Systemic lupus erythematosus is an chronic, autoimmune, inflammatory disease that progressively damages numerous organs in the body. Treatments are available, but none is specific to the disease, and they can have severe adverse effects. A CNRS team at the Institut de biologie moléculaire et cellulaire in Strasbourg has discovered a protein fragment, the P140 peptide, that is capable of treating lupus-affected mice.
A series of clinical studies was implemented by the Alsace-based company ImmuPharma France. The initial results of phase II studies in patients with the disease were published on November 26 on the website of the journal Arthritis & Rheumatism. The results are highly encouraging, and confirm that the P140 peptide may be a very good candidate for the specific treatment of this disease.
Lupus has a multifactorial, environmental and immunologic origin, and affects several million people throughout the world; in France, the number of patients is estimated to be between 80,000 and 100,000 (90% of them young women between the ages of 18 and 30 years). One of its specificities is that it takes different forms in different patients. The most common clinical signs include intense joint pain, facial skin lesions and more or less severe renal impairment. In many cases, patients experience blood disorders, pulmonary or cardiac inflammation (pleurisy, pericarditis, myocarditis), increased susceptibility to solar radiation (photosensitivity) or ulcerations affecting certain mucous membranes. They may also suffer from cerebral impairment, which is always severe.
For many years, this disease was poorly diagnosed and treated, but today it is better controlled. It nonetheless remains very incapacitating and requires life-long follow-up, with unpredictable and extremely painful flare-ups. Palliative therapies are available, but none is specific to this condition. They mainly consist in corticosteroid therapy and, in severe forms, the administration of immunosuppressant drugs that may have serious adverse effects, particularly when taken for long periods (cardiovascular disorders, obesity, diabetes, impaired fertility, some cancers and increased susceptibility to infections).
In autoimmune diseases such as lupus, the body has lost its ability to recognize its own constituents and attacks them as if they were external pathogens. In 2001, scientists in the CNRS Laboratoire d'Immunologie et chimie thérapeutiques, led by Sylviane Muller at the Institut de biologie moléculaire et cellulaire (CNRS), discovered and patented a compound that is capable of restoring the immune system to a normal status. When treated with a fragment of a nuclear protein, the P140 peptide, lupus-affected mice exhibited a lifespan similar to that of unaffected animals. Their renal disease was significantly diminished and they presented with much less severe inflammatory and joint symptoms.
The drug discovery and development company ImmuPharma, founded in 2004 by Dr Robert Zimmer with the support of Muller and two other researchers from the Laboratory, has funded all steps in the regulatory development process that led, firstly, to a phase IIa study(1) and secondly to a larger-scale phase IIb study.
The phase IIa clinical study was carried out in two centers in Bulgaria on 20 lupus patients who received three subcutaneous injections of the P140 peptide at 15-day intervals. It was shown that this peptide did not generate any adverse effects (side effects) in the patients, apart from minor redness at the injection site that rapidly regressed. The efficacy of P140 was demonstrated by a reduction in the anti-DNA auto-antibodies that are typically found in lupus patients. Immune globulin levels, which are also elevated in lupus patients, were also regulated. Another very important observation was that the international disease activity score (SLEDAI)(2) was significantly reduced in the group of patients who received the lowest dose of P140 peptide.
These results, which might have been unhoped-for after such a short period of treatment, wholly confirmed the preclinical observations obtained in the laboratory in model mice with lupus. The scientists also pointed out that this new compound has the major advantage of not affecting the overall immune system, unlike current therapies. It was shown in animals that repeated doses of P140 peptide did not affect their ability to resist viral infection, unlike immunosuppressants in general. Thus P140 peptide constitutes the first potential candidate for the specific treatment of lupus.
A phase IIb clinical study involving some 200 patients is currently under way in South America and Europe.
1) Phase I clinical studies are performed in healthy individuals to test the safety of the compounds administered. Phase II studies are then initiated in patients. During phase IIa studies, patients are told which therapeutic compound they are receiving. Then, in phase IIb studies, patients are not informed whether they are receiving the compound or a placebo.
2) The international SLEDAI score is calculated from a series of disease-specific criteria (number of joints affected, severity of pain, renal impairment, etc.). Each criterion is scored, so that a global score can then be calculated as being representative of disease severity.
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