A Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of intravenous efzofitimod in patients with pulmonary sarcoidosis

Efzofitimod is being evaluated in a double-blind, randomized,
placebo-controlled (3 mg/kg: 5 mg/kg: placebo in a 1:1:1 ratio) trial in
patients with pulmonary sarcoidosis over a 48-week treatment period (Figure 1).
The primary objective of the study is efficacy, with safety and tolerability
being secondary objectives (Section 5). The primary efficacy parameter is
average daily steroid dose with other key efficacy parameters being FVC and QoL
parameters. These parameters are consistent with treatment goals in standard
guidelines for sarcoidosis (Baughman et al, 2021b).
Figure 1: Study Schema

OCS = oral corticosteroids.
Consistent with the steroid sparing nature of the primary efficacy parameter, a
mandatory steroid taper forms one of the key elements of the study design. The
extent to which steroids may be tapered is a function of the steroid dose at
baseline and the use of concomitant immunosuppressant therapy. Randomization is
therefore stratified based on the OCS dose at baseline (< 10 mg/day versus >= 10
mg/day [prednisone or equivalent]) and the presence or absence of concomitant
immunosuppressant therapy.
The study population comprises patients with pulmonary sarcoidosis who have
chronic, symptomatic disease requiring continuous steroids with or without
immunosuppressive agents. This study will enroll patients on stable steroids of
>= 7.5 mg/day to <= 25 mg/day of prednisone equivalent. This allows for a patient
population that will benefit most from a steroid taper. Regardless of their
ability to achieve the protocol-directed OCS taper, patients will continue to
receive blinded study drug and be followed through to the end of the study.
Patients who are significantly symptomatic, as defined by a KSQ-Lung score <= 70
and a modified Medical Research Council (MRC) Dyspnea score of >= 1 will be
included in the study. Patients with less severe symptoms, who may achieve
disease remission with existing therapies are not included in the study.
The effect of efzofitimod in reversing established fibrosis is unknown.
Therefore, the study population will exclude patients with significant fibrotic
disease (> 20% fibrosis on computed tomography [CT]) or with significant
pulmonary disease potentially suggestive of fibrosis: an FVC percent predicted
of < 50% or KSQ-Lung score < 30.
Patients with comorbidities that may confound assessment of efficacy such as
pulmonary complications (eg, mycetoma, significant bronchiectasis and pulmonary
hypertension) and concomitant medications (recent use of biologic
immunomodulators) are excluded from the study. Since protocol-mandated steroid
taper is a key design element, patients who cannot undergo taper (eg, due to
Addisonian symptoms on previous taper) are also excluded.
The treatment duration is 48 weeks. This is considered adequate for a chronic
condition like sarcoidosis and is also consistent with the 48- to 52-week
treatment period for other interstitial lung diseases (King et al, 2014;
Richeldi et al, 2014).

This study has been transitioned to CTIS with ID 2023-506039-13-00 check the CTIS register for the current data.

OBJECTIVES

Primary Objective
• To assess the efficacy of efzofitimod in patients with pulmonary sarcoidosis

Secondary Objectives
• To assess the safety and tolerability of efzofitimod in patients with
pulmonary sarcoidosis

Exploratory Objectives
• To explore the utility of serum biomarkers in evaluation of interventions to
treat pulmonary sarcoidosis

Methodology:
This is a multicenter, randomized, double-blind, placebo-controlled, study
comparing the efficacy and safety of intravenous (IV) efzofitimod 3 mg/kg and 5
mg/kg versus placebo after 48 weeks of treatment.
This study will enroll adults with histologically confirmed pulmonary
sarcoidosis receiving stable treatment with oral corticosteroids (OCS), with or
without immunosuppressant therapy.
After the initial screening period (up to 4 weeks), eligible patients will be
randomized 1:1:1 to efzofitimod 3 mg/kg, efzofitimod 5 mg/kg, or placebo.
Randomization will be stratified by the presence or absence of concomitant
immunosuppressant therapy and OCS dose at baseline (< 10 mg/day versus >= 10
mg/day [prednisone or equivalent]).
During the treatment period (48 weeks), study drug will be administered as IV
infusion every 4 weeks for a total of 12 doses.
Starting on Day 15, patients will begin a protocol-directed OCS taper from a
starting dose of >= 7.5 mg/day to <= 25 mg/day of prednisone (or equivalent),
such that OCS are weaned off completely (0 mg/day) on or before Day 85 (Section
6.2.1.). The goal is to maintain patients without OCS after the taper until the
end of study. Patients who are unable to tolerate the OCS taper may receive
rescue treatment with higher OCS doses as outlined in the OCS Taper Guidelines
(Section 6.2.1.). Regardless of their ability to achieve the protocol-directed
OCS taper, patients will continue to receive blinded study drug and be followed
through to the end of the study.
Treatment with 1 oral immunosuppressant therapy at a stable dose for >= 4 weeks
prior to Day 1 is allowed, but not required. The dose should remain stable
during the study. Allowed immunosuppressants include, but are not limited to
methotrexate, azathioprine, and leflunomide. Treatment with an immunomodulator,
e.g. hydroxychloroquine is allowed in addition to treatment with 1 oral
immunosuppressant.
During the treatment period, efficacy assessments include OCS dosing
information, pulmonary function tests (primarily forced vital capacity [FVC]),
and patient-reported outcomes (King's Sarcoidosis Questionnaire [KSQ],
Leicester Cough Questionnaire [LCQ] Fatigue Assessment Scale [FAS], and Patient
Global Assessment [PGA]).
Safety will be evaluated based on adverse events (AEs), laboratory evaluations,
vital signs, and electrocardiograms (ECGs). Blood samples for the analysis of
serum efzofitimod concentrations and anti-drug antibodies will also be
collected for the assessment of immunogenicity. Infusion-related reactions,
immunogenicity, and malignancy will be evaluated as adverse events of special
interest (AESI).
Ongoing review of blinded safety and tolerability data will be performed by the
Medical Monitor and Sponsor personnel.
In addition, an external independent Data Safety Monitoring Board (DSMB) will
perform interim reviews of unblinded safety, tolerability, and immunogenicity
data and ad hoc per Sponsor request if a pattern of unexpected, clinically
significant trends or changes in other safety assessments is identified through
blinded safety data reviews. The DSMB will provide its recommendation to the
Sponsor, which may include stopping the study if required, or continuing the
study with modifications to gain more information on the safety and
tolerability of efzofitimod in patients with pulmonary sarcoidosis.
Patients will be followed after Week 48 for an additional 4 weeks.

This is a placebo-controlled, randomized, double-blind study. These terms are
explained below. Approximately 264 subjects with pulmonary sarcoidosis will
participate in this global study at up to 80 clinical sites. The study includes
3 treatment groups: 2 groups with different doses of efzofitimod and 1 group
with placebo. You will only be in one group during the study.

For this study, we will have 3 groups:
• Group 1. The people in this group will get the study drug, dose 3.0 mg/kg of
your body weight.
• Group 2. The people in this group will get the study drug, dose 5.0 mg/kg of
your body weight.
• Group 3. The people in this group will get the placebo.

You will receive intravenous (IV) infusions (delivery of medication using a
catheter inserted using a needle into your vein) of the study drug or placebo
over about 60 minutes, every 4 weeks, for a total of 12 doses

For the study, there is then a 48-week treatment period during which you will
receive the study drug once a month. You will be monitored during each infusion
of the study drug.
The clinic visits where an infusion is administered (Visit 1 through 12) may
take approximately 4 hours, while Visit 13 and end of study visit may take
approximately 2 hours. You may have up to a total of 15 clinic visits and
telephone contacts during the treatment period. The telephone contacts may take
approximately 15 minutes and will occur between clinic visits to see how you
are doing.

Finally, there will be a follow-up period when you will no longer receive study
drug; during this period, you will come back to the clinic for an End of
Treatment (EOT) Visit (Visit 13) 4 weeks after your last dose and again for an
(End of Study) EOS Visit 8 weeks after your last dose so that your study doctor
can check your health.

You may be asked to come back to the clinic or contacted by phone for follow-up
on any adverse events (side effects) that may have occurred or to obtain
additional blood testing.

Risk Benefit (Page 25 of protocol)
From limited clinical data, there are no expected toxicities for efzofitimod.
Potential toxicities were identified based on a review of the primary target
(NRP2), absence of a secondary target (NRP2 was found to be the sole binding
partner for efzofitimod identified from a screen of > 4500 cell surface
receptors including NRP1), biological nature of drug (fusion protein),
nonclinical studies (NOAEL was highest dose tested, no embryo-fetal toxicity),
and the intravenous route of administration. Based on this review, the
potential toxicities are infusion-related reactions (IRRs) and immunogenicity
(development of ADAs, Jo-1 antibodies).
Subjects with an IRR will be closely monitored for as long as medically
indicated. If symptoms constitute cardiorespiratory events, vital signs, pulse
oximetry, electrocardiogram (ECG), and infusion site examination will be
performed to monitor and manage the patient as medically indicated (see Section
8.4.1 on management of IRRs). The development of ADAs and Jo-1 antibodies will
also be monitored during the study (Table 1 and Section 6.3.4).
In a Phase 2 study, preliminary efficacy for efzofitimod was shown for its
steroid-sparing effect and improvement in FVC and sarcoidosis symptoms. These
are meaningful outcomes for patients with sarcoidosis, a chronic or progressive
disease fatal in 15% of patients.
The present benefit seems to outweigh the risk. Notwithstanding this, an
external independent Data Safety Monitoring Board (DSMB) will perform interim
reviews of unblinded safety, tolerability, and immunogenicity data. The DSMB
will conduct ad hoc reviews as per Sponsor request if a pattern of unexpected,
clinically significant trends or changes in other safety assessments is
identified through blinded safety data reviews. The DSMB will provide its
recommendation to the Sponsor, which may include stopping the study if required
or continuing the study with modifications to gain more information on the
safety and tolerability of efzofitimod in patients with pulmonary sarcoidosis.