FORMULATION DEVELOPMENT - Practical & Purposeful: Creating Novel Compounds Via Rediscovery R&D & Cannabinoid Molecules

INTRODUCTION

Long ago, physicians invented using existing drugs for new uses, also called “off-label prescribing,” stemming from an infor­mal understanding of a drug’s mechanism of action and how it might benefit patients beyond the indication for which it was studied.

Related to this physician practice is drug rediscovery, the for­mal process by which pharmaceutical companies evaluate a known drug or compound for a new indication. Drug rediscovery is also sometimes referred to as drug repositioning, reprofiling, reusing, and repurposing.

Unfortunately, despite the potential of repurposing a drug, it’s not always an attractive business prospect, given pre-existing commercialization and the inability to benefit from patent law. However, drug repurposing can be significantly less costly from a development perspective. It’s also attractive to the US FDA and other regulatory agencies, which will have confidence and famil­iarity with the drug candidate given its known safety and mecha­nism-of-action (MOA) profile.

Additionally, combining repurposed drugs with other well-known and researched compounds has the added benefit of cre­ating an entirely new drug product that can be patented — with less time and expense than what would normally be involved in developing something entirely novel.

Pharmacological interest in drug repurposing has exploded in the past several years. As of 2020, PubMed had more than 1,000 publications on the topic.¹ Thus, through a number of case studies and a broader overview of the ongoing research, we will demonstrate the value of drug repurposing for unmet treatment needs.

OVERVIEW OF OFF-LABEL USE & REPURPOSING

From the FDA’s perspective, off-label use is essentially an un­approved use for an approved drug.² This can mean using a drug for an indication it has not been officially approved for or using a drug in a patient population in which it has not been approved for. It can also mean giving a drug in a different way (ie, as an oral solution instead of a capsule) or at a different dose (ie, two tablets a day instead of one) than what the official label indicates.

Off-label prescribing is quite common, with one recent gov­ernment study from the Congressional Research Service reporting that up to 40% of all prescriptions written in the US today are for off-label use.³ In some patient populations, off-label use is par­ticularly high. One study reported that up to 97% of pediatric pa­tients are exposed to at least one off-label prescription.⁴

The Congressional Research Service cites several examples of common off-label prescribing in its 2021 report; for example, bevacizumab is FDA-approved for certain non-squamous non-small cell lung cancer and several other cancers, but it is often prescribed for wet age-related macular degeneration and dia­betic eye disease off-label.⁵

Off-label use is particularly common in cancer treatment be­cause chemotherapy drugs approved for one type of cancer could target multiple types of cancer. Repurposing of cancer drugs dates back to the original chemotherapeutics, which stemmed from re­search on the observed anti-tumor potential of applying mustard gas to skin cancers.^6-8

DRUG REPURPOSING CAN CREATE NOVEL PRODUCTS

The traditional drug-discovery process is years long, focused on identifying and studying a specific small molecule (or larger molecule biologic) that targets a particular disease and/or disease symp­tom. It requires a rigorous clinical-trial de­sign to ensure safety and efficacy in the targeted indication. New molecules also require extensive non-clinical investigation to understand the safety risks associated with the molecule. Non-clinical safety stud­ies on new molecules need to be com­pleted before clinical trials can begin, often taking years to complete, adding to the development timeline.

As such, traditional drug discovery is very expensive, and many patients may miss out on a treatment option due to the time and expense associated with thera­peutic R&D. One estimate indicates the av­erage drug development costs about $2.6 billion for about 17 years from develop­ment to molecule to market — and yet, only 2% of drug-development initiatives end up being commercialized.⁹

Drug rediscovery takes some of the risk out of creating new uses for old drugs because there is pre-existing safety and ef­ficacy data that originated from past clini­cal and post-marketing trials. There are also substantial non-clinical safety pack­ages available for approved drug sub­stances that can be referenced in NDA submissions for repurposed drugs. Further, there are many therapeutics that have reached generic status, which makes them more widely available to healthcare providers, patients, insurance providers, and manufacturers, alike.

The regulations allowing pharma­ceutical companies to submit previously generated clinical data in support of their applications for a repurposed drug prod­uct include the FDA’s 505(b)(2) pathway and the European Medicines Agency (EMA)’s Hybrid Regulatory Pathway.^10,11 In the US, the FDA may provide guidance to companies who seek it, enabling further savings of time and cost in the develop­ment stages of new drugs.

Generally, there are three ways to re­purpose an existing drug for a new indi­cation.

1. The first involves simply demonstrating that an existing drug that’s been ap­proved to treat one condition is also ef­fective in treating another indication by submitting a new study.
2. New approved uses also stem from de­veloping a new drug-delivery method that makes it safer, more effective, or more convenient (ie, developing a liq­uid formulation).
3. At Incannex, we’re focused on the third option: We are creating drug candi­dates by combining generic medications with an additional active ingredi­ent – in our case, synthetic cannabi­noid – to generate entirely new products to be studied for their safety and efficacy.

A classic example that combines the first two approaches dates all the way back to the 1970s and 1980s, when minoxidil was introduced to treat hypertension. As both men and women began to take the drug to treat their high blood pressure, they began to notice significant hair growth — a side effect called hypertri­chosis that caused hair growth on the face, arms, shoulders, and legs. This wide­spread side effect eventually led the FDA to approve minoxidil in 1979 as a topical application for androgenic alopecia (hair loss).^12,13

Other examples include duloxetine, originally developed for major depressive disorder but now used for stress-related urinary incontinence, and, famously, silde­nafil, originally developed for angina and now used for erectile dysfunction.

NEW DELIVERY METHODS FOR OLD DRUGS

The Incannex clinical drug-develop­ment pipeline incorporates the second and third approaches. For example, our inves­tigational IHL-42X program combines dronabinol, which is a synthetic form of THC that is FDA approved for treatment of chemotherapy associated nausea and vomiting as well as anorexia associated with HIV/AIDS, with acetazolamide, a car­bonic anhydrase inhibitor approved for glaucoma, idiopathic intracranial hyper­tension, congestive heart failure, altitude sickness, periodic paralysis, and epilepsy. Both of these drugs have some clinical ev­idence in treatment of obstructive sleep apnea (OSA), but neither is FDA approved for the indication. Prior to Incannex’s proof-of-concept clinical trial, the combi­nation of dronabinol and acetazolamide had not been assessed in OSA or any other indication. We have developed a unique formulation that is a fixed dose combination product that co-delivers these two molecules; this novel formulation is what is being tested in our clinical trials.

Other researchers are also seeking new delivery methods for old drugs. For example, Wyss Institute researcher Dave Mooney, PhD, has been looking at previ­ously developed compounds that work against common conditions like inflamma­tion and cancer.¹⁴

His research focuses on drugs that previously demonstrated they don’t last long enough in the body after injection or ingestion, thereby requiring higher, toxic doses to make a measurable impact. Dr. Mooney and his team solved for this by developing a hydrogel, which is a capsule made of natural materials that delivers a “therapeutic cargo” locally and in a sus­tained manner to a specific site in a pa­tient’s body. As a result, the dose needed for a therapeutic effect is often reduced, as are the potential side effects of toxicity and the frequency of treatments.

Several companies have since li­censed this hydrogel technology. Alkem Laboratories plans to use it to deliver nat­urally occurring growth factors to patients with peripheral artery disease to stimulate tissue and nerve regeneration. Both of the molecules Alkem is using are generic drugs, further demonstrating the benefits of repurposing old drugs using new deliv­ery methods.

UNLOCKING CANNABINOID POTENTIAL THROUGH COMBINATION

The Incannex clinical pipeline in­cludes two dozen drug candidates that start from drug repurposing. This ap­proach enables us to unlock the potential of an alternate source of molecules that has not yet been explored fully in the hopes of providing new treatment options for diverse patient populations.

Via its gold-standard, placebo-con­trolled research, Incannex is working with cannabinoids, combining them with generic drugs with proven safety and effi­cacy data. Additionally, Incannex is target­ing indications with significant unmet medical needs and seeking approval from the FDA and other regulatory agencies.

TARGETING UNMET MEDICAL NEEDS

For example, investigational IHL-675a is intended to address unmet needs in pain management for inflammatory conditions, which is needed given that ad­junctive pain alternatives, such as NSAIDs and COX-2 inhibitors, carry known safety concerns over time. IHL-675A is a combi­nation of generic hydroxychloroquine sul­fate (HCQ) with a cannabinoid.

Studies show that both active ingredi­ents have well-characterized, anti-inflam­matory activity when administered individually and have recently been shown by Incannex to act synergistically to inhibit production of inflammatory cytokines and reduce disease severity.¹⁵

Simultaneously, Incannex is investigat­ing IHL-42X for treatment of obstructive sleep apnea, a condition with no FDA-ap­proved pharmacological treatment options.

SUMMARY & FUTURE PERSPECTIVES

As time goes on, more and more companies will discover the benefits of drug repurposing — and how to successfully use such strategies to develop new, patentable drug products. In fact, repurposing could be exactly what’s needed to enable pharma­ceutical and biotechnology companies to more swiftly develop treatments for indications with significant unmet medical needs.

In 2011, the US National Institutes of Health and the Euro­pean Commission launched the International Rare Diseases Re­search Consortium (IRDiRC), a global public/private collaboration to support and stimulate drug repurposing for indications with small patient populations. Since then, the agency has developed the IRDiRC Drug Repurposing Guidebook to help developers nav­igate the rare-disease landscape.¹⁶

The IRDiRC has also investigated and identified 10 key fea­tures of successful drug-repurposing projects. Although the orga­nization’s focus is on rare diseases, much can be learned about repurposing drugs for other unmet medical needs as well.

As such, the most critical features identified include clearly identifying the needs of patients with unmet needs, innovation, patient collaboration, information and data gathering, and early interactions with regulatory agencies and payers.¹⁷

Several other global initiatives are ongoing to support drug repurposing. Additionally, new technologies like artificial intelli­gence and machine learning will open the doors to solutions for unmet needs that have never been considered before.

Thus, with increased collaboration, innovation, and an open­ness to considering a wider variety of molecules and compounds that may not have been fully explored, we would expect a grow­ing number of new treatments for unmet medical needs to be de­vised from old drugs going forward.

REFERENCES

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2. Food and Drug Administration. Understanding Unapproved Use of Approved Drugs “Off Label.” https://www.fda.gov/patients/learn-about-expanded-ac­cess-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label.
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10. Food and Drug Administration. Abbreviated Approval Pathways for Drug Product: 505(b)(2) or ANDA. https://www.fda.gov/drugs/cder-small-busi­ness-industry-assistance-sbia/abbreviated-approval-pathways-drug-product-505b2-or-anda.
11. European Medicines Agency. Generic and hybrid applications. https://www.ema.europa.eu/en/human-regulatory-overview/marketing-au­thorisation/generic-and-hybrid-medicines/generic-hybrid-applications.
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14. Wyss Institute. Giving old drugs new life… to save lives. https://wyss.har­vard.edu/news/giving-old-drugs-new-life-to-save-lives/.
15. Data on File. Incannex.
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Dr. Mark Bleackley is the Chief Science Officer of Incannex. He earned his PhD in Genetics from the University of British Columbia with post-doctoral training at La Trobe University and an Australian biotechnology company Hexima, Ltd. As Chief Science Officer, he oversees all research and development at Incannex, from proof-of-concept to commercialization.