Revisiting Drug Development for Older Molecules in IBD Free

In the last 2 decades, there have been major advances in the treatment of inflammatory bowel disease (IBD), with an increasing number of advanced therapies including biologics and small molecules,¹ as well as treatment strategies to guide the best use of such therapeutics.² Despite all these innovations, a “therapeutic ceiling” has emerged, with responses rates plateauing at approximately 30% to 50% for any given treatment.³ In fact, treatment response for some clinical phenotypes of IBD have remained even lower, in part due to exclusion from drug development programs. A notable example is the historical exclusion of many patients with isolated proctitis from ulcerative colitis (UC) clinical trials.⁴

One solution to this problem has been to advocate for further therapies to be developed with novel mechanisms of action. However, it is important to note that drug development is an extremely expensive and arduous process,⁵ and the time from identification of a potential molecule until late-phase clinical assessment can typically be in the region of 15 years.⁶ Additionally, the burden of IBD is increasing worldwide, including in newly industrialized countries, highlighting the need for any new treatments to also be affordable.⁷ In this regard, drug repurposing (ie, the strategy of investigating additional clinical indications for existing medications) may be highly advantageous. Repurposing can rapidly speed up the drug development timeline and be achieved at significantly lower cost than entirely novel drug development programs.⁸

One often-overlooked example of drug repurposing in IBD is that of thioguanine. It was initially developed in the 1950s for the treatment of leukemia, and since then, it has been investigated for various inflammatory disorders, including IBD.⁹ Despite the use of conventional thiopurines such as azathioprine and mercaptopurine, concerns of hepatotoxicity from thioguanine drove many away from its use in IBD. This was even after the demonstration that adverse effects were dose-dependent, without longer-term clinical implication, and typically reversible.¹⁰ In the Netherlands, however, thioguanine is currently a registered treatment option in cases of intolerance or suboptimal response to conventional thiopurines, with reassuring results reported to date with regard to efficacy, safety, and tolerance.^9,11 More recently, thioguanine has been reformulated to a topical agent for colonic and/or controlled released preparations for use in the treatment of patients with distal UC.¹⁰

In the current issue of Inflammatory Bowel Diseases, Crouwel and colleagues¹² report for the first time the use of topical thioguanine as a rescue treatment for UC after failure of several previous treatments, including nonresponse to advanced therapies such as biologic medications. Sixteen patients with distal UC from hospitals in the Netherlands, Australia, and New Zealand were retrospectively included, 7 of which were treated with enemas and 9 with suppositories. Clinical response was obtained in 13 (81%) of these patients, with a notable median time to clinical response of 14 days. Remarkably, 8 (62%) of these patients had not responded to oral thiopurines but had seemingly excellent responses to topical thioguanine.

Although not widely used, oral thioguanine has previously been shown to be an effective treatment option for IBD, with a systematic review reporting clinical improvement in 65% of patients.¹¹ Perhaps the most interesting finding was that this improvement occurred despite the majority of these patients having previously failed treatment with conventional thiopurines. On closer consideration, this finding should not have been unexpected, given that thioguanine has several pharmacokinetic advantages over both azathioprine and mercaptopurine. Although the latter 2 have a complicated metabolic pathway with multiple enzymatic steps, the metabolism of thioguanine is more straightforward, with the direct conversion to 6-thioguanine nucleotides (6-TGN), which is then responsible for the therapeutic action.⁹

Additionally, thiopurine methyltransferase (TPMT) and inosinetriphosphate pyrophosphohydrolase (ITPase), enzymes involved in the metabolism of conventional thiopurines and affecting their toxicity profile, have an almost negligible role in the metabolism of thioguanine.⁹ Therefore, the direct metabolism of thioguanine through the action of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) bypasses the production of potentially toxic methylated metabolites, as occurs with conventional thiopurines. In addition to intracellular activation, thioguanine can be directly activated by gut bacteria. This might explain why rectal mercaptopurine, unlike rectal thioguanine, was shown not to improve mucosal inflammation in experimental studies.¹³

The rectal administration of thioguanine has 2 major potential advantages over oral administration. The first is its onset of action, as demonstrated by Crouwel and colleagues. Oral thiopurines have a known delayed onset of action, which is not related to the systemic concentrations of the drug but rather explained by their mechanism of action—whereby it can take several weeks or months for inhibition of GTPase Rac1 to result in apoptosis of circulating, systemic, and activated T-lymphocytes.¹⁰ In contrast, topical administration leads to drug activation by colonic bacteria and mucosal cells. Therefore thioguanine is directly delivered to sites of active inflammation, where it induces autophagy and intracellular destruction of bacteria.¹³ In addition to a faster mechanism of action, there is also limited absorption and reduced systemic exposure from topical thioguanine, thereby reducing potential toxicity. Crouwel and colleagues also demonstrate this reduced absorption of thioguanine by confirming low levels of systemic 6-TGN following topical administration.

The need for quick, effective, safe, and inexpensive drugs in IBD is an increasingly pressing issue, particularly with the rapid rise of IBD in countries with more limited resources. Therefore, this study by Crouwel and colleagues does demonstrate impressive, albeit preliminary data in an area of unmet clinical need. Given the small numbers of patients assessed and the nonstandardized administration of treatment, these findings need to be supported by further prospective studies evaluating the role of topical thioguanine. In particular, a randomized clinical trial would enable more objective assessment of response and standardized systems of delivery to better help determine efficacy and safety of this potential treatment option. Given that adherence to treatment may be a challenge with topical therapies, other systems of drug delivery providing the same advantages should also be further evaluated, such as with controlled-released oral thioguanine tablets.¹⁰

There remain many areas of unmet clinical need in IBD, including for cases of refractory proctitis, despite the significant impact on patients’ quality of life.¹⁴ In such cases, drug repurposing presents an attractive and potentially fertile area for clinical research focus. Drug repurposing offers notable advantages with the potential for reduced time and reduced costs from investigation of therapies that have already undergone rigorous testing and/or licensing for previous clinical indications. Increasing clinical, academic, and industry collaborations to explore areas for drug repurposing in IBD should be an area of research priority. The example of topical thioguanine illustrates that this repurposing approach may offer the most benefit for clinical phenotypes with an ongoing high disease burden and for areas of IBD where treatment options still remain limited.

Author Contributions

P.S. and N.M.N. wrote and approved the final version of the manuscript.

Conflicts of Interests

P.S. and N.M.N. have no financial or personal conflicts of interest to disclose.

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