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]
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biopharmadealmakers.nature.com | September 2020 | B1
