This page contains a Flash digital edition of a book.

population of CD4+ GA Th2 cells in the periphery and within the CNS through cross-recognition of myelin antigen.9 These GA-specific Tcells was recently demonstrated that also secrete the potent brain-derived neurotrophic factor (BDNF) which induces axonal outgrowth, remyelination, regeneration, and rescue of degenerating neurons, both in brain and periphery.13

The neuroprotective effects of GA were confirmed by magnetic resonance imaging (MRI) parameters, such as magnetisation transfer and diffusion tensor imaging in a relapsing and progressive model of EAE, showing a significant reduction of myelin and neuro-axonal damage in mice treated with GA.13

In fact, GA was associated with an increased secretion of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) by GA- specific T cells both in the periphery and in the brain.14

In addition, high

expression of BDNF and other neurotrophic factors, such as neurotrophin-1 (NT-1), neurotrophin-2 (NT-2), and insulin-like growth factors-1 and -2 (IGF-1, IGF-2) were also observed in astrocytes and neurons, confirming the in situ efficacy of GA.14


immunological activity of GA begins in the periphery, although the drug is able to induce an effective modulation in the CNS.15

Its activity is mediated by the activation of GA-specific T cells able to cross the blood–brain barrier and to penetrate the CNS.15

The cross-reactivity

of GA-specific T cells with MBP can explain the in situ reactivation and the therapeutic effect of GA in the MS diseased organ, although the drug is hydrolysed in the periphery.15 Interestingly, the induction of an anti-inflammatory milieu in the CNS is sustained not only by GA-specific T cells, but also by CNS resident cells, such as astrocytes and microglia.7

the proliferation of Treg cells and the parallel suppression of Th17 cells have been demonstrated in the CNS of GA-treated mice affected by chronic and relapsing EAE.10

Pharmacokinetics and metabolism The pharmacokinetic profile of GA is not clear; it interacts at the site of injection with peripheral blood lymphocytes and is then hydrolysed.4

A substantial fraction of the 18 therapeutic dose is hydrolysed locally and

fragments of GA can be recognised by GA-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolysed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.2 Studies performed in dogs receiving subcutaneous (sc) injections of 3mg/kg GA showed that GA was detected in blood 5–10 min after injection. In two out of three dogs, the serum levels returned to baseline after six hours. A pilot study was performed in order to quantify GA in human sera after sc injection of a single, supratherapeutic dose of 60mg, to healthy volunteers.16

GA were detected in the plasma of 9 subjects out of 17. In all the nine subjects, the time to maximum concentration (Tmax) was between 15 and 30 min, except for one subject who had an additional peak at 240 min. The maximum plasma concentration (Cmax) was 69–605ng/ml. The area under the curve (AUC) in the nine subjects exhibited a large variability. In all subjects, GA levels returned to baseline after 30–60 min post-injection. In four subjects, a quantifiable amount of GA appeared again at a later time point of 240 or 360 min. Twenty-four hours after the injection of the 60mg dose, the levels of the immunorecognisable GA fragments in the serum of 15 of the 17 subjects were below the quantification limit of 25–50ng/ml.16

In this context,

An animal study showed that after administration of a single radiolabelled dose of GA, radioactivity was detected after one to two hours in rats and after two to four hours in monkeys. The highest radioactivity levels were detected in the stomach and in thyroid, the lowest level in the brain. Possibly due to its hydrophilic nature, GA is not able to cross the blood–brain barrier, exerting its therapeutic effect in the periphery rather than in the CNS.17

In animals, the main

route of elimination was urinary excretion. Interaction between GA and other drugs has not been fully evaluated, although a close monitoring of patients receiving protein-bound drugs (such as phenytoin or carbamazepine) is recommended, because GA is highly bound to plasma protein. An increased incidence of injection site reaction has been observed in GA patients receiving concurrent administration of corticosteroids.2

According to FDA classification of foetal risk due to

pharmaceuticals, GA is a category B drug.2

That is, animal studies show no risk but there are no adequate and well-controlled studies in pregnant women. As such, the US prescribing information states that: ‘GA should be used during pregnancy only if clearly needed’. In the UK prescribing information, GA is contraindicated during pregnancy, adding that ‘contraceptive cover should be considered when using this medical product’.2

GA has not been studied in

paediatric patients, elderly patients or those with renal failure.2,17 ,18

Quantifiable levels of

Clinical efficacy Clinical efficacy of GA has been investigated in a large number of studies to assess the relapse rate, the proportion of relapse-free patients, time to relapse, sustained progression and safety of the drug.

A randomised double-blind, placebo- controlled Phase II trial showed a reduction of relapse rate (RR) in patients with minimal or no disability, suggesting the importance of early treatment. In particular, there was a 75% reduction of RR over two years and an annualised reduction from 1.35 to 0.3 attacks.19 A placebo-controlled, multicentre study of 251 patients, with clinically defined MS and an Expanded Disability Status Scale (EDSS) score between 0 and 5.0. This study showed a statistically significant difference in annual RR (ARR) between GA-treated patients and the placebo group (p = 0.59 GA group versus 0.84 in the placebo group). Disease progression was determined as the proportion of patients who improved, remained stable or progressed by one or more EDSS point. When the proportion of patients who improved, were unchanged, or worsened by ≥ 1 EDSS step from baseline to conclusion (two years) was evaluated, significantly more patients receiving GA were found to have improved and more receiving placebo worsened (p = 0.037).20 Patients receiving GA therapy for up to ten consecutive years experienced an increase of mean EDSS score of 0.5 (± 1.65) and 91% of patients remained ambulatory without the requirement for a walking aid.21

After 15 years, more than

80% of patients still taking GA were walking without assistance and two- thirds of patients had not transitioned to SPMS (mean disease duration 22 years).22

No toxicity was reported,

Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24