- \n
- \nAs previously communicated, Prothena plans to explore potential partnership interest to advance PRX012 and its preclinical PRX012-TfR (transferrin receptor) antibody<\/p>\n<\/li>\n<\/ul>\n
- \n
- \nPhase 1 ASCENT clinical program established proof-of-mechanism for PRX012 as a once-monthly, subcutaneous anti-amyloid beta antibody with high binding potency, dose- and time-dependent reduction of amyloid plaque, although with a non-competitive ARIA-E profile in patients with early symptomatic Alzheimer\u2019s disease<\/p>\n<\/li>\n<\/ul>\n
DUBLIN–(BUSINESS WIRE<\/a>)–
\nProthena Corporation plc (NASDAQ:PRTA), today announced results from the Phase 1 ASCENT clinical program in participants with early symptomatic Alzheimer\u2019s disease (AD). As previously communicated, Prothena plans to explore potential partnership interest to advance PRX012 and its preclinical PRX012-TfR (transferrin receptor) antibody.<\/p>\n\nThe Phase 1 ASCENT clinical program results demonstrated PRX012 as a potential once-monthly, subcutaneous anti-amyloid beta (A\u03b2) antibody with stable pharmacokinetics, low anti-drug antibodies, low injection site reactions, and dose- and time-dependent reductions in amyloid plaque. At the 400 mg dose level, PRX012 demonstrated a mean reduction in amyloid PET to 27.47 centiloids (CL) at month 12; FDA approved anti-A\u03b2 antibodies have defined amyloid negativity thresholds of \u226430 CL or \u226424.1 CL. However, PRX012 was associated with higher overall ARIA-E rates relative to FDA approved anti-A\u03b2 antibodies, making PRX012 less appropriate for the patients studied in the ASCENT clinical program. When ARIA-E did occur, the characteristics were similar to those reported following treatment with other anti-A\u03b2 antibodies.<\/p>\n
\nBased on the profile observed in the ASCENT clinical program and feasibility work already completed on its preclinical A\u03b2-transferrin receptor antibody surrogate, Prothena believes this approach may represent an opportunity to significantly lower the risk of ARIA and quickly reduce amyloid plaque with a once-monthly subcutaneous administration. Initial preclinical studies have demonstrated substantially increased brain exposure and facilitated rapid targeting of A\u03b2 plaques in an APP\/PS1 transgenic mouse model.<\/p>\n
\n\u201cOn behalf of our entire team, we extend our continued appreciation to the patients, families, investigators, and staff whose dedication and collaboration enabled the Phase 1 ASCENT clinical program to achieve its objectives,” said Chad Swanson, Ph.D., Chief Development Officer, Prothena. \u201cWe plan to explore potential partnership interest to further develop PRX012 and PRX012-TfR.\u201d<\/p>\n
\nProthena does not plan to publicly share additional data from the ASCENT clinical program while it expects to explore potential partnership interest to advance PRX012 and PRX012-TfR.<\/p>\n
Phase 1 ASCENT Clinical Program<\/b><\/p>\n
\nThe Phase 1 ASCENT clinical program includes ASCENT-1: a randomized, double-blind, placebo-controlled single-ascending-dose trial; ASCENT-2: a randomized, double-blind, placebo-controlled six-month multiple-dose trial; and ASCENT-3: a twelve-month open-label extension trial. The objectives of the ASCENT clinical program were to determine the safety, tolerability, immunogenicity, and pharmacokinetics of PRX012. The ASCENT-2 and ASCENT-3 trials also evaluated the pharmacodynamics of PRX012, including amyloid plaque deposition as measured by positron emission tomography (PET), in participants with early symptomatic AD.<\/p>\n
\nThe results include data from the five ASCENT-2 Group A cohorts in 228 participants with early symptomatic AD who are either APO\u03b54 non-carriers or heterozygous carriers ranging in doses of PRX012 from 45 mg to 400 mg, randomized to PRX012 or placebo in a 3:1 ratio. Additional amyloid plaque reduction data from an interim read-out of ASCENT-3, the open-label extension (OLE) trial, was included.<\/p>\n
ASCENT-2 Group A: Adverse Events<\/b>1<\/sup><\/p>\n
\n
\n \n \n\u00a0<\/p>\n<\/td>\n
\n Placebo
\n
<\/b>(n=57)<\/p>\n<\/td>\n\n 45 mg
\n
<\/b>(n=25)<\/p>\n<\/td>\n\n 70 mg
\n
<\/b>(n=24)<\/p>\n<\/td>\n\n 200 mg<\/b>2
\n
<\/sup>(n=97)<\/p>\n<\/td>\n\n 400 mg
\n
<\/b>(n=24)<\/p>\n<\/td>\n<\/tr>\n\n \n Treatment Emergent
\n
Adverse Events (TEAE)<\/b><\/p>\n<\/td>\n\n \n33 (57.9%)<\/p>\n<\/td>\n
\n \n10 (40.0%)<\/p>\n<\/td>\n
\n \n13 (54.2%)<\/p>\n<\/td>\n
\n \n66 (68.0%)<\/p>\n<\/td>\n
\n \n18 (75.0%)<\/p>\n<\/td>\n<\/tr>\n
\n \n Treatment Emergent Serious Adverse Event (TESAE)<\/b><\/p>\n<\/td>\n
\n \n5 (8.8%)<\/p>\n<\/td>\n
\n \n2 (8.0%)<\/p>\n<\/td>\n
\n \n1 (4.2%)<\/p>\n<\/td>\n
\n \n7 (7.2%)<\/p>\n<\/td>\n
\n \n1 (4.2%)<\/p>\n<\/td>\n<\/tr>\n
\n \n Study drug related TESAE<\/b><\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n1 (4.2%)<\/p>\n<\/td>\n
\n \n5 (5.2%)<\/p>\n<\/td>\n
\n \n1 (4.2%)<\/p>\n<\/td>\n<\/tr>\n
\n \n TEAE Leading to Withdrawal of Study Drug<\/b><\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n1 (4.2%)<\/p>\n<\/td>\n
\n \n4 (4.1%)<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n<\/tr>\n
\n \n TEAE Leading to Withdrawal from the Study<\/b><\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n1 (4.2%)<\/p>\n<\/td>\n
\n \n1 (1.0%)<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n<\/tr>\n
\n \n Death<\/b><\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n1 (4.0%)<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n<\/tr>\n
\n \n Death due to Study Drug<\/b><\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n
\n \n0<\/p>\n<\/td>\n<\/tr>\n
\n \n Overall ARIA<\/b><\/p>\n<\/td>\n
\n \n4 (7.0%)<\/p>\n<\/td>\n
\n \n4 (16.0%)<\/p>\n<\/td>\n
\n \n5 (20.8%)<\/p>\n<\/td>\n
\n \n41 (42.3%)<\/p>\n<\/td>\n
\n \n10 (41.7%)<\/p>\n<\/td>\n<\/tr>\n
\n \n ARIA-E<\/b><\/p>\n<\/td>\n
\n \n1 (1.8%)3<\/sup><\/p>\n<\/td>\n
\n \n3 (12.0%)<\/p>\n<\/td>\n
\n \n2 (8.3%)<\/p>\n<\/td>\n
\n \n37 (38.1%)<\/p>\n<\/td>\n
\n \n10 (41.7%)<\/p>\n<\/td>\n<\/tr>\n
\n \n ARIA-H<\/b><\/p>\n<\/td>\n
\n \n4 (7.0%)<\/p>\n<\/td>\n
\n \n3 (12.0%)<\/p>\n<\/td>\n
\n \n4 (16.7%)<\/p>\n<\/td>\n
\n \n29 (29.9%)<\/p>\n<\/td>\n
\n \n8 (33.3%)<\/p>\n<\/td>\n<\/tr>\n
\n \n Concurrent
\n
ARIA-E and ARIA-H<\/b><\/p>\n<\/td>\n\n \n0<\/p>\n<\/td>\n
\n \n2 (8.0%)<\/p>\n<\/td>\n
\n \n1 (4.2%)<\/p>\n<\/td>\n
\n \n24 (24.7%)<\/p>\n<\/td>\n
\n \n8 (33.3%)<\/p>\n<\/td>\n<\/tr>\n
\n \n 1 <\/sup>Safety population includes all randomized participants who received at least one dose of study drug
\n
2 <\/sup>Participants received 200 mg dose level in two separate cohorts (a core and an expansion cohort)
\n
3<\/sup> The one placebo participant with ARIA-E was in the 70 mg cohort: 1 of 8 participants (12.5%)<\/p>\n<\/td>\n<\/tr>\n<\/table>\n\nPRX012 was generally well-tolerated across all dose cohorts of the trial. Injection site reactions in participants treated with PRX012 were low (4.1%). Treatment emergent anti-drug antibodies were low and generally transient with titer values close to the assay\u2019s detection threshold. There was one death in the study in the 45 mg dose cohort, which was determined by the investigator to be not related to study drug.<\/p>\n
Group A: Amyloid PET Centiloid (CL) Values
\n
<\/b>ASCENT-2 and ASCENT-3 Interim Data<\/p>\n
- \nPhase 1 ASCENT clinical program established proof-of-mechanism for PRX012 as a once-monthly, subcutaneous anti-amyloid beta antibody with high binding potency, dose- and time-dependent reduction of amyloid plaque, although with a non-competitive ARIA-E profile in patients with early symptomatic Alzheimer\u2019s disease<\/p>\n<\/li>\n<\/ul>\n
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