Faron Pharmaceuticals Oy (LON:FARN) believes unexpectedly high corticosteroid (steroid hormones) use by some patients may have affected the results of its Traumakine INTEREST study.
The Phase III study into acute respiratory distress syndrome (ARDS) yielded a disappointing result in May but further experiments by Faron open up the possibility that corticosteroids used in parallel to Traumakine treatment affected Traumakine’s (FP-1201-lyo) efficacy.
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Faron is presenting its revised findings on October 22 at the 31st ESICM (European Society of Intensive Care Medicine) meeting in Paris.
Faron noted that use of corticosteroids among the 296 patients in the INTEREST was high, with 59.5% of them using them.
It postulated that administering corticosteroid treatment alongside Traumakine, i.e. concomitantly, had a significant impact on mortality in the Traumakine treatment group.
Mortality was 10.6% (7/66) for those receiving Traumakine and not on corticosteroids, versus 39.7% (31/78) for those receiving Traumakine and on concomitant corticosteroids. This outcome is highly statistically significant, Faron said, and had a similar mortality rate to the treatment group in the Phase I/II study, the results of which encouraged the company to move on to a Phase III study.
Furthermore, concomitant corticosteroid use with Traumakine was also associated with worse outcomes measured by ventilator-free days (VFD) compared to non-users (median 6 VFDs vs. 14 VFDs).
Interferon beta (IFN-beta) has previously been demonstrated to increase CD73 expression in lung capillaries, which was associated with reduced mortality in ARDS patients in the Phase I/II trial; however, concomitant exposure of human lung tissue samples to hydrocortisone in ex vivo (i.e. on cells that are directly isolated from the animal) culture conditions prevents Traumakine-induced CD73 expression in lung capillaries, Faron said.
Faron believed that the inconsistent FP-1201-lyo bioactivity observed in the INTEREST trial may well, in part, be due to corticosteroid interference of IFN-beta action. Therefore, further in vitro (so-called “test tube”) and ex vivo experiments with human umbilical vein endothelial cells (cells that line the blood vessels) and human lung tissue samples were conducted. Based on these results, no issues have been detected to date in the formulation of FP-1201-lyo used in the INTEREST trial and the formulation was as active as the formulation used in the Phase I/II trial.
In lung tissue samples, the concomitant corticosteroids prevented the CD73 induction by Traumakine, which indicates similar interference of corticosteroids on IFN-beta bioactivity as observed in the INTEREST study, Faron asserted.
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To understand the reduced biomarker response to Traumakine administration, even where corticosteroids were not administered in the INTEREST study, a new FP-1201-lyo pharmacokinetic/dynamic study, YODA, is already underway in roughly 50 healthy volunteers. This will determine the optimum mechanism of administration to achieve a full biomarker response, with first results expected before the end of the year.
The YODA study may also be extended to examine the concomitant use of Traumakine and corticosteroids to get final in vivo evidence for corticosteroid interference of interaction activity.
"The controversy around administration of corticosteroids to ARDS patients has been a puzzling topic for decades where there has been an ongoing debate as to whether corticosteroids have any beneficial role, early, late or for more severe un-resolving cases,” said Dr Geoff Bellingham, a co-principal investigator of the INTEREST study.
“These new findings from the INTEREST study, where some patients were also given corticosteroids as part of their treatment, now suggest that we should control or exclude corticosteroids from future clinical research in ARDS patients. Corticosteroids have been shown to interfere with interferon-beta signalling, hence their use could block any beneficial effects of endogenous IFN-beta and may be particularly important when dosing with Traumakine. This brings fresh hope to ARDS patients as the study of Traumakine continues," he added.
Dr Marco Ranieri, also a co-principal investigator on the study, said the observation about the apparent effect of corticosteroid use was “very important”.
“This knowledge, if supported by the YODA study as well, is extremely important for ARDS patients and current practice, and it will help plan successful studies in the future for the defeat of ARDS. The concomitant use of corticosteroids and type I interferons could be prevalent in several other conditions as well (e.g. MS disease) and we believe, therefore, that the whole medical community should be more diligent with regard to their combined use,” he said.
Shares in Faron were down 3.9% at 112p in late afternoon trading.