Redx Pharma

Focus remains firmly on fibrosis and related diseases

Report | 10 July 2024

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Redx Pharma has now delisted from AIM and re-registered as a private company. The focus remains firmly on fibrosis, and key internal programmes include two clinical ROCK inhibitors and a preclinical DDR inhibitor. Management expects top-line Phase IIa data for zelasudil in IPF (idiopathic pulmonary fibrosis) during 2024, whilst initial safety data in healthy volunteers from the Phase I trial of RXC008 for fibrostenotic Crohn’s disease are expected towards end-2024. Redx also has a number of existing partnerships in place across four programmes; three with Jazz Pharmaceuticals, and one with AstraZeneca. RXC004 (zamaporvint), which recently reported Phase II data in combination with checkpoint inhibitors (CPI) for Wnt-ligand dependent cancers, has been earmarked for partnering. This note provides an overview of the current status of key programmes.

Year-end: September 30202220232024E2025E
Revenues (£m)18.74.2N/AN/A
Adj. PBT (£m)(17.3)(28.8)N/AN/A
Net Income (£m)(18.0)(33.2)N/AN/A
Cash (£m)53.918.1N/AN/A
EBITDA (£m)(15.4)(32.9)N/AN/A
Source: Redx Pharma   Note: Adjusted numbers exclude share-based payments and exceptionals.
  • Zelasudil Phase IIa data expected 2024 The lead ROCK asset is zelasudil, a selective ROCK2 inhibitor in a Phase IIa trial in IPF, with topline data expected 2024. The trial is primarily to assess safety and tolerability, but will also include initial data on efficacy endpoints. Data will inform the design of a subsequent Phase IIb programme, to include broader interstitial lung diseases (ILDs).
  • RXC008 Phase I ongoing in fibrostenotic Crohn’s The second ROCK programme is RXC008, which is in a Phase I trial for fibrostenotic Crohn’s disease. RXC008 is a GI-targeted pan-ROCK inhibitor which is expected to be used in combination with standard-of-care anti-inflammatories. The first part of the Phase I study includes healthy volunteers and will assess safety and PK data, with initial results expected by end-2024. A Phase II trial in fibrostenotic Crohn’s patients is planned.
  • Partnering remains active Redx has three collaborations with Jazz Pharmaceuticals and one with AstraZeneca. In addition, zamaporvint (RXC004), which is in development for Wnt-ligand dependent cancers, has been earmarked for partnering for further development following the Phase II combination data reported at the ESMO GI conference in June 2024.
  • Private company but focus remains the same Redx Pharma’s pipeline, which is focused on fibrotic disease, cancer, and cancer associated fibrosis, is based on its medicinal chemistry expertise, which has led to the discovery and development of six molecules which have entered the clinic, of which one (pirtobrutinib) is approved. In-house programmes focused on ROCK inhibition are being developed to key value-inflection points, and other certain assets are partnered, sometimes as early as preclinical, with four deals already in place. Redx delisted from AIM on 1 May 2024 and is now a private limited company. A matched bargain facility (provided by J P Jenkins) is in place to facilitate trading in ordinary shares.

Report

10 July 2024

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Company description

Redx Pharma specialises in the discovery and development of small molecule therapeutics, with an emphasis on fibrotic diseases. It aims to progress them through proof-of-concept studies, before evaluating options for further development.

Analysts

Lala Gregorek
lgregorek@trinitydelta.org
+44 (0) 20 3637 5043

Philippa Gardner
pgardner@trinitydelta.org
+44 (0) 20 3637 5042

Redx is focused on advancing its ROCK inhibitor portfolio, with two programmes currently in the clinic: (1) zelasudil (RXC007) in IPF; and (2) RXC008 in fibrostenotic Crohn’s disease. A selective DDR1 inhibitor (RXC009) is also in preclinical development for kidney fibrosis. Redx’s partnering activities are also active, with three collaborations with Jazz Pharmaceuticals and one with AstraZeneca. In addition, zamaporvint (RXC004) has been earmarked for partnering. An overview of Redx’s pipeline is shown in Exhibit 1.

Exhibit 1: Redx Pharma pipeline
Source: Redx Pharma   Note: GI = gastrointestinal; IND = investigational new drug application; MAPK = mitogen-activated protein kinase; MSS mCRC = microsatellite stable metastatic colorectal cancer; RAF = rapidly accelerated fibrosarcoma. ROCK: Rho associated protein kinase; KRAS: Kirsten rat sarcoma virus.

Zelasudil top-line Phase IIa IPF data in 2024

Redx’s most advanced fibrosis programme is zelasudil (RXC007), a novel highly selective small molecule inhibitor of ROCK2 (Rho Associated Coiled-Coil Containing Protein Kinase 2). It is initially being developed for idiopathic pulmonary fibrosis (IPF) and management expects topline data from the ongoing Phase IIa trial in 2024. The study is a randomised, double-blind, placebo-controlled dose ranging trial, outlined in Exhibit 2, with patients in each cohort being dosed for 12-weeks, with an option to continue for a further 12-weeks in an open label extension.

The Phase IIa study is primarily focused on the safety/tolerability profile of zelasudil in IPF patients with or without standard of care ie nintedanib or pirfenidone, and will also include initial data on efficacy endpoints. The outcome of the Phase IIa trial will define the dose that will be taken into further Phase IIb trials. On confirmation of the recommended Phase II dose, an 8-16 patient 28-day translational science sub-study will also follow, evaluating target engagement and fibrosis modification through key translational science endpoints. Recruitment into the study, randomised 3:1 between zelasudil and placebo, has been completed, with zelasudil well tolerated to date. .

Exhibit 2: Zelasudil Phase IIa study design
Source: Redx Pharma   Note: IPF: idiopathic pulmonary fibrosis; BID: twice daily; OLE: open label extension; Pbo: placebo; FVC: forced vital capacity; HRCT: high-resolution computed tomography; DLCO = carbon monoxide diffusion coefficient.

The Phase IIa study is ongoing in Europe and the UK, whilst in the US dosing of zelasudil for longer than 28-days is subject to an FDA partial hold based on skeletal muscle findings in dog toxicology studies. Preclinical work is ongoing to address this partial clinical hold. According to Redx, no similar findings have been observed in humans or other species at any dose. Redx expects to submit data from further preclinical studies to address the partial clinical hold and potentially allow for longer dosing durations in the US during 2024.

Assuming positive Phase IIa outcomes, management has outlined that the next steps for zelasudil include a larger 12-month Phase IIb study in IPF and chronic fibrosing interstitial lung disease (CF-ILD). Progressive fibrotic interstitial lung diseases (ILD) are a larger opportunity for zelasudil, with IPF representing only 20-50% of ILDs. Outside of lung fibrosis, Redx also has wider plans to expand future development of zelasudil as a fibrosis therapy, subject to funding. Opportunities that management has outlined include cancer-associated fibrosis or treatment of highly fibrotic tumours such as pancreatic cancer, with clinical development plans that include a Phase Ib study of zelasudil in combination with chemotherapy (gemcitabine/abraxane) in first line pancreatic cancer in 2025.

Prior preclinical data (covered in the October 2022 Update) have demonstrated marked reductions in collagen deposition and fibrosis in various relevant models. Phase I data confirmed zelasudil’s safety and tolerability, with no serious adverse events and only transient, reversible, mild adverse events. The pharmacokinetics were as predicted from preclinical data, and no significant effect on exposure was seen when dosed with food. The Phase I data showed a mean half-life of approximately 9-11 hours, which suggests the potential for once or twice daily dosing.

RXC008 Phase I ongoing in fibrostenotic Crohn’s

RXC008 is a GI-targeted pan-ROCK (Rho Associated Coiled-Coil Containing Protein Kinase) inhibitor in development for patients with fibrostenotic Crohn’s disease (CD). Following dosing of the first participant in the Phase I study in February 2024, it is Redx’s second wholly-owned ROCK asset to enter clinical development. RXC008 is a potent, oral, small molecule inhibitor of both ROCK1 and ROCK2 pathways that has been specifically designed to act only locally at sites of CD-associated fibrosis within the gastrointestinal (GI) tract. Low permeability and high efflux mean it localises to the gut, and in the event of any residual absorption it is rapidly metabolised by paraoxonase enzymes in the blood. This GI-restricted effect allows the targeting of both ROCK receptors but should avoid the cardiovascular side-effects (hypotension, tachycardia) associated with systemic pan-ROCK inhibition.

Exhibit 3: RX008 Phase I study protocol (healthy volunteers)
Source: Redx Pharma

The Phase I trial (Exhibit 3) is a two-part study evaluating the safety and pharmacokinetic (PK) profile of RXC008 in healthy volunteers (Part A and B). These healthy volunteer cohorts include single ascending dose (SAD) and multiple ascending dose (MAD) over 14 days, with safety as the primary endpoint and secondary endpoints evaluating PK to confirm the target profile (including data on faeces, plasma, and tissue in the MAD cohort). Management expects Phase I data by end-2024. Next steps include a planned Phase II trial in fibrostenotic CD patients, which will involve a one-month dosing safety run in to confirm minimal systemic exposure in patients (as absorption may differ from healthy volunteers), explore evidence of target engagement, and changes in circulating fibrotic biomarkers. This will be followed by a 24-week dosing study to investigate efficacy, safety, PK, target engagement and fibrotic biomarkers.

Preclinical data (covered in more detail in the February 2024 Update) have demonstrated the ability of a closely related GI-targeted ROCK inhibitor to completely reverse fibrosis to baseline levels, and the ability of RXC008 to reduce fibrosis and smooth muscle hyperplasia, which is a contributing factor to stricture development. RXC008 has also been shown to have a therapeutic effect in an adoptive T-cell transfer model (where inflammation and tissue remodelling have been induced and established), demonstrating reduced fibrosis and tissue damage. Further studies with both RXC008 monotherapy and in combination with an anti-TNF demonstrated synergies in the combination.

RXC009 for kidney fibrosis in preclinical development

Redx is also developing RXC009, a selective DDR1 inhibitor. The discoidin domain receptors, DDR1 and DDR2, are non-integrin tyrosine kinase collagen receptors. DDR1 is expressed in a variety of tissues, including the brain, kidney and lung, and abnormal expression is associated with cancer progression, fibrosis and chronic inflammatory diseases. Preclinical data in kidney fibrosis models demonstrated a reduction in markers of inflammation, kidney injury and fibrosis, and target engagement in kidney tissue, supporting use in kidney fibrosis indications such as diabetic kidney diseases and chronic kidney diseases. Redx plans to progress RXC009 to IND-enabling studies, aiming for IND submission in 2025.

Four partnership agreements in place

Redx has four partnership agreements already in place: three with Jazz Pharmaceuticals and one with AstraZeneca. Exhibit 4 summarises the respective deals. To date, upfront/milestone receipts total $58.5m.

The first agreement with Jazz Pharmaceuticals covers JZP815, a precision pan-RAF inhibitor now in Phase I, which was designed to overcome the acquired resistance mechanisms associated with currently approved B-RAF selective drugs. Around one-third of cancers involve mutations that result in uncontrolled signalling in the RAS-RAF-MAPK pathway. The second Jazz collaboration addresses an undisclosed target on the MAPK pathway, which is at an earlier pre-IND stage.

The most recent licensing deal between the two parties covers KRAS (Kirsten rat sarcoma virus), a well-validated oncology target that is one of the most frequently mutated oncogenes across many different cancer types. To date, targeting specific KRAS mutations, with the exception of G12C, has proved challenging. The Jazz/Redx KRAS programme includes both G12D selective and pan-KRAS candidate molecules.

Redx’s licence agreement with AstraZeneca centres on AZD5055 (formerly RXC006), a potent, highly selective small molecule of the porcupine receptor that is currently in development for non-oncology indications. AZD5055 targets the Wnt pathways that are critical elements in maintaining adult cell homeostasis, which includes wound healing and repair functions.

Exhibit 4: Redx Pharma partnerships
Source: Trinity Delta, Redx Pharma

Zamaporvint earmarked for partnering

Zamaporvint (RXC004) is a highly potent and selective once-daily porcupine inhibitor in development for Wnt-ligand dependent cancers in combination with immunotherapies. This has been earmarked for partnering for further development post-Phase II.

Two Phase II studies of zamaporvint in combination with a checkpoint inhibitor (CPI), shown in Exhibit 5, have completed. PORCUPINE is in genetically selected microsatellite stable metastatic colorectal cancer (MSS mCRC) in combination with nivolumab, and PORCUPINE2 is in genetically selected pancreatic cancer as monotherapy, and unselected biliary cancer in combination with pembrolizumab. Phase II data were presented at the ESMO GI conference in June 2024. In PORCUPINE, partial responses were observed in c 30% (2/7) of genetically-selected MSS mCRC patients in combination with nivolumab, a setting where anti-PD-1 therapy alone is not effective. The disease control rate at ≥16 weeks was 57% (4/7), exceeding that of zamaporvint monotherapy at 15% (2/13). In PORCUPINE2 some durable clinical benefit was observed in biliary cancer (in an all-comers, unselected patient group) but at a lower level than in genetically-selected MSS mCRC, whilst in genetically selected pancreatic cancer one partial response was seen. These data support the principal hypothesis for use in combination with immunotherapies in genetically selected GI cancers.

Exhibit 5: Zamaporvint Phase II combination programme
Source: Redx Pharma   Note: DCR = disease control rate; DoR = duration of response; ORR = overall response rate; OS = overall survival; PFS = progression free survival

Management has outlined that preclinical data suggest there is a broader opportunity for zamaporvint in potentially synergistic combinations with other therapeutic agents, including chemotherapies and MAPK inhibitors, which is beyond the scope of Redx’s resources, and outside of the priority focus.

Exhibit 6: Summary of financials
Source: Redx Pharma

 

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