Advances in genomics during this century have understandably heightened excitement in biologics, but progress made in decoding the complexity of the human genome is also re-confirming the value of small molecules as an effective treatment modality.

Despite all the attention directed at CAR-T cell therapy and CRISPR gene editing, synthetic small molecule drugs remain the workhorses of drug treatment. Nearly 90% of therapies on the market are small molecules. In 2018, a record year for novel drug approvals by the US Food and Drug Administration (FDA), more than 70% were small molecules.

However, the gap is beginning to narrow. Informa’s 2018 review of the pharmaceutical industry’s R&D pipeline, shows small molecules still dominate, but biologics are growing faster. As for the top 20 selling drugs in 2017, 12 are biologics as are seven of the top 10, according to a report from IgeaHub. Another report, from Pharmaceutical Manufacturing, predicts that six of the top 10 selling drugs in 2024 will be biologics.

Arnab Chatterjee

A major difference between small molecules and biologics, of course, is size. The former is tiny with a molecular weight of less than 1,500 daltons, said Arnab Chatterjee, Ph.D., vice president of medicinal chemistry for Calibr at Scripps Research.

The latter are significantly larger, more complex biomolecules, as much as 100 times heavier, which are produced by cells, such as antibodies, enzymes and other proteins; or cells themselves.

“Typically (small molecules) are molecules that can either be synthesized entirely from very simple organic building blocks or are compounds that can be derived from natural sources, such as carbohydrates, amino acids, nucleic acids and natural products that occur from various other species,” Chatterjee explained.

“The primary advantage,” said Jeff Jacob, chairman and CEO of Cancer Prevention Pharmaceuticals (CPP), “is that small molecules can permeate the cell membrane and access drug targets inside the cell as well as extracellular domains. Biologics are typically much too large for this.”

With all the attention given to biologics, they seem almost synonymous with genomics. However, the research is also vastly improving small molecule drug discovery as well as illuminating new uses for existing drugs.

WuXi AppTec – a leading global pharmaceutical and biopharmaceutical open access capability and technology platform – assists biotech and pharmaceutical companies from discovery to manufacturing and beyond. An important element of this support involves offering a communications platform to facilitate the exchange of ideas among the most innovative companies and the creative people behind them.

In this installment of WuXi’s communications platform on the future of drug discovery and development, experts in small molecules discuss their drug development efforts as well as the role and evolution of small molecules as an essential treatment modality. They include Arnab Chatterjee; Paul Dorman, CEO of NanOlogy; Jeff Jacob; John Houston, Ph.D., president and CEO of Arvinas; and Sofie Qiao, Ph.D., president and CEO of Vivace Therapeutics. Their complete interviews also are available on this website.

Small molecules versus biologics

The emergence of biologics as a clinical and commercial success has generated discussion in the biopharma industry on the future value of small molecule drugs.

There are advantages for each that favor one over the other. And although biologics are capturing most of the attention in new drug development, there are many good reasons why small molecule drugs remain an essential element in the medical toolbox of disease treatments.

Sofie Qiao

“One advantage that comes immediately to mind,” said Sofie Qiao of Vivace Therapeutics, “is that small molecules have much less CMC (chemistry, manufacturing and controls) complexity than biologics.”

Two other advantages, added NanOlogy’s Paul Dorman, are that small molecules “are generally much easier to make and much less expensive to manufacture on a commercial scale” than biologics such as immunotherapies.

“I would argue that the single most exciting part about small molecule drug discovery is that you are much closer to an actual product than you would be if you were to look in the arenas of biologics and cell therapies,” said Arnab Chatterjee of Calibr at Scripps Research, which is a non-profit translational research institute and division of Scripps Research.

But, as Chatterjee also observed, “There are specific disease areas such as oncology where the effects of biologics and cell therapies are very profound and there may be specific diseases like that where a small molecule may not be able to reach that level of pharmacological activity.”

Qiao added, “For genetic diseases, which have the potential of being cured by gene therapy in a single dose. Gene therapy would be much more preferable to taking a small molecule or a protein because small molecules and proteins are just modulating some functions.”

Over the next five-to-10 years, Chatterjee suggested, the discussions in drug research and development concerning the value of small molecules versus biologics likely will focus on how quickly drug candidates can demonstrate proof of concept in animals before graduating to human trials.

Right now, he said, biologics, cell therapies, and other non-small molecule modalities have a significant advantage at the preclinical, proof-of-concept stage. “The ability to generate interesting in vivo proof-of-concept using those modalities is something that can happen quite quickly,” he observed.

“With small molecules there may be work required at the early stages of discovery – that is, to get a molecule that has good enough properties to be able to show activity in a rodent disease model,” he said.

Getting to proof-of-concept more quickly, he added, “is really going to be – at the end of the day – the way small molecules will be able to close that critical gap that emerged in the last 20 years, where there have been more and more biologics, cell therapies and gene therapies presented to patients with disease.”

Where are we now?

Significant advances in drug discovery technologies and the identification of new biological targets through genomic research have vastly improved small molecule development.

Jeff Jacob

Technological advances such as “computer-aided drug design, the creation of massive chemical libraries, and advances in assay screening technology,” noted Cancer Prevention Pharmaceuticals’ Jeff Jacob, have reduced the time and inefficiency in discovering new small molecule drugs.

Meanwhile Qiao said there is also a lot more biological information available both about the target and the compound, “so more versatile, cellular in vivo read-outs are available for drug activities because of the tools and technologies available for fancy and sophisticated assays.”

Vivace’s small molecule drug development for cancer targets the Hippo-Yap pathway, which is involved in cell proliferation, programmed cell death and cell migration. The company’s research indicates the pathway is activated in gastric cancer, mesothelioma, liver cancers and uveal melanoma.  Vivace expects to begin clinical trials in late 2019.

“Essentially, the technology that has been developed from academic labs and from industry really has contributed to making (small molecule) drug discovery more efficient because of the vast amount of data available to guide the whole drug discovery process,” Qiao said.

Chatterjee added that genomics also is enabling researchers to repurpose existing small molecule drugs to treat different diseases. “This idea that finding existing molecules and existing pharmacophores in interactions with potentially new target proteins is equally as important as it is for us to find new chemicals and pharmacophores.”

For example, Jacob said, “At CPP we’ve taken an older compound (eflornithine) to new heights through our research to understand the biology. We have discovered new aspects to the drug’s mechanism of action and effects, including a role in cancer stem cells; a role in optimizing the immune system during early stages of disease; and a role of inflammation in the pathogenesis of cancer.”

In December 2018, CPP completed a Phase 3 trial of its drug CPP-1X (eflornithine) in combination with sulindac for treatment of familial adenomatous polyposis (FAP), a rare inherited disorder characterized by cancer of the colon and rectum. Results are expected early this year.

Cancer immunotherapies, the latest biologics to capture the public’s imagination, also are breathing new life into existing small molecules, such as traditional chemotherapies.

“The realization that chemotherapy agents, like paclitaxel, can have an immunogenic effect make them an attractive partner for immunotherapy,” Dorman said.

NanOlogy is using a new manufacturing technique to transform traditional chemotherapy, such as paclitaxel and docetaxel, from systemic administration to local delivery at the disease site via submicron particles of pure drug.

Paul Dorman

“We are showing that local delivery of certain chemotherapeutic agents has the potential to improve their cancer killing properties and immunogenic effects without producing the toxic side effects of systemic administration.” Dorman explained. He added that NanOlogy is advancing clinical trials in the US for local delivery of its investigational drugs in three broad therapeutic areas including gastrointestinal cancers, urological cancers and lung cancer.

In the category of new classes of small molecules, protein degradation is generating attention as an alternative strategy for attacking disease causing proteins, including those involved in cancer.

Arvinas is developing PROTACs (proteolysis targeting chimeras), which work by recruiting E3 ligase, an enzyme, to tag disease causing proteins with ubiquitin, leading to degradation and disposal of the proteins.

“(PROTACs) are small molecules wherein one end targets the protein of interest and the other end brings the E3 ligase machinery in contact with the protein of interest,” said Arvinas’ John Houston. The company initially is targeting prostate and breast cancers.

John Houston

The technology, Houston said, also enables Arvinas to attack what have been considered “undruggable targets, because finding a potent active site inhibitor has been really difficult for those proteins.”

Small molecules not only are prized for their therapeutic applications, but also they increasingly are used as an essential research tool in understanding the enormous amount of genomic data being amassed.

As Qiao said, “Biology is very complicated, and often a very powerful tool in deciphering biology is to have a good specific small molecule to study a target.”

“That is the very crux of the techniques that are being developed within the academic community,” Chatterjee added, “which I think will have profound impacts on understanding the multiplicity of interactions that small molecules have with proteins inside cells, and inside of organisms and humans.”

Where are we headed?

Typically, small molecule drugs bind to a specific target protein to alter its function. Arvinas’ PROTACs, however, represent a new class of small molecules.

As Houston explained, they “grew out of the work of Professor Craig Crews’ lab at Yale University, whose focus over a 15-year period was on protein homeostasis and the process by which cells dispose of normal proteins as well as dysfunctional or mutated proteins.”

PROTAC small molecules can bind “anywhere on a (target) protein,” Houston said, “and even a weak binder can bring the protein of interest in proximity to the ligase machinery” for disposal.

In targeting prostate cancer, Arvinas is attempting to prove that its technology can overcome the drug resistance that usually develops to existing therapies. As for breast cancer, Houston said, the company’s strategy is to show PROTACs, which are administered orally, are more potent than an existing protein degrading drug that is “given intramuscularly and degrades only 50%” of the targeted protein.

He said Arvinas’ pipeline also includes PROTACs aimed at what he describes as ‘Holy Grail’ undruggable targets involved in cancer. Other applications under consideration are in neuroscience and neurodegeneration.

Whereas Arvinas is expanding the boundaries of small molecule therapeutics, Vivace is employing a more traditional approach, creating compounds that target mutations of the Hippo-Yap pathway, which lead to cancer.

“We believe that the kinds of compounds Vivace Therapeutics has discovered so far to inhibit activation of YAP driven gene expression are providing us unique insight into the Hippo-YAP pathway,” Qiao said. “Having those small molecules as chemical tool compounds, we have gained a much better understanding of the pathway’s role in certain cancer indications and how to modulate the pathway to address those cancer indications.”

Although Vivace’s strategy is to develop a small molecule for approval as a single agent therapeutic, Qiao said the company also plans to explore combination possibilities.

“Right now, it seems that people are doing a lot of combinations in oncology, and sometimes we struggle to see good rationale,” she said. “In the future, I think combinations will become much more rational based on mechanism of action and very sophisticated hypotheses.”

The search for effective combinations with cancer immunotherapy drugs aims to expand their effectiveness for more patients. “The first generation of immunotherapy drugs, such as checkpoint inhibitors, represent a remarkable breakthrough in cancer treatment,” Dorman said. “But less than 30% of patients respond to checkpoint inhibitors and the drugs are not effective against all cancers.”

As a result, he noted, there are more than 170 clinical trials worldwide ongoing with chemotherapy agents and checkpoint inhibitors.

One example of the potential benefit of combining NanOlogy’s submicron particle paclitaxel (NanoPac) with immunotherapies emerged in data from preclinical lung cancer studies.

“What we have found is that when NanoPac is inhaled into the lungs, the local concentration and sustained release over time significantly increases tumor kill relative to systemic administration of paclitaxel,” Dorman said. “The enhanced kill results in greater exposure of tumor specific antigens, which elicits a stronger immune response. It stands to reason a stronger immune response will offer greater benefit to immunotherapies.”

Chatterjee believes small molecules can be combined with biologics aimed not only at interactions between immune cells and cancer cells, but also interactions between immune cells and infected cells, be it a bacteria or virally infected cell.

Chatterjee and his colleagues at Calibr take the basic discoveries made by scientists at Scripps and attempt to turn them into commercial products, including small molecules, biologics and cell therapies.

Staying on his theme of repurposing existing drugs, Calibr now has in development two new treatments for tuberculosis and cryptosporidium infections and both are existing small molecule drugs for other indications.

An important element of these programs, Chatterjee said, is targeting diseases that are prevalent in “underrepresented groups and underrepresented parts of the world that have not seen the profound effects of modern drug discovery in their day-to-day lives.”

Among the other development programs at Calibr is a new small molecule drug in Phase 1 trials for regenerating mesenchymal stem cells in the knee to treat osteoarthritis.

Conclusion

All the discussions over small molecules versus biologics may serve as more of a reminder that both modalities are essential in battling and eventually eliminating diseases.

As Qiao believes, “There is a place for each modality and all modalities will continue to get more versatile and efficient. So, there will be an increase in rational design into discovery of all classes of agents and also an increase in rational combination.”

But there are fundamental differences between biologics and small molecules, and Chatterjee breaks them down this way: “I think that target specificity is going to be a challenge (for small molecules) because you simply don’t have enough atoms and enough interactions. On the other hand, for cellular targets – what we already know from drug discovery over the past 150 years or so – the pharmacology that you get out of a small molecule is as good, or perhaps even more robust, than biologics and other types of modalities.”