Stelara is likely to benefit from the fall of Raptiva however topicals continue to dominate

Psoriasis is a disease of the skin that affects millions of individuals worldwide. The therapeutic landscape for psoriasis is dominated by genericized and/or nonprescription topical therapy in terms of volume. In terms of value, however, the moderate to severe psoriasis market is bolstered by the use of biologics, first approved for use in psoriasis in 2003. Recent research into prescriber trends suggests that while biologics have made a significant impact in the treatment of psoriasis, topical therapies have not been displaced, especially in patients with milder disease; moreover the future may see moves towards improved phototherapy rather than greater uptake of biologics.

According to the 180 dermatologists interviewed as part of our recent feature Psoriasis - Biologics are yet to make topical treatments obsolete, psoriasis presentation and diagnosis patterns have remained constant over the past five years, indicating an essentially unchanged point of view among psoriasis sufferers. Psoriasis epidemiology is remarkable in that 54% of psoriasis sufferers are undiagnosed and this is because 80% of affected individuals have symptoms that are so mild that they never present to a physician. Even those patients that are diagnosed are not diagnosed immediately probably reflecting, at least in part the mild nature of the disease in many individuals. Of those patients that are diagnosed 36% of patients are estimated to be suffering from mild psoriasis, 38% from moderate psoriasis and 26% from severe psoriasis. Given that biologics are only indicated for moderate to severe disease it is clear why topical therapies dominate the market in terms of volume.

In stark contrast to the consistent epidemiological picture of psoriasis, treatment trends in psoriasis have shifted, reflecting payers’ and prescribers’ evolving priorities in terms of psoriasis. One ongoing trend is the choice of topical versus biologic therapy, a trend that is dependent on geography. Absence of approved biologic therapy in Japan leads to higher use of traditional systemic agents in this market. Elsewhere however the approval of biologics for the treatment of psoriasis has seen growth in this area, albeit of a hetrogenous and regionally varied nature. In the UK where biologics are available, NICE recommends that this class should only be continued if clinical improvement is demonstrated within 12 to 16 weeks. Elsewhere in Europe the estimated use of biologic therapy varies from market to market. Of course, the situation in the US is highly influenced by insurance companies seeking to control costs.

So what is the biologic of choice in psoriasis patients? On average, 41% European physicians surveyed in the abovementioned report prefer Raptiva (efalizumab) at first line, and 20% prefer Remicade (infliximab), despite this drug’s intravenous method of administration. EU physicians may have preferred Raptiva in 2008 because it had the longest history of use in psoriasis, but its recent withdrawal from the EU for safety reasons will create a significant space for other therapies, particularly Stelara (ustekinumab), approved in the EU in January 2009.

As highlighted in yesterday’s issue of DailyUpdates, Raptiva will be phased out of the US market over the next 3 months (press release). Genentech's decision was based on the association of Raptiva with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare and usually fatal disease of the central nervous system. The Raptiva prescribing information was updated in October 2008 to include a boxed warning on the risk of serious infections, including PML, in patients receiving Raptiva. There have been three cases of diagnosed PML in patients receiving Raptiva.

According to the National Institutes of Health (NIH), between 5.8 and 7.5 million Americans have psoriasis. Of these more than 3 million are believed to have moderate to severe disease and would have been candidates for Raptiva treatment. However, Genentech estimates that just 2,000 patients in the United States may currently be receiving Raptiva for chronic plaque psoriasis. Raptiva has been therefore occupied a very small market share reflected in the fact that it has been generating sales worth just $105 million. Instead, among US dermatologists, 60% prefer Enbrel (etanercept) at first line, followed by 26% of physicians preferring Humira (adalimumab). Physicians in the US and the EU rated Stelara highly in terms of disease modification, maintenance of efficacy and dosing frequency. Clearly therefore there is considerable potential for Stelara to capture a significant portion of the market however, payers’ enthusiasm for Stelara will be crucial to the drug’s success.

While systemic therapies have revolutionized the management of moderate-to severe psoriasis, topical treatment remains the foundation of psoriasis therapy. In mild psoriasis, physicians from all countries surveyed report that at least 82% received topical therapy alone. In the US and Europe, topical therapy usage declines with increasing disease severity. In Japan, lack of biologic therapy appears to sustain high usage of topical therapy across all disease severities. Phototherapy is a treatment option for patients with moderate to severe psoriasis who have not responded to topical therapies. This is particularly the case is Germany where physicians estimate that phototherapy should be used by 54% of patients. The mean percentage of patients recommended to use phototherapy in the four other European countries is 26%; nearer to the US figure of 17% and the Japanese figure of 20%. According to US opinion leaders, technological advances in home phototherapy units, in combination with the expense and safety signals associated with biologic therapy, may inspire renewed interest in phototherapy among payers and prescribers in coming years.

The psoriasis market thus continues to evolve. As some biologics such as Raptiva fall others, most prominently Stelera will rise...at least for the moment. The use of topical agents continues however to dominate treatment choices in patients with mild disease and therefore the psoriasis arena as a whole. Commercial success in the psoriasis market will continue to demand a clear understanding not only of regional trends but also unmet needs including improved biologics for severe disease and cheap and safe alternatives to topical treatment for mildly affected patients

For further details on the psoriasis market see:

Psoriasis - Anti-TNF's lead another indication
Psoriasis - Biologics are yet to make topical treatments obsolete
The World Dermatological Market Outlook, 2009-2023

The dynamic opioid analgesic segment continues to evolve – reformulation advances rapid acting and long duration analgesics

The treatment of pain continues to suffer significant unmet needs. One of the oldest classes of analgesics, the opioids, remains a large and dynamic one which has changed significantly over the past few years.

As described in today’s featured report, Forecast Insight: Opioids, the market value for opioids was reportedly worth $8.4 billion across the 7 major markets in 2007. Growth has continued at a CAGR of 4% and is expected to grow at this rate through to 2018 at which time the market is expected to be worth $11.9 billion. This is remarkable given current market pressures including price competition, generic availability, negative stigma, and the US Risk Evaluation and Mitigation Strategy.

One drug development concept central to the opioid class is reformulation. The development of new combination therapies and delivery forms is a relatively inexpensive development process thereby presenting accessible strategies to mid- and small sized drug delivery and development companies. The attractiveness of the class is amplified by the large patient base and comparatively low market entry barriers

Reformulation of established opioids offers a useful means of treating breakthrough pain (by developing formulation with a fast onset of action) or chronic pain (by developing extended release formulations).

OxyContin, Duragesic, Kadian, Avinza and Opana are all extended-release reformulations of opioids. Duragesic has suffered from product recalls as well as generic incursion and hence a decline in revenue. Generic equivalents of Duragesic have also suffered product recalls and so OxyContin is expected to enjoy a majority market share this year with sales of $3 billion expected across the 7 major markets.

Activity in the development of extended release formulations continues however and there is a current emphasis on reducing abuse potential, frequently through the incorporation of naltrexone, an opioid receptor antagonist. The launch of several oxycodone controlled release-based opioids with anti-abuse potential will erode OxyContin’s market share in the mid-term. Despite this it is unlikely that any individual anti-abuse opioid brands will gain blockbuster revenues. This reflects unclear demand from frontline stakeholders such as prescribers and patients, and the flood of brands set to enter the market. Moreover the development of anti-abuse opioids appears to be a US-specific trend in the pipeline.

Despite the fragmented nature of anti-abuse opioids, King Pharmaceutical’s anti-abuse opioid franchise does however look set to reach blockbuster levels with combined sales of Remoxy (oxycodone controlled-release), Embeda (morphine extended release and naltrexone) and the immediate-release opioid Acurox (oxycodone and niacin) forecast to generate around $1 billion per annum by 2018

Overall the long-acting opioids market is expected to grow from $5.0 billion in 2007 to $6.1 billion in 2018 across the 7 major markets.

Reformulations enabling rapid onset of analgesia have, like extended release formulation, also gained significant attention. In particular this is to satisfy the demand for improved treatments of breakthrough pain. Actiq and Fentora are fentanyl formulations with transmucosal and buccal routes of action respectively. Choices open to physician and patient are likely to grow as dissolvable and spray formulations advance through the pipeline.

While the current market for short- and rapid acting opioids is quite low ($771m in 2007), growth is expected with sales expected to reach $1.7 billion by 2018 in the 7 major markets, representing the strongest growth rate among the opioid market. This reflects new product entries in addition to an expected increase in Fentora sales should it receive approval for non-cancer pain. The FDA issued a complete response letter for this submission in September 2008.

Unlike the anti-abuse long-acting opioids, short- and rapid-acting opioids are being developed across all three major market regions (US, 5EU and Japan). Cephalon’s Fentora is expected to remain the market leading brand in the US, however experienced local marketing partners such as Meda (Onsolis, buccal fentanyl) and Nycomed (Instanyl, intranasal fentanyl) are expected to provide significantly more competition to Cephalon in what will become an increasingly fragmented European market

All in all the opioid market remains dynamic. Hopefully development will feed through to improved treatments of pain. This editorial is based on new data reported in our current feature: Forecast Insight: Opioids - Saturation limits the commercial potential of individual brands

Other recent market research and pipeline reports:

• Pain Therapeutics - Drugs, Markets and Companies
• Breakthrough Pain - Fast-acting players will capture majority market share
  
• Peripheral Neuropathy and Neuropathic Pain, 2008
  
• Pipeline Insight: Neuropathic Pain - Emerging drugs fail to capitalize in lucrative market
  
• The Global Pain Market, 2008-2023
  
• Pipeline and Commercial Insight: Neuropathic Pain
• Back Pain - Gain competitive edge by targeting subpopulations

Kicking the habit: Nicotine Dependence - where are we now and where are we going?

Although the dangers of tobacco use have been recognized for almost half a century, nicotine dependence continues to represent a serious global health problem. According to the World Health Organization (WHO), there are currently an estimated 1.3 billion smokers in the world and at the current rate; this figure is expected to rise to 1.7 billion by 2025.

The current nicotine dependence market consists of a wide range of over-the-counter products including various formulations of nicotine replacement therapies, yet only two specific prescription drugs are approved for this indication— Chantix/Champix and bupropion.

The unmet needs and commercial potential surrounding the smoking cessation market are reflected in a new report featured by LeadDiscovery: Pipeline and Commercial Insight: Nicotine Dependence - Chantix issues overshadow vaccine potential

Other recent products:

• Smoking Cessation and Addiction Treatments: A World Market Analysis
• The Global Anti-Addiction Market, 2008-2023
• UpdatesPlus Nicotinic Receptors - Current Research and Development
• Smoking Cessation Report, 2009-2024

Approximately 150 million people in the seven major markets are estimated to be current tobacco smokers. As a result of numerous anti-smoking campaigns and strict public bans, smoking prevalence rates in the US and UK have decreased steadily over the past decade. In contrast, with smoking remaining less stigmatized and far less regulated in Germany and Japan, rates have notably remained higher.

Chantix/Champix was launched in the US and Europe in 2006 and appeared to be not only revolutionizing the smoking cessation market but also fast growing into one of Pfizer's most successful products. Recent problems have however emerged with reports of suicidal ideation leading to a label modification reflecting this risk. In addition Chantix/Champix has been related to various and diverse accidents resulting in the FAA banning the use of Chantix by airline pilots. Overall US sales figures have fallen by approximately 50%. Combating negative publicity, Pfizer has been attempting to reinstate prescriber and patient confidence in Chantix by establishing a favourable risk-benefit ratio and emphasizing the requirement for improved patient screening and follow-up. While these efforts may reverse US sales trends, there remains a massive opportunity in the developing world. Remarkably, 60% of Russian and Chinese men smoke compared to 23% in the US and UK.

Those smoking cessation products that have been launched have succeeded because marketing efforts have paralleled government initiatives. This will continue to be the case and of note a new antismoking drive has been launched in India and this should offer an environment that companies such as Pfizer and GSK could harness. In addition Pfizer, in particular, has made a point of identifying those individuals most likely to want to stop smoking and targeting marketing towards this group. Of interest a study has recently opened in Asia aimed at identifying the characteristics of individuals seeking help in the cessation of smoking. Studies such as these should help break into emerging markets.

While Champix/Chantix and bupropion are both relatively successful in the short term, only a minority of individuals achieve permanent abstinence after an initial quit attempt. This represents one of the major unmet needs of currently available treatments. This problem exists in part because of sub-optimal treatments and also because the duration of existing therapies may be too short. This in turn relates at least in part to cost. Improving overall reimbursement/cost barriers should therefore have a significant impact on the success of future quit attempts;

So what is the future? Two relatively advanced smoking cessation vaccines are in the pipeline and both are being positioned as maintenance treatments. In other words they will hopefully be able to prevent relapse and should therefore stand side by side with current options that aid cessation. The smoking cessation market has grown 84.5% from 2004 to reach $1.35 billion in 2008 across the 7 major markets. If vaccines enter the market, the authors of Pipeline and Commercial Insight: Nicotine Dependence - Chantix issues overshadow vaccine potential anticipate the market growing to over $3.81 billion in 2018.

Nabi Biopharmaceuticals’ NicVAX is in line to become the first nicotine vaccine to enter the market. Assuming Nabi will secure a suitable development partner, NicVAX is expected to generate yearly 7 major market sales of almost $1.1 billion by 2018. Development of Cytos and Novartis’s nicotine vaccine NIC-002 is behind NicVAX’s. However, Novartis’ sales and marketing experience in the central nervous system and vaccines sectors bodes well for the launch of NIC-002 and yearly sales could reach $1.0 billion in the 7 major markets by 2018.

Whether a vaccine enters the market remains to be seen as both candidates have suffered development problems (for further analysis of these issues see LeadDiscovery’s recent issues of UpdatesPlus Nicotinic Receptors).

Lower Back pain: New therapeutic opportunities open up for a “new” indication

An estimated 129 million adults suffer from back pain across the seven major markets.

Despite the size of this group of conditions, back pain remains an unmet clinical need characterized in equal measures by developmental challenges and market potential. No therapeutic agents have been specifically indicated for back pain and until recently the regulatory bodies have not even viewed the condition as a specific indication.

Our latest feature “Back Pain - Gain competitive edge by targeting subpopulations” sets out to examine key issues and unmet needs in the diagnosis and management of back pain. The report provides a thorough review of etiology, epidemiology, diagnosis and current treatment options. The report also explores potential commercial opportunities for companies intending to either penetrate, or increase, their share in this competitive market. Analysis is supported by interviews conducted with key opinion leaders in the US and Europe.

For free sample pages contact leaddisc@leaddiscovery.co.uk

Recently published reports in pain:

• Pain Therapeutics - Drugs, Markets and Companies
• Peripheral Neuropathy and Neuropathic Pain, 2008
• Pipeline Insight: Neuropathic Pain - Emerging drugs fail to capitalize in lucrative market
• CNS Market Overview - neurology, pain and psychiatry
• Pipeline and Commercial Insight: Neuropathic Pain
• The Global Pain Market, 2008-2023
• Commercial Insight: Pain Market Overview - Non-traditional analgesics and opioid reformulations to sustain sector growth

Custom analyses of the pain market and pipeline are available on request

The most important unmet need in the treatment of back pain to emerge from opinion leader interviews is for more targeted treatments. Therefore, the challenge to researchers is to provide evidence of which treatment, if any, is of most benefit for subgroups of patients with back pain. In order for this unmet need to be addressed, greater investment in basic science research is required to further our understanding of pain mechanisms.

Broadly speaking however back pain can be split into acute and chronic pain. Two areas of chronic pain under investigation are neuropathic back pain and breakthrough chronic back pain. Targeting back pain subpopulations represents a viable strategy and neuropathic back pain which affects an estimated 18 million adults across the seven major markets represents one such lucrative subpopulation.

Although targeting back pain subpopulations is viable, of the numerous companies are targeting neuropathic pain indications, to date no one product has a specific label for neuropathic back pain. Moreover, few pipeline drugs appear to be to be in development for this condition. This may in part be due to the regulatory bodies failing to recognize neuropathic back pain in its own right; it may also be due to the complexity of diagnosis.

Cephalon has tried and so far failed in breakthrough back pain with the FDA issuing a complete response letter relating to Fentora and its risk management program. Lilly has demonstrated that Duloxetine reduces back pain in individuals with depression. More directly, efficacy has also been reported in a Phase 3 chronic back pain trial with pain scores reduced by 2.4 points from baseline compared to 1.4 points on a standard 10-point rating scale. This effect was significant. Whether Lilly intends to file for a back pain label remains to be seen.

Most recently, Newron announced just this week that it has randomized the first patients to treatment in SERENA, its first phase IIb/III study of ralfinamide in patients with moderate neuropathic low back pain. Newron's ralfinamide now has the potential to become the first drug approved for the treatment of neuropathic low back pain. Ralfinamide is believed to mediate analgesic and anti-inflammatory effects through the modulation of ion channels implicated in pain and the inhibition of substance P.

A small Phase II study has previously shown that 33% of neuropathic low back pain patients demonstrated a 50% improvement following treatment with ralfinamide compared to 10% in a placebo group.

SERENA is one of potentially two large studies that will evaluate the safety and efficacy of ralfinamide compared to placebo. The study is a 12-week randomized trial being conducted in Europe and Asia that will randomize approximately 400 patients with chronic neuropathic low back pain. The primary efficacy measure of the trial will be based on the 11-point Likert Pain Scale. Secondary efficacy measures will include patients’ self ratings of the Visual Analogue Scale as well as responder rates. Patients who complete the 12 weeks of treatment will be eligible to enter a double-blind 40 week extension

Newron is anticipating SERENA data in H1 2010 and in the meantime is expecting to partner, presumably to conduct a similar study in the US and to passage through registration.

During the development of Ralfinamide various health authorities agreed that neuropathic low back pain would be treated as a specific indication. This and the headway being made by Newron suggest that other companies in the pain arena will also focus on back pain. This should hopefully result in new, and much needed treatments becoming available to patients by around 2011.

A tour around tuberculosis: The problem and its solution

Tuberculosis (TB) infects nearly 15 million people worldwide and causes the death of 1.7 million each year. Individuals, especially in Southern Africa are commonly co-infected with TB and HIV, a combination with very poor prognosis. Having been largely ignored until recently TB is currently receiving significant attention from both NGOs and also industry. The latter is evaluating new vaccines as well as second line treatments of TB. The pharmaceutical sector has been playing a significant part in the combat of HIV infection in the developing world for the past decade; it is now expected to follow suit in the related area of TB

For a detailed analysis of opportunities and development in the field of TB see our brand new feature Tuberculosis - Development pipeline shows signs of life or read on

Incidence

TB is a major cause of illness and death worldwide, especially in Asia and Africa. Globally, 14.4 million prevalent cases of TB, 9.2 million new cases and 1.7 million deaths from TB occurred in 2006. India and China have the highest incidence of TB worldwide; Asia and the Western Pacific account for 55% of global cases of TB

Sub-Saharan Africa also has a high incidence of TB accounting for 31% of global infection. In this region coinfection with HIV represents a massive problem. TB infection is found in over 50% of all new cases of HIV infection in Southern Africa and this results in a dramatic worsening of prognosis.

The seven major markets accounted for relatively small fractions of global cases and incidence has
been declining sharply in these countries over the last few decades and this has been accompanied by a fall in commercial incentives for pharmaceutical companies to invest in antituberculosis drug research, which has resulted in a paucity of new drugs.

Growing intent to treat supported by NGO efforts

Large pharma has however been showing an increasing appetite to treat developing world prominent disease and in particular companies have been lowering the cost of HIV treatment. This has been accompanied by significant efforts from NGOs and consequently two landmark documents in global TB control were launched in 2006: the Stop TB Strategy and the Global Plan to Stop TB.

The primary NGO aims are to increase detection and to improve treatment and a central component of these strategies is known as DOTS (directly observed treatment, short course). To ensure thorough treatment, it is often recommended that the patient takes his or her pills in the presence of someone who can supervise the therapy. In addition to implementing uptake of DOTS, major efforts are underway to increase TB detection and treatment

Detection
Despite the enormous global burden of TB, case detection rates are low, posing serious hurdles for TB control. The definitive diagnosis of TB requires identification of the mycobacterial pathogen in a patient’s secretions or tissues. Identification of the organism is necessary for drug susceptibility testing which further guides selection of treatment regimens. Conventional TB diagnosis continues to rely on tests such as sputum smear microscopy, culture, tuberculin skin test, and chest radiography. These tests have several limitations and perform poorly in populations affected by the HIV epidemic. Furthermore conventional tests for detection of drug resistance are time consuming, tedious, and inaccessible in most settings. In industrialized countries, newer technologies such as interferon gamma release assays for the diagnosis of latent infection and nucleic acid amplification tests and liquid culture for diagnosis of active TB disease are being increasingly used. However such tests have not been implemented in high-burden developing countries to any significant degree, mainly because the level of sophistication and cost that has, to date, made their routine application unfeasible.

Vaccines
The current TB vaccine, bacillus Calmette-Guerin (BCG) is a live vaccine that protects against severe childhood forms of disease. It also confers protection against leprosy. However it does not prevent the
reactivation of latent TB, the main source of mycobacterial spread in the community. Given the limitations of the current BCG vaccination, several novel vaccines and strategies are being investigated for both prevention and treatment of TB.

Replacement of BCG with a more effective vaccine that provides lasting protection, a new vaccine for adolescents/adults that prevents adult pulmonary TB, and an immunotherapeutic vaccine could each provide improved approaches. Given the wide use of the BCG vaccine, particularly in the developing world, a prime-boost strategy using a new TB vaccine candidate to boost the BCG vaccine is considered the best way to test and introduce new TB vaccines into endemic countries.
Public-private partnerships have been the strongest force driving TB Vaccine development. For example the Aeras Global TB Vaccine Foundation which receives NGO funding currently works on six candidate vaccines. Aeras is developing these through collaborations with companies like Crucell, GlaxoSmithKline, Sanofi Pasteur and several others. The vaccine candidates include BCG strains that have been genetically manipulated to express immunodominant antigens (recombinant BCG) and several non-living vaccines

Treatment

Although the current tuberculosis treatment regimens are highly effective they are far from ideal. Many of the drugs used have side effects and even with the optimal combination of the available drugs, the duration of treatment required for curing patients cannot be reduced below six months. As a result these regimens are associated with high rates of non-adherence leading to drug resistance and increased morality. The rise in multi drug resistant and extensively drug resistant strains has also
caused concern, particularly in the developing world. Conventional short course antibiotic therapy has remained the mainstay of treatment for tuberculosis for several decades.

In 2007 the global TB antibiotics market was worth approximately $300 million with a CAGR of 2.2% from 2004-2007. Given the low incidence of TB in the seven major markets, they accounted for approximately 40% of total sales, the balance was accounted by the rest of world which includes the majority of the high burden countries.

The classes of anti-tuberculosis drugs have traditionally been divided into first and second-line drugs, with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin being the primary first-line drugs. The most frequently recommended and effective combination is isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months followed by isoniazid and rifampicin for 4 months.

Currently second line therapy represents the area with the greatest commercial opportunity since many second line drugs have greater toxicity and in the case of XDR-TB, they are simply ineffective. Newer drugs that can substantially reduce the duration of therapy and have activity against multi drug resistant and extensively drug resistant TB strains have a strong chance of gaining commercial success. Currently the products that are being investigated include the fluoroquinolones gatifloxacin and moxifloxacin, Tibotec/Johnson & Johnson’s TMC207, Chiron Pathogenesis/TB Alliance’s PA824, Otsuka Pharmaceuticals’ OPC-67683 and Sequella’s SQ-109.

Related reports:

• Commercial Insight: HIV - Reshaping Treatment Paradigms
• The Global HIV/AIDS Market Outlook to 2012
• HIV Therapy: Prescription trends, Markets and Unmet Needs
• Pipeline Insight: HIV - Novel NNRTIs address crucial unmet need
• HIV: Markets for Diagnostics and Therapeutics