New approaches to type 1 diabetes and other autoimmune diseases

Yesterdays edition of DailyUpdates (19^th Dec, 2005) featured a paper looking at the efficacy of etanercept as a treatment of psoriasis. Both this condition and also type 1 diabetes are the focus of our recent drug discovery report, Autoimmune Disorders & Transplant Rejection - Opportunities for the Drug Development Sector,

Although psoriasis is almost 8-fold more prevalent than type 1 diabetes, it now represents a relatively minor clinical problem. This is due in part to the success of TNF blockers including etanercept. According to the study highlighted yesterday, patients rated disease severity as improving from moderate/severe to minimal/good.following treatment with etanercept and a quantitative measure of efficacy as measured by the Dermatology Life Quality Index reported that etanercept produced a 65-70% improvement. There remain a number of unmet clinical needs in the treatment of psoriasis however in general a disease once associated with uncontrollable discomfort and disfiguration of the skin as well as loss of mobility is now managable. This contrasts with type 1 diabetes.

Type 1 diabetes accounts for approximately 10% of all cases of diabetes and is characterized by the destruction of insulin-secreting beta cells in the pancreatic islets of Langerhan. This results in a loss of insulin production exposing the patient to the effects of both acute and chronic deviation in glucose balance. The therapy of choice for the disease is to inject insulin and before the discovery and isolation of insulin in the 1920s, having this type of diabetes meant certain death.

Despite the availability of insulin, in 2002 more than 50% of Americans with diagnosed type 1 diabetes failed to meet target levels of glucose control and consequently the risk of microvascular complications associated with the disease, and resultant cardiovascular problems, kidney failure, amputation and blindness remains a major problem.

Although glucose tolerance remains normal until the clinical onset of diabetes, beta-cell function and insulin release decrease even during the preclinical period. It is thought that approximately 90% of beta-cell mass must be destroyed before overt hyperglycemia will occur. Attention is now being focused on the "honeymoon period", the critical period between the times of clinical diagnosis and ample destruction of beta-cell mass, which may be exploited to find avenues that could prevent insulitis and obviate the need for insulin restoration.

It is now clear that inherited susceptibility to type 1 diabetes depends on several genes at different loci, however it is believed that an environmental trigger is also necessary to promote autoimmunity and these may include viruses, toxic chemicals, and various dietary components such as cow's milk. The ability of dietary components to act as triggers may be facilitated by increased intestinal permeability, increasing the exposure of intestinal contents to the immune system. Indeed increased gut permeability has been observed in numerous human autoimmune diseases.

The paper featured in today’s edition of DailyUpdates (20^th Dec, 2005) focuses on the pathophysiological role of zonulin, a protein that regulates intercellular tight junctions (Watts et al, 2006). Zonulin is involved in the innate immunity of the gut and, when inappropriately up-regulated, appears to play a key role in the increased intestinal permeability and pathogenesis of autoimmune diseases such as celiac disease. The objective of this study was to establish whether zonulin-dependent increased intestinal permeability plays a role in the pathogenesis of type 1 diabetes.

The study led by Alessio Fasano, CSO and co-founder of Alba Therapeutics, reported that diabetic-prone rats displayed a 35-fold increase in intestinal intraluminal zonulin levels. Zonulin up-regulation was followed by the production of autoantibodies against pancreatic beta cells, which preceded the onset of clinically evident type 1 diabetes about 25 days.

Blockade of the zonulin receptor using a peptide inhibitor (AT-1001) reduced the cumulative incidence of type 1 diabetes by 70%, despite the persistence of intraluminal zonulin up-regulation. This study offers excellent proof of concept to support the development of zonulin blockers as an approach to type 1 diabetes.

A number of further studies are however eagerly awaited. Firstly, and perhaps most obvious is a study to determine whether zonulin levels increased in patients. This should be a relatively simple study to conduct if the animal study described here reflects the clinical situation, as a clear increase in serum zonulin was measured in rodents. If zonulin levels do increase during the development of diabetes then this molecule could represent a useful marker of disease development.

Second and perhaps more important, it will be important to see how long zonulin blockade can be delayed before this approach becomes ineffective in preventing the development of diabetes. In the present study, blockade was initiated prior to an increase in anti-islet antibodies. Antibody development occurred concomitantly with zonulin over-expression and this preceded the development of diabetes. It would be interesting to determine the efficacy of zonulin blockade when commenced just after levels start to increase. This would have a number of clinical implications; not least, if zonulin is a marker of disease onset, at-risk individuals could be monitored for zonulin overexpression and then treated accordingly once increases are observed.

Finally increased gut permeability has been observed in numerous human autoimmune diseases and the over-expression of zonulin as well as its blockade could have far reaching implications. Indeed Alba Therapeutics are currently developing AT-1001 for the treatment of celiac disease. This lead compound is currently undergoing pre-clinical toxicology studies prior to being advanced into the clinic. Studies conceptualizing the targeting of zonulin for the treatment of celiac disease will be highlight in an upcoming issue of DailyUpdates

Efficacy of Enbrel (etanercept) as a treatment of psoriasis

Psoriasis has a prevalence of approximately 1500/100,000 (approximately 1 million people have the disease in the US) and affects the skin causing redness and itchiness at multiple sites. The disease can occur in various different forms, the most common of which is plaque psoriasis, a condition associated with raised, red lesions covered with a buildup of dead skin cells. For an in depth look into this disease and its treatments see our recent feature Autoimmune Disorders & Transplant Rejection - Opportunities for the Drug Development Sector,

The non-specificity of early immunomodulators such as cyclosporine and methotrexate, and consequent toxicity has driven the development of various biologic therapies that act to modulate the immune response. The first biologic medication approved by the FDA (January 2003) for the treatment of psoriasis was the T-cell modulator Amevive.

The approval of Amevive was followed by, Enbrel (etanercept), a decoy receptor that blocks tumor necrosis factor-alpha which has now been approved by the FDA for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis and ankylosing spondylitis. Even more recently Raptiva (infliximab; October 2003) was approved for the treatment of psoriasis. This monoclonal antibody neutralizes anti-TNF. About 30% of psoriasis patients suffer psoriatic arthritis, and Remicade and Humira, originally treatments of rheumatoid arthritis, have both recently been approved for the treatment of this condition. Like Raptiva, Remicade and Humira are both antibodies that neutralize anti-TNF

Overall psoriasis has greatly benefited from the advent of the TNF blockers Once a disease associated often uncontrollable burning sensation and disfiguration of the skin and frequently accompanied by loss of mobility and joint pain biologics have transformed psoriasis. The biologics can greatly improve skin lesions and reduce joint disease severity as measured by physician-reported clinical outcomes. Equally important is the patient perspective on the effect of etanercept therapy on daily life.

In their Br J Dermatol paper published this month (Dec;153(6):1192-9) and featured on the Dec 19th edition of DailyUpdates, Krueger et al assess patient-reported outcomes in patients with psoriasis receiving etanercept therapy. In this multinational, randomized, phase III trial, patients with psoriasis received placebo, etanercept 50 mg per week or etanercept 50 mg twice weekly during the initial 12-week, double-blind period. Thereafter, all patients received open-label etanercept (50 mg per week).

The study evaluated the effects of treatment on the Dermatology Life Quality Index (DLQI), Short Form-36 Health Survey (SF-36), patient rating of pruritus, and patient global assessment of psoriasis.

At week 12, DLQI total score improved by 65-70% in patients receiving etanercept compared with 6% in patients receiving placebo. Improvements were reported across multiple components of DLQI and SF-36 establishing that the efficacy of treatment was not biased towards a few aspects of the disease. Moreover, patients rated disease severity as improving from moderate/severe to minimal/good.

Based on this study, etanercept is concluded not only to improve disease activity as indicated by clinical outcomes but also by patient experiences.

Despite the efficacy of TNF blockers, two large patient surveys, one conducted by the National Psoriasis Foundation (NPF) and the other by the European Union Federation of Psoriasis Associations, have reveal that patients are dissatisfied with currently available therapeutic options. Despite the availability of new biologics, the NPF survey revealed that only 18% of survey respondents with severe psoriasis were currently receiving systemic therapy; 32% of patients indicated that their psoriasis therapy was not aggressive enough and this is partly due to the prescribing patterns of dermatologists who generally approach psoriasis in a stepwise fashion starting with conservative treatments and progressing towards biologics. This approach is becoming obsolete as the safety and efficacy of biologics is becoming established and patients with severe psoriasis should now be evaluated as candidates for first line biologic therapy.

One short-fall in the treatment of psoriasis is the lack of head-to-head studies comparing the efficacy or tolerability of the 5 approved biologic psoriasis treatments. This is important considering the expense of therapies and the need to direct the best possible treatment to patients on an individual basis. Hopefully such studies will eventually be conducted and when this occurs data should include patient-reported outcomes as described in the featured journal article.

Good tidings for all web users!

As we approach the holiday season, story has it that wise men approached from the east bearing good tidings. This year LeadDiscovery is doing the bearing (albeit from the west) and even better, these tidings are not going to cost you a penny(!) as today we introduce to you Mozilla's open-source software for faster and safer internet browsing & mail handling. We hope that you forgive us for deviating from our normal course of supplying R&D information but Mozilla's software will make using our information a less fustrating experience in the future.

A break from drug discovery! At LeadDiscovery we are dedicated to doing our bit to optimize drug discovery. Although this usually involves supplying scientific information, the utility of this information is tempered somewhat if the programs you are using makes accessing this information slow and cumbersome. We feel that it is our duty therefore to break for a moment from supplying R&D information and to introduce you to the Mozilla software that we discovered a few weeks ago.

Looking for improved web browsing & mail handling: Throughout the year our team batters the internet identifying journal articles, press releases, and reports judged to be of importance to the drug discovery community. In turn we then batter our e-mail systems distributing our DailyUpdates service, announcing this information to you, the audience.

For the past few years our team has struggled with slow and unstable web browsing through Explorer, and frequent crashes using Outlook. A few weeks ago these problems disappeared when we discovered Mozilla. This US based organization is dedicated to developing the next generation of web browser and e-mail software. The software is open source - ie it is available to anyone free of charge.

Mozilla Firefox - Faster and safer web browsing: At the beginning of December, 2005 we evaluated Firefox as a possible replacement for Microsoft's Explorer and within a few days the advantages seen in Firefox were so great all of our PCs now run off of this browser. Currently about15-30% of PCs use Firefox however this figure is rising. We recommend Firefox for anyone who regularly uses the internet due to the speed and stability with which it loads webpages. These advantages are extended still further by the inbuilt Google toolbar. Links to the Firefox download page are provided here

Mozilla Thunderbird for better mail handling: Following our positive experiences with Firefox we then went on to test Thunderbird. Our main problem with our previous mail program, Outlook, was that it frequently crashed, a problem our IT team said was inherent to pst files which the program uses to store data. In addition important mail was frequently sent to our junk box. Since we downloaded Thunderbird we have experienced almost no crashes and one of the nice aspects of this program is that the junk filter is trainable - you tell the program which mail is junk and it gradually learns to detect future junk itself. Our experience suggests that Thunderbird is a very good learner! A further useful feature of Thunderbird is that it also acts as a great RSS reader, streaming news feed as e-mail-like messages. We will leave describing RSS feeds to another time but if you are already familiar with this technology you may be interested to know that our existing RSS reader is now unused! Thunderbird can be downloaded here

We hope that you have found this entry of use and that you forgive us for deviating from our normal course of supplying R&D information...please be assured that our next offering will be well and truly back in the mold of drug discovery,

Histamine H4 receptor antagonism as a rapidly emerging approach to autoimmune disease

Histamine is a biological amine that affects a variety of functions in the human body. It has been known to participate in the mechanisms of inflammatory reaction, gastric acid secretion, and neurotransmission. Four subtypes of histamine receptor, H1-4, have been identified. The histamine H4 receptor was most recently identified in the year 2000. H4 receptors are widely expressed by components of the immune system including the spleen, thymus, and leukocytes.

Johnson & Johnson were the first company to publish on a selective histamine H4 antagonist (Jablonowski et al, 2003) and JNJ 10191584 and JNJ 7777120 have been investigated as orally active antagonists. The first few studies into the function of H4 receptors suggested that their blockade would be of benefit to allergic diseases with an eosinophilic and/or mast cell component since histamine binding to this receptor subtype stimulated the chemotaxis of both cell types.

The two papers featured in the December 5^th edition of DailyUpdates suggest that the efficacy of histamine H4 antagonists may extend to autoimmune disease. In particular the H4 subtype is now implicated in rheumatoid arthritis and inflammatory bowel disease. Both of these serious autoimmune disorders are evaluated in our recent report “Autoimmune Disorders & Transplant Rejection - Opportunities for the Drug Development Sector”. Both conditions are amongst the ten most prevalent autoimmune disorders affecting 300-600 people/100,000

Ulcerative colitis and Crohn’s disease, known collectively as inflammatory bowel disease (IBD) currently affects 0.5-1% of the Western world’s population. This translates to over one million people in America (525,000 Ulcerative Colitis, 490,000 Crohn's Disease) and four million people worldwide. Sufferers experience a range of gastrointestinal symptoms, including diarrhea, rectal bleeding and abdominal pain resulting in weight loss as well as other extraintestinal manifestation such as skin and eye disorders.

Rheumatoid arthritis is a chronic syndrome characterised by non-specific, usually symmetrical inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and peri-articular structures, with or without generalised manifestations. This disease is one of the more difficult of the autoimmune diseases to control and can do considerable damage to the joints. The condition differs from osteoarthritis not only through the obligatory involvement of the immune system but also because disease onset occurs early on in life, generally between the ages of 20 and 50, although it can begin at any age.

Although recent advances, particularly the development of TNF blockers have improved the options available for the treatment of both IBD and rheumatoid arthritis significant unmet needs remain; in particular not all patients respond to TNF blockers and those that do rarely exhibit a complete response. Thus additional molecular targets are being sought for the development of new anti-inflammatory agents. The two papers featured on yesterday’s DailyUpdates present a good case for including H4 receptors as candidate targets.

The first of the featured papers reports that treatment with JNJ 10191584 dose-dependently reducted macroscopic damage, neutrophil infiltration and tumour necrosis factor-alpha levels. JNJ 7777120 produced similar effects. The second paper reports that human synoviocytes from rheumatoid arthritis patients express H4 receptors. Further studies investigated the efficacy of H4 receptor antagonist in models of this disease are therefore eagerly awaited.

Do you have any comments on the development of H4 receptor antagonists – perhaps you have preliminary data. Please feel free to submit your comments? This will hopefully drive forward this fascinating area of immunology while at the same time providing a platform for exciting data amongst our derug development audience?