Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis--A Pilot Study

André Maier, Nikolaus Deigendesch, Kathrin Müller, Jochen H Weishaupt, Alexander Krannich, Robert Röhle, Felix Meissner, Kaaweh Molawi, Christoph Münch, Teresa Holm, Robert Meyer, Thomas Meyer, Arturo Zychlinsky, André Maier, Nikolaus Deigendesch, Kathrin Müller, Jochen H Weishaupt, Alexander Krannich, Robert Röhle, Felix Meissner, Kaaweh Molawi, Christoph Münch, Teresa Holm, Robert Meyer, Thomas Meyer, Arturo Zychlinsky

Abstract

Preclinical studies show that blocking Interleukin-1 (IL-1) retards the progression of Amyotrophic Lateral Sclerosis (ALS). We assessed the safety of Anakinra (ANA), an IL-1 receptor antagonist, in ALS patients. In a single arm pilot study we treated 17 ALS patients with ANA (100 mg) daily for one year. We selected patients with dominant or exclusive lower motor neuron degeneration (LMND) presentation, as peripheral nerves may be more accessible to the drug. Our primary endpoint was safety and tolerability. Secondary endpoints included measuring disease progression with the revised ALS functional rating scale (ALSFRSr). We also quantified serum inflammatory markers. For comparison, we generated a historical cohort of 47 patients that fit the criteria for enrollment, disease characteristics and rate of progression of the study group. Only mild adverse events occurred in ALS patients treated with ANA. Notably, we observed lower levels of cytokines and the inflammatory marker fibrinogen during the first 24 weeks of treatment. Despite of this, we could not detect a significant reduction in disease progression during the same period in patients treated with ANA compared to controls as measured by the ALSFRSr. In the second part of the treatment period we observed an increase in serum inflammatory markers. Sixteen out of the 17 patients (94%) developed antibodies against ANA. This study showed that blocking IL-1 is safe in patients with ALS. Further trials should test whether targeting IL-1 more efficiently can help treating this devastating disease.

Trial registration: ClinicalTrials.gov NCT01277315.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Study design.
Fig 1. Study design.
Fig 2. ALS disease progression.
Fig 2. ALS disease progression.
Absolute values (A) and changes from baseline (B) in ALSFRSr total score during the 12 months study period comparing the group of patients treated with ANA and the historical control.
Fig 3. Inflammatory serum parameters.
Fig 3. Inflammatory serum parameters.
Serum concentrations of the inflammatory cytokines IL–6 (A) and TNF (B) as well as the and hepatic acute phase proteins fibrinogen (C) and C-reactive protein (D) in all the patients included in the study.

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