EGFR-inhibitors have been used to treat cancer in millions of patients worldwide
A class effect in neuropathic pain - striking effects reported by 70% of patients treated.
EGFR-inhibitors do not have sedative side effects and are not addictive.
A well established drug class in oncology, but with novel mode of action against pain.
Pain relief already documented in >100 patients treated with EGFR-inhibitors at 10 clinics.
The EGFR and its
HER receptor family members
The EGFR is one of the most studied molecules in the human body.
It receives information from extracellular ligands and/or ligand independent activation, such as via SRC kinases, and transmits these signals into the cell, thereby modulating the cell’s behavior.
The EGFR can signal with another EGFR (its “twin”), as a homodimer, or it can signal with one of the other 3 HER family receptors, as a heterodimer.
Mode of action
in neuropathic pain
Since the serendipitous discovery that EGFR-inhibition leads to relief of neuropathic pain, at least five research groups have independently confirmed and/or explained the mode of action.
Although several of the EGFR's activating mechanisms, downstream signaling mediators, and end targets have been implicated, the EGFR itself has consistently been found to be critical in neuropathic pain.
Activation of the EGFR upon nerve damage, leading to translocation of critical ion channels and hyperexcitability of these neurons, is the most likely mechanism.
Potential for a targeted EGFR-inhibitor
When it comes to neuropathic pain: Not all EGFR-inhibitors are created equal – a window of opportunity?
EGFR inhibitors can be too toxic for long term use in non-cancer patients. AKIGAI founders have generated preclinical and clinical observations supporting the development of modified EGFR inhibitors that are targeted for the treatment of neuropathic pain. These modifications can lead to better pain relief, less side effects and better market protection.
The Two Routes of Administration
Several EGFR-inhibitors are approved for treatment of various cancers. These include monoclonal antibodies for intravenous use and tyrosine kinase inhibitors which come as oral tablets.
- Tyrosine kinase inhibitors
given as tablets
EGFR-inhibitors in tablet form are preferable for most cases of neuropathic pain and CRPS.
We will therefore repurpose AKI-007 tablets for the treatment of neuropathic pain. The rare disease Complex Regional Pain Syndrome (CRPS) is widely regarded as one of the most severe and debilitating pain conditions. To date, no drug has ever received FDA or EMA approval for this indication. However, we have seen frequent, dramatic and sustained effects from EGFR-inhibitors in CRPS patients. Our development candidate (AKI-007) has been granted orphan drug designation by both the FDA and EMA, reinforcing the promise of our approach.
AKIGAI is currently preparing for a Phase III clinical trial in CRPS.
As a rare disease in chronic patients, CRPS is a perfect stepping stone to entering the neuropathic pain market and will be followed by other neuropathic pain indications.
AKI-007 will relief many patients from neuropathic pain. This is not a hypothesis, but an obligation we have embarked on to fulfill.
- Monoclonal antibodies
for parenteral use
A hypothesis we have, however, is that even AKI-007 can be improved upon by a targeted and adaptive monoclonal antibody against the EGFR. This antibody will take longer to reach the patients, but it may have even stronger efficacy, reduced toxicity and improved bioavailability.
This form of administration may also be preferred in patients with acute or transient pain and among patients who cannot swallow/absorb tablets. Examples of these pain entities are cancer-related neuropathic pain, post-traumatic and post-operative neuropathic pain.
Publications
Further prospective systematic observations from an exploratory study in patients with neuropathic cancer pain.
Positive signals in a randomized, phase-II placebo-controlled proof of concept trial using EGFR-inhibition in CRPS and compressed nerve injury.
Ten institutions have reported dramatic relief of neuropathic pain after treatment with EGFR-inhibitors in >100 patients.
In summary, AKIGAI founders Christian Kersten and Marte Cameron believe that EGFR-inhibitors could ultimately help 3 out of 4 patients with neuropathic pain. “We see almost immediate effects, sometimes like turning a switch, without the need for dose titration and without central nervous system side effects or problems related to abuse and addiction”.