Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis

Abstract

The neurodegenerative aspects of chronic progressive multiple sclerosis (MS) have received increasing attention in recent years, since anti-inflammatory and immunosuppressive treatment strategies have largely failed. However, successful neuroprotection and/or neuroregeneration in MS have not been demonstrated yet. Encouraged by the multifaceted neuroprotective effects of recombinant human erythropoietin (rhEPO) in experimental models, we performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with chronic progressive MS. Main study objectives were (i) evaluating safety of long-term high-dose intravenous rhEPO treatment in MS, and (ii) collecting first evidence of potential efficacy on clinical outcome parameters. Eight MS patients, five randomly assigned to high-dose (48,000 IU), three to low-dose (8000 IU) rhEPO treatment, and, as disease controls, two drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: A 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase. Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale (EDSS), and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for three to six months after cessation of EPO application. In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested. There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings. This first pilot study demonstrates the necessity and feasibility of controlled trials using high-dose rhEPO in chronic progressive MS.

Epo and Non-hematopoietic Cells: What Do We Know?

“…Together these trials suggest future clinical applications for Epo in the treatment of psychiatric disorders characterized by cognitive dysfunction. During the first phase I/IIa study of high dose Epo treatment in patients with chronic progressive multiple sclerosis significant improvement in clinical and electrophysiological motor function as well as cognitive performance was achieved (134). Epo treatment also somewhat improved outcome for patients after subarachnoid hemorrhage (135).…”

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

“…In diseases like MS, however, the very weak hematopoietic effects of EPO, leading additionally to disease-beneficial shifts in iron stores, may make these variants unnecessary (see below). 119 Also, the safety and efficacy of these novel compounds in man need first to be confirmed in phase I studies.…”

“…To our knowledge, no EPO variants other than rhEPO itself have thus far been published in relation to the treatment of human nervous system diseases. The only studies published so far reporting on efficacy of rhEPO in human brain diseases are our own studies on ischemic stroke, schizophrenia and MS. 69,119,124 …”

“…Encouraged by the neuroprotective/neuroregenerative effects of EPO seen in our human trials, and the increasing number of positive rodent studies on EAE and related conditions, 33,67,[91][92][93][94][95][96] we initiated another investigatordriven, exploratory, open-label study (phase IIa) addressing patients suffering from either primary or secondary chronic progressive MS. 119 The main objectives of this study were: 1) to evaluate safety of long-term, high-dose intravenous EPO treatment in MS; and 2) to collect first evidence of potential efficacy of EPO on the most MSrelevant clinical outcome parameters. The study design comprised a 6-week lead-in period set up to obtain a clean estimate of baseline performance, a 12-week treatment phase with weekly intravenous applications of EPO, followed by another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment period.…”

“…With cessation of EPO treatment, most iron parameters will rapidly return to normal levels. 119,124 Interestingly, the temporary reduction in iron availability caused by EPO might even provide an additional benefit in chronic progressive MS in which iron has even been seen as an inflammation-supporting agent, and iron chelators have been proposed for treating this condition. 127 …”