Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 (aducanumab) in Subjects With Alzheimer*s Disease Who Had Previously Participated in the Aducanumab Studies 221AD103, 221AD301, 221AD302 and 221AD205

Alzheimer*s disease (AD) is the most common cause of dementia, accounting for
50% to 75% of all cases. Alzheimer*s Disease International estimates that as of
2016, there were 47 million people living with dementia worldwide, and that
this figure will increase to 131 million by 2050.

One of the most important features of AD is that a substance called amyloid
beta (a protein) is found at an elevated level in the brain. These deposits of
amyloid beta are known as plaques. It is assumed that these plaques disturb the
normal activity of the brain cells and worsen the symptoms of the disease.

The study drug, aducanumab, is an antibody therapy. Antibodies are part of the
immune system. They are produced naturally by the immune system, and they
detect and remove substances in the body that do not belong there. Antibodies
can also be produced in the laboratory. In this way, very specific antibodies
can be produced, which bind to a harmful substance in the body to remove it. It
is assumed that the study drug can fight and remove plaques in the brain of
people with early stage AD. It is presumed that, in response to this, the
deterioration of the AD can be slowed down.

In March 2019, an early review of the results from half of the participants of
the ENGAGE and EMERGE studies showed that treatment with the study drug may not
work as well as expected for participants with AD. As a result, Biogen decided
to stop all the ongoing aducanumab studies on March 21, 2019. To better
understand why this was observed, Biogen carried out additional reviews and
analyses of the results from a higher number of participants obtained before
the stopping of the trials. The new results showed that, in the EMERGE study,
the group of participants who received the high dose of aducanumab (10 mg/kg)
experienced benefits on the measures of cognition and function, such as memory,
orientation, and language, compared to the group treated with placebo. In
addition, they experienced benefits with daily activities, such as conducting
personal finances, performing household chores of cleaning, shopping, and doing
laundry, and independently traveling out of the home. In the ENGAGE study,
although the new analyses did not show the same results for the whole group of
participants who received the high dose aducanumab (10 mg/kg), the new analyses
showed that participants who received 10 mg/kg in a sustained manner had
similar benefits as in EMERGE.

Primary objective:
To evaluate the safety and tolerability of aducanumab over 100 weeks of
treatment after a wash-out period imposed by discontinuation of feeder studies
in participants who had previously received aducanumab (i.e., previously
treated participants) or who had previously received placebo (i.e.,
treatment-naïve participants).

Exploratory objectives:
1. To evaluate the long-term efficacy of aducanumab using clinical endpoints.
2. To evaluate the long-term effect of aducanumab on biomarker endpoints.
3. To evaluate the long-term effect of aducanumab on PK endpoints.

Your participation will last about 3.5 years and will consist of 4 main periods:
- The screening period lasts approximately 12 weeks
- The core treatment period, in which you receive the study drug, lasts 100
weeks
- The optional long-term extension treatment period. If you decide to
participate you will receive the study drug for another 52 weeks
- A follow-up period, in which you no longer receive the study drug, lasts for
18 weeks.

After a Screening Period, participants who meet the eligibility criteria will
receive open-label treatment. During the Treatment Period, participants will
receive IV infusions of aducanumab approximately every 4 weeks for a total
treatment duration of 100 weeks (a total of 26 doses). Eligible participants
will then enter the LTE Treatment Period and continue dosing on 10 mg/kg
aducanumab Q4W for an additional 52 weeks (a total of 152 weeks of continuous
treatment). The EOT Visit will occur at Week 154. Participants will have a
safety follow up visit 18 weeks after their last dose of study treatment. For
participants who do not enter the LTE, this FU visit will occur at Week 118.

In the core treatment period, the subject will receive the study drug as an
infusion through a vein once a month (every 4 weeks) for about 2 years.
Subjects will receive 26 infusions and each infusion will last about 1 hour.
During the LTE Treatment Period subjects will receive the study drugs for
another 52 weeks (an additional 13 doses).

As this is an open-label study the subject and the investigator will know which
dose you are receiving. Subjects will receive the study drug Aducanumab at
increasing doses as follows:
o Infusions 1 and 2 (Weeks 1 and 4): 1 mg/kg
o Infusions 3 and 4 (Weeks 8 and 12): 3 mg/kg
o Infusions 5 and 6 (Weeks 16 and 20): 6 mg/kg
o Infusions 7 to 39 (once every 4 weeks during Weeks 24-100): 10 mg/kg

There are currently no available therapies that modify the clinical course of
Alzheimer*s disease. Analyses of data collected through the end of the study
(Study 301 database lock on 15 Novebmer 2019 and Study 302 database lock on 13
November 2019, with efficacy data after 20 March 2019 censored) in the 2 Phase
3 aducanumab clinical studies showed that, in Study 302, treatment with
aducanumab significantly reduced clinical decline in patients with early
Alzheimer*s disease as measured by the prespecified primary (CDR-SB) and by the
3 secondary endpoints (ADAS-Cog 13, MMSE and ADCS-ADL-MCI) in the high-dose
group. In addition, Study 301 contained supportive data, based on post-hoc
analyses of subsets of participants who received sufficient exposure to the
highest dose (10 mg/kg) of aducanumab.

As of 01 April 2019, an estimated 3075 participants have been exposed to
aducanumab. These include 2755 Aducanumab-treated subjects from Studies 301 and
302, of whom 1345 were assigned to a target dose of 10 mg/kg. The most frequent
adverse event, among subjects from Studies 301 and 302 with a target dose of 10
mg/kg, was ARIA-E (32.9%). The majority of participants who experienced ARIA-E
did not experience symptoms during an ARIA-E episode. Symptoms reported during
ARIA-E episodes included headache, confusion, dizziness, fatigue, nausea, or
rarely seizures, including prolonged seizures. Such symptoms typically resolved
and were generally not associated with long-term clinical sequelae. Other
frequent adverse events, among subjects from Studies 301 and 302 with a target
dose of 10 mg/kg, included headache (18.7%), ARIA-H microhemorrhage (17.0%) and
ARIA-H superficial siderosis of the central nervous system (13.8%). Similar to
ARIA-E, the majority of participants with ARIA-H microhemorrhage and
ARIA-H superficial siderosis were asymptomatic. The benefit-risk profile of
aducanumab is considered positive.