Low Molecular Weight Dextran Sulphate Safe in Phase 2 Study of ALS

Ann Logan, PhD, BSc

Data from a prospective, single-arm, open-label phase 2 trial (NCT03705390) published in PLOS One showed that long-term treatment with weekly injections of 2 mg/kg of a low molecular weight dextran sulphate (ILB) compound (TikoMed AB) was safe and well tolerated, with no treatment terminations or withdrawals in patients with amyotrophic lateral sclerosis (ALS). A larger trial with longer follow-up, optimized dosing, and a formal control will be needed to establish efficacy for dextran sulphate.^1,2

From April 2019 to March 2020, 11 patients with ALS were recruited into the study and received ILB at a dose of 2 mg/kg via subcutaneous injections, given as a single injection in alternating sides of the abdomen, once per week for 10 weeks on an out-patient basis by a trial investigator. Dosing beyond 10 weeks, initially to 24 weeks, and subsequently to a maximum of 48 weeks was accompanied by a formal review at the time of extension, and subsequently every 90 days to determine whether they continued to meet eligibility criteria, and the most suitable treatment options.

As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and study treatment was suspended, along with the decision to terminate the study prematurely in October 2020. In total 8 patients continued to attend their long-term follow-up visits between June and July 2021, while the remaining 3 patients died since their previous visit. Overall, median follow-up for all patients was 21.2 months (range, 14.3-25.7).

Throughout the trial, 270 adverse events (AEs) were recorded, most of with were mild (98.1%), with 4 (1.5%) grade 2/moderate events, and 1 (0.4%) grade 3/severe event. Of these, 33.4% (n = 92) were assigned as related to ILB (bruising), 1 probably related, and 4 as possibly related. Overall, no intolerable AEs were reported during the study. The 1 serious AE, a case of raised liver function tests, was not related to ILB and was resolved without sequalae.

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Although the trial was not powered for efficacy, no patient experienced a 50% deterioration in ALS Functional Rating Scale-Revised or ALSAQ-40 scores that were predefined individual stopping criteria of the study. In addition, all patients showed stable scores on both assessments, with no clinically significant changes. During a 38-week period, data suggested no change in measured disease biomarkers of urinary p75ECD and plasma neurofilament light levels.

"Taken together, the previous study at the Sahlgrenska Hospital in Gothenburg and the more recent Birmingham trial demonstrate the safety and tolerability of ILB® in patients with ALS and further suggest a long-term slowing of disease progression in addition to the already reported rapid improvements in patient biochemistry and residual motor function,” Ann Logan, Honorary Professor of Regenerative Medicine at the University of Warwick, said in a statement.¹ "The delivery of fast functional benefit alongside long-term disease stabilization would make ILB® a unique treatment option for this devastating disease. These encouraging results indicate the future potential of ILB® to be the first disease-modifying drug to treat both familial and sporadic ALS with minimal side-effects."

Due to the small sample size with complete data (n = 3), a full pharmacokinetic evaluation of ILB could not be performed. Among those with data, pharmacokinetics of plasma human growth factor (HGF) also confirmed detectable systemic HGF release following ILB administration with a strong significant relationship between ILB and HGF concentration in the samples. In addition, the Cmax levels were similar to those seen in a previously reported ILB study but high levels of circulating HGF persisted for longer. The positive correlation between the concentration of ILB and HGF in patients’ plasma observed (R2 = 84.64%; P <.0001) confirmed previous reported of ILB dose-dependent increase in plasma HGF.

Regarding the pharmacokinetic evaluation, the study investigators wrote, "This problem was mitigated here by rejecting compromised samples that were easily identified. It is recognized that poor quality samples should be replaced at the pre-analytical stage, while at the analytical stage attention should be given to the total error in the measurements and the correct analysis of internal QC samples. It is recommended that the quality performance of laboratories collecting, storing, and analyzing samples be fully documented before clinical trial samples are analyzed."²

REFERENCES
1. Swedish company TikoMed announces successful outcome of phase II safety trial on patients with confirmed Amyotrophic Lateral Sclerosis (ALS) treated with weekly ILB® injections. News release. July 22, 2024. Accessed July 22, 2024. https://news.cision.com/let-em-know-ab/r/swedish-company-tikomed-announces-successful-outcome-of-phase-ii-safety-trial-on-patients-with-confi,c4017195
2. Srinivasan V, Homer V, Barton D, et al. 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. PLOS One. Published online July 11, 2024. doi:10.1371/journal.0291285