There has long been a consensus within the pharmaceutical industry that innovation and productivity is a critical focus. Nevertheless, the number of new molecular entities (NMEs) approved each year by FDA shows that industry has not been improving its output, despite progress in development and implementation of enabling technologies.
Over the past 20 years there has actually been a decline in NMEs approved by FDA. Furthermore, many of the NMEs approved are “me-too” molecules for disease states where first-in-class drugs are already on the market. Granted, there are other reasons for the dearth of product innovation—including regulatory issues, an increasing focus on short-term returns by some shareholders, and corporate restructuring—but the fact remains that pharmaceutical companies need NMEs with novel mechanisms and better safety and efficacy than offered in currently available drugs. Clearly, new chemistry allowing access to well known targets that have been intractable to older chemistries could provide a kick-start to the malaise in drug discovery.
A New Kind of Chemistry: Allosteric Modulation
Even as biologics, RNAi, and gene and cell therapies may provide value to patients in the short-to-medium term, small molecule drugs may one day offer patients many of the same benefits in a format that is more patient friendly (i.e. oral administration) and, potentially, with easier manufacturing and/or lower costs compared to non-pharmaceutical drugs. Allosteric modulators are an emerging class of orally available small molecule drugs that may have multiple advantages compared to traditional orthosteric drugs, including biologics.
Allosteric modulators have been shown to achieve greater selectivity, successfully modulating previously intractable therapeutic targets. In addition, orally available small molecule allosteric modulators have been discovered for targets for which only injectable biologic drugs are available. It is easier to achieve selectivity when targeting more heterogeneous allosteric binding sites on targets with therapeutic potential—such as G-Protein Coupled Receptors (GPCRs) and cytokine receptors—than an “active site,” which is often highly conserved across multiple related receptors.
Simply put, the active site on receptors acts as a switch that controls turning receptor signaling. Unlike orthosteric drugs, which turn receptors completely on or off, allosteric modulators act like a dimmer switch to mediate the intensity and frequency of receptor signaling. However, the trigger for signaling remains under the control of the endogenous ligand, which binds the target according to the physiological rhythm determined by the body. In many cases, allowing the body to retain control over initiating signaling while simply increasing or decreasing the amplitude of that signaling may offer a competitive advantage over other approaches. Although it has often been attempted with orthosteric drugs, comparable functional control over receptor signaling cannot be achieved simply by modifying the dose or delivery of orthosteric drugs.
Key Advantages of Allosteric Modulation
- Because they do not compete for the endogenous ligand binding site and exert their effects even in the presence of endogenous ligands, lower doses of allosteric modulators may have greater potency than orthosteric molecules with similar affinity for the same target. Lower dosing often leads to fewer side effects.
- Allosteric modulators can be devoid of activity in the absence of endogenous ligands, offering a less disruptive way to influence the functioning of biological systems and therefore could lead to greater safety and fewer tolerability issues.
- Because they bind on a distinct site, it is possible to create new chemical entities with unfettered intellectual property that re-address well validated GPCR targets for which there are marketed products. In such cases, the goal would be that the allosteric mechanism offer clear differentiation in terms of efficacy and/or side effects.
- It follows that highly selective allosteric modulators can be made for targets where it has been difficult to make selective orthosteric modulators. For example, orally available small molecule allosteric modulators against GLP-1 and FSH receptors—for which only peptide, protein or hormonal therapies are available—have been discovered.
- Because they bind at a separate site, it is possible to combine allosteric modulators with orthosteric drugs. For example, a positive allosteric modulator, or PAM, could be used to potentiate an orthosteric agonist. This could alleviate side effects associated with off-target effects seen at high doses of some orthosteric drugs or simply reduce cost of goods for other orthosteric drugs, especially with biologics.
History of Allosteric Modulators
The concept of allosteric modulation is not new; scientists have been discussing it since the first half of the 20th century, and some suspected such a mechanism even earlier. In the 1960s, Roche introduced the tranquilizer Valium, which later was discovered to act by allosteric modulation of gamma-aminobutyric acid (GABA) receptors. More recent allosteric modulators include Sensipar (cinacalcet, from Amgen), a calcium-sensing receptor PAM, and Selzentry (maraviroc, from Pfizer), a CCR5 NAM.
But these first-to-market drugs were found more through serendipity than through focused searches for allosteric modulators. Indeed, the industrialization of allosteric drug discovery is something that many pharma companies and venture capitalists have shied away from due to the risks and the magnitude of investment.
The search for new drugs has long focused on GPCRs, but of roughly 850 known GPCRs less than 200 have been drugged. Compounds identified through screening have typically worked at the orthosteric site, but after finding the so-called “low hanging fruit,” this approach delivers fewer and fewer hits. In the late 1990s, researchers made some breakthroughs, identifying mGluR selective ligands that didn’t bind to the active sites on glutamate receptors, including allosteric modulators, targeting the metabotropic glutamate receptor 5 (mGluR5), which was discovered by researchers at SIBIA Neurosciences in collaboration with Novartis.
The goal soon became finding similar allosteric drugs; and for this, a new type of screening assay was needed. In the mid-1990s, screening assays evolved to include biological function. When the resulting compounds started to show different types of effects on the receptor, researchers concluded allosteric modulation may be playing a role.
In 2001, Vincent Mutel, CEO of Addex Pharmaceuticals, was a pharmacologist at Roche. Almost by chance, he and his colleagues discovered an allosteric molecule that enhanced the activity of the metabotropic glutamate receptor 1 (mGluR1). This glutamate receptor subtype was not tied to any particular disease, but the finding convinced Mutel that allosteric molecules could enhance an effect as well as block.
Addex was founded in 2002 and initial discovery work focused on targeting mGluR5 for addiction. As mGluRs had been intractable to orthosteric chemistry, Dr. Mutel and his team developed biological screening tools that would detect allosteric modulators of mGluR5 and other mGluR subtypes. It turned out that the tools developed could be adapted to almost any GPCR, and eventually to other types of receptors, like cytokine receptors. GPCRs are the targets of more than 30 percent of all medicines currently on the market . The company has disclosed discovering receptors in all three GPCR families and, more recently advances in the discovery of small molecules targeting receptors such as TNF-R1, IL-1R1, GIPR and GLP-1R, targets that have previously only been addressed by injectable protein or peptide therapeutics .
Future of Allosteric Modulators
The role of specific receptor sub-types has been elucidated in many diseases; however, in many cases, it has been challenging to develop sub-type specific drugs. These cases are the low hanging fruit for allosteric modulators. For example, metabotropic glutamate receptor 5 (mGluR5) has been implicated and clinically or preclinically validated in multiple diseases for more than two decades. But it took Big Pharma more than 20 years after the cloning of the mGluR5 receptor to identify and begin testing selective molecules against this high value target. In the end most if not all the molecules targeting mGluR5 are allosteric modulators. These molecules have progressed into the clinic and are now showing efficacy in humans in a variety of indications.
Addex’s lead compound ADX10059, a negative allosteric modulator of mGluR5, has shown efficacy in separate early Phase II studies for gastroesophageal reflux disease (GERD) and migraines. Clinical and preclinical data from Addex and other groups suggest that the product also has potential in Parkinson’s disease, and certain chronic forms of anxiety and depression. Other companies already are working on mGluR5 inhibitors to treat Parkinson’s disease, Fragile X, and neuropathic pain.
The allosteric drugs also could be combined with conventional orthosteric drugs against the same target to maximize the efficacy of the orthosteric and/or allow use of lower doses. This could be a desirable strategy to minimize dose-related, off-target side effects associated with the orthosteric product while potentially also reducing the cost of goods (especially if it is a biologic).
Allosteric modulators may become a life-cycle management strategy for biologics drugs. In the future, orally available small molecule allosteric modulator may be able to replace or complement many biologic drugs. The cost of a prescription allosteric modulator could, in some cases, obviate the opportunity for bio-generic competition while preserving the profit margin of the prescription biologic.
Allosteric drug discovery and development has only just begun. Many skeptics are being won over and it is beginning to become a mainstream approach. With more than 70,000 potential allosteric modulators in its unique biased library and a growing number of proprietary biological screening tools, Addex is leading the field. Its growing pipeline and partnerships serve as increasingly irrefutable validations. The approach, however, is much bigger than one company, with many in the industry predicting that allosteric modulation will become a new therapeutic class in the medical armamentarium.
Source: findpharma.com
