REG - Redx Pharma plc - RXC004 Phase 2 Combination Arms to Open Enrolment

Redx PharmaAnnouncement

10/11/2022 14:00

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RNS Number : 0283G  Redx Pharma plc  10 November 2022

REDX PHARMA PLC

("Redx" or "the Company")

 

Redx Announces RXC004 Phase 2 Studies Will Open Patient Enrolment for
Combination Arms with Immune Checkpoint Inhibitors

 

Phase 1 data from the study of the porcupine inhibitor in combination with an
anti-PD-1 antibody presented at Society for Immunotherapy of Cancer Conference

 

 

Alderley Park, UK, 10 November 2022 Redx (AIM:REDX), the clinical-stage
biotechnology company focused on discovering and developing novel, small
molecule, highly targeted therapeutics for the treatment of cancer and
fibrotic disease, today announces that the ongoing Phase 2 clinical studies of
RXC004 will open enrolment into the combination arms, where RXC004 will be
combined with immune checkpoint inhibitors (ICIs). The PORCUPINE study of
RXC004 in genetically selected patients with microsatellite stable metastatic
colorectal cancer (MSS mCRC) will open a combination arm with nivolumab
(OPDIVO® - Bristol Myers Squibb, an anti-PD-1 antibody) and PORCUPINE 2 in
patients with biliary tract cancer will open a combination arm with
pembrolizumab (KEYTRUDA® - MSD International Business GmbH, an anti-PD-1
antibody). The recommended RXC004 dose for both combination arms is 1.5mg once
daily. Results from these open label Phase 2 studies are expected from H1
2023.

 

The poster, presented today, at the Society for Immunotherapy of Cancer (SITC)
Conference (8- 12 Nov Boston, MA, USA) provided encouraging data from the
combination module ("Module 2") of the Phase 1 clinical study of RXC004 with
nivolumab. Results from the monotherapy module ("Module 1") of the study were
previously presented at the European Society of Medical Oncology (ESMO)
Congress in September 2021 1  (#_ftn1) .

 

Tumour-derived Wnt-ligand signalling is implicated in reduced intrinsic and
adaptive resistance to ICI therapy in multiple cancers 2  (#_ftn2)  3 
(#_ftn3)  4  (#_ftn4) . Inhibition of Wnt-ligand signalling can enhance ICI
efficacy by reversing dendritic cell tolerisation, decreasing Treg cells, and
reducing the recruitment of myeloid-derived suppressor cells 5  (#_ftn5) .
RXC004 can reverse immune evasion in mouse tumour models and has potential for
clinical synergy with anti-PD-1 therapies 6  (#_ftn6) .

 

Lisa Anson, Chief Executive Officer of Redx Pharma, said: "The poster
presented today shows RXC004 to have a manageable tolerability profile in
combination with nivolumab for Wnt-ligand dependent tumours, and a PK profile
supporting once daily dosing.  We are pleased that the data support our
decision to open the combination arms of the Phase 2 proof-of-concept studies
to understand the potential efficacy of RXC004 in combination with PD-1
inhibitors., This is an exciting development, which may open up new treatment
options for patients with a very poor prognosis. We look forward to reporting
initial headline data from our Phase 2 programme from H1 2023."

 

Dr Natalie Cook, Lead Investigator of the Study, from the University of
Manchester and Christie NHS Trust, commented: "The Phase 1 study results from
RXC004 in combination with a standard dose of the PD-1 inhibitor, nivolumab,
presented today at SITC are consistent with the previously presented Phase 1
results of RXC004 as monotherapy. Together, these data support the continued
clinical development of RXC004 - both as monotherapy and in combination with
checkpoint inhibitors - as a potential targeted treatment in selected patients
with Wnt-ligand dependent cancers."

The Phase 1 trial (clinicaltrials.gov NCT03447470) evaluated RXC004, a highly
potent, selective and orally active Porcupine inhibitor as a monotherapy
(Module 1), and in combination with the approved dose of nivolumab (Module 2),
in unselected patients with advanced solid tumours for whom no standard
therapy is available. The primary objective of the open label, '3+3' dose
escalation Phase 1 study was to assess the safety and tolerability of RXC004
with additional endpoints including pharmacokinetics (PK), pharmacodynamic
effects on peripheral immune cells and preliminary anti-tumour activity, as
measured by Response Evaluation Criteria in Solid Tumours (RECIST 1.1). The
data presented at the SITC conference were from 13 patients who completed
Module 2, up to 18 October 2022. Previously 25 patients completed Module 1 and
the results, which were reported at ESMO 2021, supported commencement of the
ongoing monotherapy arms of the Phase 2 Programme.

 

Key results presented at the SITC conference highlighted:

 

RXC004 at doses of 1mg and 1.5mg once daily in combination with standard dose
nivolumab had a manageable tolerability profile, with a pharmacokinetic
profile supporting once daily dosing. The treatment related adverse event
profile reported for Module 2 was similar to that previously reported from
Module 1, with fatigue, nausea, dysgeusia ('altered taste') and decreased
appetite being reported most frequently. While the per-protocol Phase 2 dose
for RXC004 monotherapy is 2mg, RXC004 doses higher than 1.5mg were not
explored in Module 2 because of the potential for overlapping toxicity of
colitis, which was reported in Module 1, and is a known adverse effect of
immune checkpoint inhibitors. As in Module 1, the treatment combination was
administered alongside denosumab prophylaxis which, together with the low dose
of this potent molecule, averted the bone toxicity traditionally associated
with Wnt pathway inhibition.

 

Preliminary efficacy data from Module 2 supports continued investigation of
combination of RXC004 at 1.5mg dose once daily with checkpoint inhibitors. At
the cut-off date, 10 out of the 13 unselected patients in Module 2 had
RECIST-evaluable disease. Of these, 4/6 patients 7  (#_ftn7) in the 1.5mg
RXC004 cohort had RECIST stable disease as best response. Analysis of blood
samples from some patients on treatment indicated changes in peripheral immune
cell compartments consistent with those seen in preclinical models and were
suggestive of an anti-tumour immune response. Of note, CD8+ T-cell
proliferation increased in some patients and was more pronounced in patients
with stable disease. This observation is reported to correlate with improved
response to immune checkpoint inhibitors 8  (#_ftn8) .  This effect will be
further investigated in the Phase 2 programme in recurrent MSS mCRC and
biliary tract cancers, where immune checkpoint inhibitors alone are
ineffective.

 

About the Phase 2 programme for RXC004

RXC004 entered Phase 2 clinical trials in November 2021. The first study in
the Phase 2 programme, PORCUPINE, (clinicaltrials.gov NCT04907539) is focused
on patients with advanced  MSS mCRC who have progressed following treatment
with standard of care and is evaluating preliminary efficacy and safety of
RXC004 in genetically selected patients with Ring finger protein 43 (RNF43) or
R-spondin (RSPO) aberrated, advanced MSS mCRC. Given the dual mechanism of
action of RXC004, which preclinically was shown to inhibit tumour growth and
immune evasion, there is a strong rationale for immune therapy combination in
the MSS mCRC setting, and the second module of the trial will evaluate RXC004
in combination with nivolumab, a PD-1 inhibitor. This combination module is
now approved by the FDA, which will allow patient recruitment to commence in
US trial centres. A second Phase 2 study of RXC004, PORCUPINE2,
(clinicaltrials.gov NCT04907851), as a monotherapy for genetically selected
pancreatic cancer and unselected biliary cancer, a highly Wnt-ligand dependent
cancer, commenced in January 2022, and a second arm of the biliary cancer
module will evaluate RXC004 in combination with pembrolizumab, a PD-1
inhibitor. Redx expects to report topline data readouts from the Phase 2
programme starting in the first half of 2023.

 

Additional data presented at SITC by the Garvan Institute of Medical Research

In addition, a second poster on RXC004 was presented at SITC by Redx's
collaboration partner, Associate Professor Marina Pajic of the Garvan
Institute of Medical Research in New South Wales, Australia.  The poster
was titled, "Effective Co-targeting of Fibrotic and Immune Microenvironments
to Improve the Overall Anti-tumour Response in Models of Advanced Pancreatic
Cancer" and   demonstrated the therapeutic potential of RXC004 (PORCUPINE
inhibitor) and a ROCK2 selective inhibitor, in targeting fibrosis associated
with pancreatic cancer. The data showed an increased survival in mouse models
and highlights the potential of RXC004 to modulate the tumour immune
environment of pancreatic cancers.

 

A copy of both posters will be made available on the Company's website at:
 https://www.redxpharma.com/scientific-publications/
(https://www.redxpharma.com/scientific-publications/)

 

 For further information, please contact:

 Redx Pharma Plc                                                      T: +44 (0)1625 469 918

 UK Headquarters

 Caitlin Pearson, Head of Communications

 ir@redxpharma.com (mailto:ir@redxpharma.com)

 Lisa Anson, Chief Executive Officer

 US Office

 Peter Collum, Chief Financial Officer

 SPARK Advisory Partners (Nominated Adviser)                          T: +44 (0)203 368 3550
 Matt Davis/ Adam Dawes

 WG Partners LLP (Joint Broker)                                       T: +44 (0)203 705 9330
 Claes Spång/ Satheesh Nadarajah/ David Wilson

 Panmure Gordon (UK) Limited (Joint Broker)                           T: +44 (0)207 886 2500
 Rupert Dearden/ Freddy Crossley/ Emma Earl

 FTI Consulting                                                       T: +44 (0)203 727 1000
 Simon Conway/ Ciara Martin

 

About Redx Pharma Plc

Redx Pharma (AIM: REDX) is a clinical-stage biotechnology company focused on
the discovery and development of novel, small molecule, highly targeted
therapeutics for the treatment of cancer and fibrotic diseases, aiming
initially to progress them to clinical proof of concept before evaluating
options for further development and potential value creation. Redx's lead
oncology product candidate, the Porcupine inhibitor RXC004, being developed as
a targeted treatment for Wnt-dependent cancers, commenced a Phase 2 programme
in November 2021. The Company's lead fibrosis product candidate, the
selective ROCK2 inhibitor RXC007, is in development for interstitial lung
disease and commenced a Phase 2a trial for idiopathic pulmonary fibrosis
in October 2022.  Redx's third drug candidate, RXC008, a GI-targeted ROCK
inhibitor for the treatment of fibrostenotic Crohn's disease, is currently in
pre-IND stage, with Phase 1 clinical studies expected to commence in 2023.

 

The Company has a strong track record of discovering new drug candidates
through its core strengths in medicinal chemistry and translational science,
enabling the Company to discover and develop differentiated therapeutics
against biologically or clinically validated targets. The Company's
accomplishments are evidenced not only by its two wholly-owned clinical-stage
product candidates and rapidly expanding pipeline, but also by its strategic
transactions, including the sale of pirtobrutinib (RXC005, LOXO-305), a BTK
inhibitor now in Phase 3 clinical development by Eli Lilly following its
acquisition of Loxo Oncology and AZD5055/RXC006, a Porcupine inhibitor
targeting fibrotic diseases including idiopathic pulmonary fibrosis (IPF),
which AstraZeneca is progressing in a Phase 1 clinical study. In addition,
Redx has forged collaborations with Jazz Pharmaceuticals, which includes
JZP815, a pan-RAF inhibitor developed by Redx which Jazz is now progressing
through Phase 1 clinical studies and an early stage oncology research
collaboration.

 

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www.redxpharma.com/investor-centre/email-alerts/

 1  (#_ftnref1) Cook et al, 2021, ESMO Annual Congress

 2  (#_ftnref2) Spranger and Gajewski 2018 Nat Rev Cancer. 18(3): 139-147

 3  (#_ftnref3) Rodriguez et al 2018 Rodriguez-Pascual et al . Cancer Drug
Resist 2019;2:980-93

 4  (#_ftnref4) Luke et al 2019, Clin. Cancer Res. 25(10):3074-3083

 5  (#_ftnref5) Devito et al, 2021 Cell Reports 35, 109071, May 4, 2021

 6  (#_ftnref6) Phillips et al, 2022, Cancer Res Commun. 2(9):914-928.

 7  (#_ftnref7) One patient each with: signet cell rectal cancer (loss of
function mutation; ring finger protein 43), pleural epithelioid mesothelioma,
malignant pulmonary cylindroma, recurrent solitary fibrous tumour of pleura

 8  (#_ftnref8) Huang et al. 2017, Nature, 545; 60-65.

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