Faron Pharma Regulatory News (FARN)

Faron Pharmaceuticals Ltd

("Faron" or the "Company")

INTEREST trial update

Routine corticosteroid treatment correlates with increased mortality and decreased Traumakine efficacy

INTEREST trial results and statistical analyses to be presented at 31st ESICM (European Society of Intensive Care Medicine) meeting in Paris

TURKU - FINLAND, 22 October 2018 - Faron Pharmaceuticals Ltd ("Faron") (LON: FARN), the clinical stage biopharmaceutical company, today announces more detailed analysis of data from the Traumakine INTEREST study related to corticosteroids used in parallel to Traumakine treatment and their effect on Traumakine efficacy. This follows the Company's announcement of 13 September 2018 where it was noted that analysis of the INTEREST trial data had shown that other concurrent and widely used acute respiratory distress syndrome (ARDS) treatments had had a significant effect on mortality in the trial. These data will be presented today by INTEREST study investigators, Professors Geoff Bellingan (University College London Hospitals), and Marco Ranieri (University of Rome) at the 31st ESICM (European Society of Intensive Care Medicine) meeting in Paris.

As previously reported, inconsistent interferon-beta (IFN-beta) biomarker (MxA and CD73) induction was observed across the treatment group, but a sub-group of patients with a biomarker response showed a reduced day 28 (D28) mortality. To further investigate this selective benefit among the Traumakine-treated ARDS patients, further post-hoc data analysis has been carried out by the trial investigators which has found that concomitant use of corticosteroids and Traumakine appeared to affect both the mortality and biomarker appearance in the INTEREST study patients.

The following key findings will be presented at ESICM:

· Corticosteroid use was high among INTEREST trial patients (176/296, 59.5%)

· Concomitant corticosteroid treatment 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 (p

· 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, p= 0.03)

· IFN-beta has previously been demonstrated to increase CD73 expression in lung capillaries(1) 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 culture conditions prevents Traumakine induced CD73 expression in lung capillaries

Of note, we also observed that the use of corticosteroids in the placebo group was associated with an increased mortality of 27.6% compared to no use of corticosteroids of 14.8% (p= 0.075). In the group receiving corticosteroids there was a significantly higher APACHE II (acute physiology and chronic health evaluation) score (23.4 versus 20.4, p=0.0007) and SOFA (sequential organ failure assessment) score (10.4 vs 9.5, p=0.0428) but this difference does not, we believe, explain the scale of mortality difference associated with corticosteroid use versus non-use. Additionally, in a genetic analysis of a subset of patients treated with Traumakine, Faron has identified an altered (polymorphic) regulatory motif for the glucocorticoid receptor of the interferon-alpha/beta receptor beta chain which Faron believes could be associated with those patients who responded to traumakine (p=0.007) and which may confer corticosteroid resistance and impact IFN-beta action.

The Company 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 and ex vivo experiments with human endothelial HUVEC cells 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.

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 approximately 50 healthy volunteers. This will determine the optimum mechanism of administration to achieve a full biomarker response with first results expected in Q4 2018. The YODA study may also be extended to examine concomitant use of Traumakine and corticosteroids to get final in vivo evidence for corticosteroid interference of interaction activity.

Dr Matti Karvonen, Chief Medical Officer of Faron, said: "At this stage it appears possible that unexpectedly high corticosteroid use in the INTEREST trial may have masked the treatment benefit of Traumakine in ARDS patients. Therefore, the Company and the investigators await data from the ongoing Phase III ARDS trial with Japanese partner Maruishi, expected later this year, and further experimental data on lung tissue samples and YODA results, to determine the next steps for Traumakine's development." 

Commenting on the results, Dr Geoff Bellingan, co-Principal Investigator of the INTEREST study, said: "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. 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(2) 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."

Dr Marco Ranieri, co-Principal Investigator of the INTEREST study, said: "Whilst we were disappointed with the initial results from the INTEREST study, we have now made a very important observation that corticosteroid use significantly disturbs both administered and endogenous interferon-beta activity making it possibly a harmful drug in the acute phase of ARDS. 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."

The cited references:

(1) Bellingan G, Maksimow M, Howell DC, Stotz M, Beale R, Beatty M, Walsh T, Binning A, Davidson A, Kuper M, Shah S, Cooper J, Waris M, Yegutkin GG, Jalkanen J, Salmi M, Piippo I, Jalkanen M, Montgomery H, Jalkanen S (2014) The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study. Lancet Respiratory Medicine 2: 97-104.

(2) Flammer JR, Dobrovolna J, Kennedy MA, Chinenov Y, Glass CK, Ivashkiv LB and Rogatsky I (2010) The type I interferon signaling pathway is a target for glucocorticoid inhibition. Molecular and Cellular Biology 30: 4564.

Today's presentation by INTEREST study investigators, Professors Geoff Bellingan and Marco Ranieri is available to view at www.faron.com 

For more information please contact:

Faron Pharmaceuticals Ltd

Dr Markku Jalkanen, Chief Executive Officer

investor.relations@faron.com 

Consilium Strategic Communications

Mary-Jane Elliott, Matthew Neal, Lindsey Neville

Phone: +44 (0)20 3709 5700

E-mail: faron@consilium-comms.com

Westwicke Partners, IR (US)

Chris Brinzey

Phone: 01 339 970 2843

E-Mail: chris.brinzey@westwicke.com

Panmure Gordon (UK) Limited, Nomad and Broker

Emma Earl, Freddy Crossley

Phone: +44 207 886 2500

About Faron Pharmaceuticals Ltd

Faron (AIM:FARN) is a clinical stage biopharmaceutical company developing novel treatments for medical conditions with significant unmet needs. The Company currently has a pipeline focusing on acute organ traumas, vascular damage and cancer immunotherapy. The Company's lead candidate Traumakine, to prevent vascular leakage and organ failures, is currently the only treatment for Acute Respiratory Distress Syndrome (ARDS) undergoing Phase III clinical trials and in 2017 received advice from US FDA to proceed directly to BLA submission following completion of EU and Japanese Phase III studies. There is currently no approved pharmaceutical treatment for ARDS. An additional European Phase II Traumakine trial is underway for the Rupture of Abdominal Aorta Aneurysm ("RAAA"). Faron's second candidate Clevegen is a ground breaking pre-clinical anti-Clever-1 antibody. Clevegen has the ability to switch immune suppression to immune activation in various conditions, with potential across oncology, infectious disease and vaccine development. This novel macrophage-directed immuno-oncology switch called Turn-on-your-Immunity or Turn-It may be used alone or in combination with other immune checkpoint molecules for the treatment of cancer patients. Faron is based in Turku, Finland. Further information is available at  www.faron.com