INZ-701 for ENPP1 Deficiency
Recruiting in Palo Alto (17 mi)
+11 other locations
Age: < 18
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Inozyme Pharma
Must not be taking: Corticosteroids, FGF23 inhibitors, Bisphosphonates
Disqualifiers: Clinically significant disease, Orthopedic surgery, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing INZ-701, a treatment that replaces a missing enzyme, in children with a rare genetic disorder called ENPP1 Deficiency. The goal is to see if it is safe and effective. The treatment helps by providing the enzyme their bodies lack.
Will I have to stop taking my current medications?
You may need to stop taking certain medications. Specifically, you cannot take systemic corticosteroids (more than 5 mg of prednisone per day), anti-fibroblast growth factor 23, oral or IV bisphosphonates, calcitriol, or other active forms of vitamin D3 within 7 days before the study starts, and oral phosphate supplements within 36 hours before the study if you are in the INZ-701 group.
What makes the drug INZ-701 unique for treating ENPP1 Deficiency?
INZ-701 is unique because it is a recombinant protein (a lab-made protein) designed to replace the missing or defective enzyme in people with ENPP1 Deficiency, which is a rare condition with no standard treatments. This drug works by mimicking the natural enzyme's function, potentially addressing the root cause of the disease.
12345Eligibility Criteria
This trial is for children with ENPP1 Deficiency, showing specific bone abnormalities and growth plate activity. They must be between 1-12 years old, not pregnant or breastfeeding, willing to use contraception if applicable, and have certain vitamin D levels. Those who've had recent surgery or used certain medications like systemic corticosteroids are excluded.Inclusion Criteria
Your plasma PPi concentration is less than 1400 nM at the time of screening.
I am between 1 and 12 years old.
I am not pregnant or breastfeeding.
+8 more
Exclusion Criteria
In the opinion of the Investigator, has clinically significant disease or laboratory abnormality not associated with ENPP1 Deficiency that will preclude study participation and/or may confound the interpretation of study results
I am not taking high doses of steroids, anti-FGF23 drugs, or bisphosphonates.
I am not currently in another clinical study or haven't taken any investigational drugs recently.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
7 weeks
Randomized Treatment
Participants receive either INZ-701 or control treatment for 52 weeks
52 weeks
Weekly visits for subcutaneous injections
Open-label Extension
All participants may receive INZ-701 after the randomized treatment period
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
1 visit (in-person) for End of Study Safety assessment
Participant Groups
The ENERGY 3 Study tests the safety and effectiveness of INZ-701 compared to conventional therapy in treating skeletal issues caused by ENPP1 Deficiency in children. Participants will either receive INZ-701 or stick with standard treatments to see which works better.
2Treatment groups
Experimental Treatment
Active Control
Group I: INZ-701Experimental Treatment1 Intervention
Subjects randomized to the INZ-701 arm will be administered a 2.4 mg/kg once weekly dose by subcutaneous (SC) injection for the duration of the 52-week Randomized Treatment Period and the Open-label Extension Period.
Group II: Control Arm (Conventional Therapy)Active Control1 Intervention
Subjects randomized to the control arm will continue taking their conventional therapy as clinically indicated by their treating physician for the duration of the 52-week Randomized Treatment Period.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Boston Children's HospitalBoston, MA
Nationwide Children's HospitalColumbus, OH
Cook Children's Medical CenterFort Worth, TX
The Children's Hospital of PhiladelphiaPhiladelphia, PA
More Trial Locations
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Who Is Running the Clinical Trial?
Inozyme PharmaLead Sponsor
References
INPP4A-related genetic and phenotypic spectrum and functional relevance of subcellular targeting of INPP4A isoforms. [2023]Type I inositol polyphosphate-4-phosphatase (INPP4A) belongs to the group of phosphoinositide phosphatases controlling proliferation, apoptosis, and endosome function by hydrolyzing phosphatidylinositol 3,4-bisphosphate. INPP4A produces multiple transcripts encoding shorter and longer INPP4A isoforms with hydrophilic or hydrophobic C-terminus. Biallelic INPP4A truncating variants cause a spectrum of neurodevelopmental disorders ranging from moderate intellectual disability to postnatal microcephaly with developmental and epileptic encephalopathy and (ponto)cerebellar hypoplasia. We report a girl with the novel homozygous INPP4A variant NM_001134224.2:c.2840del/p.(Gly947Glufs*12) (isoform d). She presented with postnatal microcephaly, global developmental delay, visual impairment, myoclonic seizures, and pontocerebellar hypoplasia and died at the age of 27 months. The level of mutant INPP4A mRNAs in proband-derived leukocytes was comparable to controls suggesting production of C-terminally altered INPP4A isoforms. We transiently expressed eGFP-tagged INPP4A isoform a (NM_004027.3) wildtype and p.(Gly908Glufs*12) mutant [p.(Gly947Glufs*12) according to NM_001134224.2] as well as INPP4A isoform b (NM_001566.2) wildtype and p.(Asp915Alafs*2) mutant, previously reported in family members with moderate intellectual disability, in HeLa cells and determined their subcellular distributions. While INPP4A isoform a was preferentially found in perinuclear clusters co-localizing with the GTPase Rab5, isoform b showed a net-like distribution, possibly localizing near and/or on microtubules. Quantification of intracellular localization patterns of the two INPP4A mutants revealed significant differences compared with the respective wildtype and similarity with each other. Our data suggests an important non-redundant function of INPP4A isoforms with hydrophobic or hydrophilic C-terminus in the brain.
Nerve conduction velocity is regulated by the inositol polyphosphate-4-phosphatase II gene. [2016]Impairment of nerve conduction is common in neurodegenerative and neuroinflammatory diseases such as multiple sclerosis (MS), and measurement of evoked potentials (visual, motor, or sensory) has been widely used for diagnosis and recently also as a prognostic marker for MS. We used a classical genetic approach to identify novel genes controlling nerve conduction. First, we used quantitative trait mapping in F2 progeny of B10/SJL mice to identify EAE31, a locus controlling latency of motor evoked potentials (MEPs) and clinical onset of experimental autoimmune encephalomyelitis. Then, by combining congenic mapping, in silico haplotype analyses, and comparative genomics we identified inositol polyphosphate-4-phosphatase, type II (Inpp4b) as the quantitative trait gene for EAE31. Sequence variants of Inpp4b (C/A, exon 13; A/C, exon 14) were identified as differing among multiple mouse strains and correlated with individual cortical MEP latency differences. To evaluate the functional relevance of the amino acid exchanges at positions S474R and H548P, we generated transgenic mice carrying the longer-latency allele (Inpp4b(474R/548P)) in the C57BL/6J background. Inpp4b(474R/548P) mice exhibited significantly longer cortical MEP latencies (4.5 ± 0.22 ms versus 3.7 ± 0.13 ms; P = 1.04 × 10(-9)), indicating that INPP4B regulates nerve conduction velocity. An association of an INPP4B polymorphism (rs13102150) with MS was observed in German and Spanish MS cohorts (3676 controls and 911 cases) (P = 8.8 × 10(-3)).
Attenuated cerebellar phenotypes in Inpp4a truncation mutants with preserved phosphatase activity. [2023]Phosphoinositides (PIPs) act as intracellular signaling molecules that regulate various cellular processes. Abnormalities in PIP metabolism cause various pathological conditions, including neurodegenerative diseases, cancer and immune disorders. Several neurological diseases with diverse phenotypes, such as ataxia with cerebellar atrophy or intellectual disability without brain malformation, are caused by mutations in INPP4A, which encodes a phosphoinositide phosphatase. We examined two strains of Inpp4a mutant mice with distinct cerebellar phenotypes: the Inpp4aΔEx1,2 mutant exhibited striatal degeneration without cerebellar atrophy, and the Inpp4aΔEx23 mutant exhibited a severe striatal phenotype with cerebellar atrophy. Both strains exhibited reduced expression of Inpp4a mutant proteins in the cerebellum. N-terminal-truncated Inpp4a proteins were expressed from the Inpp4aΔEx1,2 allele by alternative translation initiation and had phosphatase activity for PI(3,4)P2, whereas the Inpp4a mutant protein encoded by Inpp4aΔEx23 completely lacked phosphatase activity. Our results indicate that the diverse phenotypes observed in Inpp4a-related neurological diseases could be due to the varying protein expression levels and retained phosphatase activity in different Inpp4a variants. These findings provide insights into the role of INPP4A mutations in disease pathogenesis and may help to develop personalized therapy.
Two unrelated fetuses with ITPR1 missense variants and fetal hydrops. [2023]We describe two fetuses from unrelated families with likely pathogenic variants in ITPR1 that presented with nonimmune fetal hydrops. Trio exome sequencing revealed a de novo heterozygous likely pathogenic missense variant c.7636G > A (p.Val2531Met) in ITPR1 (NM_001378452.1) in proband 1 and a de novo heterozygous likely pathogenic missense variant c.34G > A [p.Gly12Arg] in proband 2. Variants in ITPR1 have been associated with several genetic conditions, including spinocerebellar ataxia 15, spinocerebellar ataxia 29, and Gillespie syndrome. Our report on two patients details a previously undescribed severe fetal presentation of nonimmune hydrops fetalis associated with missense variants in the ITPR1 gene.
PPP2R1A-Related Neurodevelopmental Disorder: The First Korean Case with a Novel Variant of PPP2R1A and Literature Review. [2023]In 2015, germline mutations in PPP2R1A were found to cause neurodevelopmental disorders (NDDs). To date, fewer than 50 cases of PPP2R1A-related NDDs have been reported. Here, we report the first Korean case of PPP2R1A-related NDD harboring a novel de novo missense PPP2R1A variant with previously unreported clinical features. The proband, a 12-month-old female, presented with developmental delay, intractable epilepsy, microcephaly, and feeding difficulties. Brain magnetic resonance imaging showed a Dandy-Walker continuum with corpus callosum hypoplasia, periventricular leukomalacia, and brainstem and diffuse cerebral atrophy. Next-generation sequencing-based targeted gene panel testing for NDDs revealed a novel heterozygous missense variant of PPP2R1A:c.650A>G, p.(Gln217Arg). Sanger sequencing confirmed it as de novo, as neither parent carried this variant. These findings expand the phenotypic and genotypic spectra of PPP2R1A variants.