On August 28, 2012, Eli Lilly & Co (NYSE:LLY) announced it was discontinuing development of LY2140023, an investigational pomaglumetad methionil for the treatment of schizophrenia. The news does not come as a surprise to us, considering that Lilly told us in July that the drug failed to meet its primary endpoint in a phase 3 clinical study. Management at Lilly previously believed that pomaglumetad methionil, a glutamatergic-based agonist on mGlu2/3, would offer an improved side effect and tolerability profile over existing atypical antipsychotic drugs because the mGlu2/3 receptor is not associated with motor dysfunction, reproductive hormone irregularity, weight gain and lipid elevation. Unfortunately for Eli Lilly, management could not prove targeting the mGlu2/3 receptor improved positive or negative symptoms of the disease.
Investors in Addex Therapeutics (OTC:ADDXF) might be wondering what this all means for the company's phase 2 candidate, ADX71149. Addex' ADX71149, currently partnered with Johnson & Johnson (NYSE:JNJ), is a positive allosteric modulator (PAM) of metabotropic glutamate receptor 2 (mGluR2). J&J and Addex believe that ADX71149 has the potential to be the first oral, non-dopaminergic drug that addresses both the positive and negative symptoms of schizophrenia, with an improved side effect and tolerability profile compared to atypical antipsychotics.
... A Little Background On Allosteric Modulators ...
In a conventional biologic pathway, the body's own signaling molecule may turn on (agonist) or turn off (antagonist) a signal transduction by binding to a specific receptor protein on the surface of the cell membrane. These signaling molecules may be neurotransmitters, chemokines, hormones, growth factors, cytokines, etc. In the simplest terms, the binding of these signaling factors to the receptor site elicits a physiological response. This physiological response could be gene activation, cell proliferation or apoptosis, metabolic alteration, or the triggering another cellular signal transduction cascade.
Pharmaceutical and biotechnology companies may seek to develop drugs - small molecules or biologics / peptides - that bind to the targeted receptor to inhibit or enhance this signal transduction. The more specific the molecule is for the binding site, the lower the potential for off-site binding and unwanted side-effects. Drug candidates can also look to bind to the extracellular signal itself, altering its binding potential on the cell membrane receptor site.
An inhibitory drug competes with the body's own signal to mute the secondary response. Another drug may look to mimic the body's own signaling molecule to enhance the secondary response. Generally speaking, conventional small molecule drugs, when binding to the receptor site, work like a light switch with respect to the secondary signal transduction - they either turn it "on" or turn if "off."
Dose-ranging studies are conducted to find the proper concentration of the drug necessary to turn on or turn off the proper number of cells in an effort to find the right balance between efficacy and unwanted side-effects. Primarily, these drugs work in competition with the body's own cellular cascade to affect a therapeutic benefit.
Allosteric modulators operate under an entirely different model. Instead of working in competition with the body's own signaling molecules, they work in concert (symmetry model). And instead of acting like a light switch with respect to turning on or turning off the signal, they act more like a dimmer switch - raising or lowering the signal. Allosteric modulators do not bind to the receptor site. They are an effector molecule that binds to an allosteric (other non-active) site on the cell membrane. The body's own signal ligand is free to bind without competition to the target site. This creates a number of benefits with respect to drug development:
- It allows for concomitant dosing of allosteric molecules with existing small molecules to target one pathway (e.g. lowering the dose and enhancing the signal of an existing small molecule). An existing drug therapy may have a small therapeutic window based on poor tolerability at an effective dose. Using an allosteric modulator may allow for the same level of efficacy with a lower dose of the small molecule, improving tolerability.
- Similarly, when large ligand binding sites (peptide receptors) are needed to elicit a therapeutic response, small molecules are ineffective. In a disease state, the natural peptide may be under-produced and thus the signal muted. Allosteric modulators can be used to amplify the body's muted response due to the underlying disease.
- By keeping the body's own natural ligand in place as the signaling molecule, it reduces the effects of "off-target" orthosteric agonists (or antagonists) binding by a conventional small molecule drug, potentially reducing side-effects in improving tolerability.
- While one extracellular signaling molecule (neurotransmitter, hormones, cytokines, etc.) may bind to multiple target sites eliciting different physiological responses, allosteric modulators are highly specific for the allosteric site on the cell membrane. Highly specific binding of the allosteric modulator allows for greater sensitivity on the target response, while limiting impact on other pathways in a related family.
Allosteric Modulators Reduce "Off-Target" Binding
There are two types of allosteric modulators: Negative Allosteric Modulators (NAMs) work to dim the signal to the cell by binding to an effector site on the cell membrane, and Positive Allosteric Modulators (PAMs) work to enhance the signal to the cell by binding to an effector site (often a different site than the NAM) on the cell membrane.
Allosteric Modulators - A Better Light Switch
The idea behind Addex' ADX71149 is simple. In normal neurotransmission, there is a balance of glutamate at the dopaminergic terminal. Glutamate is a powerful transmitter in the brain and integral to the normal functioning of memory, learning and perception. Too much glutamate can lead to seizures and the death of brain cells. In the schizophrenia disease state, the dopaminergic terminal may be flooded with excess glutamate, causes both positive and negative symptoms of the disease. ADX71149 is designed to bring the balance back to a more normalized state.
In January 2005, Addex and Johnson & Johnson entered into a worldwide research collaboration and license agreement to discover, develop and commercialize novel compounds modulating allosterically G-Protein Coupled Receptors for the treatment of anxiety, depression, schizophrenia and Alzheimer's disease. The deal came with €7.2 million for two years of research funding by J&J, which was later expanded when the duo selected ADX71149 to move into clinical studies.
As a result, ADX71149 is now in the hands of Janssen Pharmaceuticals at J&J. J&J handles all costs associated with development of ADX71149. Addex has received a total of €10.2 million in upfront and milestone payments to date on ADX71149, with the potential to receive an additional €109 million in future milestones and potential low double-digit royalties on worldwide sales once commercialized.
...Differences From Lilly's Drug...
Off the cusp, Lilly's mGlu2/3 agonist and Addex' mGlu2-PAM may seem rather similar. But there are some key differences that we see. Lilly's drug was a conventional small molecule that works by mimicking the body's own signaling molecule to enhance the uptake of glutamate. It looked to turn the light switch on, and keep it on. Addex' drug is a positive allosteric modulator (PAM). It looks to increase the efficiency at the receptor - i.e. making the light brighter.
Bioavailability may have played an important role in Lilly's failure. LY2140023 did not penetrate the blood brain barrier in preclinical studies, so Lilly had to reformulate using a pro-drug. Addex tells us this is not an issue for ADX71149.
The history with LY2140023 isn't all that impressive. The drug had mixed phase 2 success, meeting statistical significant in one phase 2 trial in September 2007 but failing another in April 2009. Lilly decided to proceed into phase 3, focusing on a predefined genetic subpopulation of schizophrenics - a strategy of which we have never been a big fan. J&J seems a bit more realistic with ADX71149, believing that the future for the drug lies as an adjunct therapy targeting patients with a more difficult-to-treat negative symptoms of schizophrenia, which include social withdrawal, depression, anxiety, apathy, attention deficit disorder, alogia, anhedonia, asociality, and avolition. The concept builds off the advantages of allosteric modulators, allowing for concomitant dosing to amplify the body's response without bring on new side effects.
J&J is testing ADX71149 in a phase 2a trial initiated in March 2011, a move which triggered a €2 million milestone payment to Addex. The trial is a double-blind, placebo-control, EU-centric study seeking to enroll 105 patients with schizophrenia. The trial studies ADX71149 as an adjunct therapy aiming to reduce positive symptoms or predominant negative symptoms or in subjects with insufficient response to clozapine. Endpoints will examine tolerability, safety and efficacy. We expect data from this phase 2a study by the end of the year.