ADVERTISEMENT FEATURE ADVERTISER RETAINS SOLE RESPONSIBILITY FOR CONTENT 4D pharma PLC www.4dpharmaplc.com Revolutionary new medicines from the human gut microbiome Using its MicroRx platform, 4D pharma is pioneering the development of an emerging class of therapeutics known as live biotherapeutic products to treat a range of indications from cancer and respiratory disease to neurodegeneration. The gut microbiome—the microorganisms inhab- iting the human gastrointestinal tract—plays important roles in health and disease, affecting not only the local environment but also the immune, metabolic and even nervous systems, modulating diverse disease pathways throughout the body. Defining the microbiome space is 4D pharma and its pioneering live biotherapeutic products (LBPs), an emerging class of medicines based on single strains of commensal bacteria. “We understand mechanistically how specific bacteria interact with the host, and exploit this functionality to treat a range of diseases,” said CEO Duncan Peyton. From its extensive library of bacterial strains, 4D uses its MicroRx platform to identify and character- ize candidates that modulate disease pathways (Fig. 1). “MicroRx gives us a comprehensive under- standing of how specific bacteria impact the human body at the molecular level, allowing us to rationally select live biotherapeutic candidates with profiles relevant for particular aspects of disease,” explained Alex Stevenson, CSO. “Each strain is selected for its functionality, via a defined mechanism of action, in a targeted drug-discovery approach.” Therapeutic activity is then validated using industry standard animal models before entering the clinic. 4D has multiple clinical-stage programs in immuno-oncology, COVID-19, irritable bowel syndrome, inflammatory bowel disease and asthma, and pre-clinical programs in neurodegenerative and autoimmune conditions. The end-to-end company also has its own current good manufacturing prac- tice (cGMP)-certified manufacturing facility. LBPs are developed to meet the same safety and efficacy standards as any other drug, but having been refined by millennia of co-evolution do not require optimization. “By avoiding the toxicity that often compromises conventional drugs, develop- ment timelines and risk are dramatically reduced,” explained Stevenson. The productivity of 4D’s MicroRx platform is exemplified by its pipeline and the largest intellectual property portfolio in the space. Its MicroRx platform and approach to live biotherapeutic development attracted a research collaboration with Merck & Co. in 2019 to discover LBPs for use in novel vaccines, build- ing on an existing clinical collaboration in oncology. First oncology clinical data for a live biotherapeutic 4D’s lead immuno-oncology candidate, MRx0518, is in a phase 1/2 trial in combination with Merck & Co.’s Keytruda (pembrolizumab) for solid tumors with acquired resistance to checkpoint immunotherapy. Mechanistic work identified the MRx0518 bacterial flagellin protein as a potent TLR5 agonist, stimulating innate and adaptive anti-tumor immune responses. MRx0518 demonstrated anti-tumor activity in mul- tiple animal models of cancer, as a monotherapy and in combination with checkpoint inhibitors. Demonstrating the rapid development of LBPs, 4D moved from discovery to first-in-class proof- of-concept clinical data for a live biotherapeutic in oncology in just 4 years. Data from the ongoing trial indicate that MRx0518 can re-engage response to checkpoint immunotherapy in heavily pre-treated patients with acquired resistance. “Using MRx0518 to increase response in refractory patients with no other therapeutic options is hugely significant for the industry,” said Peyton. Targeting the gut-brain axis More recently, MicroRx has identified two bacterial strains, MRx0005 and MRx0029, with potentially disease-modifying activity targeting multiple pro- cesses involved in neurodegenerative diseases such as Parkinson disease (PD). Motor function deterioration characteristic of PD is due to accumulation of misfolded α-synuclein and loss of dopamine-producing neurons; patients also typically suffer from gastrointestinal symp- toms and ‘leaky gut’. MRx0005 and MRx0029 have multiple effects, reducing α-synuclein-induced neuroinflammation, protecting from oxidative stress and increasing expression of tight-junction pro- teins, improving gut barrier integrity. Interestingly, MRx0029 can induce a dopaminergic phenotype in undifferentiated neuronal cells, suggesting a potential ‘neuroregenerative’ capability. The neuroprotective therapeutic effects of these complementary functions have been demonstrated in an animal model of PD. 4D is now planning a first- in-man study in patients with PD. “By targeting mul- tiple aspects of disease pathology, our LBPs offer a potentially disease-modifying treatment for patients with neurodegenerative diseases,” said Stevenson. Wide-spectrum partnering 4D is seeking to partner at all stages—from platform collaborations utilizing MicroRx in new areas, to co-development of clinical or clinic-ready programs, including expanding development of immuno-oncology candidate MRx0518 with new combination therapies, following the first-in-class proof-of-concept data. “MicroRx is a highly productive platform and our pipeline demonstrates the breadth of its potential. We have generated first-in-class positive oncology data, validating our approach. A fully integrated company, with expertise from discovery through manufacturing to regulatory and clinical, 4D is the perfect partner, with a new approach to therapeu- tics that is safer and quicker than traditional drug development,” said Peyton. “Live biotherapeutics have the potential to transform the way many dis- eases are treated.” Effector molecules MicroRx Host response assays Genome mining Omics analysis Understanding mechanism Gastrointestinal Inflammation & autoimmune Asthma & COVID-19 Vaccines Immuno-oncology World first positive clinical data for a live biotherapeutic in cancer Neurodegeneration Leverage the gut–brain axis to develop disease-modifying therapies Pipeline Fig. 1 | 4D’s MicroRx platform. A multi-faceted workflow allowing comprehensive functional characterization of single strains of bacteria (top) and the development of a broad pipeline of therapeutic candidates (bottom). Jacob Masters, Corporate Development 4D pharma PLC Leeds, UK Tel: + 44 113 895 0146 Email: [email protected] CONTACT biopharmadealmakers.nature.com | September 2020 | B1
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A D V E R T I S E M E N T F E A T U R E
A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T
4D pharma PLCwww.4dpharmaplc.com
Revolutionary new medicines fromthe human gut microbiomeUsing its MicroRx platform, 4D pharma is pioneering the development of an emerging class of therapeutics known aslive biotherapeutic products to treat a range of indications from cancer and respiratory disease to neurodegeneration.
The gut microbiome—the microorganisms inhab-iting the human gastrointestinal tract—playsimportant roles in health and disease, affecting notonly the local environment but also the immune,metabolic and even nervous systems, modulatingdiverse disease pathways throughout the body.
Defining the microbiome space is 4D pharma andits pioneering live biotherapeutic products (LBPs),an emerging class of medicines based on singlestrains of commensal bacteria. “We understandmechanistically how specific bacteria interact withthe host, and exploit this functionality to treat arange of diseases,” said CEO Duncan Peyton.
From its extensive library of bacterial strains, 4Duses its MicroRx platform to identify and character-ize candidates that modulate disease pathways(Fig. 1). “MicroRx gives us a comprehensive under-standing of how specific bacteria impact the humanbody at the molecular level, allowing us to rationallyselect live biotherapeutic candidates with profilesrelevant for particular aspects of disease,” explainedAlex Stevenson, CSO. “Each strain is selected for itsfunctionality, via a defined mechanism of action, ina targeted drug-discovery approach.”
Therapeutic activity is then validated usingindustry standard animal models before enteringthe clinic. 4D has multiple clinical-stage programsin immuno-oncology, COVID-19, irritable bowelsyndrome, inflammatory bowel disease and asthma,and pre-clinical programs in neurodegenerative andautoimmune conditions. The end-to-end companyalso has its own current good manufacturing prac-tice (cGMP)-certified manufacturing facility.
LBPs are developed to meet the same safety andefficacy standards as any other drug, but havingbeen refined by millennia of co-evolution do notrequire optimization. “By avoiding the toxicity thatoften compromises conventional drugs, develop-ment timelines and risk are dramatically reduced,”explained Stevenson.
The productivity of 4D’s MicroRx platform isexemplified by its pipeline and the largest intellectualproperty portfolio in the space. Its MicroRx platformand approach to live biotherapeutic developmentattracted a research collaboration with Merck & Co. in2019 to discover LBPs for use in novel vaccines, build-ing on an existing clinical collaboration in oncology.
First oncology clinical datafor a live biotherapeutic4D’s lead immuno-oncology candidate, MRx0518, isin a phase 1/2 trial in combination with Merck & Co.’sKeytruda (pembrolizumab) for solid tumors withacquired resistance to checkpoint immunotherapy.
Mechanistic work identified the MRx0518 bacterialflagellin protein as a potent TLR5 agonist, stimulatinginnate and adaptive anti-tumor immune responses.MRx0518 demonstrated anti-tumor activity in mul-tiple animal models of cancer, as a monotherapy andin combination with checkpoint inhibitors.
Demonstrating the rapid development of LBPs,4D moved from discovery to first-in-class proof-of-concept clinical data for a live biotherapeutic inoncology in just 4 years. Data from the ongoing trialindicate that MRx0518 can re-engage response tocheckpoint immunotherapy in heavily pre-treatedpatients with acquired resistance. “Using MRx0518to increase response in refractory patients with noother therapeutic options is hugely significant forthe industry,” said Peyton.
Targeting the gut-brain axisMore recently, MicroRx has identified two bacterialstrains, MRx0005 and MRx0029, with potentiallydisease-modifying activity targeting multiple pro-cesses involved in neurodegenerative diseases suchas Parkinson disease (PD).
Motor function deterioration characteristic of PDis due to accumulation of misfolded α-synucleinand loss of dopamine-producing neurons; patientsalso typically suffer from gastrointestinal symp-toms and ‘leaky gut’. MRx0005 and MRx0029have multiple effects, reducing α-synuclein-inducedneuroinflammation, protecting from oxidative stressand increasing expression of tight-junction pro-teins, improving gut barrier integrity. Interestingly,MRx0029 can induce a dopaminergic phenotypein undifferentiated neuronal cells, suggesting apotential ‘neuroregenerative’ capability.
The neuroprotective therapeutic effects of thesecomplementary functions have been demonstratedin an animal model of PD. 4D is now planning a first-in-man study in patients with PD. “By targeting mul-tiple aspects of disease pathology, our LBPs offer apotentially disease-modifying treatment for patientswith neurodegenerative diseases,” said Stevenson.
Wide-spectrum partnering4D is seeking to partner at all stages—fromplatform collaborations utilizing MicroRx in newareas, to co-development of clinical or clinic-readyprograms, including expanding development ofimmuno-oncology candidate MRx0518 with newcombination therapies, following the first-in-classproof-of-concept data.
“MicroRx is a highly productive platform and ourpipeline demonstrates the breadth of its potential.We have generated first-in-class positive oncologydata, validating our approach. A fully integratedcompany, with expertise from discovery throughmanufacturing to regulatory and clinical, 4D is theperfect partner, with a new approach to therapeu-tics that is safer and quicker than traditional drugdevelopment,” said Peyton. “Live biotherapeuticshave the potential to transform the way many dis-eases are treated.”
Effector moleculesMicroRxHost response assays
Genome mining
Omics analysis
Understanding mechanism
Gastrointestinal
Inflammation &autoimmune
Asthma &COVID-19
Vaccines
Immuno-oncologyWorld first positive clinical data for a
live biotherapeutic in cancer
NeurodegenerationLeverage the gut–brain axis to develop
disease-modifying therapies
Pipeline
Fig. 1 | 4D’s MicroRx platform. A multi-faceted workflow allowing comprehensive functional characterizationof single strains of bacteria (top) and the development of a broad pipeline of therapeutic candidates (bottom).
Jacob Masters, Corporate Development4D pharma PLCLeeds, UKTel: + 44 113 895 0146Email: [email protected]
CON
TACT
biopharmadealmakers.nature.com | September 2020 | B1
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