Biogen plans to pursue regulatory approval for aducanumab, an investigational treatment for early Alzheimer’s disease (AD), after consulting with the U.S. Food and Drug Administration (FDA). The Phase 3 EMERGE Study met its primary endpoint showing a significant reduction in clinical decline, and Biogen believes that results from a subset of patients in the Phase 3 ENGAGE Study who received sufficient exposure to high dose aducanumab support the findings from EMERGE. Patients who received aducanumab experienced significant benefits on measures of cognition and function such as memory, orientation, and language. Patients also experienced benefits on activities of daily living including conducting personal finances, performing household chores such as cleaning, shopping, and doing laundry, and independently traveling out of the home. If approved, aducanumab would become the first therapy to reduce the clinical decline of Alzheimer’s disease and would also be the first therapy to demonstrate that removing amyloid beta resulted in better clinical outcomes.

The decision to file is based on a new analysis, conducted by Biogen in consultation with the FDA, of a larger dataset from the Phase 3 clinical studies that were discontinued in March 2019 following a futility analysis. This new analysis of a larger dataset that includes additional data that became available after the pre-specified futility analysis shows that aducanumab is pharmacologically and clinically active as determined by dose-dependent effects in reducing brain amyloid and in reducing clinical decline as assessed by the pre-specified primary endpoint Clinical Dementia Rating-Sum of Boxes (CDR-SB). In both studies, the safety and tolerability profile of aducanumab was consistent with prior studies of aducanumab.

“With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s. This is the result of groundbreaking research and is a testament to Biogen’s steadfast determination to follow the science and do the right thing for patients,” said Michel Vounatsos, Chief Executive Officer at Biogen. “We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.”

Based on discussions with the FDA, the Company plans to file a Biologics License Application (BLA) in early 2020 and will continue dialogue with regulatory authorities in international markets including Europe and Japan. The BLA submission will include data from the Phase 1/1b studies as well as the complete set of data from the Phase 3 studies.

The Company aims to offer access to aducanumab to eligible patients previously enrolled in the Phase 3 studies, the long-term extension study for the Phase 1b PRIME study, and the EVOLVE safety study. Biogen will work towards this goal with regulatory authorities and principal investigators with a sense of urgency.

Study Results
EMERGE (1,638 patients) and ENGAGE (1,647 patients) were Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies designed to evaluate the efficacy and safety of two dosing regimens of aducanumab. These studies were discontinued on March 21, 2019, following the results of a pre-specified futility analysis which relied on an earlier and smaller dataset. The futility analysis was based on data available as of December 26, 2018, from 1,748 patients who had the opportunity to complete the 18-month study period and predicted that both studies were unlikely to meet their primary endpoint upon completion. Futility analyses are common in large clinical studies and use statistical modeling to attempt to predict the outcome of the studies based on a number of pre-specified assumptions and criteria.

Following the discontinuation of EMERGE and ENGAGE, additional data from these studies became available resulting in a larger dataset, which included a total of 3,285 patients, 2,066 of whom had the opportunity to complete the full 18 months of treatment. A new extensive analysis of this larger dataset showed a different outcome than the outcome predicted by the futility analysis. Specifically, the new analysis of this larger dataset showed EMERGE to be statistically significant on the pre-specified primary endpoint (P=0.01). Biogen believes that data from a subset of ENGAGE support the findings from EMERGE, though ENGAGE did not meet its primary endpoint. Biogen consulted with external advisors and the FDA on these different results and their implications.

“This large dataset represents the first time a Phase 3 study has demonstrated that clearance of aggregated amyloid beta can reduce the clinical decline of Alzheimer’s disease, providing new hope for the medical community, the patients, and their families,” said Dr. Anton Porsteinsson, William B. and Sheila Konar Professor of Psychiatry, Neurology and Neuroscience, director of the University of Rochester Alzheimer’s Disease Care, Research and Education Program (AD-CARE), and principal investigator. “There is tremendous unmet medical need, and the Alzheimer’s disease community has been waiting for this moment. I commend Biogen, the FDA, the medical community, and the patients and their study partners for their persistence in working to make today’s announcement a reality.”

In EMERGE, which met its pre-specified primary endpoint in the new analysis, patients treated with high dose aducanumab showed a significant reduction of clinical decline from baseline in CDR-SB scores at 78 weeks (23% versus placebo, P=0.01). In EMERGE, patients treated with high dose aducanumab also showed a consistent reduction of clinical decline as measured by the pre-specified secondary endpoints: the Mini-Mental State Examination (MMSE; 15% versus placebo, P=0.06), the AD Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo, P=0.01), and the AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo, P=0.001). Imaging of amyloid plaque deposition in EMERGE demonstrated that amyloid plaque burden was reduced with low and high dose aducanumab compared to placebo at 26 and 78 weeks (P<0.001). Additional biomarker data of tau levels in the cerebrospinal fluid supported these clinical findings. Biogen believes that data from patients in ENGAGE who achieved sufficient exposure to high dose aducanumab supported the findings of EMERGE.

In both studies, the most commonly reported adverse events were amyloid-related imaging abnormalities-edema (ARIA-E) and headache. The majority of patients with ARIA-E did not experience symptoms during the ARIA-E episode, and ARIA-E episodes generally resolved within 4 to 16 weeks, typically without long-term clinical sequelae. Biogen plans to present further detail on the new analysis of the larger dataset from EMERGE and ENGAGE at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in December 2019.

After reviewing the data in consultation with the FDA, Biogen believes that the difference between the results of the new analysis of the larger dataset and the outcome predicted by the futility analysis was largely due to patients’ greater exposure to high dose aducanumab. Multiple factors contributed to the greater exposure to aducanumab in the new analysis of the larger dataset, including data on a greater number of patients, a longer average duration of exposure to high dose, the timing of protocol amendments that allowed a greater proportion of patients to receive high dose, and the timing and pre-specified criteria of the futility analysis.

Source: Biogen (press release)

ProQR Therapeutics, a company dedicated to changing lives through the creation of transformative RNA medicines for severe genetic rare diseases, today announced positive top-line results from the PQ-110-001 study, a Phase 1/2 dose range finding, first-in-human trial of sepofarsen (QR-110) in patients with Leber’s congenital amaurosis 10 (LCA10) due to the p.Cys998X mutation in the CEP290 gene.

“We reported today that patients receiving sepofarsen had a clinically meaningful improvement in vision, and in some cases the patient’s vision improved to a level that could be deemed life changing. This is very encouraging for the LCA10 community and the Inherited Retinal Disease community as a whole,” said Stephen R. Russell, MD, Schrage Professor of Ophthalmology and Visual Sciences and Principal Investigator at the University of Iowa. “LCA10 is a severe inherited retinal disease that leads to blindness, and for which there is currently no treatment.”

David Rodman, M.D., Executive Vice President of Research & Development of ProQR, said, “We are very pleased with the data reported from the Phase 1/2 study, in which LCA10 patients treated with sepofarsen experienced a rapid and durable improvement in vision. The top-line data from this study strengthen our confidence in the design of the ongoing Phase 2/3 trial, which could be the sole registration trial for the sepofarsen program. We appreciate the patients’ and medical communities’ ongoing support for the sepofarsen clinical studies, and we will continue to work with the regulators to advance this program as efficiently as possible.”

Top-line results from the Phase 1/2 trial

Based on positive 3-month interim results from the Phase 1/2 trial (Nature Medicine 2018) the Phase 2/3 Illuminate trial was initiated earlier this year. The 12-month top-line results from the Phase 1/2 trial that will be presented today confirm durable activity of sepofarsen for up to one year in patients with LCA10. Furthermore, the results support the assumptions used in the design and powering of Illuminate, including:

• the target registration dose (80 µg with a 160 µg loading dose) was associated with a clinically meaningful and statistically significant improvement in vision and had a favorable benefit/risk profile,
• a six-month dosing frequency, as used in Illuminate, was associated with durable improvements in vision,
• the response observed at 12 months in the target registration dose was equal to or greater than the response at the 3-month interim analysis,
• and subjects with better vision than light perception (BCVA> LogMAR 3.0) at baseline, the study population in Illuminate, were more likely to respond to treatment with sepofarsen.

Table: Change from baseline in treated eye

Analysis: Pooled analysis: Unpaired t-test, between group change from baseline versus untreated. Target registration dose group: MMRM with repeated measures, within group change from baseline versus baseline

Visual acuity

Statistically significant improvement from baseline in best corrected visual acuity (BCVA) was observed as assessed by the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart and the Berkeley Rudimentary Vision Test (BRVT). In the pooled analysis with all patients after twelve months of treatment, the mean improvement (and standard error of mean, SEM) was -0.55 LogMAR (SEM 0.26). The mean change in the untreated contralateral eye was -0.11 LogMAR (SEM 0.07).

In the target registration dose group, the mean change from baseline at twelve months was -0.93 LogMAR (SEM 0.43) with four of six subjects showing an improvement of more than -0.3 LogMAR from baseline equivalent to 3 lines, or 15 letters, on ETDRS chart (generally considered clinically meaningful by US regulators). Five of six subjects showed an improvement greater than -0.2 LogMAR (generally considered clinically meaningful by EU regulators). The mean change in the untreated contralateral eye in this group was -0.22 LogMAR (SEM 0.11). In all five subjects in this group, in which a six-month dosing frequency was explored, the observed benefit in visual acuity was maintained during the twelve-month follow up.

Full field stimulus threshold test (FST)

Improvements in visual function were supported by a meaningful increase in the ability to detect flashes of red or blue light as determined by the FST test. In the pooled analysis after twelve months, mean improvement in red light sensitivity was -0.92 log Cd/m² (SEM 0.18) and improvement in blue light sensitivity was -0.79 log Cd/m² (SEM 0.23). The mean change in the untreated contralateral eye was -0.16 log Cd/m² (SEM 0.16) for red light and 0.02 log Cd/m² (SEM 0.11) for blue light.

In the target registration dose group, the mean change from baseline at twelve months in red light sensitivity was -0.66 log Cd/m² (SEM 0.14) and improvement in blue light sensitivity was -0.63 log Cd/m² (SEM 0.31). Three of six subjects showed an improvement of greater than -0.5 log Cd/m² for blue light, which can be regarded as clinically meaningful. Five of six showed a clinically meaningful improvement for red light. The mean change in the untreated contralateral eye in this group was 0.05 log Cd/m² (SEM 0.17) for red light and -0.12 log Cd/m² (SEM 0.16) for blue light.

Mobility course

Most patients demonstrated improvement in functional vision, as assessed using a series of mobility courses at increasing difficulty and multiple light intensities. In the pooled analysis the mean improvement for patients navigating the mobility course after twelve months of treatment was 2.5 levels (SEM 0.99). The mean change in the untreated contralateral eye was 1.75 (SEM 0.75). This increase was likely due to a training effect. An adjusted mobility course endpoint is being validated in parallel with the Illuminate trial.

In the target registration dose group, the mean change at twelve months of treatment was 4.0 levels (SEM 1.27) with five of six subjects improving by more than 2.0 levels, which can be regarded as clinically meaningful. The mean change in the untreated contralateral eye was 2.7 levels (SEM 1.11).

SafetySubjects received up to four doses of sepofarsen (range 1-4), and all eleven subjects in the study completed twelve months of follow up. This represents data equivalent to over 4,000 treatment days. Sepofarsen was observed to be well-tolerated with manageable safety findings. In total, eight cases of lens opacities (cataract) were observed (three in the target registration dose cohort and five in high dose cohort). All six of the subjects that had lens replacement surgery regained their pre-cataract vision. Four cases (in three subjects) of retinal findings were observed in the now retired 320/160 µg dose group: Two incidences of mild cystoid macular edema were resolved with topical treatment and two incidences of subclinical retinal thinning stabilized within two months of last dose without additional treatment.

Source ProQR (press release)