Alfred Sandrock
Head of Research and Development at Biogen
Thank you, Michel. And good morning everyone. As always, I'd like to start by thanking the Biogen team for their hard work as we continue to advance our R&D programs. In addition to key readouts in major depressive disorder and ALS, we hosted an R&D Investor Day to tell you about our pipeline programs, research capabilities and expertise. I encourage you to take a look at these presentations on our website.
Let me now start with Alzheimer's disease, beginning with aducanumab. At the R&D Day presentation earlier this month, I underscored the importance of determining the relationship between drug to biology, as well as biology to disease during the drug development process. In late June, FDA made data from the drug approval package of ADUHELM publicly available. The clinical pharmacology review included in the approval package addresses some of these key relationships as shown in the next 2 slides.
This first slide shows the relationship between the amyloid plaque burden as measured by the observed SUVr score versus drug exposure as measured by the predicted cumulative AUC, both at Week 78, taking into account all of the data from both Phase 3 trials of aducanumab. The relationship between exposure to aducanumab and amyloid plaque reduction is consistent across the two studies and shows that amyloid plaque burden decreases as the cumulative drug exposure increases.
The next slide shows another figure from the same document which plots the relationship between the reduction in amyloid plaque burden as measured by SUVr and the preservation of clinical function as measured by the CDR Sum of Boxes across multiple dose levels of several anti-A beta antibodies. Studies 301 and 302 are referred to as Study 2 and Study 1, respectively, in the ADUHELM label. When viewed together, these data from six different anti-amyloid antibodies show that there is an association between amyloid plaque reduction and a reduction in clinical decline and that greater degrees of amyloid plaque reduction are needed for a reduction in clinical decline.
At the annual AAIC meeting in July, we presented additional data from the EMERGE, ENGAGE and PRIME trials, which showed that aducanumab treatment led to a reduction in amyloid plaques as well as downstream biomarkers of Alzheimers disease pathophysiology and that this also led to a slowing of clinical decline. We are looking forward to presenting more data from our aducanumab trials, including the baseline data from the EMBARK study at the upcoming CTAD meeting next month in Boston.
We're also looking forward to presenting, at the earliest possible opportunity at a scientific venue, new data on plasma P181-tau, reflecting a downstream biological and clinical effects of aducanumab, which I believe will be of great interest to scientists and clinicians. By way of reminder, amyloid plaques containing A-beta protein and neurofibrillary tangles containing phosphorylated tau are the defining pathophysiologic features of Alzheimer's disease. Finally, I'm happy to say that we are on track to soon publish the Phase 3 aducanumab trial results in a major peer-reviewed journal.
This quarter, we also submitted a draft protocol for the required Phase 4 confirmatory trial of aducanumab to the FDA. As I have said before, we have fully resourced the study and aim to complete it ahead of schedule. A key goal of the confirmatory study is to ensure that we enroll appropriate numbers of Alzheimer's disease patients from underrepresented populations. It is estimated that by 2030, nearly 40% of all Americans living with Alzheimer's disease will be African-American or Latinx and therefore having sufficient participation of these communities is especially important to reflect the diversity of the disease in the real world. Through the Phase 4 confirmatory study, as well as ICARE AD, we aim to provide further evidence of the clinical benefits and risks associated with aducanumab treatment.
Outside of the United States, we are under regulatory review in multiple geographies, including the EU, where we are actively preparing for a scientific advisory group meeting as part of the CHMP review process.
Turning to lecanemab, we are looking forward to when we can potentially provide to add the amyloid antibody options for Alzheimer's disease patients. As previously announced, our collaboration partner Eisai recently initiated a rolling submission of the lecanemab beta to the FDA for potential accelerated approval. We expect this submission to be complete sometime in 2022.
Moving to MS, we presented new data at the annual ECTRIMS meeting last week, including primary results from the NOVA Phase 3b study evaluating the efficacy of TYSABRI extended interval dosing versus the approved every four-week dosing. A real world claims-based analysis of relapse and hospitalization rates in MS patients treated with natalizumab versus ocrelizumab, a new analysis of the EVOLVE-MS-2 data focusing on the impact of dose titration on the GI tolerability of VUMERITY relative to TECFIDERA, and data from the MS PATHS showing that 100% of people with MS treated with natalizumab, interferons or fumarates achieved an antibody response following COVID-19 vaccination, as compared to 40% of MS patients treated with anti-CD20 or S1P therapies.
With respect to the introduction of VUMERITY in the EU, we were happy to learn of the approval in Switzerland as well as the positive CHMP opinion and look forward to the final EMA decision.
In neuropsychiatry, we were excited to see the results of the Phase 2 study of zuranolone in major depressive disorder recently completed by Shionogi. The Phase 2 trial was similar in design to the other studies evaluating zuranolone and MDD and compared 20 and 30 milligram doses of zuranolone to placebo in Japanese patients with MDD. The results of this study further support the safety and efficacy profile of zuranolone in that it demonstrated rapid onset and significant reductions in the HAM-D-17 score at Day 3, Day 8 and Day 15.
Additionally, while not statistically significant, we see separation from placebo for both the 20 and 30 milligrams zuranolone treatment arms out to Day 57. All adverse events in the study were mild to moderate, and consistent with the known safety profile of zuranolone. The Shionogi study is now the third double blind placebo-controlled trial evaluating zuranolone in MDD where the primary endpoint of the change in the HAM-D score at Day 15 was met. These results in MDD are in addition to the efficacy of zuranolone in PPD as observed in the ROBIN study.
Given the consistent results observed across the zuranolone trials, Biogen and Sage have announced plans to submit an NDA to the FDA in the second half of 2022. The planned initial submission package will be used to seek approval of zuranolone for the treatment of major depressive disorder and an additional filing for postpartum depression is anticipated in the first half of 2023. Additionally, the CORAL study designed to evaluate zuranolone as an acute rapid response therapy when co-initiated with standard antidepressant therapy is now fully enrolled with topline data expected in early 2022.
Moving to neuromuscular disorders. Earlier this week, we announced results from the pivotal Phase 3 study evaluating tofersen in people with SOD1 mediated ALS. The Phase 3 or VALOR study utilized the study enrichment approach to stratify participants into faster and slower progressing cohorts. We were disappointed when we learnt that the study did not meet the primary endpoint of a statistically significant change from baseline to Week 28 in the ALS functional rating scale in the fast-to-progressing population. Nevertheless, we did observe encouraging trends favoring tofersen across multiple secondary and exploratory measures of biological and clinical activity, including assessments of motor function, respiratory function, muscle strength and quality of life. Moreover, a pre-specified integration of data from the Phase 3 study and its ongoing open label extension study reinforce these findings and showed that early tofersen initiation led to a slower decline across these measures.
Beyond the clinical measures, we observed reductions in CSF SOD1 as compared to placebo, suggesting target engagement was achieved. Moreover, on the key secondary endpoint of a change in plasma neurofilament light, a potential marker of neuronal degeneration, we observed reductions of 67% in the faster progressing patients and 48% in the slower progressing patients with tofersen treatment relative to placebo. To our knowledge, this represents the greatest reductions in plasma neurofilament levels ever observed in an ALS clinical trial. Most adverse events in the Phase 3 study were mild to moderate in severity and many were consistent with ALS disease progression or lumbar puncture-related events. Serious adverse events, including transverse myelitis, were seen in some patients receiving tofersen.
Based on the results of the Phase 3 study, we are actively engaging regulators, the medical community, patient advocacy groups and other key stakeholders around the world to determine next steps for tofersen. Additionally, following discussions with key medical experts and ethicists, we plan to provide early access of tofersen to all eligible SOD1-ALS patients through an expanded access program. Given the possible importance of early treatment of SOD1-ALS, we continue to enroll patients in the ATLAS study, a Phase 3 trial of tofersen initiated in clinically pre-symptomatic SOD1 mutation carriers. Our hope is that treating patients earlier in the disease may provide the best opportunity to slow or even delay the onset of this terrible disease.
Also in neuromuscular disorders, this quarter, we announced our plans to initiate ASCEND, a Phase 3b study which aims to evaluate whether treatment with an investigational higher dose of nusinersen has the potential to improve clinical outcomes in patients previously treated with risdiplam. Our SPINRAZA data indicate that exposure remains similar as patients age and grow. We are also advancing the ongoing DEVOTE study evaluating the safety and efficacy of higher exposures of SPINRAZA as our pre-clinical studies indicate that we ought to be able to safely increase its dose. With the DEVOTE and ASCEND studies, we hope to be able to further inform SMA treatment and address the remaining unmet needs of patients.
In summary, as I described during our recent R&D Investor Day, we believe the science is breaking and that this is exactly the right time to be pioneers in neuroscience. By leveraging a deep understanding of human genetics and disease biology, we are working to usher in the future of neurotherapeutics where we identify the right patients and treat early, perhaps even before the onset of symptoms, to meaningfully delay or even prevent disease progression.
I will now turn the call over to Mike.
