Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial

Abstract

Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-alpha) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-alpha pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-alpha inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.

Figure 1

ALSFRS over time for each of the 19 subjects in the study that had at least one post-baseline measurement for this parameter. [Table: see text]

Figure 2

FVC at baseline: mean of 97, range 74–117. X axis is days. Y axis is percentage expected. [Table: see text]

Figure 3

SF 36 at baseline: mean of 98.0, range 77–108. [Table: see text]

Figure 4

Mortality with treatment (dotted line is mortality for controls in the topiramate clinical trial (27)). There was a significant (p =0.02) difference in survival between the two groups. Dashed lines are confidence intervais. Bold line is Kaplan-Meier estimate.

Figure 5

Representative histopathological and immunohistochemical changes observed at autopsy in ALS patient who had taken thalidomide for 13 months. Skeletal muscle displays typical grouped atrophy of myofibers (A). Sural nerve3 which usually shows no or minimal changes in most ALS patients, displays active Wallerian degeneration in patients who have received thalidomide (arrows point to digestion chambers of Cajal, B). Degenerating lower motor neurons within the spinal cord anterior horns display cytoplasmic skein-like aggregates (arrows) that immunostain for TDP-43 (C) and have surrounding microgliosis {CD-68 immunostaining} (D).

Figure 6

Average serum cytokine concentrations in four ALS patients who remained on thalidomide for nine months. Serum was collected prior to thalidomide treatment (baseline) and at 3, 6, and 9 months after thalidomide treatment. No cytokine had significantly higher or lower values compared to baseline values (paired t-test).

Figure 7

TNF-α concentrations in pooled normal human sera and in sera from ALS patients taken prior to thalidomide treatment (baseline, n = 17), and at 3 (n = 17), 6 (n =6), and 9 (n =4) months after thalidomide treatment. There was only a small increase in TNF-α concentration at three months after thalidomide treatment compared to baseline (p =0.045, paired t-test).