INTERVIEW: Clinuvel's Scenesse and the patient factor in drug assessments
This article was originally published in SRA
Not many pharmaceutical executives would take credit for helping to steer the European Medicines Agency in a particular direction when it comes to assessing new innovative medicines. But that's what Philippe Wolgen, CEO of the Australian rare diseases company Clinuvel, claims to have achieved when he decided to seek EU approval for the ground-breaking phototoxicity drug Scenesse with the close involvement of patients and physicians.
Scenesse, an orphan drug containing afamelanotide, was approved by the European Commission in December 2014 for the treatment of adults with erythropoietic protoporphyria (EPP), a rare genetic disorder characterized by extreme intolerance to light that affects some 10,000 people worldwide1.
As well as being a first-in-class drug for a previously untreatable condition, Scenesse was the first product for which the views and experiences of patients were formally integrated into the EMA's decision-making process, by involving them in discussions on the benefits and risks of the product at the EMA's main scientific committee, the CHMP.
Dr Wolgen says that his company's approach to the evaluation of Scenesse played a part in the EMA's shift towards giving patients a more formal role in new drug assessments, which culminated in last October's announcement that the agency was to run a new pilot project whereby patients could be invited to take part in product-specific discussions at the CHMP on a more regular basis2.
This was a major step forward for the EMA. The agency had been encouraging patient involvement in its work since the early 2000s, and patients had contributed to benefit-risk evaluations through their participation in scientific advisory group and ad hoc expert group meetings. However, they had not taken part in actual benefit-risk discussions at CHMP plenary meetings. Under the new pilot, patients invited to CHMP meetings will be able to take an active part in the discussions, ask the company questions, and so on, although they will not play any part in the decision-making process.
Dr Wolgen dates the genesis of this development to 2007, when Clinuvel began talking to the agency about Scenesse and how a novel therapy for an unmet medical need should best be evaluated. The company's primary challenge was how to engage patients, expert physicians and academics in a proposed novel therapy with an innovative mode of action. One way to do this, Dr Wolgen said, was to get the EMA to listen to those experts and patients, and this was something that Clinuvel began to press for from 2009.
Dr Wolgen says things gathered pace when Guido Rasi took over as EMA executive director in November 2011. Professor Rasi was forced to step aside in November last year, just three years into his five-year tenure, as a result of a civil service tribunal ruling that resulted in his appointment being annulled on procedural grounds after a fellow candidate for the job filed a conflict of interest complaint.
Dr Wolgen considers this a great loss for the agency. He says that while the debate about the way the appointment was made may be procedurally right, "it shouldn't cause a man of that stature to have to leave; it is a loss for the entire European pharmaceutical sector". He added that "we usually are very quick to criticize regulators, but one should also acknowledge the good when one comes across it".
The eventual result of Clinuvel's efforts was that it "became the first company where patients were called to a plenary session of the CHMP, in September 2014," Dr Wolgen says3. "Until then, there had been no cases where patients could be heard in the same room as the CHMP. We were called to the meeting to present our case and the data on the drug, and then we were sent out of the room where the CHMP held its deliberations with patients and physicians behind closed doors. So pharmaceutical history was written."
Looking in from the outside, Dr Wolgen continues, "you could say, 'Isn't this to be expected, to get those affected by a disease to talk to the regulators?' The answer is of course, yes, it's logical, but legislators and administrators are risk averse and take a long time to adopt novel methodology."
So was the agency's shift towards closer patient involvement really driven by the Scenesse application? "Absolutely, we know it was. For two and a half years we had been deliberating and debating, and things had been polarized. We said to the agency you can't review a novel methodology, chemistry, novel formulation, a novel disorder, something you have never evaluated, without actually hearing the patients and physicians. In the end, in the last six months, they converted to the same opinion."
What do patients and doctors want?
Dr Wolgen, who trained as a craniofacial surgeon and took over as CEO of Clinuvel in 2005, says that the Scenesse experience reflects his company's general philosophy about drug development. He believes that decisions on whether to develop a particular drug should not be based on what the company wants to do, but on what its eventual users and prescribers actually need. And to find that out, you need to consult them and keep them on board through the drug development process.
"It should not be industry that dictates what drugs should come to market," he says. "So in that sense we have operated this company very differently from other pharmaceutical companies."
To support the drug development program, Clinuvel went to great lengths to rally expert opinion behind the product. "In the very classical and old-fashioned way, you would bring the board and the management team together and say now we will find a solution for a disease. We did it slightly differently. We said you might have a technology that is safe and effective, but do patients and physicians actually want the drug?"
To find out, the company set out to locate "all the porphyria experts in the world" and invited them to a conference to discuss EPP patients' need for therapy, the severity of the disorder, the disabilities faced by the patients, and so on. Patient bodies were brought in too at that point. "Early on we understood that it is not a case of some managers trying to set down the program – it needed to be driven by academics and patient associations."
The company also took care to keep the academics on board throughout the development process, and to take their views into account at every stage. "We always went to the head of the centre and said 'do we absolutely need to develop this drug for the next 10 years?' Then later we got them together after each study and asked whether we should continue development. That meant they were empowered. If only a small percentage of physicians had said no, we would have stopped the program. But there was unanimous support."
Another benefit of this approach is that the company can be confident that its product will be used by those it is intended for. "You have support from the doctors who will be your prescribers after approval," Dr Wolgen observes. "The problem that you often see in orphan drug development is that you might get a drug approved, but if no one wants to prescribe or reimburse it, then you don't have a product. In this climate, you have to be absolutely certain there is a need for a product."
The approval process
With the EMA putting a stronger emphasis on a risk-based approach to drug approval, more and more innovative drugs for unmet needs are taking special routes to the market, and Scenesse is no exception.
It was recommended by the CHMP for approval under the "exceptional circumstances" rule, which is designed for use where the condition treated is so rare that company is unlikely ever to be able to provide comprehensive data on the product, or where it would be unethical to gather that information.
EPP is a rare and unusual disease that is triggered by exposure to light, and those affected tend to stay indoors and may lead something of a reclusive existence. If they do expose their skin to daylight they can experience second degree burns, swelling, burning, itching and redness of the skin. Other than avoiding daylight, there have been no treatments available – until now.
The active substance in Scenesse, afamelanotide, is a chemical analogue of alpha-melanocyte stimulating hormone that increases the melanin content of the skin without exposure of the skin to the damaging effects of ultraviolet radiation. Development of Scenesse as a dermatological drug in at-risk individuals began in 2005, and the following year the company commenced a clinical program focusing on EPP.
The product, which is delivered via a subcutaneous dissolving implant about the size of a grain of rice, was tested in five trials in around 350 adult patients across Australia, Europe and the US, and was filed for EU approval in February 2012. The CHMP's positive opinion in October last year was followed by a European Commission marketing authorization in December. Many trial subjects went on to receive the product under compassionate-use programs.
The CHMP said the benefits of Scenesse were a reduction in light sensitivity and a consequent limited increase in the time patients can spend in daylight or sunlight. Although the additional time spent in sunlight was small, it took into account the possible improvements in quality of life, the unmet medical need in patients with EPP, and the mild side effects seen during short-term treatment with the medicine. The most common adverse events were nausea, headache and implant site reactions, although there were side-effects too - the most common being headache, nausea, nasopharyngitis, migraine, abdominal pain, fatigue, lethargy and somnolence.
At the beginning of the development program for Scenesse, Clinuvel had been unsure whether to take the "exceptional circumstances" route or to seek "conditional approval", where a product is allowed on the market on the condition that more data are generated, after which the temporary approval can be converted into a full one.
"We were confident in the safety of our product, but we weren’t sure about efficacy, so we talked to the agency about this early on," Dr Wolgen says. "We asked how you measure the impact on the patient's life, as it is light particles that trigger the condition, and there is no other condition where this happens, so we had a big debate on efficacy."
It soon became clear which avenue the company should take. With Scenesse, there was always going to be a lack of robust efficacy data because of the difficulty of conducting placebo controlled trials and the fact that patients are unwilling to expose themselves to too much sunlight for fear of developing the symptoms of phototoxicity.
In the Phase III trials, Clinuvel assessed changes in patients' ability to spend time in direct sunlight without pain and the improvements in quality of life. "We measured the hours or minutes per day that patients dared to go outside, particularly in the spring and summer. We measured their quality of life when they started the trial and when they completed it," Dr Wolgen said.
However, "we said we don't think we will ever be in a position to provide comprehensive data, simply because there are no scientific instruments to accurately measure the number of photons per day, so in the end they accepted it wasn't ethical to require patients to go outside and get burned, and that there were no instruments to measure the effects. That is what led to exceptional circumstances approval. That fits as we will monitor patients long term, but we can't generate any more data."
Under the exceptional circumstances rules, Clinuvel is setting up a post-marketing program to monitor ongoing safety and efficacy, which will include the establishment of patient and disease registries. A Phase IV pharmacokinetic study in 12 EPP patients will also be conducted, in accordance with the pharmacovigilance plan developed by the company and the EMA.
The company
As well as breaking new ground by insisting on the key role of patients and physicians, Clinuvel took a slightly unorthodox approach to securing investment and building up a strong and loyal development team.
Like all small companies embarking on the development of a novel drug, Clinuvel had need of outside funding. As a former equity analyst who had held positions in private pharma firms in Europe, Dr Wolgen was instrumental in raising US$86m to fund the Scenesse development program.
He says he sought out "a unique pool of investors who had the same vision and shared the same strategy". They were what he calls "exotic – some are not from the life sciences at all, we have tech investors, the founders of Facebook, some pension funds. The investors who put their money into this development are uncharacteristic for life sciences."
Why? The company had a firm vision for where it wanted to take the product and how it wanted to bring it to market. Historically, Dr Wolgen says, Scenesse had attracted attention because "everyone thought that, as a tanning agent, it could be the next Botox – but we were absolutely against the use of this product as a beautifying cosmetic. Most life science companies are agnostic as to the use of their product, and the more money they make the happier they are. If you discover the next Botox everyone jumps on it, but by definition we didn't want these investors in the company."
Clinuvel also needed a strong development team to see the program through, and as with the choice of investors, the company was clear about the kind of people it wanted on board. "It was clear in 2005, when we recapitalized the company and turned it around and repositioned it, that we needed to have a group of unique individuals. Typically you would find drug development people in other pharmaceutical companies, that is how this industry works, with a lot of cross-pollination."
Clinuvel went about things differently. "Half of our people have no pharmaceutical industry background and come from totally different walks of life, but they all have a very entrepreneurial and can-do attitude, and that is pretty refreshing in this industry." The company does, he says, have some people who worked for some time in the pharmaceutical area, but "they were selected for their aptitude and attitude, rather than their CV".
Its core group has now been with the company for seven years, and the key managers for around 10, which Dr Wolgen believes is a result of giving people responsibility and a sense of ownership. "I pay a lot of attention to the retention of staff, as that is where knowledge can leak. You want the skill set to stay in house, not to go out of the back door. We incentivize people well, I would say slightly above the market, and we give them a lot of responsibility at a young age."
He says that the employees took ownership of the project and that much of its success was due to the attitude of the company's board members. "I had a board that supported this strategy, whereas most conservative boards would say 'are you mad?' You do need the most senior pharmaceutical professionals in a company, we had a few of those, but the majority were people with a wonderful attitude, and that goes a long way."
Pricing and reimbursement
It's one thing getting a drug approved, but quite another persuading doctors to prescribe it and payers to fund it, and in recent years of course companies are increasingly signing up to access deals such as pay for performance agreements where expensive novel products are involved.
In the case of Scenesse, Clinuvel found a way in via compassionate-use and special access schemes. "We had a fortunate breakthrough in 2010 as demand from academics and patients was very high, and that led to special access schemes in Italy and Switzerland, which meant that the regulators accepted the product and agreed to full reimbursement," Dr Wolgen says.
"We began with compassionate use by giving patients the drug free of charge for a year after the trial, and once this program finished, patients and doctors wanted to continue with it. They went to the regulators and insurance companies to ask for treatment to carry on and this led both governments and agencies to say yes, in 2010 in Italy and in 2011 in Switzerland." In May 2010, in fact, Scenesse became the first dermatological drug to be listed under the Italian 648/96 law, allowing doctors to prescribe the as yet unauthorized product to individuals with EPP, with the cost of the drug being reimbursed by the Italian national health system.
This means that over the past few years Clinuvel has gained experience in what payers want and expect from the drug, and is now approaching other European countries to discuss pricing and reimbursement.
P&R will always be an issue where medicines – particularly expensive orphan drugs – are concerned. Public awareness of the costs of novel drug therapy has been heightened in recent years by the astronomical price tags on drugs such Alexion's Soliris (eculizumab). Highly effective they may be, but how can healthcare systems bear the cost?
The best way to approach the P&R authorities is to define the disorder well, define the symptoms, and look at the returns you need to generate, says Dr Wolgen. "You need to be cognizant of the fact that you need to have a fair price for the population you are going to treat, and it needs to be in balance with other disorders of a similar ilk. You should be looking at the benefits of the drug for patients, what it can do that could not be done before, how many patients you expect to take it per year, and whether that meets your need to recoup what you have spent on developing it."
In the case of orphan drugs in particular, he cautions against having excessive financial aspirations. "If you are going into an orphan drug development program because you want to command the highest prices, you have already made a strategic error. There are a number of companies that have said openly they are going into orphan drugs as orphan pricing is so attractive. This is disproportionately taking advantage.
"However, if you believe there is a need for the drug and you can generate sufficient returns for 10-11 years of investment, that model stands up and this is what you should discuss with the insurers."
Asked about the price he is seeking for Scenesse, Dr Wolgen suggests it will be on a par with other products with a similar profile. "It needs to be in line with hematology drugs and those for chronic and orphan diseases with repetitive use and where the impact on the quality of life is one of the highest – for example, no normal existence versus normal existence, choice of career, impact on children, teens and adults, and so on. You find that with some diseases like hemophilia it is the same risk profile."
Where next for Scenesse?
Now that it has secured approval for Scenesse in Europe, Clinuvel has its sights set on several other markets, although its global reach will be limited by local conditions and differences in the prevalence of EPP around the world.
In the US, where a Phase III study was completed in 2013, the company plans to submit much the same data package as it did in the EU, and is currently hoping to meet the Food and Drug Administration in the first or second quarter of the year to explain the "exceptional circumstances" approval in Europe. "Then we will see how they view our data package, and we will know when we can file, but I believe that the US will have to adopt a very different review process than usual."
It will also be filed in Switzerland and Australia for EPP, "but that's it. We will probably not file anywhere else". The choices, Dr Wolgen explains, are defined by local conditions. In Latin America, for example, the EPP population is very dispersed, and there is no community of experts as such. There are some experts in Argentina and Brazil, but it is difficult to get a comprehensive dossier together with no patients taking the drug there. And even if the company could get clinical trials going, compliance would be a problem because of the long distances involved in traveling to the nearest centre. "It is not out of the question, but it is very difficult."
Clinuvel is also pursuing the approval of Scenesse in a second indication, vitiligo. Another skin-related disorder without any known cure, vitiligo affects some 45 million people, mainly with darker skin complexions, and is characterized by the appearance of lighter depigmented patches of skin.
Here again, the approval strategy depends on local factors, as vitiligo is seen mainly in North America and Asia. "We are starting in the US as there are more experts there, before we go to Asia. We did the first trial in the US, which was very successful, and now we are doing a trial in Singapore." Dr Wolgen says Singapore has an "interesting demographic mix of Chinese, Indian, Malaysian and Eurasian people, all with different skin complexions".
Beyond that, the company is looking at other indications for Scenesse, including Hailey-Hailey disease (which causes the eruption of plaque-like lesions and ulceration in skin folds), polymorphous light eruption (PLE), skin cancers, and solar urticaria. It is also investigating other products from the same family as Scenesse, one of which is CUV9900, a melanocortin that has shown promise as a skin protectant.
Meanwhile, just weeks after the EU approval of Scenesse, Clinuvel opened a new facility in Leatherhead, UK, which will be the company's main distribution centre for European markets, and its first presence in the country. Dr Wolgen says the location was chosen for its proximity to London and its two major airports (Heathrow and Gatwick). "We are hiring and have already placed some people there, we are quite excited, it's a nice part of the world," he said.
Amid the growing political debate over the future of the UK within the EU, this would also seem to be something of a vote of confidence in its continuing EU membership. "You always need a presence in the EU. We looked at many countries, and the choice is very limited. There are 28 countries, but only one or two where you want to be. The UK was an easy choice."
References
- European Commission, Community register of medicinal products for human use, website accessed 3 March 2015, http://ec.europa.eu/health/documents/community-register/html/h969.htm ]
- EMA, Pilot phase to involve patients in benefit/risk discussions at CHMP meetings, 23 October 2014, www.ema.europa.eu/docs/en_GB/document_library/Other/2014/09/WC500173509.pdf
- Orphan drug kicks off EMA project to involve patients in benefit-risk assessments, Scrip Regulatory Affairs, 29 September 2014