Biogen Inc. (BIIB) Earnings Call Transcript & Summary

Hello. My name is Samantha Budd Haeberlein. And on behalf of the authors listed here, I'm going to take you through a presentation of EMERGE and ENGAGE topline result, which were 2 Phase III studies to evaluate aducanumab in patients with early Alzheimer's disease. This presentation may include forward-looking statements. The aducanumab Phase III studies called EMERGE and ENGAGE were 2 identical 18-month duration, randomized, double-blind, placebo-controlled Phase III studies. They enrolled 3,285 patients at 348 sites in 20 countries which are listed to the right. The population study were early Alzheimer's disease, which included subjects with MCI due to Alzheimer's disease and mild Alzheimer's disease dementia. There were 2 dosing regimens, a low and a high dosing regimen and placebo, randomized 1:1:1. And the primary endpoint was changed from baseline of CDR sum of boxes at 18 months. There were other endpoints, including the secondaries MMSE, ADAS-Cog 13, ADCS-ADL-MCI and substudies which examined the effect on proximal and disease-related biomarkers. A 2 doses study were stratified by the presence of the ApoE4 gene. In the low dose, ApoE4 noncarriers were titrated to 6 milligram per kilogram. And ApoE4 carriers were titrated to 3 milligram per kilogram. These dosing regimens were maintained throughout the study. In the high dose regimen at the beginning of the study, ApoE4 carriers were titrated to 6 milligram per kilogram, which is the green line. And the ApoE4 noncarriers were titrated to 10 milligram per kilogram. During the conduct of this study, the protocols were changed such that in the high dose regimen, the ApoE4 carriers were also able to be titrated to the 10 milligram per kilogram. And this was an amendment, which is known as Protocol Version 4. The high dose, having changed partway through the study, did have a significant impact on the dosing received by subjects prior to Protocol Version 4. You see the number -- the average cumulative dose listed here is 116 milligram per kilograms. Post that protocol amendment, that rose to 153 milligram per kilogram. Now I'm going to take you through the top line results of EMERGE and ENGAGE. The baseline demographics for both studies are listed here, and they were well balanced across arms and across both studies. Listed here are the baseline disease characteristics which were also well balanced across the arms and balanced across the studies. The baseline disease characteristics included a mean score of MMSE of around 26, and the other measures are consistent with the population that was expected to be recruited. Listed here is the patient disposition. In EMERGE, 1,643 subjects were randomized and 1,638 of those subjects were dosed. In ENGAGE, 1,653 subjects were randomized and of those, 1,647 were dosed. Listed here are those who discontinued treatment during the conduct of the study, which is between 15% to 27% approximately. And beneath that, are listed the subjects who fully withdrew from the study. Those who discontinued were encouraged to stay in the study and continue to contribute to the measures at the later time points. Overall, this is quite a low discontinuation rate. However, the studies were terminated early, and so the numbers of subjects who completed the placebo-controlled period listed at the bottom is approximately 50% across the arms. Here are the prespecified primary and secondary endpoints at week 78. As I mentioned, CDR sum of boxes was the primary endpoint. If we start with the EMERGE study on the left of the table here and looking at the high dose, there is a difference versus placebo at week 78 of 22% and a p-value of 0.01. Going down in the multiplicity adjusted secondaries. MMSE has a difference of 18% and a p-value of less than 0.05. ADAS-Cog has a 27% difference from placebo and a p-value of 0.0097. And the ADCS-ADL-MCI scale has a 40% difference from placebo and a p-value of 0.006 (sic) [ 0.0006 ]. In the low dose, there are intermediate numerical differences from placebo. However, none of these reached the level of statistical significance. Moving to the right of these tables, the ENGAGE study in a similar fashion. We have the CDR sum of boxes which does not have a separation from placebo. And neither do we see a separation in MMSE and we see a small numerical difference in ADAS-Cog and ADCS. None of these reached a level of statistical significance. In the low dose of the ENGAGE study, we see values that are similar in their numerical levels to those in the low dose of the EMERGE study. However, as in the EMERGE study, the low dose for ENGAGE did not achieve statistical significance. And so we have with EMERGE in the high dose a positive result. These plots are showing the longitudinal change from baseline in the CDR sum of boxes. The gray lines are the placebo, the magenta are the high dose and the blue is the low dose. And you can see in EMERGE how the separation begins and then continues to separate over time. Whereas in ENGAGE, there is no separation from placebo at any of the time points. Amyloid PET measurements were also taken in both studies, and these plots show on the left EMERGE. The gray line is placebo, no change essentially from baseline to week 78. Whereas in the low and high dose, you see a dose and time-dependent reduction in the amyloid PET signal. With ENGAGE, you see a similar pattern with no change in placebo, but a dose and time-dependent reduction, which is statistically significant at all points in both the low and the high dose. Noticeably, the change from -- the difference from placebo in the high dose of ENGAGE is, however, lower than that we see in the EMERGE study. Looking back at the median cumulative dose in these PET subgroups, we also see that the median cumulative dose in the ENGAGE PET subgroup is 126 milligram per kilogram. Whereas in the EMERGE study, the median cumulative dose was 140 milligram per kilogram. And so we have a higher median cumulative dose in the EMERGE high dose substudy. CSF biomarkers of tau pathology and neurodegeneration were also assessed in both studies. On the left, with EMERGE, the assessment of phospho-tau, a specific marker of tau pathology in Alzheimer's disease, we see a dose-dependent and statistically significant reduction of phospho-tau in EMERGE. We see a similar pattern, a numerical dose dependency of total tau in EMERGE. However, this did not achieve statistical significance. When we look at ENGAGE, we don't see quite the same pattern. We see a statistically significant but not necessarily dose-dependent difference in phospho-tau with both low and high dose, having a magnitude of change similar to the low dose in EMERGE. And in total tau, we see a signal in low dose but no signal in high dose and no statistical significance. A small subgroup was conducted to assess the effects of aducanumab in EMERGE and ENGAGE on a tau PET measure using the tau PET ligand MK6240. 3 regions were prespecified, those were the medial temporal composite, temporal and frontal composite. And I'm showing the results of those here. Over time, there was a continued increase in the signal in the placebo individuals shown by the gray bars in each of the regions. And in each of the regions, you see an impact of the low and the high dose, which in the medial temporal composite achieved statistical significance at both doses. Whereas, in the temporal and frontal composite, the effect of aducanumab was only observed in the high dose. Here, I'm showing representative images of patients in the tau PET substudy. On the left, you see individuals in the placebo arm who had tau PET. And you can see at baseline, the signal of the tau PET ligand and a follow-up which was intended to be at week 78 but was on average at 14 months from baseline. You do see an increase in the signal in the same regions such as the anterior rhinal cortex or the temporal regions as in the baseline, but you also see an increase in spreading of that signal. Whereas in the aducanumab-treated subjects, here, looking only at the high dose groups, the signal in the follow-up tends to be reduced in those areas in which you -- in which it is present at the baseline, and you do not see any new areas really showing accumulation of tau pathology. Moving then to the safety summary. Here are the overall safety summary. And I'm showing the -- that there were essentially similar levels of AEs and SAEs across all dose arms. There were 16 deaths in the study, and those were also distributed across the arms. Looking adverse events with an incidence above 10%. Those included ARIA-E, headache, ARIA-H and nasopharyngitis. And with the exception of ARIA, the adverse events were those anticipated in this patient population or consistent with this patient population. And here, we can see the percent of ARIA-E is dose-dependent in both studies and is an average of 25% in the low dose and 35% in the high dose. Looking a little more closely at the incidence of ARIA. As we have shown previously, ARIA was increase in ApoE4 carriers versus noncarriers. The majority of individuals who had an experience of ARIA were asymptomatic with only 1/3 of individuals experiencing symptoms. The symptoms that were reported in patients with ARIA include headache, disease, visual disturbances, nausea and vomiting. The ARIA-E episodes generally resolved as measured by MRI within 4 to 16 weeks. And the majority of patients who experienced ARIA were able to continue their investigational treatment. To try and understand why the 2 studies had different outcomes, we looked to assess the impact of the change in the protocol that changed the dose for the ApoE4 carriers from 6 milligram to 10 milligram per kilogram. And we used the consent to the Protocol Version 4 as one way to identify individuals who had either the opportunity for all 14 doses of 10 milligram per kilogram, and that's the group that we are calling the post-PV4 population. These are patients who had -- who were selected to -- have consented to the protocol and had the full opportunity for all 14 doses of 10-milligram per kilogram, and this would enable us to assess the treatment effect in both studies under the intended dosing regimen. And it would also maintain the balance of ApoE4 carriers and noncarriers in this selected population, i.e. it preserved randomization to select a subgroup in this way. The post-PV4 population had a median cumulative dose at week 78 of 153 milligram per kilogram. Whereas in the pre-PV4 population, this included all ApoE4 carriers who did not consent to Protocol Version 4, and so they had 6-milligram per kilogram, but it also included ApoE4 noncarriers who did receive 10-milligram per kilogram, and ApoE4 carriers who had the opportunity for less than 14 doses of 10 milligram per kilogram. And the average dose -- sorry, the median cumulative dose in this population was 116 milligram per kilogram, so lower than the post-PV4 population. So to go back to the primary results, the primary endpoint for both EMERGE and ENGAGE, as I showed you earlier, and CDR sum of boxes in the high dose group was a 22% difference from placebo in EMERGE and a 2% difference in ENGAGE. If we now look at the post-PV4 population, we have a minus 30% effect in the post-PV4 population in CDR sum of boxes in EMERGE and a minus 27% difference from placebo in the ENGAGE population. So essentially, in EMERGE, the signal remains. Whereas in ENGAGE, there was no previous signal. However, when patients had the full opportunity for the 14 doses of 10 milligram per kilogram, we do identify a difference from placebo. And here are the line charts of those populations. So in summary, following study termination based on futility, there was an analysis of a larger dataset. In EMERGE, the high dose aducanumab reduced clinical decline as measured by both the primary and secondary endpoints. In ENGAGE, aducanumab did not reduce the clinical decline. However, in a post-hoc analysis, data from a subset of patients exposed to high-dose aducanumab support the positive findings of EMERGE. In substudies, aducanumab also showed an effect on disease-related biomarkers. The most common AEs in these studies were ARIA-E and headache. We are finalizing and implementing a redosing study with the aim to offer access to aducanumab for all eligible patients previously enrolled in the aducanumab clinical studies.