safety & efficacy of dcr-phxc in patients with ph1 and esrd

Conditions: Primary Hyperoxaluria Type 1; End Stage Renal Disease

Summary: the aim of this study is to evaluate dcr-phxc in participants with ph1 and severe renal impairment, with or without dialysis.

this is an open-label, repeat-dose, phase 2 study of dcr-phxc in participants with ph1 and severe renal impairment, with or without dialysis. following the up-to-35- day screening period, participants will return to the clinic for monthly dosing visits through day 180. participants successfully completing the day 180 visit will continue on to an extended follow-up period and receive open-label dcr-phxc for an additional 5 years, or until dcr-phxc is commercially available, whichever comes first. as participants in this extended treatment period will return to the clinic only every 3 months, participants and/or their caregivers may be trained in the at-home administration of dcr-phxc or home health nurses may assist with administration of dcr -phxc. the total duration of the study is approximately 5 years from first participant, first visit, to last participant, last day 180 visit, with up to an additional 5 years of extended follow-up.

Eligibility criteria:
inclusion criteria: 1. four age groups of participants will be enrolled: 1. adults and adolescents (aged ≥ 12 years) 2. children 6 to 11 years of age 3. children 2 to 5 years of age 4. infants and newborns from birth to \< 2 years of age 2. . documented diagnosis of ph1, confirmed by genotyping 3. estimated gfr at screening \<30ml/min normalized to 1.73m\^2 bsa 4. mean of 2 plasma oxalate \>20μmol/l during screening 5. for participants receiving hemodialysis or peritoneal dialysis total duration of hemodialysis or peritoneal dialysis must be less than 24 months and hemodialysis or peritoneal dialysis regimen must have been stable for at least 2 weeks prior to screening. 6. male or female 1. male participants: * a male participant with a female partner of childbearing potential must agree to use contraception during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period. 2. female participants: * a female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (wocbp). * or * a wocbp who agrees to follow the contraceptive guidance during the treatment period and for at least 12 weeks after the last dose of study intervention and agrees to refrain from harvesting/freezing eggs during this period. 3. contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 7. participant (and/or participant's parent or legal guardian if participant is a minor \[defined as patient \<18 years of age, or younger than the age of majority according to local regulations\]) is capable of giving signed informed consent, which includes compliance with the requirement and restrictions listed in the informed consent form (icf) and in the protocol. 1. adolescents (12 to \< 18 years of age, or older than 12 years but younger than the age of majority according to local regulations) must be able to provide written assent for participation. 2. for children younger than 12 years of age, assent will be based on local regulations 8. affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations) exclusion criteria: 1. prior hepatic transplantation; or scheduled transplantation within 6 months of day 1. prior renal transplantation is allowed. 2. documented evidence of clinical manifestations of severe systemic oxalosis (including preexisting retinal, heart, or skin calcifications, or history of severe bone pain, pathological fractures, or bone deformations) 3. presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact patient safety including, but not restricted to: 1. severe intercurrent illness 2. known causes of active liver disease/injury (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis) 3. non-ph related conditions contributing to renal insufficiency 4. physician concerns about intake of drugs of abuse or excessive alcohol intake, or history of excessive alcohol intake in the 2 years prior to enrollment (defined as ≥ 21 units of alcohol per week in men and ≥ 14 units of alcohol per week in women; where a "unit" of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1ounce shot of hard liquor) 4. use of an rnai drug, other dcr-phxc, within the last 6 months 5. history of one or more of the following reactions to an oligonucleotide-based therapy: 1. severe thrombocytopenia (platelet count ≤ 100,000/µl) 2. hepatotoxicity, defined as alanine transaminase (alt) or aspartate transaminase (ast) \> 3 times the upper limit of normal (uln) and total bilirubin \> 2 × uln or international normalized ratio (inr) \>1.5 3. severe flu-like symptoms leading to discontinuation of therapy 4. localized skin reaction from the injection (graded severe) leading to discontinuation of therapy 5. coagulopathy/clinically significant prolongation of clotting time 6. participation in any clinical study in which they received an investigational medicinal product (imp) other than dcr-phxc within 4 months before screening. 7. liver function test abnormalities: alt and/or ast \>1.5 × uln for age and gender 8. positive anti-double-stranded deoxyribonucleic acid (anti-dsdna) antibody test at screening 9. known hypersensitivity to dcr-phxc or any of its ingredients 10. inability or unwillingness to comply with the specified study procedures, including the lifestyle considerations

Keywords: ph1 esrd