BLUJEPA / Gepotidacin APPROVED FOR UNCOMPLICATED UTI – 1

GSK’s pipeline in anti-infectives is impressive. It comprises drugs for bacterial, mycobacterial, fungal, viral infections, and for malaria; in addition, they have a number of vaccines in development.  Several antibiotics are listed on their website targeting UTI pathogens, and one of them was just approved, namely gepotidacin / Blujepa, a gyrase/topoisomerase IV inhibitor, that has been in development for quite some time.  It is a bactericidal drug with a MoA similar but not identical to the quinolone class of anti-infectives.

Despite its relatively broad antibacterial spectrum, only two indications, uncomplicated uUTI and urogenital GC, are being pursued.  This is a bit counterintuitive but can be explained in the context of the following limitations: (1)  the high doses required to reach fAUC/MIC, which is the PK/PD driver of efficacy, (2) a dose-dependent QT-effect; and (3) the size and number of pills required with standard dosing. Two fairly large pills twice daily for 5 days will be difficult to comply with.  However, none of this is a significant impediment for IV dosing, esp. in the context of more serious infections.  In earlier days GSK mentioned plans for cUTI and cIAI studies, but the present company website lists no additional indications for gepotidacin.  As the ABSSSI study results  were not stellar (see our last blog), marketing will have to deal with a very limited set of indications, uUTI now and uGC later.

Microbiologic spectrum usually dictates the selection of indications for further development for new antibiotics.  The microbiological response in clinical studies is what matters most to us.

We are firm believers in the microbe theory of infections and don’t need surrogates like clinical response to assess efficacy. For the uUTI indication, eradication of the causative uropathogen on urine culture is all we care to see. We trust that clinical cure will follow microbial eradication.

We are confident that the key factor in a uUTI program is the microbiological eradication rate.  This has been true since the work by Koch and Pasteur 150 years ago and been confirmed by thousands of antibiotic studies ever since.

The FDA felt the same way in the 1992 Points to Consider guidance to industry[1], and made bacteriologic clearance the determining antibiotic efficacy in UTI studies.  Since then the Agency has changed course and introduced a combination of ‘clinical and micro response’ as the primary endpoint.  There are good reasons for this approach in diseases for which the underlying pathology is less well understood.  This is not the case, however, in infectious diseases indications, all of which should follow an organism-based approach for efficacy assessment.  We know of no example in which the ‘feel/function/survive’ mantra introduced by the statistician Prof. Fleming and supported by Dr. Power, FDA, has added value to any UTI study.

Now let’s get back to the Wagenlehner EAGLE study publication[2].  Most ink is spent on explaining arcane protocol details which are important for registration studies but make reading articles like this one so tedious to understand.  For clinicians who do not have time to grind through the lengthy Lancet article (15 pages main report plus 30 pages of supplemental data), the publishers graciously provide a brief boxed section and mention the “Added value of this study”.  Their conclusion is succinct and states that

“Gepotidacin was non-inferior to nitrofurantoin”

We agree: this conclusion is correct within the constraints of the selection criteria for patients.   

After reviewing the microbiological response data from both studies, we feel confident that gepotidacin will be a useful new uUTI agent. In the table below we combined the micro responses from the EAGLE-2 and -3 studies. Gepotidacin performed well and was numerically better than nitrofurantoin for all E.coli and subcategories of drug-resistant isolates.  We can comfortably state the following:

“Gepotidacin has numerically better E.coli coverage than nitrofurantoin”

NOTE: The table above shows microbiological success at test-of-cure by baseline qualifying uropathogen (micro-ITT NTF-S population)

This is no minor achievement even if the micro-response rates are not as high as one would like. The days of E.coli being 80-90% susceptible to any antibiotic are over.  E.coli was and remains the main pathogen to consider in uUTI; all other pathogens were isolated much less frequently. Klebsiella was the next most common organism, but the numbers are small.

Please note that the tabulated outcomes do not reflect the real world picture.  In FDA registration trials, only those pathogens get counted that are susceptible to both study drugs.  Put another way, uropathogens susceptible to only 1 study drug or not susceptible to either are not included in the EAGLE studies.  Patients on QT-prolonging drugs were excluded.

It would be nice to know more about those ‘non-qualifying’ patients, esp. those excluded because of study drug-resistant pathogens.  How were they treated and how well did they do?  This data is probably available, and there may be a follow-up publication to tell us more.  The EAGLE studies were large enough to justify additional publications; there is so much useful information beyond the main study objective and outcome.  Stay tuned: If the Blujepa approval comes with post-marketing commitments, we may learn more…

As an underappreciated byproduct of large well-conducted studies like the EAGLE program, we also learn a lot about comparator drugs.  In this case, it bears repeating that nitrofurantoin, an old, underused, very safe antibiotic for uUTI, is still an excellent choice for “non-pregnant individuals assigned female at birth”, to use the Lancet language².

Last point: the Blujepa label stipulates that gepotidacin is approved for infections caused by ‘susceptible uropathogens’.  Does this mean that a urine culture is required prior to prescribing Blujepa?  This would run contrary to general practice, as uUTI patients with tell-tale symptoms and a positive urine dipstick are usually treated empirically.  Except for cases with repeat uUTIs or non-response to prior treatment, cultures are not routinely done.  FDA reviewers are not expected to change clinical practice – this is neither their expertise nor their mandate.

Maybe FDA assumes very little uptake in the market given the rather restrictive label they imposed.  How will Blujepa fare commercially against a very cheap competitor like nitrofurantoin which was equipotent and better tolerated.  This is not the topic for today.  The question is would this program have survived at GSK without BARDA funding. This government grant of ~USD 270 mio easily paid for most of the clinical program.

ABBREVIATIONS
micro-ITT               intent-to-treat population with a qualifying uropathogen at entry
micro-response      organism microbiological response
NTF-S                    nitrofurantoin-susceptible

REFERENCES
[1] US Food and Drug Administration, Division of Anti-Infective Drug Products. Points to consider: clinical development and labeling of anti-infective drug products, 1992
[2] Wagenlehner F. Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials.  2024.  https://doi.org/10.1016/S0140-6736(23)02196-7
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