Our approach to the treatment of ATTR is to employ the RNAi mechanism to knockdown the disease-causing TTR protein, which is primarily synthesized in the liver. Patisiran employs a TTR-targeting siRNA that knocks down both wild-type and all mutant forms of TTR in a lipid nanoparticle formulation that targets delivery to the liver; it is administered by intravenous infusion. The therapeutic hypothesis that lowering TTR will result in clinical benefit is supported by data from FAP patients receiving liver transplants, and from other systemic amyloidotic diseases, which show that as little as a 50% reduction of the disease-causing protein can result in disease improvement or stabilization.
In November 2013, we presented positive Phase 2 data, which showed that multiple doses of patisiran led to robust and statistically significant knockdown of serum TTR protein levels of up to 96%, with mean levels of TTR knockdown exceeding 85%. Knockdown of TTR was found to be rapid, dose dependent, and durable, and similar activity was observed toward both wild-type and mutant protein. In addition, patisiran was found to be generally well tolerated in this study.
Patients participating in the Phase 2 study were eligible to participate in an open-label extension (OLE) study. In April 2014, we reported positive initial data from the Phase 2 OLE study. Preliminary results from this ongoing study showed that multiple doses of patisiran achieved sustained knockdown of serum TTR protein levels at the approximately 80% target level through 168 days. In addition, OLE results showed a favorable tolerability profile with up to eight doses administered. These data provide the first clinical evidence of sustained RNAi-mediated TTR knockdown in FAP patients beyond two doses of patisiran.
In addition, we presented results of a 283-patient natural history study of patients with FAP. This cross-sectional analysis demonstrated a rapid progression in Neuropathy Impairment Score (NIS) and a high correlation of this measurement with disease severity. These results give us confidence that our APOLLO Phase 3 trial of patisiran in FAP patients is robustly powered to show the potential impact of TTR lowering on the mNIS+7 endpoint used in that study.
In April 2014, we also presented some pre-clinical data showing that the degree of TTR knockdown in a mouse disease model was highly correlated with regression of TTR tissue deposits. In addition, comparative studies performed with a TTR stabilizer and a TTR-specific antisense oligonucleotide (ASO) showed RNAi therapeutics targeting TTR to have superior pharmacologic profiles. These data suggest that the 80% TTR knockdown target level achieved in clinical studies with patisiran could facilitate a reduced pathogenic accumulation of TTR amyloid, and possibly even a regression of TTR amyloid, in patients with ATTR. The comparative data demonstrate the superior activity of RNAi therapeutics over stabilizers toward regression of TTR deposits, and establish greater TTR knockdown with over 100-fold lower tissue exposure for RNAi therapeutics versus ASOs. Taken together, we believe that these new pre-clinical data highlight the potential for RNAi therapeutics targeting TTR to emerge as an optimal approach for the treatment of ATTR.
In August 2013, Alnylam and collaborators published results of its Phase 1 study of patisiran in the New England Journal of Medicine (Coelho et al., N Engl J Med 2013;369:819-29.) The Phase 1 study, performed in normal human volunteers, was the first ever to demonstrate human proof of concept for RNAi therapeutics. In the study, patisiran administration resulted in rapid, dose-dependent, and durable knockdown of serum TTR of up to 94%. In addition, the effects of patisiran were shown to be specific and mediated by an RNAi mechanism of action.