1 September 2024
Reduced neurotoxicity with SPL's dendrimer enhanced oxaliplatin
Melbourne, Australia: Starpharma Holdings Ltd (ASX: SPL, OTCQX: SPHRY) today announced further positive results for its Dendrimer-Enhanced Oxaliplatin (DEO), specifically that its dendrimer version of oxaliplatin results in a significant reduction in the serious neurotoxicity commonly seen with oxaliplatin.
Oxaliplatin is widely used primarily to treat colon and colorectal cancer and it achieved sales of approximately US$2B in 2012. The leading brand is ELOXATIN® marketed by Sanofi.
Neurological adverse effects are the dose-limiting toxicity for ELOXATIN® (oxaliplatin) with peripheral neuropathy occurring in around 85-95% of patients[1]. The neuropathy caused by the drug takes two main forms, one which is often triggered by cold and is usually transient, and another more serious form that results in chronic neuropathic pain and disturbances of nerve function which can lead to difficulties in fine motor tasks such as writing or using a computer keyboard.
In this blinded study, conducted at the University of Maryland in Baltimore[2], Starpharma’s novel, proprietary Dendrimer-Enhanced Oxaliplatin showed significantly reduced neurotoxicity in validated animal models for both forms of these neuropathies. In fact, both neuropathies were reduced with Dendrimer-Enhanced Oxaliplatin compared to oxaliplatin alone, even when DEO was used at twice the dose of oxaliplatin.
The finding of significantly reduced neurotoxicity with DEO follows results released in September which demonstrated Starpharma’s Dendrimer-Enhanced Oxaliplatin also both improved anti-cancer efficacy and resulted in reduced bone marrow toxicity, when compared to ELOXATIN® in a mouse model of colon cancer.
“The neuropathy which occurs commonly with oxaliplatin is a serious and debilitating condition for patients and often lasts for years. In the clinic typically the intensity and duration of symptoms of neuropathy increase as the cumulative dose of oxaliplatin increases and may lead to the need for dose reduction or even treatment cessation. For this reason clinicians and patients agree that it would be of tremendous benefit if it were possible to reduce or prevent this most unpleasant side effect,” said Starpharma chief executive Dr Jackie Fairley.
The dose limiting toxicity of this widely used drug, marketed by Sanofi, is known to cause short-term disordered nerve function (cold sensitivity) coinciding with cycles of treatment and also longer-term nerve damage in the hands and feet (peripheral neuropathy) which, for many patients, will be life-long.
“What we’ve now shown here with our dendrimer version of oxaliplatin, is that, in addition to earlier reported advantages in efficacy and reduced blood toxicity, we are also able to reduce the primary dose-limiting neurotoxic side-effect of ELOXATIN® - even at double the dose. This is very exciting news indeed,” added Dr Fairley.
“Just the reduction in neurotoxicity alone would represent a significant advantage for oxaliplatin but when considered alongside the earlier improvements in efficacy and reduced bone marrow toxicity, this finding demonstrates that our dendrimer technology can deliver a considerable overall enhancement to this blockbuster drug. The beneficial characteristics of Starpharma’s dendrimer technology have also been shown in other drugs including the chemotherapeutics docetaxel and doxorubicin,” she said.
Starpharma has already announced it is advancing Dendrimer-Enhanced Oxaliplatin derivatives into development, based on the positive results of the earlier pre-clinical trials.
These results showing a reduction in the neurotoxic effect with the dendrimer version (DEO) compared to ELOXATIN® were conducted by leading researchers in the field of drug induced neuropathy at the University of Maryland in Baltimore[3]. In commenting on the significance of these results lead researcher, Professor Susan G. Dorsey, Director, University of Maryland, Baltimore, Center for Pain Studies, said:
“We see these findings are very significant because this condition is a serious clinical problem and the dendrimer version of oxaliplatin clearly shows a reduced level of neurotoxicity. We are unaware of any other examples of this effect reported for other oxaliplatin formulations in the literature.”
Study Description and Findings
The chronic neurotoxicity of ELOXATIN® and Dendrimer-Enhanced Oxaliplatin (DEO) was assessed as follows in a mouse model:
All mice (8 per group) underwent neurologic assessments prior to drug treatment. They were treated twice weekly for 4 weeks (a total of 8 doses) with either oxaliplatin (1.75mg/kg platinum equivalents) or DEO (3.5 mg/kg platinum equivalents). Neurologic assessments were then conducted weekly for 4 weeks. All assessments were conducted in a blinded manner using a standardised protocol.
Two neurologic assessments previously validated for oxaliplatin were used - assessing responses to mechanical and thermal stimuli (Von Frey and cold sensitivity). Mechanical allodynia[4] is sensitivity to a stimulus that would not normally cause a reaction. The reduced response to stimuli for oxaliplatin and DEO was measured using the Von Frey assessment method and plotted as % reduction from baseline (Figure 1). Thermal sensitivity was assessed by recording response to cold stimuli (Figure 2).
Results:
1. DEO results in reduced peripheral neuropathy compared to oxaliplatin
Figure 1 – Mechanical allodynia (increased sensitivity) measured using Von Frey
As can be seen from Figure 1, the DEO treated animals exhibited a significantly reduced mechanical allodynia throughout the 4 week experiment despite the fact that DEO treated mice were dosed at 3.5mg/kg platinum equivalents which was twice the platinum dose that given to the ELOXATIN® treated animals (1.75mg/kg platinum equivalents). This suggests a marked reduction in the neurotoxic effect for DEO compared to ELOXATIN®.
2. DEO results in reduced cold sensitivity compared to oxaliplatin
Figure 2 – Cold allodynia (increased sensitivity to cold) measured using Cold Plate
As can be seen from Figure 2, the DEO treated animals exhibited a significantly reduced cold allodynia at weeks 3 and 4. This also suggests a marked reduction in the neurotoxic effect for DEO compared to ELOXATIN®.
Conclusion
In September Starpharma reported advancing its Dendrimer-Enhanced Oxaliplatin derivatives into development following impressive improved tumour-inhibiting effectiveness and reduced bone marrow toxicity. This latest data, demonstrating the reduced neurotoxicity of Dendrimer-Enhanced Oxaliplatin, indicates a further commercial enhancement of this product candidate.
This further demonstration of the advantages the Company’s dendrimer technology adds to a growing body of data on the platform’s ability to provide clinically valuable benefits over existing products. These provide us with much confidence as we progress our most advanced product candidate - dendrimer-docetaxel into the clinic later this year.
The commercially attractive findings reported here for oxaliplatin add to the growing list of advantages offered by the company’s proprietary dendrimer nanoparticle technology across a range of therapeutic agents. These include:
- enhanced tumour efficacy
- reduction in several important toxicities
- improved solubility
- tumour targeting
- half-life extension and
- Manufacturing advantages such as improved product stability, high particle loading, and scalability.
Starpharma’s Dendrimer-Enhanced Oxaliplatins are protected by a portfolio of filed and granted patents, both for the molecules themselves, and on Starpharma’s underlying drug delivery technology.
[1] ELOXATIN® Product Information; Sanofi-Aventis.co.uk
[2] Professor Susan G. Dorsey, Director, University of Maryland Center for Pain Studies, School of Medicine, University of Maryland Baltimore and Professor Cynthia L. Renn, University of Maryland Center for Pain Studies.
[3] Professor Susan G. Dorsey, Director, University of Maryland Center for Pain Studies, School of Medicine, University of Maryland Baltimore and Professor Cynthia L. Renn, University of Maryland Center for Pain Studies.
[4] Allodynia is a condition in which pain arises from a stimulus that would not normally be experienced as painful.
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