INTRATHECAL CILIARY NEUROTROPHIC FACTOR DELIVERY FOR TREATMENT OF AMYOTROPHIC-LATERAL-SCLEROSIS (PHASE-I TRIAL)

OBJECTIVE: This Phase I trial of ciliary neurotrophic factor (CNTF) de livered intrathecally for the treatment of patients with amyotrophic l ateral sclerosis was designed to determine the safety of this new mode of administration as well as the pharmacokinetics and drug distributi on. METHODS: CNTF was administered using a drug pump implanted into th e lumbar subarachnoid space in each of four patients with amyotrophic lateral sclerosis. Escalating doses (0.4, 0.8, 1.6, 4, and 8 mu g/h) w ere infused for 48 hours per week in 2-week cycles until the highest t olerated dose was achieved. Patients were observed for side effects, a nd standardized muscle and respiratory function tests were performed. Cerebrospinal fluid (CSF) levels of CNTF were determined using simulta neous lumbar and cervical taps. Plasma and CSF levels of antibodies, C SF cells and protein, and routine blood chemistries were monitored, as were weight and vital signs. RESULTS: Pharmacokinetic studies of four patients demonstrated that the distribution and clearance of recombin ant human (rH)CNTF are similar to those of many small, water-soluble a gents (morphine, baclofen, clonidine) and that the steady-state concen tration of rHCNTF at the cervical lever was 18 to 36% of that at the l umbar level. Lumbar CSF levels were in the range of 44 to 1230 ng/ml. Intrathecally administered rHCNTF had different adverse effects than t he systemically delivered drug. With intrathecal administration, no as thenia, fever, chills, nausea, weight loss, increased cough, or sputum production was found. All patients who received rHCNTF intrathecally experienced dose-related CSF pleocytosis (primarily lymphocytic) and r ises in protein levels. No clinical signs of meningeal irritation, suc h as stiff neck, photophobias, or nausea, were seen. However, one pati ent who had lumbar spinal stenosis developed severe burning and crampi ng leg pain. A second patient developed a severe headache and leg and back cramping. No abnormal clinical chemistry or hematological finding s were encountered. Plasma levels of rHCNTF were below detection. Anti bodies to rHCNTF were found in the systemic circulation of only one pa tient. The gradual decline in motor strength and performance of standa rd skills did not improve or worsen. CONCLUSIONS: In this first trial of a recombinant neurotrophic factor to be administered intrathecally by drug pump, the CNTF was well distributed along the spinal canal. Pa in syndromes (headache, radicular pain) that were dose-related occurre d in two patients, but systemic side effects, which had been observed with subcutaneous rHCNTF, did not occur. Intrathecal drug pump deliver y of neurotrophic factors may be the most appropriate way in which to test the efficacy of these high-molecular weight proteins, because hig h CSF levels can be achieved without significant systemic side effects .