Technology & Strategy

Nature has been a source of medicines for millennia, with many drugs developed from plants and, since the discovery of penicillin, microbial sources (see more here and here). However, combinatorial chemistry shifted the focus of drug discovery efforts in the mid 1990's from Nature to the laboratory bench.

Why Natural Products? Polypharmacology as a desirable goal

A number of recent reports (for example here and here) point to a revision of the single-target dominant paradigm in the drug discovery strategies since the mid 1990's. Interestingly, the analysis by Swinney and Anthony of discovery strategies found that most first-in-class drugs were discovered by phenotypic screening. As pointed out recently by Douglas B. Kell, classical drug discovery started with an organism displaying a disease phenotype and involved the assay of various drugs to identify one or more that was efficacious. There was no need to discover (let alone start with) a postulated mechanism of drug action; for a successful drug, this could come later (often much later). This ‘function first’ approach (equivalent to ‘forward’ genetics), has lead to the discovery of many drugs, most of them natural products, that are still in use (and mainly still without detailed knowledge of their mechanisms of action).

On the other hand, as a result of the genome sequencing programs, drug discovery changed to an approach that was based on the ability of chemicals to bind to or inhibit chosen molecular targets in vitro at low concentrations in vitro. This would then necessarily be followed by tests of efficacy in whole organisms. This approach is thus ‘target-first’, and is equivalent to ‘reverse’ genetics, and (despite some spectacular new molecules that work on selected patients) has been rather ineffectual because the vast majority of small molecule drugs (90–95%) fail to go forward, even from the ‘first into humans’ phase, to become successful and marketable drugs; a set of phenomena known as ‘attrition’.

EntreChem focus on natural product analogs is a bet to go back to data-driven science, rather than hypothesis-driven research, in a quest to avoid attrition, especially the lack of efficacy of drugs in Phase II studies, and to explore the potential of multi-targeted drugs as compared to single-target combination approaches.

EntreChem strategy

EntreChem strategy for bringing Natural Products back in the forefront of Drug Discovery avoids the early stages of the classical Natural Products-based drug discovery programs (isolation of environmental samples, extract analysis, de-replication, lead identification) and starts with a known lead compound (either an approved, clinical-stage or bioactive molecule) over which we apply our technology to obtain new analogs difficult to obtain by other methods, effectively representing a barrier of entry to others (aside from filed IP).

These new analogs are the source of better candidates for preclinical development, since the small-size, focused, libraries allow phenotypic screening including in vivo testing to prioritize low toxicity, high bioactivity analogs.

Additionally, since we obtain analogs of products with somewhat known properties, we are reducing risks, both technical and commercial, associated to previously unknown product families.

How we make Drugs

Advances in bacterial recombinant DNA technology have enabled the cloning of gene clusters involved in the biosynthesis of many bioactive Natural Products produced by microorganisms, as well as detailed knowledge of their metabolic pathways, significantly raising the potential of the combinatorial biosynthesis field in the last decade. Complementary to chemical synthesis and microbial fermentation, the manipulation of genes governing secondary metabolic pathways offers a promising alternative for preparation of complex Natural Products and their analogs biosynthetically.

To learn more about our co-founders contribution to the field, see J Antibiot (Tokyo). 2011 Jan; 64(1): 51-7

Gene clusters encoding many Natural Products have been cloned and characterized, and it is now possible to introduce specific structural alterations into a natural product in the presence of abundant functional groups by rational manipulation of the gene cluster governing its biosynthesis. The resulting molecules can be produced in recombinant bacterium by large-scale fermentation and purified and isolated by conventional downstream processes.

A particular aspect of our technology is the development of a series of “sugar plasmids”, able to direct the biosynthesis of rare sugars that form part of numerous bioactive compounds of interest in the clinical, agricultural or veterinary markets. Some high-profile reviews by our co-founders on this topic can be found here and here. These plasmids, combined with several flexible glycosyl transferases capable of recognizing and transferring different sugars that participate in biosynthesis of bioactive compounds, allow building focused libraries of analogs with altered carbohydrate profile. This is especially relevant, since sugar decorating domains are often considered responsible for the modulation of the drug interaction with biological targets.

Privileged Position of Natural Products in Drug Space

According to a recent study by Bauer et al, principal component analysis of 20 structural and physicochemical characteristics of 40 top-selling drugs, 60 natural products and 20 compounds from commercial drug-like libraries, illustrates that Natural Products interrogate a different area of chemical space than synthetic compounds.

Most non-Natural Product drugs and drug-like leads explore underrepresented regions of biologically relevant chemical space, effectively missing opportunities to discover new targets as evidenced by the space covered by approved Natural Product drugs. As a result, libraries of drug-like molecules have proven ineffective against a variety of challenging targets, such as protein–protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries can be developed based on underrepresented scaffolds and regions of chemical space associated with natural products.

Value Chain & Business Model

The Value Chain of New Drugs for Human Health is a time and money-consuming endeavor that typically lasts over 10 years, and it is full of uncertainties, so success is contingent to meet, among others, many technical milestones along the way to commercialization. This complexity provides opportunities for innovators willing to exploit specific technology advantages.

EntreChem is an example of company developing drugs and their supply-enabling technology, in a promising category that bigger companies abandoned since advances in the field were mostly left to academic groups and their spin offs.

Our core activities are the generation of New Molecules, analogs of bioactive compounds, the supply of these for biological in vitro and in vivo testing and the development of an optimized process for the production of the candidate drugs.

We study pharmacological aspects, including mechanism of action, pharmacokinetics and pharmacodynamics both internally and with the help of a top-quality collaborator network. We also perform in vivo toxicity and efficacy testing in rodents, taking advantage of our access to a local SPF vivarium.

Our activities during this start-up phase are, thus localized in the upstream portion of the Value Chain, the entry point being discovery of new molecules obtained by licensing-in agreements with the University of our co-founders and more recently by our own internal R&D efforts.

EntreChem Business Model consists of developing viable compounds through the value chain in order to reach significant technical milestones to the point of licensing-out to a company positioned downstream in the value chain that would take the product through late clinical trials and commercialization. Our corporate strategy is to develop the product until Phase II and then license out.

This business model is supported by the market dynamics, which in the pharmaceutical industry is based on the "Licensing out Licensing In" model, reflecting the highly complex value chain, which very few companies can afford to navigate in its entirety.

In the last 10 years, the contribution of licensed-in products (discovered and partially developed by others) to total sales in the World Drug Discovery Industry has risen from less than 20% to over 40%.

SOURCE: Frost and Sullivan

The average up-front payments of the drugs depend largely on the development stage of the drug at the moment of licensing. The most advanced the drug candidate, the higher the upfront payment.

SOURCE: Elsevier's Strategic Transactions