting and planning, but it also helps in communications to give our broader audience a realistic idea of the timelines ahead and some of the hurdles we may face.

Predicting timelines in drug development is an imprecise business fraught – each case or drug needs to be indivudally assessed, there are no comparables – but it is nonetheless one method by which we can anticipate the period of time required before any decision from the European Medicines Agency (EMA) is published.

The EMA has a set process by which orphan drugs are evaluated. Following an orphan designation in Europe – the recognition that a drug may have the potential to treat a rare disease – the EMA will use the Centralised Procedure (CP) to review the drug’s marketing authorisation application (MAA). Under the CP, two ‘co-rapporteurs’ are appointed to review the complete dossier. These are individuals within two of the recognised national EMA authorities (such as ANSM in France, BfARM in Germany, MHRA in the UK and AIFA in Italy) who act as the central contact points for the EMA’s review.

These two individuals (or, more specifically, the agencies they represent) review the dossier in-depth and ask questions of a company along the way on behalf of all EMA agencies represented. The process then follows a set of formal steps, running to a 210 day ‘clock’ in a standard review:

1. Validation. Once a MAA dossier is submitted, the first step is to ‘validate’ all the documents in the dossier to ensure they are present and have been formatted according to the EMA’s requirements. This usually takes 1-2 months (but can take longer if there are serious errors or omissions).
2. Clock start and initial review. Following validation, the EMA gives the co-rapporteurs 120 days to perform and initial review of the dossier. After 80 days, an Assessment Report is submitted to the sponsor, with a list of unofficial questions which have already been raised by the dossier. At day 120 the co-rapporteurs submit an official list of questions to the sponsor, raising key issues within the dossier, including any found during inspections of manufacturing, non-clinical and clinical study sites.
3. Clock stop and up to six month response time. At day 120 the official clock is ‘stopped’ and the sponsor is given three months to respond to all questions submitted by the co-rapporteurs. A further three months can be given..
4. Clock start and 60 day review. Once the sponsor has responded, the clock restarts (day 121) and the EMA has a further 60 days to review the response and raise any outstanding issues.
5. Clock stop at day 180 and up to three month response time. At day 180 the clock is stopped again when the EMA raises further questions. At this point the EMA can also request an oral explanation of the sponsor – to present before a panel of regulatory authorities and medical experts and discuss the MAA dossier. The sponsor is given up to 3 months to prepare their response (whether in writing or for an Oral Explanation meeting).
6. Clock start and preparation of CHMP opinion. When the response is delivered by the sponsor, the clock starts again at day 181 and the EMA’s Committee for Medicinal Products for Human Use (CHMP) is given 30 days to prepare a final opinion on the product’s dossier; the final hurdle to EMA approval. The CHMP can issue one of three opinions: approval, conditional approval and rejection (a negative opinion). An approval may also occur with ‘Exceptional circumstances’ – a situation where data may not prove that a drug is safe and effective beyond all doubt, but recognises that this may not be possible and places further obligations on a sponsor following an approval (16 of the 65 orphan drugs approved by the EMA¹ have been approved with Exceptional circumstances).

One final step exists, however, once the CHMP approves a drug, which is to forward the opinion in all languages of the European Union to the European Commission to adopt the drug under relevant laws, finally allowing its marketing across Europe. For orphan drugs this final step can take as little as 48 days, but the reported average is about 88 days.

Next week I’ll look at some of the orphan drug approval statistics in greater depth to gain a sense of how long the approval process for SCENESSE® (afamelanotide) may take.

- Lachlan

¹ Refers to the 65 orphan drug European Public Assessment Reports (EPARs) available at time of writing for orphan drugs on the EMA’s website. Jakavi, a recently approved drug, is at the moment excluded from these numbers. I’ll explain this analysis process in greater depth next week.

- Lachlan

Image reference:

“Skyline Brussel bij zonsondergang” posted to Flickr.com by Erasmushogeschool Brussels on January 7, 2009 <http://www.flickr.com/photos/erasmushogeschool/3179373114/>

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/>

Since we publicly announced our vitiligo program in 2010, the entire Clinuvel team has aimed to gain a better understand this disease, its possible causes and how SCENESSE® (afamelanotide) may become a vital tool in a dermatologist’s arsenal for vitiligo.

We’ve also worked closely with the broader vitiligo community to better communicate the program’s goals and limitations (if you missed them, you can see the first two videos in a series of interviews between Mr Lee Thomas and our CEO here) as well as reaching out to individuals with vitiligo to better understand how this disease impacts upon lives. For me, one of the most prominent recurring topics in discussions, emails, phone calls and online is the lack of treatment for vitiligo and the frustrations of physicians and patients alike at treatment inconsistency.

Vitiligo is an insidious disease. While it causes no physical harm, the manner in which individuals lose their skin pigmentation can play constantly on their minds. Imagine waking every morning, expecting to see a slightly altered face in the mirror or different hands at your keyboard, feeling as if your identity was constantly under siege. This change in visual identity can lead to serious mental health issues and being ostracised from society or the breakdown of marriages. Compounding this further, stress itself can be a ‘trigger’ for vitiligo – one of many factors which has been linked to the onset of further pigment loss.

Unfortunately, we don’t understand the exact cause of vitiligo. While one can quickly dismiss myths about the disease, both genetic and autoimmune factors are suspected of playing some role. Current understanding suggests that an over active immune system within individuals with vitiligo attacks melanocytes in their skin, causing melanocyte cells to die and subsequent depigmentation. Without an exact cause in vitiligo, however, it is difficult to identify how it may be treated.

The frontline treatments for the disease take a two step approach: firstly aiming to halt the immune system from attacking melanocytes and causing depigmentation to spread, and secondly repigmenting skin via either melanocyte transplant or melanocyte stem cell (‘melanoblast’) stimulation. Some treatments aim to achieve both. Narrowband ultraviolet B (NB-UVB), for example, is known to suppress the immune system locally as well as penetrating to the depth of the hair follicle in skin to activate melanoblast migration. Unfortunately, however, treatments take a long time (NB-UVB, for example, is often administered 2-3 times every week for several years) and are notoriously inconsistent: not every patient will experience repigmentation, nor will it be universal. Even in those cases where repigmentation is seen, treatments often only halt the depigmentation process for a limited period of time before the vitiligo is triggered once more.

Over the past two years I’ve spoken with a large number of patients and families living with vitiligo from all over the world. I’ve also had the opportunity to hear from a number of world-leading vitiligo treatment specialists, both in conference situations and private conversation. In so many instances, due to their own lived experiences, the responses to our approach are the same: most are curious about our program, but approach it with cautious optimism.

This has prompted two responses from Clinuvel, to ensure we can properly evaluate the drug in our pilot study and to keep the vitiligo community abreast of our progress. The first is from our clinical team: following the completion of treatment in the current studies (CUV101 in Europe and CUV102 in the USA), patients will undergo a six month dermatological follow up to determine their levels of repigmentation and any possible disease recurrence. The second comes from a communications perspective: the team has sought to identify and converse with as many members of the vitiligo community as is possible, both 1-1 and through our various online and social media outlets.

Our vitiligo program has some way to come before we are satisfied that the drug is a safe and effective treatment and could present a package of data to satisfy the strict regulatory demand. Despite this, the company will continue to integrate itself as appropriately as it can to helping the vitiligo community and discussing our drug and program.

- Lachlan

References

• Chan MF & Chua TL, (2012). “The effectiveness of therapeutic interventions on quality of life for vitiligo patients: A systematic review”. Int J Nursing Prac, 18:396-405.
• Linthorst Homan MW, et al (2009). “The burden of vitiligo: Patient characteristics associated with quality of life”. JAAD, 61:411-20.
• Ongenae K, et al (2005). “Psychosocial effects of vitiligo”. JEADV 20:1-8.

Image reference

Two images showing a patient’s elbow before treatment and following exposure to 108 narrowband UVB treatments over 29 months. Images courtesy of Pearl E Grimes MD.

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/>

The last five years have brought much change in the global pharmaceutical industry. As one of thousands of firms working in the space, we’ve taken a novel approach to try and overcome the challenges such change has presented.

This approach has taken us close to achieving what few of these firms will – proving that a new drug is safe and effective in its treatment of a disease and getting the product approved by the regulatory authorities. Every day the team and I have learnt something new that has helped us in this quest.

Over the next few months – coming from a different perspective as head of communications – I will try to share some of this knowledge with you via the blog; looking at how and why we do what we do, and trying to address some of the most common questions the company encounters on a day to day basis. I welcome your thoughts and feedback, either through comments on the blog, via Facebook, or directly via email to mail@clinuvel.com

- Lachlan Hay, Head of Global Network and Communications, Clinuvel