Disease Modifying Treatment for Hemolytic Disorders
溶血性疾病的疾病修饰治疗
基本信息
- 批准号:10254750
- 负责人:
- 金额:$ 53.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAdverse eventAffectAffinityAlternative Complement PathwayAnemiaAnimalsBilirubinBindingBloodBlood TransfusionBlood specimenCell DeathCellsCharacteristicsClinicalClinical MarkersClinical ResearchComplementComplement 3aComplement 3bComplement 5aComplement Membrane Attack ComplexContractsControl GroupsCyclic GMPCytolysisDataDependenceDepositionDiagnosisDiseaseDoseDrug KineticsEnsureErythrocytesExhibitsFDA approvedFatigueFemaleGuidelinesHalf-LifeHemoglobinHemoglobin CHemoglobin concentration resultHemolysisHost DefenseHumanIn VitroInfectionInflammation MediatorsIntravenousIntravenous infusion proceduresKidney FailureLactate DehydrogenaseLeadLengthLiver FailureMacaca mulattaMeasuresMediatingMeningitisModelingMonitorMonkeysMonoclonal AntibodiesMutationMyasthenia GravisNeuromyelitis OpticaNevadaOrganPathway interactionsPatient Outcomes AssessmentsPatientsPharmaceutical PreparationsPhasePhase II Clinical TrialsPilot ProjectsPlasmaPrevalenceProcessProductionPrognosisProperdinPropertyProteinsRare DiseasesRecoveryReportingReticulocyte countRhesusRiversSafetySamplingSecondary toSerious Adverse EventSerumSyndromeTestingTherapeuticTimeTissuesToxicologyTransfusionVaccinationVial devicecGMP productioncell bankcell typeclinical candidatecookingcostcross reactivitydrug candidateefficacious treatmenthealthy volunteerhuman tissuein vivo evaluationinhibitor/antagonistmalemanufacturing processnovel therapeuticsopen labelovertreatmentparoxysmal nocturnal hemoglobinuriapathogenphase 1 studyphase 2 studyphase I trialphase II trialphase III trialpreventsecondary infectionsuccesstreatment grouptrial comparing
项目摘要
ABSTRACT
Our lead drug candidate is being developed as a disease modifying, potent and efficacious treatment for
paroxysmal nocturnal hemoglobinuria (PNH), an “orphan disease”, and is anticipated to be far superior to the
current monotherapy Soliris (Eculizumab) treatment. Soliris blocks both the classical (CP) and the alternative
(AP) pathways of complement, and is used in treatment of PNH, atypical uremic syndrome (aHUS),
neuromyelitis optica (NMO), and myasthenia gravis (MG). The FDA approved Soliris in 2007 despite its
possessing two troubling properties: a) uncontrolled extravascular hemolysis (EVH) that causes incurable
anemia and b) vulnerability to secondary infections due to blockade of the classical pathway (CP) which is
required for host defense, despite vaccination against such ailments as meningitis. Because there is no other
treatment for PNH currently approved by the FDA, use of Soliris continues to increase yearly.
Our clinical candidate is a selective inhibitor of the AP and does not block the CP. By mechanistically blocking
the upstream AP specifically, the two issues deficient during Soliris treatment can be addressed. Our lead
drug: a) blocks AP-mediated C3b formation and deposition on erythrocytes and therefore prevents EVH, and
b) does not block the CP, which is required for host defense against pathogens and infection. Further to this,
potential success of this drug in effectively treating PNH is supported by the following characteristics: a) high
affinity binding, b) high potency of AP inhibition, c) inhibition of AP-mediated lactate dehydrogenase (LDH)
release, d) lack of CP inhibition, e) successful toxicology studies, and f) completion of a successful phase I
clinical. A streamlined cGMP manufacturing process has been established, and guarantees robust production
of the quality material for treatment. Given this unique mechanism of action, we believe that this drug will
provide benefits in diseases where specific blockade of proximal AP is required. Preliminary data from the
recently completed phase I trial in 48 healthy volunteers suggests that the drug candidate completely blocks
the AP at 1mg/kg, and does not block the CP at any of the doses tested, confirming the beneficial therapeutic
potency of this monoclonal antibody. Furthermore, administration of the lead drug did not require loading doses
and was deemed safe in humans with no reported severe adverse events. This ensures that administration of
this drug is patient friendly. Results from this phase I trial are supported by multiple in vitro and ex vivo studies
on normal human serum and blood, and serum from naïve and Soliris treated PNH patients.
This submission outlines a proposed phase II PNH clinical study to examine the effects and benefits of
NovelMed's lead drug in PNH naïve patients, compared to use as an add-on to Soliris treated PNH subjects.
Dosing of our clinical candidate is proposed at a single dose of 10 mg/kg administered every 4 weeks for 3
months in this pilot study in PNH patients. Plasma samples will be evaluated for pharmacokinetics, AP
inhibition, CP inhibition, presence of ADA, LDH release, hemoglobin levels, C3b cellular deposition, erythrocyte
lysis, PNH clone size, as well as other clinical markers of anemia. If successful, this AP-specific inhibitor will
replace Soliris as a far superior and potent therapy for the complications associated with PNH.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rekha Bansal其他文献
Rekha Bansal的其他文献
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{{ truncateString('Rekha Bansal', 18)}}的其他基金
Preclinical and Clinical Evaluation of Humanized NM9405
人源化NM9405的临床前和临床评价
- 批准号:
8647587 - 财政年份:2014
- 资助金额:
$ 53.32万 - 项目类别:
Preclinical and Clinical Evaluation of Humanized NM9405
人源化NM9405的临床前和临床评价
- 批准号:
8925257 - 财政年份:2014
- 资助金额:
$ 53.32万 - 项目类别:
Preclinical and Clinical Evaluation of Humanized NM9405
人源化NM9405的临床前和临床评价
- 批准号:
9038429 - 财政年份:2014
- 资助金额:
$ 53.32万 - 项目类别:
Alternative Pathway Inhibitors for Orphan Indication
用于孤儿适应症的替代途径抑制剂
- 批准号:
8524040 - 财政年份:2013
- 资助金额:
$ 53.32万 - 项目类别:
Alternative Pathway Inhibitors for Orphan Indication
用于孤儿适应症的替代途径抑制剂
- 批准号:
8883970 - 财政年份:2013
- 资助金额:
$ 53.32万 - 项目类别:
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