Background

Chemotherapy-induced peripheral neuropathy (CIPN) is caused by many chemotherapeutic drugs, such as taxanes (e.g. paclitaxel), vinca alkaloids (e.g. vincristine), platins, bortezomib, ixabepilone and thalidomide.

Symptoms:

Numbness to touch and vibration
Sensitivity to temperature, touch and pain
Burning pain
Described as “walking on needles”.

High frequency for chemotherapeutic drugs, with up to 50% of patients experiencing it for paclitaxel. For some chemotherapeutics, symptoms debut after treatment is concluded and might persist for several years after last chemotherapy dose.

Thus, CIPN impacts drug efficacy and long-term quality of life. With an increasing proportion of patients surviving their cancers, this is of particular concern.

No effective treatment is available. Several substances were shown to be effective in animal models, but this has not translated into clinical efficacy. Novel targets and drugs are warranted for this devastating toxicity.

Technology Overview

TBS’ group has recently shown that neurons in the peripheral nervous system express drug transporters that facilitate extrusion of chemotherapeutics.
The invention is attempting to increase expression of a drug transporter involved in the extrusion of chemotherapy from these cells (neurons), which should help protect neuronal cells from chemotherapy-induced neurotoxicity.
TBS’ group has shown that inhibiting activity of the efflux transporter P-glycoprotein causes exacerbated neuronal toxicity in cell models and that this extends to humans.
- Additionally, they have shown that increasing expression (inducing) of P-glycoprotein by rifampicin leads to neuroprotection against paclitaxel-induced peripheral neuropathy. They predict that this may extend to other chemotherapeutics such as docetaxel and vincristine as well and that P-glycoprotein induction could be mediated by other inducers such as (but not limited to) carbamazepine and dexamethasone.
The idea is to develop a dermal application of a drug that induces P-glycoprotein. This should lead to increased efflux of chemotherapy in sensory neurons and may protect cancer patients against CIPN.
There are currently no treatments for this (CIPN) debilitating side effect.
The group’s findings are based on state-of-the-art stem cell systems.
This invention is dermally applied inducers of P-glycoprotein to protect the patient’s nerve cells from chemotherapy induced damage. The treatment must be local (e.g. a lotion applied for a few days before chemotherapy), as a systemic delivery would counteract the patient’s chemotherapy. Various topical formulations are currently being tested in the lab.
Compared to other on-going efforts to alleviate CIPN, the drugs proposed here are already approved and marketed globally for other diseases. Thus, regulatory approval for a topical medication comprising one of these drugs should be more straight-forward than for a new drug
This proposal is the first direct mechanism-based treatment of chemotherapy-induced peripheral neuropathy. Current treatments are either cumbersome (i.e. cryotherapy of hands/feet to treat neuropathy) or systemic (i.e. neurologic drugs such as gabapentin) and their efficacy is very limited.

Figure 1: Inhibition of drug transporter (P-gp) leads to a higher degree of CIPN Figure 2: Induction of P-gp with rifampicin protects neurons from CIPN

Benefits

More effective cancer treatment (avoid chemotherapy dose reduction due to CIPN)
Higher quality of life
- For cancer patients receiving chemotherapy (avoid acute CIPN symptoms)
- For cancer survivors (avoid chronic CIPN)
Patent protection for use in combination with off-patent or close to off-patent drugs causing CIPN (taxanes, vinca alkaloids, bortezomib)
Candidate drugs Rifampicin have been on the market since 1968 – no topical formulations approved
Topical products pass regulatory processes more easily than internal drug products

Protection Against Chemotherapy-Induced Neurotoxicity

Patents

IP Status

Seeking