MAP Pharmaceuticals (CA, USA) have announced that their pediatric asthma product candidate, unit dose budesonide (UDB), demonstrated lower systemic drug exposure compared with the currently marketed conventional nebulized budesonide. It hoped that UDB will be able to be administered more rapidly and provide efficacy at lower doses than conventional nebulized budesonide, the current leading treatment for pediatric asthma.
Of the approximately 20 million diagnosed asthma patients in the USA, it is estimated that 6.8 million of these are children under 18 years of age and 1.2 million are children under 5 years of age.
The preferred treatment to reduce inflammation and maintain control of asthma in the long term is the prophylactic use of inhaled corticosteroids. Young children lack the breathing coordination required for pressurized metered-dose inhalers and do not have the lung capacity required to use dry-powder inhalers. As a result, children under 5 years of age typically use a nebulizer to administer their inhaled corticosteroid medication.
Budesonide is an inhaled corticosteroid that has been used for over 20 years and has been proven to be both safe and efficacious. At present, nebulized budesonide is the leading treatment for pediatric asthma.
MAP Pharmacuticals is developing UDB, a new version of conventional nebulized budesonide, for the treatment of asthma in children aged between 1 and 8 years. The product is now in a late stage of development – it is currently being evaluated as part of a Phase III clinical program.
In this most recent comparative pharmacokinetic trial, UDB demonstrated shorter nebulization times and similar maximum blood concentrations but demonstrated more rapid times to maximum blood concentrations compared with conventional nebulized budesonide. Furthermore, no serious adverse events were reported in the trial. “We believe [these results] provide additional support for the safety of our next generation pediatric asthma therapy” says Timothy Nelson, President and Chief Executive Officer of MAP Pharmaceuticals.
Source: MAP Pharmaceuticals, Inc., CA, USA ir.mappharma.com
Positive results from a psoriasis Phase IIa clinical trial
Drug name: AN2728
Drug nature: Phosphodiesterase 4 inhibitor
Manufacturer: Anacor Pharmaceuticals, CA, USA
Indication: Treatment of psoriasis
Development: Phase IIa clinical trial
Anacor Pharmaceuticals (CA, USA) has announced the results from a Phase IIa clinical trial of AN2728, their topical anti-inflammatory drug candidate for the treatment of psoriasis. The results of this study are promising, suggesting that AN2728 may be used to effectively treat psoriasis in a clinical setting.
Psoriasis is a chronic inflammatory skin disease that affects approximately 10 million people worldwide. The disease is characterized by red, thickened and scaly patches of skin, typically found at the elbows, knees, scalp and genital area. Psoriasis is often bilateral and symmetrical, meaning sufferers commonly have these characteristic patches located at a similar position on their left and right sides and on their front and back.
The recently completed trial took advantage of this bilateral characteristic; in a double-blinded fashion, 35 patients treated one of their psoriasis patches with an ointment containing 5% AN2728 and the corresponding patch on their opposite side with the vehicle ointment, twice-daily for a 4-week period.
In 69% of patients, the area treated with AN2728 improved more than the vehicle-treated area by the end of the 28-day trial. Moreover, over the course of the trial, psoriasis patches treated with AN2728 continued to improve, suggesting that longer-term treatment with the drug may be even more efficacious.
AN2728 works by inhibiting phosphodiesterase 4, an enzyme critical for the production of TNF-α and other cytokines. The drug, therefore, acts to suppress the inflammatory response associated with psoriasis, dampening down the immune reaction responsible for the condition.
The results are certainly encouraging for sufferers of the disease; it is believed that AN2728 has the potential to be a safe and effective therapy for the majority of mild-to-moderate psoriasis patients. Furthermore, since AN2728 is applied topically, it is anticipated that the risk of systemic side effects are likely to be relatively low in comparison to systemically administered drugs.
Source: Anacor Pharmaceuticals, CA, USA www.anacor.com
Tocilizumab appears to be effective in both adult and juvenile forms of arthritis
The antiarthritis drug, tocilizumab, appears to be effective in both adults and children, according to the results of two recently published Phase III trials of the drug. The results of these studies suggest that tocilizumab could prove to be a safe and effective treatment option for both adult and juvenile forms of arthritis.
Adult rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that causes the immune system to attack the joints. The disease has a systemic effect on the sufferer and is associated with progressive joint damage, pain and disability. Another form of arthritis causing chronic joint inflammation, systemic-onset juvenile idiopathic arthritis (SOJIA), is a more specific childhood form of arthritis of unknown etiology.
The activity of IL-6, a proinflammatory cytokine involved in the immune response, is involved in the pathogenesis of both conditions. The aim of both recently published studies was to assess the therapeutic effects of blocking IL-6 via inhibition of the IL-6 receptor with tocilizumab, an anti-IL-6-receptor monoclonal antibody.
The first of the two studies included 623 adults with moderate-to-severe RA and data from the trial suggest that tocilizumab is able to rapidly improve the signs and symptoms of the disease. These findings are significant because many arthritis sufferers continue to experience debilitating symptoms of join pain and stiffness, despite treatment with existing therapies.
In the second study, 56 children and young adults, aged 2-19 years, with SOJIA were examined and, akin to what was found in the previous study, those treated with tocilizumab demonstrated sustained clinical improvement. It is particularly encouraging that tocilizumab was able to improve the symptoms of SOJIA since it is very common for this form of arthritis to be unresponsive to standard arthritis treatment regimens.
The results of these two recent Phase III trials indicate that inhibition of IL-6-mediated proinflammatory effects using tocilizumab is an effective treatment for patients with both adult and juvenile forms of arthritis. Significantly, for children and adults suffering from arthritis refractory to conventional treatment, tocilizumab may be an important new treatment option in the control of their difficult-to-manage disorder.
Sources: Smolen JS, Beaulieu A , Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371(9617), 987–997 (2008); Yokota S, Imagawa T, Mori M et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal Phase III trial. Lancet 371(9617) 998–1006 (2008).
Initiation of a Phase I clinical trial for a p38/Tie2 inhibitor
Drug name: ARRY-614
Drug nature: p38/Tie2 inhibitor
Manufacturer: Array BioPharma Inc., CO, USA
Indication: Treatment of cancers and certain inflammatory diseases
Development: Phase I clinical trial
Array BioPharma Inc. (CO, USA) has filed an investigational new drug (IND) application for ARRY-614, an active p38/Tie2 inhibitor, with the US FDA and has initiated a Phase I clinical trial. It is hoped that the compound will prove to be safe and effective for the treatment of cancers and certain inflammatory diseases.
Aberrant tissue proliferation is a characteristic of cancer and several chronic inflammatory conditions. Such uncontrolled cell growth can be caused by the increased production of certain cytokines and it is well-known that angiogenesis – the growth, differentiation and maintenance of new blood vessels – plays a key role in the process.
p38, a protein kinase, regulates the production of many proinflammatory and proproliferative cytokines, such as TNF, IL-6 and IL-2, and Tie2, a receptor tyrosine kinase, is known to play an important role in angiogenesis.
ARRY-614 is an orally active compound that potently inhibits both p38 and Tie2 and it is hoped that the drug will prove to be an effective treatment for cancer and inflammation. “We believe the dual inhibition of p38 and Tie2 may produce additive and/or synergistic effects with other therapies in treating multiple myeloma and other cancers as well as certain inflammatory diseases,” said John Yates, Chief Medical Officer of Array BioPharma. “We look forward to seeing ARRY-614’s clinical progress so we can test this hypothesis.”
Results from previous trials of ARRY-614 are certainly promising; in preclinical models of human cancer and arthritis, the drug has been shown to block angiogenesis, inhibit inflammation and antagonize tumor growth. Moreover, the drug has shown few side effects in these preclinical models, even with prolonged dosing.
Initially, the compound will be tested for safety, tolerability, exposure and inhibition of mechanism-related biomarkers in normal, healthy volunteers. It is hoped that this compound will have broad therapeutic benefits in a number of different cancers as well as various chronic autoinflammatory diseases.
Source: Array BioPharma Inc., CO, USA www.arraybiopharma.com
EMEA concludes new advice for Tysabri® is required
The EMEA has concluded that new warnings should be added to the product information for Tysabri® (natalizumab), alerting doctors and patients to the risk of liver injury.
Tysabri is used as an infusion (drip into a vein) to treat patients with relapsing–remitting MS when conventional IFN-β treatment is not adequate or when the disease is severe and rapidly getting worse.
Since it was first marketed in 2004, there have been a number of reports of liver injury in patients receiving Tysabri. In this context, the term ‘liver injury’ describes any side effects observed that could be an indication of the liver not functioning properly, such as raised levels of liver enzymes, liver inflammation or jaundice.
The EMEA is aware of 29 reports of liver injury in patients receiving Tysabri, with approximately two thirds of these cases classified as serious. Despite these reports, the product information for Tysabri does not, at present, include any warnings on the possible risk of liver injury.
The EMEA’s Committee for Medicinal Products for Human Use (CHMP) concluded that the product information for Tysabri should be updated to include information regarding the risk of liver injury.
Doctors must be made aware of these risks so that they can ensure all patients to whom they prescribe the drug have their liver function monitored appropriately. It is also essential that patients receiving Tysabri are informed of the possibility of liver damage and advised to consult their doctor if they observe any signs of liver malfunction (e.g., yellowing of the skin or the whites of the eyes or unusual darkening of the urine).
The CHMP has requested for Elan, the marketing authorization holder for Tysabri, to implement the appropriate changes to the marketing authorization for the drug. Once the requested changes have been completed, further advice will be given to healthcare professionals and patients as appropriate.
Source: European Medicines Evaluation Agency www.emea.europa.eu
New tool to study multiple sclerosis
A whole-body suit that can change the temperature of the wearer, together with an infrared camera that painlessly tracks eye movements, is being used to study the mysterious link between body temperature and the severity of multiple sclerosis (MS) symptoms. Importantly, this new system could be used to test the efficacy of new therapies, providing a means of assessing their ability to reduce heat-induced MS symptoms.
Multiple sclerosis is an autoimmune disorder of the CNS, affecting the brain, spinal cord and optic nerves. Symptoms of MS include fatigue, coordination difficulties and bladder and vision problems.
The new technique measures one aspect of MS, known as Uhthoff’s phenomenon, whereby the severity of the aforementioned symptoms worsens as the MS sufferer’s body temperature rises. Researchers have long known about Uhthoff’s phenomenon, named after the German ophthalmologist who reported that some people have temporary vision problems in hot weather or following exercise.
Using a body suit that is able to change the body temperature and an infrared camera to track eye movements, researchers demonstrated that, as the body temperature of MS patients rises, so does the severity of internuclear ophthalmoplegia (INO), an eye-movement disorder.
When rapidly looking from one object to another, the eyes normally move at the same speed. In a person with INO, one eye moves more slowly than the other. Increasing the body temperature increased the difference between the relative motions of the two eyes, whereas cooling the body temperature caused the two eyes to synchronize better.
INO is an easy-to-measure heat-induced MS symptom, which can serve as an indirect measure of harder-to-measure heat-induced symptoms, such as fatigue and bladder problems. Therefore, monitoring INO using this novel technique could be used as a clinical test to determine a patient’s susceptibility to heat-related MS symptoms.
Moreover, the system could be used to trial numerous different therapies for the treatment of MS, testing the ability of drug candidates to relieve heat-related symptoms of the disease.
Source: The University of Texas Southwestern Medical Center, TX, USA www.utsouthwestern.edu