A new kid on the budesonide block

In a Phase IIa study in active ulcerative colitis, Fellermann et al. ¹ investigated a new prolonged release budesonide formulation developed by Falk Pharma, and showed improvement of clinical, endoscopic and histological scores. After 8 weeks of treatment with 9 mg/day, clinical remission was achieved in 47.5%. Endoscopic remission was somewhat higher, and histological remission slightly lower. All patients included were refractory to mesalamine. Limitations of the study are manyfold: limited number of intention-to-treat patients (n = 61), limited effect and not a limited control group but actually none. In addition, there is a colonic-release preparation on the market already. So, what’s the point? Another ‘me too’?

Budesonide is characterised by an extensive hepatic first-pass extraction and a CYP3A-mediated metabolism to 16α- and 6β-hydroxybudesonide comprising only 1–10% activity of the parent compound. ² Notably, original budesonide exhibits a 200-fold higher affinity to the glucocorticoid receptor compared to cortisol. From the approved multimatrix (MMX) formulation developed by Cosmo Pharma, release begins at a pH of >7, ² but colonic pH during active colitis may actually be lower. The Falk formulation, in contrast, is claimed to be released at a pH of >6, but no data are given. Interestingly, maximal budesonide serum concentrations following MMX are about double those reported in the present study ³ but manyfold higher with the standard ileal release. ¹ The difference between the prolonged release formulations is likely due to the differing galenic formulations where budesonide is either distributed more homogeneously in the MMX-tablet (Cosmo) or reserved to a core layer surrounded by a carbomer swelling and a prolonged release layer (mixture of two ammonio methacrylate copolymers) surrounded by a gastro-resistant layer (Falk).

What about efficacy? It is, of course, notoriously contraindicated to compare different studies numerically with different cohorts and end points. With this in mind, the new galenic version compares favourably to the old budesonide MMX and others. In the CORE I trial, 9 mg/day of budesonide MMX achieved remission in mild-to-moderate ulcerative colitis after 8 weeks in 17.9% (compared to 7.4% in the placebo group). ⁴ The identically designed CORE II reported similar data, with a combined clinical and endoscopic end point (for some reason, clinical remission rates are not given). ⁵ This combined end point was also significant in a pooled analysis of both studies, but remarkably it was not significantly different in extensive/pancolitis. ⁶ In a third trial ⁷ focusing on a mesalamine-refractory cohort, in line with the Fellermann et al. study, the combined end point was achieved in 13.0% versus 7.5% (placebo), but clinical remission alone was comparable in both groups (suggesting that endoscopic remission made the difference). Unfortunately, endoscopy did not correlate well with histologic remission at study initiation, leading to the exclusion of many patients with endoscopic but not histological remission after randomisation. The CORE authors discussed extensively why end-point achievements were so low compared to standard medications and blamed the strict end-point criteria.^4–6 On the other hand, we have become acquainted with (but not accustomed to) similarly low remission rates after 8 weeks using adalimumab (16.5%), golimumab (17.8%), vedolizumab (16.9%), ustekinumab (15.6%) or tofacitinib (17.6%). ⁸ As long as there is a significant difference versus placebo, the pharmaceutical companies are happy, the Food and Drug Administration and European Medicines Agency are satisfied and the drug is approved for the indication. Notwithstanding, patient expectations and views are strikingly different, which becomes obvious if a doctor explains the number needed to treat (NNT) in the range of 10–18^4,7 to a patient. In comparison, with the biologicals mentioned above and tofacitinib, the NNTs are in a similar range from 8 to 14. ⁸ The patient may need some guidance in calculating his chances to benefit from the drug (as do some doctors), but some raised eyebrows may well be observed. It needs to be confirmed that the new galenic form of budesonide presented by Fellermann et al. indeed also achieves remission rates in the systemic steroid range in larger and, this time, controlled trials. So, close but no cigar!

What about side effects? As usual, several adverse events occurred in the current study, ¹ but no typical Cushing’s symptoms. Remarkably, morning cortisol levels were virtually unaffected, possibly related to the low budesonide serum concentrations. In comparison, budesonide MMX at 9 mg/day resulted in a clear drop, although still within the normal range. ⁹ In this pooled safety analysis, Lichtenstein et al. concluded that budesonide MMX was not associated with glucocorticoid-related side effects. It may be a different issue in the long term, but most of us will be reluctant to use any steroid on a maintenance basis anyway. Finally, it should be emphasised in particular that patients with liver disease are prone to significant budesonide toxicity, probably due to shunting and limited functional reserve.

Thus, the current uncontrolled trial of this novel budesonide prolonged release preparation for (hopefully) colonic delivery gives a hint of efficacy and minimal toxicity, suggesting that the benefit/risk ratio may be positive. The ongoing definite Phase III controlled trial will give a better answer.

Postscriptum

After every speech in the Roman senate, Cato the Elder repeated ‘ceterum censeo: Carthaginem esse delendam’ until Carthago was ultimately destroyed, following his persistence. Looking at the mere numbers of purported efficacy quoted above, it seems obvious that suffering from colitis will not cease unless we find a really novel type of therapy, probably one addressing the antimicrobial mucus barrier. ¹⁰ Ceterum censeo: we should also be persistent and finally treat the cause of this disease and not just secondary phenomena with improved but ages-old substances such as glucocorticoids.