Biotechnology profile: Bright future for Clinuvel (ASX:CUV)

This feature appeared in the March/April 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

Australia has a mixed relationship with the sun. We all know that exposure to sunlight can be damaging, with melanoma of the skin being the fourth most prevalent cancer in this country. Yet even with the known threat, many Australians find themselves drawn to basking in the rays of the sun in the hope of cultivating a deep and lustrous tan.

However, for some people, even a few minutes of exposure to sunlight is entirely out of the question. These people suffer from erythropoietic protoporphyria (EPP), which is a rare inherited form of porphyria that results in extreme phototoxicity. Exposure to sunlight and artificial blue light results in intense pain and burning with usual antipruritics (anti-itching) treatments failing to alleviate the symptoms.

Others suffer from polymorphous light eruption (PLE or PMLE), a much more common ailment that is likened to ‘sun poisoning’. This is a seasonal condition that appears through the spring-to-autumn months and results in intense itching or burning red vesicles that appear on the skin within 30 minutes of exposure to the sun.

For both these disorders there is no known cure and little in the way of treatment other than staying well clear of sunlight and living life in the shade – an unappealing prospect for many.

It’s these and similar disorders that Victorian-based biopharmaceutical, Clinuvel (ASX:CUV), has targeted with the development of its photoprotective drug afamelanotide, which is currently undergoing late-stage clinical trials in Australia and Europe. “In many ways we’re treating diseases that have never been addressed effectively before,” says Director and CEO of Clinuvel, Dr Philippe Wolgen.

Dark tan
Afamelanotide works by effectively giving a boost to the body’s natural defences against light – ultraviolet (UV) light in particular. This is especially important for individuals with light skin, who are particularly prone to disorders like EPP and PLE. “The Caucasian population – fair skinned, blue eyes, blond hair – are highly deficient in the UV response of their skin,” says Wolgen. “The risk borne by fair-skinned individuals is due to a deficiency of a specific receptor of the skin cell, MC1R, melanocortin 1 receptor. This is the master receptor that regulates pigment producing skin cells, melanocytes.”

People with fair skin fail to produce an adequate rate and quality of melanin, which constitutes the photoprotective pigmentation of skin and hence protects against UVA and UVB. “Most people with fair skin produce a reddish ineffective pigmentation, pheomelanin, but what you really want is the darker pigmentation, eumelanin, to protect against non-ionising radiation,” says Wolgen.

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Afamelanotide is an analogue of the natural peptide, alpha-melanocyte stimulating hormone (-MSH), which is normally released by skin cells in response to UV radiation, stimulating melanocytes to release melanin – i.e. giving you a protective tan. However, -MSH has a very short half-life, disappearing in a matter of seconds. Afamelanotide has a slight tweak compared with its natural analogue which gives it a more potent effect and a longer half-life.

The upshot is that when a patient is administered a subcutaneous implant containing afamelanotide, levels in the skin of protective melanin increase within a couple of days without needing any exposure to sunlight. It’s a tan that happens in the dark.

Besides EPP and PLE, afamelanotide is also being trialled for its ability to prevent a number of other photosensitivity disorders including squamous cell carcinoma (SCC), which are non-melanoma skin cancers, and actinic keratosis (AK), common precursors to skin cancers that look like dark flaky patches or bumps. The drug has been shown to prevent another rare and debilitating disorder, solar urticaria (SU), which is an anaphylactic reaction to light – sunlight and artificial lighting – resulting in painful itchy welts.

It can also be used alongside photodynamic therapy (PDT) for cancer. This is where the patient is treated by a potent photosensitiser and then has their tumours exposed to intense light, which kills the cancer cells. However, a side-effect of the treatment is extreme photosensitivity, meaning the patient must be kept away from light sources for three months following treatment.

Strategic decisions
Afamelanotide has already traversed much of the long road of clinical trials and is currently in phase III for EPP and PLE and phase II for SCC and AK. It also has orphan drug designation in the US, EU and Switzerland. And by all accounts, the trials are going well. So well, in fact, that a majority of trial patients in Europe and Australia as well as their physicians wanted to continue treatment with afamelanotide after the trial had ended. “That’s the most positive news we could expect,” says Wolgen.

But it also presented Clinuvel with a problem: the physicians wanted Clinuvel to continue to provide afamelanotide to their patients at no cost through a so-called ‘compassionate use programme’. “That’s difficult in a public company because you’re using your shareholders’ money to supply the drug free of charge.”

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However, Clinuvel agreed to supply afamelanotide beyond the end of the trials in Europe. “My personal view is that this business should be about doing something good for diseases and the rewards will come later,” says Wolgen.

Yet, ultimately, developing a new drug is a business, and that means occasionally tough decision will have to be made on pragmatic and economic grounds. Such as in the case of the decision in February by Clinuvel to defer trials for SU and PDT in order to focus efforts on getting afamelanotide approved for EPP and PLE.

Unlike EPP and PLE, which have no treatment, SU is currently treated with antihistamines, although with limited success. Yet, due to the nature of the regulatory process, it’s significantly harder to get a new drug approved when there is already a treatment for its specific ailment, even if that treatment is inferior.

“In the recent announcement where we looked at SU, we had an interesting phenomenon – a paradox,” says Wolgen. “We have a clinical community worldwide that supports use of afamelanotide in SU. However, the EU regulators expressed in meetings that they recognised the severity of the disease, but the first line of treatment would be antihistamines. The medical community doesn’t necessarily agree antihistamines are a first line therapy, but, currently, it’s a therapy by default because there is nothing else.

“We support that view. But, will you be able to compete with a tablet that costs a quarter of a cent to produce? The answer is probably not. So although there is a scientific rationale, and there is a patient and physician support, if you don’t think it’s economically viable in a smaller population, then it doesn’t make sense to prolong development in that application. This is one of the decisions you make as a company. It’s not always popular because patients don’t get the drug. But a public company is required to carefully balance out these decisions.”

That said, Clinuvel hasn’t abandoned SU altogether. Assuming success with afamelanotide’s application to EPP and PLE, the company may revisit SU in the future. “If, down the line, the medical community supports it, we’ll do it in sequence.”

This is emblematic of Wolgen’s self-proclaimed “realist” view about the pharmaceutical industry. “I’m very risk averse,” he says. “I’m not an optimist in this industry – it’s not an innate trait of mine, but simply dictated by the number of drug approvals.”

As such, Clinuvel has taken a pre-emptive stance when it comes to its trials policy. This means not waiting to hear those three fateful words from the regulator: “one more trial”, which can prove very costly – perhaps fatal – for some ventures. “We don’t want to wait for that before the results of the first phase III trial,” says Wolgen.

“We want a second and third trial in order to have no surprises at regulatory submission stage. The shareholders don’t always like it, because it means more expense or more delays, but they probably do agree that it is better to have a product approved in time than a regulatory rejection. I see a major change in the regulatory landscape, to the extent that drug safety is much more important than efficacy. Long term safety of a drug is dictating market access rather than whether a drug works. The FDA and EMA are very prone to show companies the door if the safety is not proven.”

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Bright future
2010 is shaping up to be an exciting year for Clinuvel. It is embarking on a second phase III trial on EPP in Europe, and awaiting FDA approval to start another in the US. It is also compiling the results of a recent confirmatory pharmacokinetic study held in the US. If all goes well, it could file for marketing approval in Europe before the end of this year.

Given the nature of afamelanotide, which targets very specific disorders, treated by a relatively specialist clinics, it also makes distribution of the drug more attractive and compelling than if it was a more mass market affair or if it had numerous competitors. As a result, Clinuvel is considering undertaking marketing and distribution itself, although it may also seek out a partner as well. One way or the other, the decision will be made shortly, says Wolgen.

If approval is forthcoming, it’ll not only be good news for those suffering from photosensitivity, but it’ll also be good news for Clinuvel’s shareholders. As well as an endorsement of Clinuvel’s management and its “realist” approach to achieving regulatory approval.

Not only was the decision made to conduct multiple clinical trials, but also to focus efforts on the application with the highest chance of success. Capital raising was also timed well, with most of the money for the development of afamelanotide raised in 2006 and 2007, before the GFC reared its ugly head. While the GFC did increase the cost of conducting clinical trials, and put a dent into the perceived value of the company, Clinuvel was able to push on with development relatively unhindered.

And even though Clinuvel spreads its operations between Australia, Switzerland and the US, it’s still quintessentially an Australian company. “One of the better decisions we’ve made was keeping the company here,” says Wolgen. “UV and skin cancer are a very Australia subject. Being an Australian company lends you instant credibility in this domain, in so many ways we are exporting our Australian know-how.”

This feature appeared in the March/April 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.