PROTAGONIST THERAPEUTICS, INC. — Department of Health and Human Services SBIR Phase II: NHLBI

Description

Abstract Developing the required biomarkers that define ferroportin target engagement and impact on downstream signaling for clinical translation Iron is essential for lifebut is also highly toxicConsequentlyiron acquisitiontransportstorage and utilization are tightly regulatedHepcidin is the master regulator of ironit controls the uptake of iron from diet and the release from iron stores through its interaction with the iron transporter ferroportinDysfunctional hepcidin production can cause serious health issuesincludingthalassemia and hereditary hemochromatosisIn both diseaseslow hepcidin levels increase intestinal iron absorption and increase release of recycled iron from the reticuloendothelial systemwhich causes depletion of macrophage ironrelatively lower levels of serum ferritinincreased liver iron concentrationand free iron release into the circulationcausing organ damageWithout treatmentiron continues to accumulateand a considerable proportion of patients eventually reach toxic iron overload levelsPatients with iron overload diseases are currently treated with combinations of phlebotomyblood transfusions and or iron chelatorsdepending on the diseasePhlebotomy and blood transfusions are inconvenient and require hospital visitswhile chelation therapy is associated with considerable toxicityThusthere is a significant need for new treatments that are safer and better toleratedBecause of hepcidinandapos s complicateddisulfide structureinsolubilityaggregation potential and rapid clearanceit is unsuitable as a treatment and hepcidin mimetics have been proposed as potential therapeuticsTo overcome the physicochemical limitations of hepcidinProtagonist engineered more potentstablesoluble and efficacious alternative scaffolds using a purposefully built structure based drug design environmentVectrixDuring the SBIR Phase I proposalthe hepcidin mimetic PTGwas developed after optimizing potencystabilitysolubility and other physicochemical propertiesThe overall objective of this Phase II SBIR proposal is to develop methods for characterizing in vivo target engagementincluding pharmacokinetic and pharmacodynamic methods to characterize the binding of PTGto ferroportin and how binding affects downstream biomarkers and efficacyThese biomarkers will be used to aid dose selections and to provide earlystage clinical proof of conceptThe specific objectives are todevelop methods to characterize the extent of target engagementTEof ferroportindevelop pharmacodynamicPDbiomarkers that describe the effect of ferroportin engagement on downstream signalingcorrelate the TE and effect on PD biomarkers with efficacy in a preclinical model of thalassemiaprovide further mechanistic data on the clinical utility of PTGThese are important steps towards our ultimate objective of demonstrating clinical benefit in late stage clinical trialsThe biomarkers developed in this study will permit the assessment of mechanism specific and diseaserelated parameters to guide clinical design Project Narrative Toxic overload of iron is a significant threat to the health of patients with hemochromatosis andthalassemiaEach yearover one million patients suffer from ineffective erythropoiesis and or iron overload in the USCurrent treatments are inconvenientrequiring visits to hospitalor have significant safety concernsProtagonist has developed a mimetic of hepcidina hormone that is the master regulator of ironThis mimeticPTGis currently in Phaseclinical trials and it is expected to be safer and more convenient for patients in treating these genetic diseasesThis Phase II SBIR proposal describes the development of target engagement and pharmacodynamic biomarkers to provide robust translation of preclinical results to the patient population