A Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Ambulatory and Non-Ambulatory Participants with Spinal Muscular Atrophy with Open-Label Extension (RESILIENT)

Taldefgrobep alfa is expected to preserve and improve muscle strength primarily
by increasing the size of existing muscle fibers.

Data from a first-in-human, combined single and multiple ascending dose
(SAD/MAD) study in normal healthy volunteers (NHVs) (CN001-001) indicate that
taldefgrobep alfa administered SC at single doses up to 180 mg, and multiple
doses up to 180 mg weekly (Q1W) and of 45 mg
every 2 weeks of are generally safe and well tolerated. Pharmacokinetic (PK)
data indicate that plasma concentrations of total taldefgrobep alfa (serum free
taldefgrobep alfa plus taldefgrobep alfa-myostatin complex) increase in a dose
related fashion. Similarly, the extent and duration of
serum free myostatin suppression increases in a dose related fashion. Treatment
with 5 weekly doses of 45 mg or more of taldefgrobep alfa was associated with
increases in thigh muscle volume and total lean body mass in NHVs.

Data from a Phase 1b/2 (CN001-006 [other study identifier WN40226]),
multi-site, randomized, placebo-controlled multiple ascending SC dose study to
evaluate the safety, tolerability and PK of taldefgrobep alfa in 43 ambulatory
boys (>=5 to <11 years of age) with DMD indicate that repeated dosing up to 35
mg or 50 mg (based on body weight) was generally safe and well tolerated in a
24-week double-blind phase and 48-week open-label phase. There was dose
dependent suppression of free serum myostatin from baseline and MRI and DXA
data was consistent with a positive beneficial effect on muscle health.

A Phase 2/3 (CN001-016 [other study identifier WN40227]) multi-center,
randomized, double-blind, placebo-controlled study was conducted to assess the
efficacy, safety and tolerability of two different weekly doses of taldefgrobep
alfa SC in ambulatory boys ( >=6 to <12 years of age) with DMD taking
corticosteroids (n=166). Taldefgrobep alfa was generally safe and
well-tolerated. A futility analysis based on the primary endpoint of the change
from baseline in the North Star Ambulatory Assessment (NSAA) Total Score at
Week 48, showed no notable treatment difference either between the pooled
treatment group or by assigned treatment (low or high dose) and placebo in the
intent to treat population. Thus, the study was terminated.

Based on the available nonclinical and clinical data, no special precautions
for taldefgrobep alfa use are indicated. Data from prior clinical studies
suggest that taldefgrobep alfa is generally safe and well tolerated. Potential
risks of taldefgrobep alfa are consistent with other biologics and include
hypersensitivity reactions and immunogenicity.

Current standard of care includes disease modifying therapies which increase
SMN protein production, thus improving survival, decreasing the need for
respiratory intervention, and significantly improving motor function. Despite
these treatments, a high unmet need for safe and effective treatments in SMA
remains, as many participants still experience significant weakness,
respiratory limitations and reduced levels of function.

Anti-myostatin agents have been tested in many neuromuscular syndromes and
diseases to enhance muscle size and performance. Although many of these studies
have failed to show clinically statistical significance, recent non-clinical
and clinical data have shown that preventing myostatin signalling can lead to
therapeutic potential in addressing muscle and bone deficiencies in SMA
participants.

Taldefgrobep alfa is a novel anti-myostatin that acts both by binding mature
myostatin dimer and also blocking he signaling of the ActIIRb pathway. The
probability of success is also improved with the introduction of SMN therapies
as standard of care, thereby enhancing the potential for a clinical benefit.

This study has been transitioned to CTIS with ID 2024-511852-42-00 check the CTIS register for the current data.

Primary Objective:
To evaluate the efficacy of taldefgrobep alfa in participants who are already
taking a stable dose of nusinersen or risdiplam or have a history of
onasemnogene abeparvovec-xioi, compared to placebo, measured by change in the
32 item Motor Function Measure (MFM-32) total score
between Baseline and Week 48.

Secondary Objectives:
To compare the efficacy of taldefgrobep alfa to placebo using the Revised Upper
Limb Module (RULM);
To compare the efficacy of taldefgrobep alfa to placebo using the Revised
Hammersmith Scale (RHS);
To assess the safety and tolerability of taldefgrobep alfa including change
from baseline in lean body mass and bone mineral density on DXA scan at Week
48, Tanner staging for puberty monitoring, new or worsening lab abnormalities,
injection acceptability assessment, treatment-related adverse events (AEs),
serious AEs, and AEs leading to discontinuation;
To assess pharmacokinetic (PK) parameters of taldefgrobep as estimated with
population PK
modeling.

Exploratory Objectives:
To evaluate change in time to run 10 meters as measured by RHS item 19,
comparing taldefgrobep alfa and placebo;
To evaluate change in time to rise from floor as measured by RHS item 25,
comparing taldefgrobep alfa and placebo;
To evaluate change from Baseline in number of WHO motor development milestones
attained;
To evaluate the participant quality of life using the proxy-reported SMAIS-ULM
total score comparing taldefgrobep alfa and placebo;
To evaluate the participant quality of life using the self-reported SMAIS-ULM
total score comparing taldefgrobep alfa and placebo (for participants age >=12);
To evaluate the caregiver quality of life using the ACEND caregiver-reported
total score comparing taldefgrobep alfa and placebo;
To evaluate the change in pulmonary function with % predicted forced vital
capacity (ppFVC), maximum inspiratory pressure (MIP), and maximum expiratory
pressure (MEP);
To evaluate change in lean body mass from baseline on DXA scan, comparing
taldefgrobep alfa and placebo;
To assess target engagement and other pharmacodynamic biomarkers;
To assess immunogenicity;
To assess the proportion of participants rated by clinician as improved in the
Clinician*s Global Impression of Change (CGI-C) scale comparing taldefgrobep
alfa and placebo;
To evaluate relationships between taldefgrobep drug exposure and efficacy and
safety
endpoints of interest, as warranted.

BHV2000-301 is a Phase 3, multicenter, randomized, double-blind,
placebo-controlled, 2 arm study designed to assess the efficacy and safety of
taldefgrobep alfa in study participants with SMA who are stable on standard of
care therapy including risdiplam, nusinersen, or who have a history of
treatment with onasemnogene abeparvovec-xioi. Eligible participants will have
the opportunity to continue in a 48-week open-label extension (OLE) phase.

Per the protocol, study participants who complete the 48 week Double-blind
phase have the option to participate in the 48 week Open Label Extension phase
of the study to receive taldefgrobep alfa. A plan to provide taldefgrobep alfa
to participants following their completion of the 48 week Open Label Extension
is not currently in place, although Biohaven recognizes that this is
important. As the study progresses, Biohaven will explore and review potential
options and consider an optimal plan for continuation of taldefgrobep alfa to
those participants who complete the 48-week Open Label Extension and are
determined by the Investigator to be receiving a benefit.

A 1-weekly subcutaneous injection of Aldefgrobep Alfa (35 or 50 mg in 0,7 ml,
based on subject's weight) or placebo (0,7 ml) for the duration of 48 weeks.
Eligible participants will have the opportunity to continue in a 48-week
open-label extension (OLE) phase (1-weekly subcutaneous injection of
Aldefgrobep Alfa, 35 or 50 mg in 0,7 ml, based on subject's weight).

Taldefgrobep alfa is a novel myostatin antagonist that is being developed as a
therapeutic to increase muscle mass and strength. The active study drug may
help to relieve SMA symptoms.

Burden - Subjects will undergo the following tests/assessments:
(Standard) Physical Examination and physical measurements (height, weight,
temperature, blood pressure, heart rate): 6 times (double-blinded phase), 4
times (open-label extension phase);
Venapunction: 6 times (double-blinded phase), 4 times (open-label extension
phase);
Subcutaneous injection (IP): 47 times in double-blinded phase and 47 times in
open-label extension phase;
DXA scan: 3 times in double-blind phase;
12-lead ECG: 3 times (double-blinded phase), 1 time (open-label extension
phase);
Pregnancy test: Monthly home tests (urine) as appropriate and 6 times on site
(double-blinded phase) and 4 times during open-label extension phase;
Pubertal status will be assessed (for both male and female participants)
according to Tanner staging at Baseline and at least every 12 months until the
end of the study participant*s participation in the trial or until the study
participant reaches Tanner stage V (whichever comes first). Self-reported
Tanner staging or records from pediatric assessments in standard of care
settings are acceptable;
Columbia-Suicide Severity Rating Scale (from the age of 6): 6 times
(double-blinded phase), 4 times (open-label extension phase);
Efficacy Assessments (MFM-32, RULM, RHS, WHO developmental milestones): 6 times
(double-blinded phase), 2 times open-label extension phase;
Efficacy Assessments (SMAIS-ULM, Spirometry, ACEND): 3 times (double-blinded
phase), 1 time (open-label extension phase);
CGI-C: 2 times (double-blinded phase), 1 time (open-label extension phase).

Risks/burden related to study treatment:
Prior to the start of this clinical study, a total of 359 participants had
received taldefgrobep alfa, including 179 healthy participants and 180 boys
with Duchenne Muscular Dystrophy (DMD) and has been generally well tolerated.
For additional information, please see the current Investigator Brochure.

The side effects reported in completed studies are listed below by how often
they occurred.
Among healthy adult humans who received taldefgrobep alfa administered
subcutaneously (SC) at single doses up to 180 mg, and multiple doses up to 180
mg weekly and of 45 mg every 2 weeks, the most common side effects were mild
injection site redness and rash. These adverse events did not require stopping
of study drug and were not accompanied by systemic signs or symptoms, such as
fever or high levels of white blood cells (eosinophilia).

In a clinical trial in boys with DMD 5 to 11 years old on taldefgrobep alfa
doses up to 35 mg or 50 mg (based on body weight) once weekly, the following
side effects were seen in those receiving taldefgrobep alfa:

Very common (may affect more than 1 in 10 people, 10%):
• Vomiting (37.2%)
• Swelling of the nose and throat (37.2%)
• Headache (37.2%)
• Upper respiratory tract infection (34.9%)
• Fall (32.6%)
• Fever (30.2%)
• Diarrhea (30.2%)
• Cough (30.2%)
• Injection site bruising (27.9%)
• Injection site inflammation with rash (erythema) (27.9%)
• Injection site redness (27.9%)
• Pain in extremity limb (20.9%)
• Nasal congestion (20.9%)

The most frequently reported side effects thought to be related to study drug
treatment were:

Common (may affect up to 1 in 10 people, 10%):
• Injection site rash (7.0%)
• Injection site pain (7.0%)
• Injection site bleeding (4.7%)
• Injection site reaction (4.7%)
• Flushing (4.7%)
• Injection site discomfort (2.3%)
• Injection site itchiness (2.3%)
• Injection site swelling (2.3%)
• Strep throat (2.3%)
• Headache (2.3%)

In a clinical trial in boys with DMD 6-12 years old on taldefgrobep alfa low
dose (7.5mg or 15mg) or high dose (35mg or 50mg) based on weight, once weekly,
the following side effects were seen (see below):

The most frequently reported side effects thought to be related to study drug
treatment were:
Very common (may affect more than 1 in 10 people) by taldefgrobep alfa low and
high dose groups:
• Nasopharyngitis (swelling of the nose and throat)
• Injection site erythema (redness)
• Headache
• Fever
• Cough
• Vomiting
• Arthralgia (joint pain)
• Back pain
• Upper respiratory tract infection
• Extremity pain
• Rash
• Upper abdominal pain
• Nausea
• Nosebleeds

Common (may affect up to 1 in 10 people, 10%) by taldefgrobep alfa subdivided
into low and high dose groups:
• Back pain (4.4% high dose)
• Upper respiratory tract infection (7.2% low dose)
• Extremity pain (7.2% low dose)
• Rash (7.2% low dose)
• Upper abdominal pain (7.2% low dose)
• Nausea (2.9% low dose)
• Nosebleeds (4.3% low dose)

Studies have shown that there may be a small decrease of immunization
effectiveness while taking Taldefgrobep alfa, but this is a small decrease and
not expected.

Allergic reaction risks:
There is a small but real risk of allergic reactions that can be
life-threatening or fatal.

Risks/burden related to study procedures:
Subcutaneous Injection of Study drug/Placebo - Local pain, bruising, bleeding,
blood clot formation, a rash and in rare instances an infection might occur at
the site of injection. There is also the possibility of dizziness or fainting
while being injected.
Blood Draw - Local pain, bruising, bleeding, blood clot formation, and in rare
instances an infection might occur at the site of the needle stick where blood
is drawn. There is also the possibility of dizziness or fainting while blood is
being drawn.
Electrocardiogram (ECG) - The ECG procedure may cause minimal discomfort during
the attachment and removal of the ECG leads to and from the skin (skin
irritation from the electrode adhesive or develop contact dermatitis)
DXA Scan - The DXA scan may cause discomfort as the subject will need to be
still and may have to hold their breath for a few seconds.
In the DXA exam a small amount of radiation will be used. The amount of
radiation (energy) is very small -- less than one tenth the dose of a chest
x-ray, and less than a day*s exposure to natural radiation. It is not dangerous
if the subject have to have an examination or treatment with radiation for a
medical reason.

Benefit and group relatedness:
SMA is an inherited neuromuscular disease characterized by muscle atrophy due
to degeneration of lower motor neurons. The primary symptom is severe muscle
weakness. Medications recently approved for certain subsets of SMA patients
target the Survival Motor Neuron 1 (SMN1) gene
and SMN2 transcript and may help to preserve motor neurons. However, despite
the availability of these SOC medications, SMA remains a progressive and
debilitating condition. No treatment that specifically targets muscle weakness
is currently available. Taldefgrobep alfa is a novel
myostatin antagonist that is being developed as a therapeutic to increase
muscle mass and strength. The high unmet need for treatments for SMA, together
with the available preclinical and clinical data with taldefgrobep alfa,
provide a compelling and favorable overall benefit-risk assessment for the
development of taldefgrobep alfa as a treatment for SMA. The safety monitoring
in the planned clinical study will minimize the potential risks to study
participants. It is crucial to develop treatment to prevent (further) increase
of muscle atrophy as quickly as possible. The study population represents the
future target group.