A randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and effects on heterotopic bone formation of REGN2477 in patients with Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressive (FOP) is a devastating ultra-rare
autosomal dominant genetic disease for which there is no effective treatment
currently. It is caused by mutations in the ACVR1 gene (also known as ALK2,
Shore 2006). Preclinical data generated at Regeneron Pharmaceuticals, Inc.
(Regeneron) provide strong rationale for evaluating REGN2477, an anti activin A
antibody, for the treatment of this disease.

The FOP disease is characterized by childhood onset and life-long episodic and
progressive heterotopic ossification (HO) in soft tissues, which can lead to
joint immobility, skeletal deformity, and severe disability. Early mortality
is common, often in the fifth decade, principally due to cardiorespiratory
failure from thoracic insufficiency syndrome. Disease flare-up episodes, often
reported by patients as acute onset of painful or non-painful soft tissue
swelling, joint stiffness, or loss of joint mobility, are not predictable in
their occurrence, are variable in severity and duration (from days to many
months), and do not always result in HO (Pignolo 2016, Kaplan 2016). Pain
associated with FOP disease activity may be severe and even refractory to
opioid analgesics. Heterotopic bone formation and disability may develop
insidiously without acute flare-up symptoms (Pignolo 2016). Bone scintigraphy
and the more sensitive and specific 18F-NaF PET method readily detect multiple
focal HO lesions with abnormally high uptake of bone homing tracers in body
regions where patients with FOP report experiencing flare-up symptoms and in
regions without symptoms (Fang 1986, Herford 2003, Trikha 2005, Tulchinsky
2007, Eekhoff 2016). There are currently no effective treatments to prevent or
inhibit HO in patients with FOP. Surgical attempts to remove the heterotopic
bone in patients with FOP result in more aggressive episodes of HO and are
rarely conducted. Disease flare-ups are typically treated with high doses of
glucocorticoids or non-steroidal anti inflammatory medications, however, these
agents have not been shown to affect the course of HO.

Regeneron has developed a murine model of FOP that conditionally expresses the
most common mutation variant of ACVR1, ACVR1[R206H], which is seen in patients
with FOP, and recreates key features of the human disease. This animal model
displays heterotopic bone formation in soft tissues, spontaneously or following
tissue injury, and exacerbation following surgical resection of bony lesions.
In this model, blockade of activin A by REGN2477 not only prevented the onset
of HO if given prophylactically prior to induction of HO, but also halted the
progression of pre-existing HO if given as a treatment after HO has been
induced (Hatsell 2015, see IB). Recent in vitro studies demonstrated that
different mutations in the ACVR1 receptor transduced BMP signaling when
stimulated with activin A (Hino 2015). These data indicate that REGN2477 may
suppress HO for patients with FOP who have ACVR1 mutations other than
ACVR1[R206H]. Taken together, these results suggest that REGN2477 may provide
beneficial clinical impact on HO in patients with FOP, irrespective of the
underlying ACVR1 mutation. Preclinical imaging data support the use of both
18F-NaF PET and CT to follow disease progression and treatment.

The LUMINA-1 study is currently ongoing, and all patients have completed Period
1 (double-blind, placebo-controlled period). The study database for the
analysis of Period 1 was locked (19 Nov 2019 for clinical results and 13 Dec
2019 for imaging results). The results of the primary efficacy and safety
analysis for Period 1, after adult patients received 7 monthly infusions of
either REGN2477 or placebo with at least 28 weeks of follow-up, showed that
REGN2477 reduced average total lesion activity (by 18F-NaF PET) from baseline
over 28 weeks by approximately 25% (LS mean difference) compared to placebo
(p=0.0741; see IB for details). Correspondingly, there was an approximate 25%
(LS mean difference) decrease in bone lesion volume (both new and existing
lesions) compared to placebo as measured by CT (p=0.373). These results were
largely driven by marked decreases of nearly 90% in the incidence of new
lesions irrespective of imaging modality (p<0.01). The percent of patients who
developed 1 or more new HO lesions as assessed by PET was lower in the REGN2477
treatment group (3 of 20 patients [15%]) as compared to placebo (11 of 24
patients [45.8%]) through week 28 (prespecified p=0.050). Similarly, the
percent of patients who developed new HO lesions as assessed by CT was again
lower in the REGN2477 treatment group (3 of 20 patients [15%]) compared to
placebo (11 of 24 patients [45.8%]) through week 28 (post-hoc p=0.050). The
identification of lesions as "new" versus "existing" at baseline was specified
in the imaging charter. Taken together, these results indicate that while
REGN2477 has a relatively modest treatment effect on the attenuation of
existing lesions, there was a large effect preventing the occurrence of new
lesions.

In addition, an analysis to compare low-dose CT-only and PET/CT reads on new HO
lesions from the LUMINA-1 study was performed by the Sponsor. Low-dose CT-only
reads (ie, in the absence of PET scan) were performed by 2 new independent
blind readers and a new blinded adjudicator. The readers and adjudicator
assessments were entered into a separate electronic data capture (EDC) system.
The CT-only reads and lesion quantification were carried out following the same
procedures described in the Imaging Review Charter.

This analysis to compare the performance between PET/CT and low-dose CT-only
showed there was no marked difference detected in the performance between
PET/CT and CT reads (p=0.75). Specifically, the CT-only reading methodology
reconfirmed the REGN2477 treatment effects on number or percentage of patients
with new lesions, total number of new lesions, and volume of new lesions seen
by the primary PET/CT reading methodology. Thirty-eight new lesions were
identified by the CT-only reads and 30 new lesions were identified by the
PET/CT reads. Only 1 lesion out of 38 new lesions identified by the CT-only
reads was in REGN2477 group, and 3 out of 30 new lesions identified by the
PET/CT reads were in REGN2477 group.

Additional to the data indicating that activin A mostly serves to initiate the
biologic events that ultimate result in heterotopic bone formation, the
incidence of patient-reported flare ups was also reduced by 50% (prespecified
p=0.032), while investigator-reported AEs of flare ups were 10% for REGN2477
and 42% for placebo (post-hoc p=0.039). A favorable trend for reduced daily
average pain as measured by NRS was seen in the REGN2477 groups compared to
placebo.

These data have prompted the definition of separate study hypotheses for the
open-label treatment period (week 28 to week 56; Section 3.2) and addition of
endpoints consistent with these hypotheses to confirm the efficacy of REGN2477
in preventing the formation of new HO and reducing flare-ups (Section 4.3).

Further details of REGN2477 clinical data and preclinical data to support
clinical development may be found in the IB.

Primary Objective:
The primary safety objective of the study is to assess the safety and
tolerability of REGN2477 in male and female patients with fibrodysplasia
ossificans progressiva (FOP).

The primary efficacy objective of the study is to assess the effect of REGN2477
versus placebo on the change from baseline in heterotopic ossification (HO) in
patients with FOP, as determined by 18-NaF uptake in HO lesions by positron
emission tomography (PET) and in total volume of HO lesions by computed
tomography (CT).

Secondary Objectives:
The secondary objectives of the study are:
- To compare the effect of REGN2477 versus placebo on pain due to FOP, as
measured by the area under the curve (AUC) for pain based on daily numeric
rating scale (NRS) scores
- To assess the effect of REGN2477 versus placebo on the change from baseline
in HO, as determined by the number of new HO lesions identified by 18F-NaF PET
or by CT
- To assess the effect of REGN2477 versus placebo on the change from baseline
in 18F-NaF standardized uptake value maximum (SUVmax) of individual active HO
site(s) by PET
- To assess the effect of REGN2477, between week 28 and week 56, on the number,
activity, and volume of HO lesions identified by 18F-NaF PET or by CT in
patients who switch from placebo to REGN2477 at week 28 versus the same
patients between baseline and week 28
- To assess the effect of REGN2477 versus placebo on the change from baseline
in biochemical markers of bone formation
- To characterize the concentration of total activin A at baseline and over
time following the first dose of study drug
- To characterize the concentration-time profile (pharmacokinetics [PK]) of
REGN2477 in patients with FOP
- To assess the immunogenicity of REGN2477

This is a phase 2, randomized, placebo-controlled, 2-period study designed to
evaluate the safety, tolerability, PK, and effects on heterotopic bone
formation of repeated doses of 10 mg/kg REGN2477 administered intravenously
(IV), every 4 weeks (Q4W) in adult patients with FOP. Up to 40 patients with
FOP disease activity may be enrolled at multiple sites globally to yield
approximately 24 or more patients with the classic type I activin A receptor
with a R206H mutation (ACVR1[R206H]) and active HO at baseline as determined by
18F-NaF PET/CT.

This study consists of a screening/baseline period (day -28 to day -1), 2
treatment periods, and a follow up treatment period. The 3 treatment periods
are:
- Period 1: a 6-month randomized double blind placebo-controlled treatment
period
- Period 2: a 6-month open-label REGN2477 treatment period
- Period 3: a follow-up treatment period with REGN2477 continuing until
patients have completed the week 76 visit, and all data have been collected and
validated through the time when the last patient randomized into the study
completes the week 28 visit (Period 1), and results of the primary analyses of
safety and efficacy are available to the sponsor.

Patients who meet initial eligibility screening will have baseline procedures
conducted.

In light of the public health emergency related to the COVID-19 pandemic, the
continuity of clinical study conduct and oversight may require implementation
of temporary or alternative mechanisms. Examples of alternative mechanisms may
include, but are not limited to, any of the following: phone contact, virtual
visits, telemedicine visits, online meetings, non-invasive remote monitoring
devices, use of local clinic or laboratory locations, and home visits by
skilled staff. All temporary mechanisms utilized, and deviations from planned
study procedures in response to COVID-19 are to be documented as being related
to COVID-19 and will remain in effect only for the duration of the public
health emergency and/or until the COVID-19 pandemic is deemed manageable and no
longer interfering with the conduct of trials at individual sites.

During Period 1, patients will be randomized to receive REGN2477 at 10 mg/kg
dose or matching placebo, administered IV Q4W through week 24, for a total of 7
doses. Randomization will be stratified by gender, by classic ACVR1[R206H]
mutation/different ACVR1 mutations, and by presence/absence of baseline active
HO lesions as determined by 18F-NaF PET/CT. Index HO lesion identified at
baseline and new HO lesions will be assessed by imaging endpoint measures
including whole body 18F-NaF PET and whole body low dose CT at week 8 (day 57
[± 7 days]), and week 28 (day 197 [± 7 days]). Serum samples for the
determination of REGN2477 concentrations and anti-drug antibody (ADA) will be
collected.

To ensure safety, individual patients will be closely monitored and safety of
each dose of study drug will be reviewed by the investigator and Regeneron
medical monitor prior to administering the subsequent repeated dose. The safety
review to be conducted by the investigator and Regeneron medical monitor prior
to study drug infusions on visits 2, 5, 6 and 7 (Period 1) and visits 11, 12,
13 and 14 (Period 2) will include evaluation of laboratory test (hematology,
blood chemistry and urinalysis) results collected as part of these visits. For
the remaining study visits, assessment of results of hematology, blood
chemistry and urinalysis tests planned for these same visits may be performed,
but will not be required prior to study drug infusion. The decision not to wait
for the results of these exams, processed at the study*s central laboratory,
should be made on a case-by-case basis, if the patient*s clinical condition,
adverse event profile, and assessment of vital signs, ECGs and previous
laboratory test results indicate that the patient is suitable to receive the
next dose of study drug. For the study visits after week 56 (Period 3), the
need for a safety review by the investigator and Regeneron medical monitor will
be decided on a case-by-case basis. In addition, the Independent Data
Monitoring Committee (IDMC) will regularly monitor the unblinded safety data.
In the event that a significant tolerability issue or safety concern is
identified, dose modification or study drug discontinuation may be implemented.

All patients who complete the Period 1 double-blind treatment will receive
REGN2477 open-label in Period 2, administered IV at a dose of 10 mg/kg Q4W
through week 52, for a total of 7 doses. For patients previously treated with
placebo drug, week 28 (day 197) assessments will be considered as pretreatment
baseline for safety and efficacy analysis of this period of the study. Serum
samples for the determination of REGN2477 concentrations and ADA will be
collected.

Index HO lesion identified at baseline and new HO lesions will be assessed by
imaging endpoint measures including whole body 18F-NaF PET and whole body low
dose CT at week 56 (day 393 [± 7 days]), and at week 76 (day 533 [.± 7 days]).

In light of the public health emergency related to the COVID-19 pandemic,
Investigators may perform study visit 18 (week 56) imaging exam employing only
whole body low-dose CT scans. Assessment of imaging endpoints without the PET
scan may be implemented to mitigate the delay to acquire images due to the
inaccessibility to PET/CT imaging centers and/or unavailability of the 18F-NaF
tracer. In addition, the timing for study visit 18 (week 56) is flexible as
long as any changes are documented. This low-dose CT scan may be performed by
trained staff either at study site or at other clinical sites with access to a
qualified CT scanner or using a mobile qualified CT scanner at a local
community healthcare setting close to patient or at a home visit, contingent
upon prior concurrence and approval from the Investigator and Regeneron medical
director.

Individual patient dose modification will be determined on a case-by-case basis
as described in the protocol. Study level dose modification will be determined
by the sponsor upon recommendation of the IDMC following their review of
safety, PK, and total activin A (target engagement) data available at the
time.

During the follow-up treatment period with REGN2477 (Period 3), from week 56
until the end of study, efficacy and safety procedures will be performed, and
serum samples for the determination of REGN2477 concentrations and ADA will be
collected. Each patient will continue to receive REGN2477, provided that no
safety signals are identified during continuous monitoring of the study by the
investigator, medical monitor and IDMC. In addition, during this period, all
patients will be required to maintain contraception.

REGN2477 10 mg/kg, administered IV Q4W or REGN2477-matching placebo,
administered IV Q4W

Please refer to appendix C of the subject information sheet for an overview of
the side effects and possible risks of the study.