Alnylam - ALN-TTRSC-003 - TTR Cardiac Amyloidosis
Research type
Research Study
Full title
A Phase 2, Open-label Extension Study to Evaluate the Long-Term Safety, Clinical Activity, and Pharmacokinetics of ALN-TTRSC in Patients with Transthyretin (TTR) Cardiac Amyloidosis Who Have Previously Received ALN-TTRSC.
IRAS ID
157909
Contact name
Julian Gillmore
Contact email
Sponsor organisation
Alnylam Pharmaceuticals Inc
Eudract number
2014-001229-34
Research summary
TTR is a protein produced predominantly by hepatocytes (liver cells). Transthyretin related amyloidosis (ATTR) is a disease caused by deposition of TTR amyloid fibrils in various body tissues. Cardiac and neuronal extracellullar deposition of these fibrils culminates in life-threatening cardiomyopathy and/or debilitating neuropathy. Following symptom onset, quality of life is severely impacted and the disease proceeds inexorably to death. Patients are largely managed with supportive care aimed at alleviating heart failure symptoms; there are currently no approved therapies for TTR cardiac amyloidosis and there exists a high unmet need for novel approaches to treatment. RNA interference (RNAi) are naturally occurring cellular mechanisms for regulating gene expression that are mediated by small interfering ribonucleic acids (siRNAs). siRNAs can be designed to target endogenous disease genes. ALN-TTRSC is comprised of a small interfering RNA (siRNA) targeting mutant and wild type TTR mRNA.
The therapeutic hypothesis for this treatment is that lowering of serum TTR protein through inhibition of hepatic production may result in clinical benefit. Support for this approach comes from evidence that lowering of the amyloidogenic protein by >/= 50% improves clinical outcomes in other amyloidotic disorders including AL and AA amyloidosis. Currently, 12 patients are enrolled into the ALN-TTRSC-002 study Preliminary data show >80% TTR knockdown with 5 and 7.5 mg/kg. Multiple doses of ALN-TTRSC have been generally safe and well tolerated with a similar safety profile that was observed in the Phase 1 study in healthy volunteers as well as in patients from preliminary Phase 2 results. Patients completing Study ALN-TTRSC-002 are eligible to enrol into the Phase 2, open-label, extension study (ALN-TTRSC-003) designed to evaluate the safety and tolerability of long-term ALN-TTRSC dosing; there will be 5 daily doses followed by weekly dosing. Additional information will be evaluated including PK, PD, and clinical activity. Patients will receive 500 mg ALN-TTRSC weekly for approximately 2 years.
REC name
London - Central Research Ethics Committee
REC reference
14/LO/1091
Date of REC Opinion
18 Jul 2014
REC opinion
Further Information Favourable Opinion