During the past decade, advances in biologics and generic biosimilars – with their promise of a more targeted disease approach – have grabbed  the headlines and have overshadowed traditional small molecules.

Yet, statistics show there are more than 8,000 small molecules in active research and development, and almost 90% of therapies on the market today are small molecule compounds. Small molecule development is generally less expensive than biologics and the compounds are easier to manufacture and scale-up to commercial quantities.

For Tucson, AZ-based Cancer Prevention Pharmaceuticals  (CPP), a small molecule approach provides the best way forward in developing the first effective therapy for familial adenomatous polyposis (FAP), a rare inherited disorder characterized by cancer of the large intestine (colon) and rectum.

People with the classic type of FAP may begin to develop multiple noncancerous polyps in the colon as early as their teenage years. Unless the colon is removed, these polyps will become cancerous. Currently, treatment options are limited.  

CPP’s lead small molecule therapy product, CPP-1X/sul, is being developed to minimize the occurrence and/or recurrence of problematic polyps and tumors associated with this debilitating disease and is nearing completion of Phase 3 clinical trial.

At the helm of CPP is Chairman and CEO Jeff Jacob. In 2004, Jacob founded Systems Medicine Inc., a startup company developing new cancer drugs. He served as the CEO until the company was sold in 2007. Jacob is a founding board member and served as chief program officer of the Critical Path Institute (C-Path). Between 1987 and 2004 Jacob worked with Research Corporation Technologies (RCT) as senior vice president. He currently serves on the Board of C-Path, RCT, and the Frederick Gardner Cottrell Research Foundation.

As part of a WuXi AppTec Communications series, we recently spoke with Jacob about the current and future role of small molecules in medicine.

WuXi: How diverse are small molecule drugs today? How would you define small molecules?

Jeff Jacob: Small molecules still represent the vast majority of drugs on the market. These are drugs that have low molecular weight so they can work inside the cell as well as outside. Because of this important need, academic labs and private companies create databases of chemical compounds far beyond what is available in typical pharmaceutical company compound collections.

Examples include the chemical universe database GDB-17 of 166.4 billion organic small molecules and a smaller subset called the fragment database FDB-17 of 10 million fragment-like molecules with up to 17 heavy atoms.  Others include ZINC15, a free database of 750 million commercially-available compounds for virtual screening, including 230 million in 3D formats ready for docking; and Enamine’s REAL database of 650 million molecules searchable via REAL Space Navigator software, and 337 million molecules searchable at EnamineStore.

So, you see how having so many accessible compounds can make drug research and development easier to work with than biologics, and they are generally less costly.

An alternative approach to access new drug-like small molecule chemical space for hit exploration is using DNA-encoded library technology (DELT). Owing to the “split-and-pool” nature of DELT synthesis, it becomes possible to make huge numbers of compounds in a cost and time efficient manner (millions to billions of compounds).

WuXi: How has small molecule drug discovery changed?

Jeff Jacob: Traditionally, medicinal chemistry was a time-intensive, fairly inefficient process. Today, thanks to computer-aided drug design, the creation of massive chemical libraries, and advances in assay screening technology, this process is much more efficient from “hit to lead” and then to process/scale-up steps to provide drug for the development process.

Of specific interest to me, is how artificial intelligence (AI) based tools are now being explored at all stages of drug discovery and development — from research data mining and assisting in target identification and validation to helping come up with novel lead compounds and drug candidates, and predicting their properties and risks.  It will also be interesting to watch as these tools get applied to chemical process scale-up optimization and clinical trial design.

WuXi: Do small molecule drugs have advantages over biologics and other treatment modalities, such as cell and gene therapies? If so, what are they?

Jeff Jacob: Typically the primary advantage 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.

Small molecules may also be able to access CNS (central nervous system) targets that are separated by the tight blood-brain barrier.  Small molecules are also much more stable and non-immunogenic compared to biologics, and lend themselves to oral delivery versus large molecules.  Small molecules are also typically much less expensive to manufacture than biologics.   We believe these advantages make our small molecule drug CPP-1X/sul a better approach for FAP.

WuXi: Are small molecules being used to improve our understanding of biology? Is so, how are you unraveling new biology with small molecules?

Jeff Jacob: Absolutely. 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.

This has allowed us to address precancerous disease conditions such as FAP, which is the subject of a pivotal trial our company is running.   FAP is rare disease affecting more than 100,000 people in China.

WuXi:  What are the differences in market pricing between new small molecule drugs and biologics? How will these differences change over the next five-to-10 years?

Jeff Jacob:  Traditionally biologics have been much more expensive than small molecules, and I would expect that trend to continue over the next five-to-10 years.  One significant reason is the ability to genericize a small molecule and induce game-changing competition and price erosion.

For biologics, it is much more expense to make the drug, but also more expensive to attempt a biosimilar approval program.  Furthermore, biosimilars have regulatory market exclusivity for 12 years versus five years for a new small molecule, which limits competition and the extent of price erosion.

WuXi: How are small molecules being used in combination with biologics? For example, what is their effect in combination with biologics, such as immuno-oncologic therapies?

Jeff Jacob: I think antibody-drug conjugates (ADCs) are exciting approaches that literally combine the targeting capability of an Ab (antibody) with the drug activity of a small molecule.  There are other approaches including ours, which uses a polyamine regulator – our lead compound CPP-1X – to modulate the immune system in early disease development and support the prevention of full blown disease.

Having a small molecule like CPP-1X allows us to attack a rare disease like FAP to control and mitigate the effects of the disease.  This would be more challenging and hard to justify with a biologic approach.

WuXi: What kinds of small molecules is your company developing? How were they discovered? What diseases are you targeting?

Jeff Jacob: We are developing small molecules, originating from traditional medicinal chemistry approaches, which are intended to regulate and modulate the polyamine pathway.

These drugs target specific enzymes and other targets that affect polyamine synthesis and transport. This approach is relevant to a variety of cancers, autoimmune diseases, and even neurodegenerative diseases.   Our predecessors and partners who discovered the key compounds used good old fashioned synthetic chemistry to target this myriad of diseases, including the cancer and rare conditions which we are pursuing.

Our pipeline includes FAP, colorectal cancer maintenance therapy, pancreatic cancer, early onset type 1 diabetes, neuroblastoma, gastric cancer, and others.

WuXi: How will the drug modality mix – our toolbox for disease treatment – evolve over the next five-to-10 years?

Jeff Jacob:  A lot is being put into the promise of CAR-T immunotherapy for cancer and for gene editing technologies such as CRISPR.  Both of these are at an early stage of development from my perspective, but I expect they will play a role after some bumps in the road which happens to all new technology.

I believe that cellular therapies and microbiome-based approaches to treating disease will also continue to evolve and play an important role in the future.  CPP will continue to monitor these advances and leverage new insights to expand its small molecule portfolio.