Pharmaceutical companies and their development partners are continually looking for safe, efficient ways to accelerate delivery of therapies to the patients that need them—especially in the face of the COVID-19 pandemic. One appealing path to new treatments is to explore ways to repurpose a drug intended for one indication and repurpose it for another.
Maciej Czerwinski (MC), director in the scientific consulting department of contract research organization (CRO) Sekisui XenoTech, spoke with Outsourcing-Pharma (OSP) about how repurposing existing drugs can help developers save time and funding in the discovery process.
OSP: Could you please share the ‘elevator presentation’ of XenoTech—who you are, what you do, key capabilities/specialties and what sets you apart from the competition?
MC: Sekisuki XenoTech is a contract research organization (CRO) specializing in nonclinical drug metabolism and drug-drug interaction studies.
Over 27 years, we have grown to serve 98% of the top pharma companies (as well as medium, small and virtual pharma, biotech, research institutions and universities, and more) by assisting them with pharmacokinetics-related safety studies for the drug candidates they are developing, usually before clinical trials. Our leadership and expertise is trusted by industry professionals and academics alike to provide superior services and products, industry-leading research, and new techniques.
There’s a lot of nuance to understanding pharmacokinetic properties of drug candidates. How they enter and exit specific cells, how long they stay, how they get metabolized by enzymes and what metabolites are formed—all these properties make up the research area called ADME (absorption, distribution, metabolism and excretion).
ADME represents a key area of preclinical investigation to determine whether a drug is going to be dangerous to someone and to make sure it’s in the correct dose and form to produce the therapeutic effect it’s meant to. In vitro and in vivo studies planned with a consultative approach and tailored study design are key to achieving useful, reliable ADME data for a successful investigational new drug (IND) application.
Drug-drug interactions (DDIs) are a preventable cause of adverse drug reactions which kill or hurt 350,000 hospitalized patients per year. DDI potential can be evaluated using in vitro data and is encouraged by regulatory authorities to be appropriately investigated early in a drug’s development.
Our clients come to us because we are global experts in predicting potential DDI issues in the lab before they could happen in a clinical trial volunteer. Doing these studies earlier and with a trusted expert not only instills confidence in your data but saves money and reduces your risk of late-stage surprises or failure.
OSP: Could you please tell us a bit about what drug repurposing efforts might look like in a more typical environment (i.e. outside a pandemic)?
MC: Typically, sponsors can go through the 505(b)(2) regulatory pathway to repurpose or reposition a drug that already has drug safety data from previous preclinical work, in addition to relevant published research that may provide updated or supplemental information.
Regardless of indication, it is the FDA’s job to ensure that the drug meets current safety thresholds and to hold preexisting data to expectations based on current scientific understanding of the many factors involved in safety. For any sponsor we work with who is aiming to take legacy data off the shelf and enter clinical trials for a new purpose, what’s important is to look at the whole picture and fill in the gaps between what they have and what they need to meet regulatory expectations of a complete drug-drug interaction risk evaluation.
This is especially important now, because in January 2020 the FDA published Final Guidance for In Vitro Drug Interaction Studies with some minute, but in some cases critical, updates in what they expect to see in order to give the green light for the clinic. If a sponsor has drug interaction data from a drug they’re hoping to repurpose and the studies were conducted and analyzed according to pre-January 2020 recommendations— there’s a risk that it might not be fit for approval now. DDI gap analysis makes up only a small part of the overall process of getting a repurposed drug clinic-ready, but when it comes to drug safety the small pieces can be make-or-break.
OSP: How has that effort looked in the race to find drugs suitable for repurposing as a COVID-19 treatment?
MC: For the race to provide any and all pieces needed to combat a global pandemic—multiple vaccines, treatments to combat infection, medications tailored to alleviate symptoms and side effects— time is of the essence. As we’ve seen in the US, companies are pulling all the stops when it comes to funding and in many cases find little to no trouble coming up with capital, a hurdle that normally may prevent a developer from moving forward.
In these cases, the rate-limiting factor could be conducting all the relevant studies and interpreting the data to make a strong case for clinical entry. To do this, you can either start from square one— which typically involves years of research—or some lucky sponsors may find that they have something in the vaults or on the shelf that could be a good candidate to repurpose or reposition.
If a compound with promising qualities has been approved for market already or was stopped in clinical trials, it could go through the drug repurposing track.
The FDA encourages this kind of resourcefulness, providing several efficient options to drug developers in situations of urgency like we’re seeing with COVID-19. Expedited approval can be granted in some instances. For others, the 505(b)(2) pathway is a great way to take a good look at existing data, conduct some additional studies if needed to meet current expectations, and get them in the door ahead of other candidates.
OSP: Please share some of the key benefits of repurposing a drug for treatment, as opposed to discovering novel drugs.
MC: Drug repurposing is a beneficial process to both patients and the pharmaceutical developers. Patients benefit from added ‘mileage’ of a compound—when multiple treatments are developed from one therapeutically active molecule, then more people of different circumstances are helped by that one drug.
As for the companies funding and executing the development of the repurposed drugs, the money and time saved from repositioning can free up resources to bring other promising molecules through the pipeline.
The FDA has provided an expedited path for prospective COVID therapies that circumvents much of the regulatory red tape for drugs which have been already approved for the market for one indication but show promise to be able to aid in COVID treatment as well. This makes the path from A to B almost entirely dependent on proof of efficacious results in the clinic, without the extraneous administrative processes typical in drug development.
Outside of the special case of COVID, the 505(b)(2) repurposing still presents an efficient strategy for sponsors-- and not just for drugs that exist in the market already. It represents a second chance for drugs that would otherwise be regarded as dead, having failed to demonstrate efficacy in the clinic for their original indication.
The money and time already invested in those compounds is wasted if not for this opportunity, but repurposing allows sponsors to explore other avenues to the market. It does take a certain amount of luck; drugs are selected early in discovery with a specific therapeutic effect in mind.
Not all compounds have potential for other therapeutic needs, and even for those that do it’s difficult to identify what those alternatives might be. But for some compounds, it’s a viable, efficient second chance for success.
OSP: What are the challenges associated with repurposing?
MC: Beyond identifying a promising new indication a drug could treat, one big challenge sponsors face while getting their applications ready for submission is to design critical studies that maximize use of the existing data. That would include thorough evaluation of the old data in light of current regulatory requirements; this is a challenge our own consultants are very familiar with—thinking first about what the data shows, what was the state of regulatory expectations at the time the data were analyzed, how has it changed since then, and then developing a tactical plan for how to effectively and efficiently fill the gaps.
Other considerations can be important as well. For components like DDI risk, often the FDA will grant conditional approval for the clinic that directs the sponsor to get more data later through clinical or nonclinical studies. This information is helpful in shaping up the data package for the 505(b)(2) and can save money in the long run by obtaining in vitro data in the place of a full DDI human study later on.
OSP: What advice would you give researchers and developers pursuing existing drugs that might be good COVID candidates?
MC: Take joy in the fact that a lot of the work and studies are already done, but don’t box yourself into the expectation that ALL of the data are there already.
Drug metabolism and especially drug transporter science is growing fast and even in the last few years there have been lots of changes in expectations for a solid data package. If there is a gap or an unanswered question—the best thing to do is address it early, with in vitro experiments where you can, instead of having to design a much more time- and capitol-intensive clinical DDI study later on. That’s why a lot of developers feel it’s worth it to get a second set of eyes on a DDI package before IND or the repurposing pathway application—it’s cheaper to just make sure there’s nothing missed than to have to address it later.
Also, if there are unanswered DDI questions, it could handicap your clinical design by excluding potential volunteers taking medications that could possibly risk a DDI. If you can answer the question up front and show there is no risk, you could be saving yourself from limitations down the line.
OSP: What steps can they take to ensure they are working fast, but not risking patient or trial-participant safety?
MC: Conduct a thorough review of all existing data and recognize that some studies done in the past were performed to different standards of scientific rigor or quality. It may be easy in this position to think, “well, in 2015 this data package made it through IND approval so surely it would make it to the clinic as it is.” But that would be a mistake.
Sponsors should remember that standards of drug safety constantly evolve as new research, methods, and failures accumulate. Ours is an industry built and polished by science; better drugs and better development processes come from learning and revision of what already exists. Even if a data set is only a few years old, special attention to relevant scholarship and regulatory updates is key to ensuring that data set will withstand today’s scrutiny.
OSP: How can teams best avoid adverse reactions from DDI with potential COVID-19 treatments?
MC: Outsourcing to a specialized CRO is a great option. There are so many choices to make when it comes to DDI risk assessment, from which studies to conduct to how to design the experiments to properly fit the molecule to interpreting a full data set in a way that paints an accurate picture of disposition and illuminates potential issues.
Standard studies include perpetrator potential studies (enzyme induction, enzyme inhibition), drug transporter studies, and drug metabolism studies. Additionally, cytokine release studies may be helpful in assessing dysregulation of cytokine expression posited as a COVID-related risk factor in recent research.
Having someone on your side with the experience, training, and scholarship to foresee proper alignment of these components and get the job done right is essential. Simply having DDI data is not enough to show the FDA, EMA, or PMDA that your drug is going to be safe in a clinical setting when administered to patients who may be taking other medications as well.
The way to do it is to understand the data in context of current guidance, published research, and the narrow scientific overlap between molecular biology, chemistry, physiology, and pharmacology. When you’re armed with reliable data and that kind of expertise, your chances of success are way higher and you can be confident in your submission.
