A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial

Abstract

Background: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics.

Patients and methods: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28.

Findings: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection.

Interpretation: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

Trial registration: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.

Fig 1. ALS trial profile.

CONSORT diagram of the ALS trial.

Fig 2. Patients’ treatment during the ALS trial.

Swimmer plot to visualise adherence to trial treatment and ordered by patients’ treatment duration.

Fig 3. Symptom progression and quality of life of patients during the ALS trial.

Trajectories of ALSFRS-R scores (A) and ALSAQ-40 Summary Index scores (B) through time during the ALS trial. Patients’ data are presented as the safetypopulation, with the solid line showing those who are also in the per-protocol population. Each patient is presented as a different coloured line.

Fig 4. Pharmacokinetics of ILB^®.

Repeated measures of the plasma concentration of ILB^® per patient are shown. Plasma samples were analysed before, and 0.5, 1.0, 2.0, 2.5, 3.0, 4.0, and 6.0 hours after initial ILB^® injection via a fluorescence probe assay (Heparin Red^® Kit). * Indicates in which datasets half-life could not be calculated (see S7 Appendix). Note: Each patient with a complete pharmacokinetic sample series is presented as a different coloured line. Results from four patients were not included due to haemolysis of the plasma in some of their samples. In addition, the results from one patient’s samples were not included due to an incomplete pharmacokinetic series. The sample prior to ILB^® administration for one patient was not analysed/missing but all other samples were collected and have, therefore, been included.

Fig 5. Pharmacokinetics of HGF and relationship with ILB^®.

Repeated measures of the plasma concentration of human growth factor (HGF) per patient are shown (A). Plasma samples were analysed before, and 0.5, 1.0, 2.0, 2.5, 3.0, 4.0, 6.0 hours after initial ILB^® injection via Quantikine^® ELISA immunoassay. Concentrations of plasma HGF and ILB^® measured at the same time points were plotted against each other to assess their relationship (B). Note: Each patient with a compete pharmacokinetic sample series is presented as a different coloured line. The results from four patients were not included due to haemolysis of the plasma in some of their samples. In addition, one patient’s sample data were not included due to an incomplete pharmacokinetic series. The sample prior to ILB^® administration for one patient was not analysed/missing but all other samples were collected and have, therefore, been included.

Fig 6. Biomarkers of ALS progression.

Where available, concentrations of the disease progression markers, urinary p75 extracellular domain (p75^ECD) (A) and plasma neurofilament light chain (NfL) (B), were measured via ELISA. Patients’ data are presented as the safety population, with the solid lines those who are also in the per-protocol population. Each patient is presented as a different coloured line.