Abstract

The pharmaceutical industry is being squeezed by a drug development process that is slowing the flow of new products through the pipeline.  As a result, there is a tremendous backlog of “best-in-class” new and late stage drug leads that are being discovered more quickly than the pharmaceutical industry can develop them.  Thus, at time when they are needed most, some of the industry’s most valuable leads remain unexploited and under explored.  There is, however, tremendous opportunity in this backlog of challenging but active molecules.   The development of an advanced platform technology that can reduce the time and cost to bring these new products to market can re-energize the pharmaceutical industry, and propel it decades into the future.

From Where Will the Next Blockbusters Come?

There is a deep sense of anxiety in both the financial and healthcare sectors given the current state of the pharmaceutical industry.  At a time when high profile drug classes are being withdrawn, patent protection is expiring and pharmaceutical companies are pinning their financial health on second and third generation “me too medicines”,  never has so money much been spent on research and development with so little result. 

Companies are taking longer than ever to bring products to market, and periods of market exclusivity are diminishing rapidly.  Even after a medicine is discovered teams of engineers, biologists, chemists and physicists must spend long hours figuring out how to mass produce the results achieved by an individual scientist at the lab bench.  Often promising experiments are not replicable on a large scale - the reaction may give off extreme heat, or cause an explosion, or release a toxic gas. The research may fail because it is not possible to manufacture the drug safely or to the proper specifications.

More importantly, in an industry where new product pipelines are everything, there are not enough drugs in the piepeline.  Investigational new drug applications have decreased alarmingly over the last decade, and the expanding role of biotechnology has introduced even more uncertainty into the industry.  When one biologic drug can cost a patient as much as $25,000 per year, how many drugs of this type can a patient afford or will the health care system absorb?

The era of new, high-margin small molecule drugs is quickly vanishing, and pharmaceutical companies are looking for ways to maintain a constant flow of new products.  Traditional small molecule drugs will undoubtedly remain part of the industry’s focus, as will large molecules and the continued expansion into biotech.  The question is “Will these developments provide a strong enough platform to sustain the industry’s growth?”

Macrocycles: The Next Generation of Blockbusters

Pharmaceutical companies, academic institutions and research organizations have discovered countless molecules that are ready to be developed, but are substantially more expensive to move through the pipeline with current research and development methods.  These formulas are subsequently relegated to the file cabinets, which results in the postponement of new drugs until a new, less expensive means of development is discovered.

These drug leads, collectively referred to as macrocycles, are a particularly rich source of novel drug candidates that combine the potency and selectivity of large molecules with the preferred properties of small molecules.  Although some scientists may challenge the assertion that macrocycles make better drugs than both small and large molecules, the data is overwhelming.  Molecules in nature are often brought to a bioactive conformation by ring formation (macrocyclization).

Macrocycles are small to medium sized natural, semi-natural, or artificial molecules where the atoms are connected in a fashion such that they form a ring. These molecules occupy the vast area of chemical space that lies between small molecules and large molecules, but have been largely unexploited due to the difficulties associated with their synthesis.  Until now, methodologies for producing macrocycles required years of work, produced large amounts of toxic waste, required large and expensive manufacturing facilities, and yet still produced very low yields of the desired material. 

Despite these past difficulties, however, a great deal of research is still conducted using macrocycles. The cyclic structure of these molecules make them particularly attractive drug targets since it protects them from destruction by the human body, and increases their effectiveness compared with their linear analogs by constraining it to an active form. 

A recent Harvard study demonstrated that cyclization of biologically-active linear compounds increased the specificity of responses and was the DOMINANT factor in global activity patterns. As a result, the potential for creating blockbuster leads from macrocycles is enormous, where hit rates in some macrocyclic libraries are as high as 1 in 100, very much better than is seen in small molecule libraries where the figure is closer to 1 in 10,000.

Ready access to these molecules will energize an industry that is starved for new products - enabling companies to quickly expand their product pipeline with cutting-edge, first-in-class pharmaceuticals, and accelerate research on pioneering pharmaceuticals that would not otherwise be viable for many years into the future. 

So Why Don’t More Macrocycles Make it to Market?

Naturally-occurring macrocycles are highly evolved, highly specific, and can be highly effective toward the gene products with which they coevolved.  And for more than 50 years these macrocycles have been a wellspring of drugs and drug leads, serving as the inspiration for nearly every new drug class introduced by the pharmaceutical industry.  Industry icons such as Insulin, FK-506, Taxol, and Vancomycin are all macrocycles.  

Accordingly, macrocycles constitute a major class of pharmaceutical agents currently under pre-clinical and clinical investigation for the treatment of virtually every disease.  Furthermore, macrocycles are key components in drug delivery and diagnostic technologies. 

Notwithstanding their long history as lead compounds, very few intact macrocycles make it to market.  This difficulty is NOT due to a small number of promising leads.  Quite the contrary, over the past decade, the number of macrocycles has increased in an explosive manner.   In fact, the macrocyclic structure is arguably the most diverse structure found in nature. 

Paradoxically, the cyclic nature of this class of molecules has made it notoriously difficult and expensive to obtain them in sufficient quantities – the poster-child for the challenges associated with bringing scientific discoveries from the laboratory to the marketplace.  While some of these compounds are available from biological sources in quantities sufficient for basic research or initial clinical studies, others need to be produced by semi- or total synthesis.  And unfortunately, the constant incremental improvement of biological and synthetic methods available to the pharmaceutical industry has not kept pace with the level of complexity found in the industry’s most promising lead compounds. 

Thus, regardless of the overwhelming clinical success of macrocycles, many valuable leads have been abandoned in late stages of development OR were marketed as less potent linear analogs. 

Unfortunately for the pharmaceutical industry, stockholders and patients, these linear analogs rarely if ever achieve the therapeutic benchmark established by their cyclic ancestors.  Thus, the staggering potential of macrocyclic research and development is largely unrealized as the result of the inability of the art to provide a practical method for making such compounds.

ODIN Industries Provides the Key to Macrocycle Research and Development

 ODIN Industries is a molecular engineering company that has developed an advanced platform technology for the preparation of macrocyclic compounds.  This is a timely solution that expands the range of innovative new molecular entities that are accessible to the pharmaceutical industry. 

ODIN’s new “high concentration” synthetic process dramatically simplifies the preparation of many new and late-stage drug leads by using robust proprietary methods with high selectivity for the desired product.  This allows pharmaceutical companies to cost-effectively move macrocycles from their drug discovery programs to the marketplace.  This is a significant achievement, since the necessity of obtaining even gram quantities of these molecules has been the major stumbling block in their development. 

Some of the unique features and benefits of ODIN’s technology include:

• Versatile methods that will enable the preparation of all important macrocycles using compact synthetic schemes, so that no useful compound is inaccessible to practical synthesis

• Synthetic procedures that can be varied systematically for the purpose of optimizing specific properties of the reaction products

• Efficient methods that not only produce small samples of the new material,  but are suitable for large scale manufacturing so that entirely new synthetic schemes DO NOT need to be invented

• Efficient processes such that compact chemical plants can make required amounts of product efficiently, safely, and with minimal environmental impact

The bottom line is this – ODIN’s technology gives the pharmaceutical industry the ability to exploit vast, undeveloped chemical space, re-establish strong patent protection, and deliver big margins on molecules that have had small or no profit margins.

Best of all, in many instances ODIN’s technology can be operational in research laboratories throughout the world within months, integrated into existing facilities without the need for additional infrastructure or a new brain trust.