A phase II study of ARA 290 as therapeutic strategy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects 1% of
the general population. Patients present with symmetric joint swelling and
systemic inflammation. The inflammatory response in RA is associated with
over-production and over-expression of tumor necrosis factor (TNF).
Uncontrolled active RA leads to joint destruction, disability, and
co-morbidities such as cardiovascular disease. RA is associated with increased
mortality and reduced life expectancy. Cardiovascular disease is one of the
most common causes of death in RA patients, with a 50% increased risk of
cardiovascular related death compared to the general population. Active
inflammation is one of the predictors of cardiovascular morbidity and mortality
in RA patients.

Drug management of RA has undergone dramatic changes in the past 3 decades,
with an expansion of the amount of different available drugs. The use of DMARDs
like methotrexate (MTX), sulfasalazine and leflunomide has now been well
established. In addition to these, several biological agents, targeting TNF,
the interleukin-1 or 6 receptor, B lymhocytes or T-cell co-stimulation have
been developed for the treatment of RA. However, with the available drugs and
strategies, up to 20% do not achieve low disease activity and many patients
remain partial responders. Remission is only achieved in 22-49%, depending on
the definition.

Erythropoietin (EPO) is a well-known stimulator of erythrocyte production and
widely used in the treatment of anemia caused by kidney disease, cancer, or
chronic inflammation. Over the past decade, it has become evident that
erythropoietin, besides its positive effect on hematopoiesis, possesses many
other biological activities that can generally be summarized as counteracting
the actions of proinflammatory cytokines and their deleterious effects in
tissue injury.
Cross-talk between the circulating hematopoietic and the local tissue
protective pools of EPO is avoided by the presence of EPO receptor isoforms
that differ greatly in their affinity for EPO. The tissue protective receptor
exhibits a lower affinity for EPO (2-20 nM) and therefore does not respond to
EPO at concentrations present within the circulation, but rather only to high
levels of locally produced EPO. Secondly, in hematopoiesis, the homodimer is
expressed continuously by a population of red cell precursors that require
constant circulating EPO to enable survival. In contrast, the tissue protective
receptor typically is not expressed until after the occurrence of injury or
significant metabolic stress and only requires a brief exposure to EPO to
trigger sustained biological activity.
When employed at the high doses required for adequate tissue protection, EPO
unfortunately possesses use-limiting side effects, particularly in converting
the vasculature into a prothrombotic state, which leads to an increased risk of
life-threatening thromboses, as has been observed particularly in injured
patients or those with cancer.
Therefore a number of nonerythropoietic tissue protective cytokines (TPCs) have
been developed that interact exclusively with the tissue protective receptor,
but lack an effect on the hematopoietic receptor. These compounds have been
shown to exhibit tissue protective effects but not to induce endothelial cell
activation or thrombocyte activation.
ARA 290 is an 11-amino acid, linear peptide that is being developed as a tissue
protective peptide. ARA 290 mimics the tissue protective pharmacology of
erythropoietin but is devoid of its haematopoietic effects.
In preclinical models, ARA 290 has been shown to exhibit general
anti-inflammatory activities. In RA patients, clinical trials investigating the
use of recombinant human erythropoietin to correct anemia, showed that disease
activity was reduced after treatment. These observations suggest that
activation of the tissue protective erythropoietin receptor may reduce disease
activity in patients with active RA. To that end we now propose to perform a
clinical study of ARA 290 in patients with active RA.

This is an open label proof of principle study, in 14 patients. The objective
of the study is to test the efficacy and safety of ARA 290 in patients with
active rheumatoid arthritis. To assess the efficacy, disease activity is
examined based on joint examination, functional ability, functional health and
wellbeing and mood and symptoms of depression based on questionnaires and
systemic inflammation based on laboratory investigation. Safety is assessed by
registering any adverse events and serious events, patient reported as well as
discovered by physical examination and laboratory investigation.

Patients that are eligible for participation, because they have active
rheumatoid arthritis, will be recruted by their rheumatologist and informed by
the research physician. After receiving informed consent, the investigation
will start.
During the first visit, the patient will be screened to find out if the patient
meets all the criteria. If this is the case, randomisation will take place.
Patients will be devided into two groups. Each patient will be treated for 4
weeks.
The first groups will visit the hospital once a week to be treated with ARA 290
(iv in 2 minutes, than half an hour observation) and have a physical
examination. Blood will be drawn and disease activity will be assessed.
In addition to these visits, the second group will come to the hospital for
treatment a second and a third time. The first group receives 4 gifts of RA
290, the second group receives 12. Each group will consist of 6 patients.
At the beginning and at the end of these 4 weeks, functional ability,
functional health and well being and mood and symptoms of depression will be
evaluated using validated questionnaires (HAQ, SF-36 and BDI-II respectively).
The HAQ will be filled out weekly. A month after the last visit, another visit
will take place to perform a physical examination, draw blood and assess
disease activity and disability.
After this, patients will be contacted by telephone every month (until 6 months
after the last treatment) to ask if the disease activity is still low. If this
is not the case, patients will be asked to return to the hospital for a last
evaluation of disease activity and systemic inflammation.
During the investigation, patients will be asked about side effects regularly.

Iv treatment with 2 mg ARA 290 thrice or once a week during 4 weeks.

Burden: patients have to come to the hospital for a screening, then for 1 month
come to the hospital once or thrice a week, depending on the randomisation, and
then for two more visits after treatment.

Risk: Patients continue using their own medication during treatment with ARA
290 so the risk of a further rise of disease activity is not elevated compared
to when patients would not participate in the investigation.
There are no known side effects of ARA 290. Patients could experience unknown
side effects or have an allergic reaction.

Discomfort: iv treatment and venipunctures could cause bruising.