Novel small molecule drug discovery platform harnesses immune system to defeat cancers, viral infections and inflammatory diseases, explains R.P. “Kris” Iyer
More than 300 million patients worldwide are infected with the hepatitis B virus (HBV). Each year, more than a million of these patients die from the virus, which is also a major cause of liver cancer and cirrhosis. Worldwide, cancer claims the lives of millions more. Chronic HBV, cancer and a variety of inflammatory diseases are caused by immune dysfunction at the cellular level. Now, the power of nucleic acid technology is being harnessed to design small molecule nucleic acid hybrid (SMNH) drugs that harness the patient’s own immune system to defeat these cancers and cure viral diseases at global scales.
Small molecule nucleic acid hybrid chemistry
Nucleotides are building blocks of DNA and RNA (collectively called nucleic acids) that, along with proteins, constitute the fundamental operational components of all cells. Normal cellular function depends on a complex, interconnected network of biochemical processes that rely entirely on highly precise recognition, and very specific interaction among nucleotides, proteins and nucleic acids. Diseases occur when cellular function goes awry due to aberrant cellular processes. Drugs used to treat many diseases are designed to restore normal cellular processes in a diseased cell. To achieve this, a drug must have properties that enable it to mimic the recognition and interaction between cellular components that would help jump-start and restore normal cell function.
Based on nucleic acid structure, uniquely designed SMNH drugs are being developed that are endowed with recognition and interaction properties closely mimicking what nature employs in its normal cellular function. These SMNH compounds are designed with properties that enable them to recognise and interact with nucleic acids and proteins much like natural nucleotides and nucleic acids and proteins do in cells.
Furthermore, chemical modifications to these SMNH compounds give them drug-like properties, enabling them to be formulated for use as tablets/capsules, injections or other dosage forms. Thus, SMNH compounds have several advantages: they have novel mechanisms of action, including induction of the innate immune response; they can be administered by multiple routes of delivery, including oral administration; and they can target a broad range of diseases, including viral, oncological and inflammatory diseases.
For example, Spring Bank is developing SMNH compounds focusing on diseases that cause immune system dysfunction in microbial infections, cancer and inflammatory disease. The SMNH compounds are designed to restore the function of the immune system for viral clearance, tumour elimination and attenuation of inflammation.
In addition to designing synthetic molecules that recognise and interact in cellular processes, to benefit patients the drugs must be safe and readily accessible.
Many modern treatments require a combination of small molecule drugs to achieve an optimal therapeutic benefit, but some drug combinations can have a sub-optimal effect or have side effects due to drug-drug interactions. This is because most small molecule drugs are subject to metabolism by enzymes in the liver, since the liver perceives the drugs as foreign substances to be eliminated from the body. The liver uses a plethora of enzymes to convert drugs into water-soluble forms for elimination from the body. Unfortunately, when multiple drugs are used in combination or simultaneously, these enzymes cannot function efficiently. This leads to inadequate metabolism, or build-up of the individual drugs in higher levels in the blood, leading to potential toxicity. Such drug-drug interactions can also result in sub-therapeutic levels of the individual drugs.
By contrast, SMNH compounds are chemically modified at key sites in the molecule to confer druggability attributes while retaining their ability to interact with target cellular components. Thus, SMNH compounds possess the pharmaceutical attributes of small molecule drugs and yet have better aqueous solubility, less metabolic liability and less likelihood of drug-drug interactions. The compounds can therefore be combined with other drugs when needed.
Being small molecules, SMNH compounds are also relatively easily manufactured in larger scale by well-established processes and operations commonly employed in the pharmaceutical world. Many currently used small molecule drugs require numerous steps for large-scale manufacture. On the other hand, manufacture of these compounds involves fewer steps. The ability to readily manufacture compounds at larger scale enables substantial reduction in the cost of goods and can provide easier access to drugs for millions of patients suffering from a variety of diseases.
SMNH compound application examples
Hepatitis B. Chronic HBV patients have a dysfunctional immune system that is unable to clear the virus from the body. Current drugs for HBV, such as nucleosides or nucleotides (Nucs) are designed primarily to suppress viral replication. These drugs do not eliminate the virus, have side effects and require life-long therapy – stoppage of treatment results in viral rebound. There is therefore a significant need for drugs that can affect “functional cure” of chronic HBV during a finite duration of therapy. This can be achieved by a combination of drugs in which immunomodulation will be the key component.
One example of such a drug using SMNH chemistry is Inarigivir, a small molecule developed by Spring Bank for the treatment of chronic hepatitis B virus infection. Designed to be selectively activated within HBV-infected cells, Inarigivir binds the cellular protein, retinoic acid-inducible gene 1 (RIG-I), to both inhibit viral replication and cause the induction of intracellular interferon signalling pathways for antiviral defence. Inarigivir is orally bioavailable and has the potential to be part of a simple, safe and selective combinatorial treatment modality that can significantly enhance the functional cure rates for patients with chronic HBV during a finite duration of therapy. Inarigivir is currently in global Phase II clinical trials against HBV.
Cancer. Current cancer treatments include a variety of modalities, including surgery, radiation, chemotherapy with cytotoxic drugs and targeted agents. Each modality is associated with significant risk of relapse due to resistance development and metastasis upon treatment cessation, as well as, considerable side effects and tolerability issues. Recently, therapies designed to activate the host immune system using a class of drugs called “check-point inhibitors” have shown much promise by providing durable cancer cure in a subset of cancer patients. Indeed, immunotherapy is revolutionising the treatment of cancer – patients who have failed all available therapeutic options are now being cured. Spring Bank has developed SMNH compounds as a powerful new class of immunotherapeutic agents for cancer treatment that can be combined with other agents such as checkpoint inhibitors to enhance cancer cure rates.
STimulator of INterferon Genes (STING) is an integral component of the body’s innate immune system that senses cytosolic DNA and produces interferon, which is necessary for fighting cancer and viral infections. Targeting this protein potentially enables modulation of the body’s immune response to eliminate cancer. For example, Spring Bank has designed a platform of SMNH compounds that form nanostructures that enable them to enter cells readily, bind to STING to activate the interferon pathway, recruit immune cells for tumour killing and also make cold tumours hot. These attributes make them potent immunotherapeutic agents. The lead compound SB 11285 has recently entered clinical trials. Some other water-soluble STING agonist drugs developed by other companies do not enter cells readily and therefore lack the same efficacy.
In addition, several existing STING agonists currently in clinical trials for solid tumours are administered exclusively by direct injection into tumours, which is an inefficient and often painful process that requires considerable resources only available through specialised treatment facilities and hospital care. Effective engagement of the immune system to attack a tumour requires key specialised immune cells to traffic from the periphery to the tumour site. With drugs injected directly into tumours, the critical tumour-attacking immune cells might not exist in adequate numbers at a tumour site. To ensure that an immunotherapeutic agent can safely and effectively harness the immune system through the activation of the STING pathway, compounds may need to be administered by systemic routes, for example, intravenous (IV) or subcutaneous. This could also enable treatment of many cancers that are not accessible by intratumoral injection.
IV administration of cancer drugs is a commonly accepted modality in current cancer treatment, which often requires a combination of drugs. Furthermore, IV administration of a STING agonist would enable combination therapy in a typical hospital setting. For example, SB 11285, a potent STING agonist developed by Spring Bank that can be administered by multiple routes, including IV and IT, has just entered clinical trials for treatment of cancers, Looking ahead, to achieve targeted delivery to the site of the tumour, these STING agonists are also being conjugated with antibodies to form antibody-drug conjugates (ADCs).
The SMNH chemistry outlook
SMNH compounds are relatively easy to manufacture and offer multiple potential administration routes, including oral and intravenous. Endowed with a novel mechanism of action, they demonstrate the potential to treat large populations facing deadly diseases such as chronic HBV infection and cancer. In addition to viral and oncological applications, SMNH compounds are being designed as immunomodulatory agents for the treatment of numerous common and rare inflammatory diseases, including Lupus, Sjogren’s syndrome, Aicardi’s Goutières syndrome, Parkinson’s disease and multiple sclerosis. As this novel drug development platform evolves, the experience gained in discovering drugs designed to treat HBV, cancer and inflammatory diseases can be applied broadly to other diseases, including cardiovascular, metabolic and central nervous system disorders.
R.P. “Kris” Iyer, is chief scientific officer at Spring Bank Pharmaceuticals.