UK recommendation for Merck's Simponi but it may struggle to make an impact in the rheumatoid arthritis market

For further information on the rheumatoid arthritis market:

• Stakeholder Insight: Rheumatoid arthritis
• Pipeline Insight: Disease Modification in Rheumatoid Arthritis - New drug targets compete in crowded market

The National Institute for Health and Clinical Excellence has recommended Simponi for psoriatic arthritis. Based on this, Datamonitor believes that the drug will gain further positive recommendations in other rheumatology indications. However, while Simponi does have dosing advantages over other approved biologics, it is unlikely to make a huge impact on the UK market.

The recommendation of Simponi (golimumab; Merck & Co.) for the treatment of active and progressive psoriatic arthritis (PsA) represents a u-turn by the UK's National Institute for Health and Clinical Excellence (NICE). Having previously issued negative draft guidance, NICE's newfound faith in the drug is based on a review of additional information. This is positive news for Merck & Co., although NICE is yet to issue the final guidance to the NHS (likely due by April 2011).

Simponi represents the fourth tumor necrosis factor (TNF) inhibitor to become available for psoriatic arthritis in the UK, following in the wake of Enbrel (etanercept; Amgen/Pfizer), Remicade (infliximab; Johnson & Johnson/Merck), and Humira (adalimumab; Abbott). However, the recommendation comes with the condition that Simponi should be used in the same way as other TNF inhibitors, namely after patients have failed two prior traditional disease-modifying antirheumatic drugs, administered either individually or in combination. NICE arrived at this conclusion after deeming that there was no clinical evidence to distinguish Simponi from its competition. Furthermore, NICE has demanded that Merck provide the higher 100mg Simponi prefilled syringe at the same price as the 50mg dose. Explaining this, the Appraisal Committee felt that Simponi was not as cost-effective as Enbrel, and that the 50mg dose had acceptable comparability to Remicade and Humira.

NICE is still reviewing Simponi for ankylosing spondylitis (AS) and rheumatoid arthritis (RA), with outcome dates expected in October and June 2011, respectively. The PsA recommendation bodes well for Simponi in these additional indications. Indeed, the potential recommendation in RA may well mirror what happened in PsA.

In October 2010, NICE did not recommend Simponi for the treatment of RA in patients who have had therapy with a TNF inhibitor and for whom rituximab is appropriate, placing it further behind recent entrant and close competitor Cimzia (certolizumab; UCB), which was approved for RA under a cost-sharing scheme in February 2010. While Cimzia was approved ahead of Simponi in the UK for RA, Merck wisely submitted Simponi for RA, PsA, and AS in the EU simultaneously (Cimzia is still in Phase III for PsA and AS). Together with its monthly subcutaneous dosing, this may generate advantages for Simponi in all three indications.

Datamonitor forecasts that, if approved, Simponi could generate RA sales of over $20m by 2019 in the UK. However, opinion leaders have warned that as a new drug Simponi may not be a preferred agent in RA or indeed in PsA, with rheumatologists likely to remain loyal to established, tried and tested brands.

What effect will the availability of HPV vaccines really have on cervical cancer

According to Epidemiology: Cervical Cancer, during 2010, it was estimated that 35,898 women will develop cervical cancer in the seven major markets. Of this number 13,170 cases will have been in the US and approximately 18,000 in the EU5.

The good news is that between 2010 and 2020, total cervical cancer incident cases in the seven major markets are expected to decrease slightly by 4%. This change is due to This weak decreasing trend is due to forecast decreases in incidence rates alongside forecasted increases in the most susceptible populations.

One recent advance that should contribute to a gradual fall in the numbers of women suffering cervical cancer is the availability of HPV vaccines.

HPV is the primary cause of cervical cancer and two vaccines have recently been made available to prevent infection with HPV.

Merck and its European marketing partner Sanofi-Pasteur launched Gardasil in the US and Europe in 2006. This was followed in 2007 by GSK's launch of Cervarix in Europe and later in 2010 in the US (see Infectious Diseases Vaccine Market Overview for more on the vaccine market).

The ultimate success of HPV vaccines in reducing the incidence of cervical cancer will be dictated by uptake. It is believed that uptake of about 80% is required for "herd immunity" - in other words 80% of girls in the target age range must be vaccinated to drive the eradication of HPV.

UK Department of Health figures suggested that by 2009, approximately 70% of 12-to-13-year-olds in England had been fully vaccinated. This high uptake is due in part to full state funding of the vaccine. The HPV vaccine is offered free of charge to the target population in Germany, Italy and the UK.

So, good news in some of the largest EU countries but elsewhere in Europe the picture is not as good. In France 65% of the cost is borne by the social security scheme and a recent report in the March issue of the Journal Vaccine by Fagot et al reports that just 33% of girls of the age of 14 years in 2007 and 24% in 2008 were reimbursed for required 3 doses of HPV vaccine.

This low rate of reimbursement is reflected in reports last year of low uptake. According to a Parisian study, reported by Rouzier and Giordanella, HPV vaccine coverage for female adolescents is around 17%, with less than half of girls vaccinated receiving all three doses.

According to the cervical cancer epidemiology report France has one of the lowest incidences of cervical cancer in Europe but based on the current uptake of HPV vaccine this may not continue to be the case.

Ipilimumab continues to push forward expectations for the treatment of melanoma

Exciting news has emerged from BMS on its anti-CTLA-4 mAb, ipilimumab. The antibody has met its primary endpoint, overall survival, in a study looking at first line treatment of metastatic melanoma. The level of improvement in overall survival has yet to be disclosed. Data will be presented at ASCO this year.

Ipilimumab is currently under review around the world but for patients with later stage disease that has already been treated. Pivotal data from NCT00094653 reported that ipilimumab improved median overall survival by close to four months in those with previously treated melanoma, compared with an experimental therapeutic cancer vaccine, gp100, which has been extensively tested in the disease. Median overall survival for ipilimumab alone was 10.1 months versus 6.4 months for gp100 alone. A US decision on whether to approve ipilimumab based on these data has been set for March.

If given the go-ahead, ilipimumab could become the first new therapy approved for melanoma in more than a decade in the US. EU approval of the product in this indication is also anticipated for this year.

Currently, most melanoma is diagnosed at an early stage, with surgery proving curative in many patients. For advanced disease, current treatment options are inadequate, with only three approved drugs: interferon alpha-2b in the adjuvant setting, and dacarbazine and interleukin-2 for metastatic disease. Most patients are therefore treated in clinical trials.

Approved products for melanoma confer only mediocre response rates with minimal effects on survival, and high levels of toxicity, thus restricting their use to certain patients. Unmet needs therefore prevail, highlighting the urgent need to develop novel therapeutics offering significant clinical improvements over existing treatment options.

Depending on the final first line data it is inevitable that BMS will file for a first line indication.

The possibility of filing as a first line therapy has led to share prices peaking at an increase of 6% and Credit Suisse analysts raising their expectations for the drug. A proce of $30,000 per patient per year had been placed on ipilimumab but analysts predict that a first line indication could double this figure leading to peak global ipilimumab sales of in excess of $2 billion.

For further reading on the melanoma market see:

Stakeholder Opinions: Melanoma

Melanoma - Drug Pipeline Analysis and Market Forecasts to 2015

Pipeline Report - Neuronal alpha 7 nicotinic receptors: Candidates for the treatment of Alzheimers disease and Schizophrenia

To order this order click here

Neuronal nicotinic receptors (nAChR) have been gaining interest over the past decade as a potential target for both therapeutic and, more recently, imaging agents. Various peripheral disorders such as inflammation are now being encompassed by nicotinic receptor drug discovery which has, in the past focused on CNS indications.

The first α7 nAChR agents are nearing the market. This report describes the proof of concept supporting the development of this class specifically for Alzheimer’s disease and schizophrenia.

α7nAChRs are selectively expressed in the brain, particularly in regions implicated in cognitive function and especially Alzheimer’s disease and schizophrenia.

A large body of evidence supports the development of α7nAChR ligands for the treatment of Alzheimer’s disease. Nicotinic agonists may directly block the deleterious effects of αβ42 mediated through α7nAChRs. The efficacy of α7nAChR seen in trials to data is however more likely to reflect the enhancement of physiological cognitive pathways and domains which are compromised during Alzheimer’s such as working memory are stimulated by α7nAChR agonists.

The most popular approach to α7 nAChR drug development for Alzheimer’s disease has been to develop partial agonists although some of these partial agonists may actually be co-agonists. This new concept involves ACh docking in one receptor binding site and the agonist binding the second site. This results in synergy ACh and ACh esterase inhibitors (eg Donepezil).

Schizophrenia is associated with multiple overlapping symptoms including positive symptoms (eg psychoses); negative symptoms (eg flatness) and cognitive disorders. Treatments are only available for positive symptoms even though negative symptoms and cognitive impairment significantly reduce the patient’s quality of life.

Seven domains of cognition are deficient in schizophrenia. These include: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, processing speed, reasoning and problem solving and social cognition. α7 nAChR involvement has been reported for most of these domains supporting the development of this class for CIAS.

A number of pharmacological options exist for the development of α7nAChR ligands for CIAS. Most promising, but underutilized, may be allosteric modulators (PAMs) as this approach can upregulate cholinergic pathways without subjecting the α7 nAChR to continuous stimulation and potential toxicity.

A total of 8 α7 nAChR candidates are currently in the clinic. Of these, 2 Phase 2 candidates are for non-CNS indications (diabetes and asthma; TC-6987 and ASM-024) while Neuroderm’s ND0801 is in Phase 2 development for ADHD. ND0801 appears to be a nicotine formulation. This leaves 4 candidates in Phase 2 and 1 in Phase 1 development for CIAS and/or Alzheimer’s disease. We believe that the Phase 1 candidate, XY 4083 has been terminated with its parent company, Xytis possibly no longer trading.

The 4 Phase 2 candidates are RG3487 (Roche; Alzheimer’s); EVP6124 (En Vivo; Alzheimer’s and CIAS); TC-5619 (Targacept; CIAS as well as ADHD) and AQW051 (Novartis; CIAS). Very little is known about AQW051.

EVP6124 and RG3487 lead the α7 nAChR field. Both are described as co-agonists but RG3487 has additional 5HT3 antagonist activity. A Phase 2b study of RG3487 in Alzheimer’s is due to read out in May 2011 while EVP6124 is in Phase 2b trials for both Alzheimer’s and CIAS. The Alzheimer’s study should read out at around the same time as the RG3487 study in mid-2011; the CIAS study should read out a little earlier. En Vivo could gain first in class status although the company does not have a development partner outside of Asia and this could delay matters.

TC-5619 currently sits a little behind EVP6124, in Phase 2a for CIAS (as well as ADHD); it is not currently competing with RG3487 as the two are being developed for different indications. This may change if Alzheimer’s disease is adopted as a target. Like EVP6124, TC-5619 does not antagonize the 5HT3 receptor. One intriguing difference is that TC-5616 appears to have activity against cognitive decline as well as positive and negative symptoms of CIAS. This has yet to be disclosed for EVP6124 and if this remains the case TC-5619 will have a major advantage. The Phase 2b study of EVP6124 should address this issue.

In the CNS arena, α7nAChR development now seems to be quite mature. All molecules are in Phase 2 with little following up in Phase 1 or from preclinical development. There was at one stage significant activity around the development of PAMs although this has not resulted in clinical success. A number of companies, including some large ones that were interested in the α7nAChR appear now to be less interested. We believe that the next surge of interest will come as the class is developed for non-CNS disorders, a trail being blazed by Targacept and Asmacure.

The α7 nAChR field has resembled a drug discovery graveyard over recent years. We believe that Xytis and CoMentis who were both developing clinical stage candidates are in effect no longer trading although this requires confirmation. A number of notable terminations have also been reported.

Sanofi-aventis was developing α7 nAChR agonist SSR-180711 for the treatment of Alzheimer's disease and CIAS however development was terminated, reportedly due to cataract development. We believe that Sanofi-aventis is however attempting to get back into the clinic.

NeuroSearch entered into a research and license agreement with Abbott in 1999 however this collaboration does not appear to have been productive. α4ß2 agonists have stalled while development of an α7 nAChR agonist was stopped for what we believe to be PK issues.

AstraZeneca started a Phase 2a schizophrenia study of α7 nAChR agonist AZD-0328 in 2008 but development stopped in April 2009.

Pfizer has had moderate success in the α4ß2 field with varenicline despite concerns over neuropsychiatric adverse events. Success around α7 nAChR candidates has been poor with at least three candidates entering the clinic only to be terminated for cardiovascular reasons.

Despite the attrition rate of α7 nAChR molecules and the apparently empty early stage pipeline, of course any of the larger companies that have previously been active in the field could rapidly emerge with a new clinical stage candidate.

Understanding the link between nicotinic receptors and amyloid toxicity in Alzheimer's disease

Research around nicotinic receptors has largely focused on cognition. Consequently nicotinic receptor ligands have been developed for various disorders associated with cognitive dysfunction such as schizophrenia, ADHD and Alzheimer's disease.

Involvement of nicotinic receptors in Alzheimer's disease particularly interesting as, in addition to improving cognition through direct effects on nerve pathways, a growing body of data have demonstrated the ability of α7 nicotinic agonists to reduce amyloid toxicity in the brain. Amyloid1-42 has been associated with the development of Alzheimer's.

Exactly how α7 nicotinic agonists impact on the effect of amyloid is unknown. Some believe that agonists prevent amyloid binding to, and excessively activating hippocampal cells. Another hypothesis can be postulated supported by data appearing in the February issue of Neurochemical research. This research suggests that activation of α4β2 nAChR by nicotine decreases BACE1 expression. BACE1 is responsible for the production of Aβ, and this was suggested by the authors to explain why levels are reduced in hippocampal neurons following nicotinic receptor stimulation.

The full paper can be accessed through http://www.leaddiscovery.co.uk/articles/21336821 - if you are involved in the development of nicotinic agents you may also be interested in LeadDiscovery's monthly service UpdatesPlus-Nicotinic receptors - http://www.leaddiscovery.co.uk/updatesplus

Further information about Alzheimer's disease for pharmaceutical personel:

Alzheimer's Disease: Current Treatment Practices and Opportunities, 2010

Repligen reports Phase 3 RG1068 data: Improved MRI imaging of pancreatic and biliary disease expected to reduced ERCP procedures

According to a recent report, Medical Imaging Markets: MRI and Ultrasound the market for MRI continues to grow despite the recession. This is due to improvements in MRI cameras and also imaging agents.

One advance which likely to further drive the use of MRI, specifically in the area of pancreobiliary imaging is Repligen's RG1068. Yesterday, the company announced Phase 3 data supporting the use of RG1068 in combination with MRI for the diagnosis of pancreatic and biliary disease.

Diagnosis of pancreatic and biliary disease can be achieved through MRI or ERCP.

ERCP (endoscopic retrograde cholangiopancreatography) is a procedure used to image the pancreas and bile duct. The procedure involves the local introduction of water soluble iodine-based contrast media directly through the biliary and pancreatic ducts under endoscopic guidance. This then allows imaging using X-ray.

ERCP is considered a good test for diagnosis of ampullary cancers, chronic pancreatitis and duct stones. The procedure also has the advantage of being able biopsy and/or treat at the same time as diagnose. Balanced against this advantage however is the risk of adverse events such as hypersensitivity. In addition the procedure is invasive requiring patient sedation and requires considerable clinical experience. Ideally, ERCP should be reserved for those at greatest need.

MRCP offers an alternative to ERCP. Use of MRCP was first reported in 1991. This procedure replaces endoscopic intervention with an MRI and so is less invasive. One disadvantage however is that image quality may not be as good as with ERCP. RG1068 offers the potential to address this situation.

RG1068 is a synthetic version of human secretin, which stimulates the secretion of pancreatic fluid into the pancreatic ducts, thereby filling the ducts with water, which improves the ability to visualize pancreatic abnormalities. The FDA has granted RG1068 Orphan Drug status and Fast Track Designation, and Repligen estimates that there are approximately 300,000 MRI procedures conducted in the U.S. and Europe each year that could directly benefit from the addition of RG1068.

The Phase 3 data evaluated the ability of RG1068 to improve: sensitivity of detection of
abnormalities without a meaningful lose of specificity; and image quality. Both measures were improved. This contrast with an earlier analysis of the data based on which the study failed to meet its end-points. This was due to "flawed analysis due to deficiencies in performance by the contract research organization overseeing the original analysis". The FDA approved the re-read.

If, based on these data, RG1068 is approved the numbers of ERCP procedures conducted are likely to fall as patients in which the procedure is not required are triaged to alternative therapeutic regimens. Although absolute numbers of ERCP procedures may fall, improvements in endoscopy technology means that success in those procedures that are conducted may increase.

According to The World Market for Gastrointestinal Endoscopy Equipment, the GI endoscopy market is expanding due to improved technologies such as robotics. This expansion covers all types of GI diseases and is primarily being driven by the increase in GI cancers. We expect that ERCP will benefit from such advances but will increasingly be used after initial MRI diagnosis.

Edible vaccine for Alzheimer's disease?

Just read a really cool report from a Japanese group of researchers who are developing a possible new approach to Alzheimer's disease. Fellow geeks will know that Alzheimer's is caused by an excess of a protein called beta amyloid. One possible way of treating the disease is to develop a vaccine that generates antibodies able to bind beta amyloid. That is exactly what the Japanese group has done but with a twist...they have engineered rice to express beta amyloid. Hey presto, one edible vaccine. It has been tested in preclinical models and found to work. The rice is eaten and anbodies are produce. Next step - can the antibodies cause the removal of beta amyloid and reversal of disease. Geeks like me can read on at http://www.leaddiscovery.co.uk/articles/21307566