SBIR-STTR Award

NovelMed has developed an anti-properdin antibody (hNM9405) for the treatment of intra & extravascular lysis in paroxysmal nocturnal hemoglobinuria (PNH). The selection of this antibody was based on positive results obtained from in vitro, ex vivo, in vivo, and PK/PD studies in rabbits and primates. These strong positive results have provided a firm foundation for initiation of our Phase I clinical trial. Our lead drug candidate is indicated for PNH, an "orphan disease," and aims to fill an urgent need for this devastating condition. With this application, NovelMed is proposing to conduct Investigational New Drug (IND) enabling studies for its lead drug candidate. In PNH, red blood cells (RBCs) are attacked by the body's own complement activation products causing significant cell lysis. RBC lysis increases the levels of hemolglobin and lactate dehydrogenase (LDH) in the circulating blood. Elevated levels of these compounds cause further damage to multiple organs, ultimately risking total organ failure(s) of one or multiple organs. The chronic nature of the disease necessitates a safe, highly effective, and low cost therapeutic which can prevent erythrocyte lysis in vivo. NovelMed's lead therapeutic, hNM9405, is a specific inhibitor of the alternative complement pathway. This upstream inhibitor of the complement system prevents the formation of both C3b, a key molecule for extravascular hemolysis (EVH), and C5b-9, a key molecule for intravascular hemolysis (IVH). Moreover, hNM9405 selectively blocks the alternative pathway without compromising the full functionality of the classical pathway. Full functionality of the classical pathway is required in order to maintain optimal immune host defense. Preliminary in vitro, ex vivo, and in vivo studies have demonstrated that hNM9405; 1) prevents the formation of C3a, C3b, C5a, C5b and C5b-9; 2) prevents the lysis of erythrocytes from PNH and rabbit sera; 3) inhibits the production of LDH, and 4) displays long PK and AP inhibition in non-human primates. This proposal will evaluate efficacy of our lead drug candidate in human Phase I trial. In planning for the development of the Phase 1 clinical protocol, NovelMed has engaged key leaders in the PNH field. The Phase 1 trial is being proposed in approximately 30 healthy human subjects in an Open-Label, Single Ascending Dose (SAD) escalation study to evaluate the safety and pharmacokinetics of hNM9405. These studies will form the basis of regulatory filings for the FDA. The two specific aims of this proposal are: a) perform GLP safety studies in non-human primates with single and repeat dose toxicological studies and b) perform Phase I clinical safety studies in human healthy volunteers to evaluate the safety and pharmacokinetics of hNM9405 as a therapeutic. It is anticipated that successful completion of the Phase I study will lead to further trials with the eventual goal of registration, FDA approval and launch of hNM9405 as a new treatment for PNH, via prevention of hemolysis in PNH patients without the chronic knockout of host defense.

Public Health Relevance Statement:


Public Health Relevance:
The estimated prevalence of PNH is 13-20 cases per million. Patients diagnosed with PNH are given a dim prognosis which includes an approximate median survival of 15 years from the time of their initial diagnosis. Extravascular and intravascular hemolyses are two major contributing factors to the anemia seen in PNH patients which contributes to significant kidney damage and ultimately death. This proposal is for the development of hNM9405, a significantly improved therapeutic over currently approved Eculizumab, to prevent excessive hemolysis in PNH patients. The hNM9405 blocks the alternative pathway arm of the complement pathway, without blocking the classical pathway required for host defense, and thereby is expected to be a much more powerful treatment. Because PNH is an orphan disease, clinical development timelines are shorter and FDA approval is expected to be faster as compared to other non-orphan indications.

Project Terms:
activation product; Affect; Alternative Complement Pathway; Anemia; Animals; Antibodies; Antibody Formation; arm; base; Binding (Molecular Function); Blood; Blood specimen; Businesses; Cells; Cessation of life; Chronic; Clinical; Clinical Protocols; cohort; Complement; Complement 3a; Complement 3b; Complement 5a; Complement Activation; complement C5b; Complement Inactivators; Complement Membrane Attack Complex; complement pathway; complement system; Contractor; Control Groups; cost; cross reactivity; Cytolysis; design; Development; Development Plans; Diagnosis; Disease; dosage; Dose; Double-Blind Method; drug candidate; Drug Kinetics; Erythrocytes; experience; FDA approved; Female; Foundations; Functional disorder; Goals; Half-Life; Health; healthy volunteer; Hemolysis; Host Defense; Hour; Human; human study; human subject; Immune; improved; In Vitro; in vitro Model; in vivo; Individual; Inflammation Mediators; inhibitor/antagonist; Intravenous; Intravenous infusion procedures; Investigational Drugs; Investigational New Drug Application; Kidney; Kidney Failure; Knock-out; Lactate Dehydrogenase; Lead; Left; Liver Failure; Macaca mulatta; male; meetings; Monitor; Monkeys; Monoclonal Antibodies; Nature; nonhuman primate; open label; Organ; Organ failure; Orphan; Oryctolagus cuniculus; outcome forecast; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; phase 1 study; Phase I Clinical Trials; Placebo Control; Placebos; Play; preclinical evaluation; Prevalence; prevent; Prevention; Primates; Process; Production; Properdin; public health relevance; Randomized; Rare Diseases; rat Piga protein; Recovery; research clinical testing; Research Design; Risk; Safety; safety study; Saline; Serum; success; Testing; Therapeutic; Time; TimeLine; Tissues; Transfusion; Work

NovelMed has developed an anti-properdin antibody (hNM9405) for the treatment of intra and extravascular lysis in paroxysmal nocturnal hemoglobinuria (PNH). The selection of this antibody was based on positive results obtained from in vitro, ex vivo, in vivo, and PK/PD studies in rabbits and primates. These strong positive results have provided a firm foundation for initiation of our Phase I clinical trial. Our lead drug candidate is indicated for PNH, an "orphan disease," and aims to fill an urgent need for this devastating condition. With this application, NovelMed is proposing to conduct Investigational New Drug (IND) enabling studies for its lead drug candidate. In PNH, red blood cells (RBCs) are attacked by the body's own complement activation products causing significant cell lysis. RBC lysis increases the levels of hemolglobin and lactate dehydrogenase (LDH) in the circulating blood. Elevated levels of these compounds cause further damage to multiple organs, ultimately risking total organ failure(s) of one or multiple organs. The chronic nature of the disease necessitates a safe, highly effective, and low cost therapeutic which can prevent erythrocyte lysis in vivo. NovelMed's lead therapeutic, hNM9405, is a specific inhibitor of the alternative complement pathway. This upstream inhibitor of the complement system prevents the formation of both C3b, a key molecule for extravascular hemolysis (EVH), and C5b-9, a key molecule for intravascular hemolysis (IVH). Moreover, hNM9405 selectively blocks the alternative pathway without compromising the full functionality of the classical pathway. Full functionality of the classical pathway is required in order to maintain optimal immune host defense. Preliminary in vitro, ex vivo, and in vivo studies have demonstrated that hNM9405; 1) prevents the formation of C3a, C3b, C5a, C5b and C5b-9; 2) prevents the lysis of erythrocytes from PNH and rabbit sera; 3) inhibits the production of LDH, and 4) displays long PK and AP inhibition in non-human primates. This proposal will evaluate efficacy of our lead drug candidate in human Phase I trial. In planning for the development of the Phase 1 clinical protocol, NovelMed has engaged key leaders in the PNH field. The Phase 1 trial is being proposed in approximately 30 healthy human subjects in an Open-Label, Single Ascending Dose (SAD) escalation study to evaluate the safety and pharmacokinetics of hNM9405. These studies will form the basis of regulatory filings for the FDA. The two specific aims of this proposal are: a) perform GLP safety studies in non-human primates with single and repeat dose toxicological studies and b) perform Phase I clinical safety studies in human healthy volunteers to evaluate the safety and pharmacokinetics of hNM9405 as a therapeutic. It is anticipated that successful completion of the Phase I study will lead to further trials with the eventual goal of registration, FDA approval and launch of hNM9405 as a new treatment for PNH, via prevention of hemolysis in PNH patients without the chronic knockout of host defense.

Public Health Relevance Statement:


Public Health Relevance:
The estimated prevalence of PNH is 13-20 cases per million. Patients diagnosed with PNH are given a dim prognosis which includes an approximate median survival of 15 years from the time of their initial diagnosis. Extravascular and intravascular hemolyses are two major contributing factors to the anemia seen in PNH patients which contributes to significant kidney damage and ultimately death. This proposal is for the development of hNM9405, a significantly improved therapeutic over currently approved Eculizumab, to prevent excessive hemolysis in PNH patients. The hNM9405 blocks the alternative pathway arm of the complement pathway, without blocking the classical pathway required for host defense, and thereby is expected to be a much more powerful treatment. Because PNH is an orphan disease, clinical development timelines are shorter and FDA approval is expected to be faster as compared to other non-orphan indications.

NIH Spending Category:
Biotechnology; Clinical Research; Clinical Trials and Supportive Activities; Hematology; Prevention

Project Terms:
activation product; Affect; Alternative Complement Pathway; Anemia; Animals; Antibodies; Antibody Response; arm; base; Binding (Molecular Function); Blood; Blood specimen; Businesses; Cells; Cessation of life; Chronic; Clinical; Clinical Protocols; cohort; Complement; Complement 3a; Complement 3b; Complement 5a; Complement Activation; complement C5b; Complement Inactivators; Complement Membrane Attack Complex; complement pathway; complement system; Contractor; Control Groups; cost; cross reactivity; Cytolysis; design; Development; Development Plans; Diagnosis; Disease; dosage; Dose; Double-Blind Method; drug candidate; Drug Kinetics; Erythrocytes; experience; FDA approved; Female; Foundations; Functional disorder; Goals; Half-Life; Health; healthy volunteer; Hemolysis; Host Defense; Hour; Human; human study; human subject; Immune; improved; In Vitro; in vitro Model; in vivo; Individual; Inflammation Mediators; inhibitor/antagonist; Intravenous; Intravenous infusion procedures; Investigational Drugs; Investigational New Drug Application; Kidney; Kidney Failure; Knock-out; Lactate Dehydrogenase; Lead; Left; Liver Failure; Macaca mulatta; male; meetings; Monitor; Monkeys; Monoclonal Antibodies; Nature; nonhuman primate; open label; Organ; Organ failure; Orphan; Oryctolagus cuniculus; outcome forecast; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; phase 1 study; Phase I Clinical Trials; phase I trial; Placebo Control; Placebos; Play; preclinical evaluation; Prevalence; prevent; Prevention; Primates; Process; Production; Properdin; Randomized; Rare Diseases; rat Piga protein; Recovery; research clinical testing; Research Design; Risk; Safety; safety study; Saline; Serum; success; Testing; Therapeutic; Time; TimeLine; Tissues; Transfusion; Work