ESMO 2021: RXC004 monotherapy Phase I study results
Update | 21 September 2021
ESMO 2021: RXC004 monotherapy Phase I study results
Update | 21 September 2021
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Redx Pharma has two in-house clinical programmes, of which RXC004, a Porcupine inhibitor, is poised to start Phase II trials. Data from the Phase I monotherapy study were presented at ESMO showing RXC004 to be safe and well tolerated at doses up to 2mg. Treatment related adverse events were dose-related and in line with the “on-target” effects of Porcupine inhibition. While the 25 patients studied were not genetically selected, there were encouraging signals of activity in those with Wnt ligand driven tumours, with five of seven such patients showing stable disease. The Phase II programme will evaluate activity in Wnt ligand driven tumours in pancreatic, biliary, and MSS metastatic colorectal cancers. Redx’s last reported cash of £39.9m provides funding through to end-2022, covering several important value inflection points. Our current rNPV-based valuation is £350.7m, equivalent to 128p/share; start of RXC004 Phase II studies would prompt an increase to £398.8m, or 145p/share.
|Year-end: September 30||2019||2020||2021E||2022E|
|Adj. PBT (£m)||(7.5)||(9.5)||(19.9)||(26.2)|
|Net Income (£m)||(4.3)||(9.2)||(20.5)||(26.8)|
|Adj. EPS (p)||(4.0)||(5.6)||(7.7)||(9.4)|
21 September 2021
|Shares in issue||274.8m|
|12 month range||48.4-129.9p|
|Primary exchange||AIM London|
Redx Pharma specialises in the discovery and development of small molecule therapeutics, with an emphasis on oncology and fibrotic diseases. It aims to initially progress them through proof-of-concept studies, before evaluating options for further development and value creation.
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Presentation of initial Phase I data from Redx Pharma’s lead in-house oncology programme, porcupine inhibitor RXC004, at ESMO 2021 marks an important milestone for the company. The data confirms that RXC004 has a therapeutic window, with manageable side effects and early indications of efficacy in genetically selected tumours. RXC004 is one of four programmes in Redx Pharma’s well-balanced R&D portfolio in oncology and fibrosis. Recent milestone receipts have highlighted the continued progress with the two partnered programmes (with AstraZeneca and Jazz Pharmaceuticals), but, in our view, it will be the progress of the in-house assets RXC004 (Porcupine) and RXC007 (ROCK2) that will be transformative. Both are novel small molecules that address large medical needs. Phase I data for RXC004 supports the upcoming start of Phase II trials in Wnt ligand driven tumours as monotherapy and in combination with a checkpoint inhibitor. Phase II start would see our valuation rise to £398.8m, equivalent to 145p/share (98p/share fully diluted), vs our current valuation of £350.7m, equivalent to 128p/share (86p/share fully diluted).
Redx Pharma’s key differentiator is its acknowledged medicinal chemistry expertise. As we have covered in detail in previous notes, given its size, its historic track record is outstanding, with a proven ability to generate clinically, and commercially, attractive products. Redx Pharma employs this expertise to develop innovative small molecule pharmaceuticals, with the aim of creating best-in-class compounds (Exhibit 1) that address complex biological pathways. Its current pipeline consists of four clinical programmes, two of which (RXC004 and RXC007) are being developed in-house through to at least Phase II proof-of-concept studies and the others are partnered with AstraZeneca and Jazz Pharmaceuticals. Last reported cash of £39.9m (end-March 2021) means Redx Pharma is well funded, with ample resources to achieve multiple value inflection points.
The pipeline (Exhibit 2) includes two clinical stage in-house programmes: porcupine inhibitor RXC004 and ROCK2 inhibitor RXC007, which are in Phase I trials for cancer and in healthy volunteers respectively. The lead indication for RXC007 in Phase II will be idiopathic pulmonary fibrosis (IPF). A second porcupine inhibitor, RXC006, is licensed to AstraZeneca and is likely to enter clinical trials later this year or in early 2022; the start of the RXC006 Phase I trial would trigger the payment of the balance of the $17m in preclinical milestones due under the August 2020 licencing deal. A further programme, a pan-RAF inhibitor known as JPZ815, is partnered with Jazz Pharmaceuticals, and is completing preclinical development ahead of US Phase I trials that are expected to start in 2022. Several earlier-stage, internal research programmes in Crohn’s disease, oncology and fibrosis are also underway.
Recent news flow has highlighted the continuing progress seen across both Redx Pharma’s and its partnered programmes. A Virtual R&D Day on October 11, with a number of clinical experts presenting, should provide additional insights on the status and promise of RXC004. While COVID-19 restrictions remain a sensitivity with respect to timings across its pipeline (impacts on patient recruitment into clinical trials is a known industry-wide consequence), we anticipate Redx Pharma will maintain the current momentum and make significant strategic progress. Ahead of this event, and on the back of the data presented at ESMO 2021, we focus on the recent progress in the two proprietary programmes in this note, in particular, on RXC004.
RXC004 is a porcupine inhibitor under evaluation as both monotherapy and in combination with checkpoint inhibitors (CPIs) in various solid tumours. Porcupine (Porcn) is a membrane-bound enzyme (MBOAT) that enables a key step required for the secretion, transportation, and activity of Wnt ligands. The Wnt (Wingless type) signalling pathways are increasingly recognised as an attractive, albeit challenging, drug target. Wnt signalling has been known as a key oncogenic pathway in multiple cancers for nearly 40 years, with clinical progress hampered by the sheer complexity of the cascades, their key role in so many biological functions (they are involved in virtually all aspects of embryonic development and in the control of homeostasis in adult tissues), and the need to better identify suitable patient and tumour types for treatment.
Wnt is linked to a wide range of conserved biological processes with Wnt signalling activating what can be considered for our purposes two distinct pathways: the canonical (β-catenin) and non-canonical (non-β-catenin) systems. These diverse cascades impinge on multiple developmental decisions through the control of cell-cell communication and play a key role in tissue homeostasis and repair. The canonical cascade is a key regulator of normal development and tissue homeostasis, and its disruption underlies the initiation and progression of multiple different tumour types. The β‐catenin‐independent (non-canonical) cascade is similarly complex, with new interactions identified as academic research in the Wnt field gathers pace. The two notable non-canonical pathways can be classified as planar cell polarity (PCP) and Ca2+ signalling. Both canonical and non-canonical cascades are also implicated in cancer progression: they are known to impact the tumour micro-environment (TME) to promote tumour cell survival and therapeutic resistance (eg through PI3K-AKT).
Porcupine sits at a strategic node, with all 19 secreted Wnt family members dependent upon the same biosynthetic enzymes to supply a single fatty acid adduct (palmitoylation) that is required to enable their transport, secretion, and activity. Following palmitoylation, Wnt ligands are secreted to form various Wnt receptor complexes, with RNF43 (Ring finger protein 43) and ZNRF3 (zinc and ring finger protein 3) being key regulators. The RSPO (R-spondin) family is an inhibitor of RNF43/ZNRF3, so deactivating mutations in RNF43/ZNRF3 or activating RSPO fusions can increase levels of the Wnt receptor complex and lead to increased ligand-dependent signalling. Hence, tumour cells that are dependent on Wnt ligands would be sensitive to Porcupine inhibition.
The broad influence of the Wnt pathways means systemic blockade of porcupine and, subsequent global elimination of Wnt signalling, is unwelcome. The actual effect of the porcupine enzyme is dependent on the cell type and the physiological context and, for any therapeutic inhibition, a key concern is avoiding undesired, yet still on-target, effects (such as on gut homeostasis and bone metabolism). The key is careful target selection and then to establish, and operate within, an appropriate therapeutic window.
Targeting appropriate cancer types is important. As mentioned, inhibiting porcupine notably impacts growth of tumours carrying specific gene mutations such as RNF43 or fusions in the RSPO gene family. Such mutations are found in many solid tumours, especially in difficult to treat colorectal (eg c 19% of all cases carry RNF43 mutations), biliary tract (c 70%), and pancreatic cancers (c 10%). Head and neck squamous cell carcinoma (HNSCC) cell lines carrying related mutations also appear particularly sensitive to porcupine inhibition.
Additionally, there is evidence of a strong correlation between porcupine inhibition and immune tolerance within the TME. Hence, interacting with porcupine pathways may result in both a direct effect on tumour cells and indirectly through facilitating improved immune responses; for instance, preventing emerging resistance to a checkpoint inhibitor (CPI) or enabling existing tolerance to be overcome (turning a “cold” tumour “hot”).
RXC004 is a highly selective and potent porcupine inhibitor which, in preclinical studies, was shown to have promising direct anti-tumour activity in Wnt ligand driven cancer lines and to enhance the immune response in the tumour microenvironment. Redx Pharma is studying RXC004 both as monotherapy and in combination with checkpoint inhibitors in various solid tumours. The RXC004 Phase I programme consists of three modules in an all-comers population each evaluating a different setting: Module 1 is monotherapy with continuous dosing; Module 2 is in combination with the PD-1 checkpoint inhibitor nivolumab (Opdivo, Bristol Myers Squibb); and Module 3 will explore intermittent dosing schedules. Successful outcomes will support the initiation of equivalent Phase II proof of concept studies, albeit in patients with Wnt ligand driven tumours, as both monotherapy and in PD-1 combinations. The first clinical results from this programme presented at ESMO 2021, confirmed that RXC004 has a therapeutic window and is applicable to genetically selected Wnt ligand driven tumours.
The first clinical study, Module 1, a dose escalation Phase I trial to examine the safety and tolerability of RXC004, reported results at ESMO 2021. This study enrolled 25 patients across five centres in the UK, with 24 patients at five dose levels ranging from 0.5mg to 3.0mg (Exhibit 4). The first patient was treated with a 10mg dose which was not tolerated. Patients enrolled in the study had unselected advanced solid tumours and had received a median three prior lines of therapy, with no standard treatment options remaining. The primary endpoints were safety and tolerability, alongside pharmacokinetics (PK) and pharmacodynamics (PD), and evaluation of preliminary indications of efficacy.
The key finding is RXC004 is safe and well tolerated at the selected Phase II dose, with treatment related adverse events being dose-related and in line with the expected profile for Porcupine inhibition (Exhibit 5). Dose limiting toxicities (DLTs) were seen in four patients: unsurprisingly, these were most extensive in the 10mg patient who experienced diarrhoea, colitis, and fragility fractures, as well as fatigue, nausea, decreased appetite and dysgeusia (loss of taste); in the 3mg group one patient had colitis and one had ileitis; the remaining patient, in the 2mg group, developed pancreatitis. Importantly, prophylactic administration of denosumab (Prolia/Xgeva, Amgen), a RANK ligand inhibitor that decreases bone breakdown, successfully prevented disruption of bone metabolism and incidence of spontaneous fractures.
In terms of dose selection, the 2mg RXC004 dose struck the ideal balance, achieving an attractive PK/PD profile, with once-daily dosing maintaining levels above the activity target ranges derived from preclinical studies, with containable adverse effects. This once daily dosing profile appears to differentiate RXC004 from other Porcupine inhibitors which have half-lives supporting either twice daily (Novartis’ WNT974) dosing or dosing every other day (A*STAR’s ETC-159).
The data presented at ESMO also showed early signs of efficacy. We note that the patients enrolled were not selected for Wnt ligand driven tumours; however, this was retrospectively analysed. In total, 18 patients had RECIST evaluable disease, of which seven patients had Wnt ligand dependent tumours, six had Wnt ligand independent tumours, and the remaining five had tumours of unknown status. With the caveats that the study was small (18 patients with RECIST evaluable disease), the patients were not genetically selected, and they were also heavily pre-treated, there were encouraging signs of stable disease with five of the seven Wnt ligand dependent patients showing a durable disease control (Exhibit 6). In contrast, the eleven patients with unknown or Wnt ligand independent disease showed a progressive disease. The median treatment duration for the seven Wnt ligand dependent tumours was 13.1 weeks (range was 8.4 to 25.4) versus 6.6 weeks (5.4 to 7.3) for the unknown/Wnt-ligand independent tumours. The study conclusions are summarised in Exhibit 7.
The Phase I study of RXC004 in combination with PD-1 checkpoint inhibitor nivolumab (Opdivo, Bristol Myers Squibb) is currently underway. Its primary aim is to examine the safety of RXC004 when used in combination; although, as in the monotherapy Phase I study, some efficacy signals may become apparent. The Phase I combination study is expected to complete during H221.
The RXC004 Phase II programme, both as monotherapy and in combination with nivolumab, is set to initiate in H221 (COVID restrictions permitting). The monotherapy trial is an open label, multi-centre, multi-arm, study to evaluate efficacy and safety of a 2mg once daily dose of RXC004 in 40 patients with Wnt ligand driven tumours. The first arm will recruit patients with RNF43 loss of function (LoF) mutation-positive pancreatic ductal adenocarcinoma (PDAC). The second arm will recruit patients with biliary tract cancer (BTC), where selection will not be required as BTC typically has a high Wnt ligand dependency (>70% of cases). The aim is to have c 15 evaluable patients enrolled in each arm. These tumour types have limited treatment options and poor five-year survival rates (<3% for biliary tract and pancreatic cancer).
The second Phase II study will recruit c 50 RNF43 and/or RSPO fusion selected patients with aberrant microsatellite stable (MSS) metastatic colorectal cancer that have progressed following current standard of care treatment. This follows a similar open label, multi-centre, multi-arm format and will include a monotherapy arm and a combination arm. The combination will be with nivolumab, with the RP2D confirmed once the Phase I study has reported. Each arm will aim to have c 20 evaluable patients. Whilst treatment with a checkpoint inhibitor has transformed many solid tumour outcomes, the results with MSS mCRC are less compelling (five-year survival rates are c 14%) and suitable combinations with other agents are being sought. All patients will receive denosumab prophylaxis to avert possible bone toxicity. Both studies are planned to commence in H221, and initial results could be available from mid-2022 onwards.
In addition to RXC004, four other porcupine inhibitors are known to be in clinical development for oncology indications:
The recently published WNT974 Phase I study provides a useful context for RXC004’s ESMO data. The results showed good tolerance, with the most reported adverse events of dysgeusia (loss of taste), gastrointestinal events, and fatigue. Dysgeusia (47% of patients) and bone-related disorders (6%) are consistent with Wnt pathway inhibition and can be considered on-target effects. Although the study evaluated 98 patients, these were not screened for the appropriate genetic mutations. No responses were seen by RECIST criteria; 16% of patients had stable disease (median duration 19.9 weeks). Examining individual patient data suggests 28 patients had an appropriate genetic profile (loss of function RNF43 or RPSO fusion without downstream APC mutations) and the anti-tumour activity was found here. Clearly, whilst encouraging, such retrospective analysis should be considered as indicative only.
The key message, in our view, is that careful patient selection for the appropriate tumour genetic profile is an essential prerequisite for any Porcupine inhibitor monotherapy Phase II trial to be able to demonstrate statistically significant clinical efficacy.
RXC007 is a novel and highly specific small molecule that selectively targets the ROCK2 (Rho Associated Coiled-Coil Containing Protein Kinase 2) receptor. It embarked on its first Phase I study in June 2021; this study, in healthy volunteers, will explore RXC007’s safety profile and is expected to read out in H122. These data will guide the dosing and structure of the RXC007 Phase II programme.
ROCK2 is a biologically and clinically validated target that has been shown to sit at a nodal point in a cell signalling pathway, where it modulates inflammatory response and fibrotic processes. The ROCK pathways mediate a broad range of cellular responses that involve the actin cytoskeleton and are important regulators of cellular growth, migration, metabolism, and apoptosis. The importance of ROCK has been known for some time, but the chemistry is complex and historically identifying safe and effective selective inhibitors has proved challenging.
RXC007 is a particularly exciting programme that has shown promising results in preclinical models of a number of fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), a progressive lung condition with a notably poor prognosis, and liver fibrotic indications such as Non-Alcoholic Steatohepatitis (NASH). Development will initially be focussed on IPF, which has been selected as the lead indication because of the clear clinical need, limited treatment options, and sizeable market opportunity (Globaldata estimates it will be worth $3.6bn by 2029).
Few ROCK2 inhibitors are known to be in clinical development, with RXC007 believed to be only the second. The ROCK class has recently been the focus of industry attention following Sanofi’s decision in September 2021 to acquire Kadmon (NASDAQ: KDMN) in an all-cash deal worth $1.9bn. The deal centres on Rezurock (belumosudil), a selective ROCK2 inhibitor that is a first-in-class treatment for chronic graft-versus-host disease (cGVHD). In July 2021 the FDA approved Rezurock for use in adult and paediatric patients 12 years and older who have failed at least two prior lines of systemic therapy. Kadmon is also developing a second ROCK inhibitor, KD045, that has generated positive preclinical results in lung, kidney, and liver fibrosis models.
We will review our valuation once RXC004 initiates the first of its Phase II trials, with our success probability expected to increase from 18% to 30% to reflect this clinical progress. Once this is included, our valuation would rise to £398.8m, equivalent to 146p/share (98p/share fully diluted), which compares to our current valuation of £350.7m, equivalent to 128p/share (86p/share fully diluted). Exhibit 9 summarises the outputs and underlying assumptions of our valuation model, while a detailed overview of our methodology, explaining our conservative approach, is provided in our September 2020 Initiation.
R&D investment is expected to further increase as RXC004 and RXC007 proceed to their next clinical value-inflection points, earlier stage assets approach IND filing, and discovery engine research activities ramp up. For FY21 we forecast R&D spend of £28.0m and £34.6m for FY22, with G&A rising more modestly due to inflation and an expanding organisation. On our forecasts Redx Pharma’s £39.9m in cash (at end-March 2021) provides a runway through 2022. Importantly, this will fund completion of RXC004 Phase I immunotherapy combination trials and planned Phase II monotherapy and combination studies, completion of RXC007 Phase I and initiation of planned RXC007 Phase II trials, as well as expansion of oncology and fibrosis research and identification of suitable next wave development candidates.
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