Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial

Design

Multicenter, double-blind, randomized placebo-controlled phase 2/3 study with an open-label extension period

N= 231

Objective

To assess the efficacy and safety of B ­cell depletion with inebilizumab as a monotherapy in reducing the risk of attacks and disability in neuromyelitis optica spectrum disorder (NMOSD)

Study Groups

Astrocyte water channel aquaporin-4 (AQP4-IgG-seropositive; n= 213)

Placebo (n= 52)

Inebilizumab (n= 161)

Intention to treat population (n= 230)

Placebo (n= 56)

Inebilizumab (n= 174)

Inclusion Criteria

Age ≥18 years, diagnosis of NMOSD, Expanded Disability Status Scale (EDSS) score ≤ 8, history of either at least one attack requiring rescue therapy during the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening

Exclusion Criteria

Any condition that, in the opinion of the investigator, would interfere with the evaluation or administration of the investigational product or interpretation of patient safety or study results; concurrent/previous enrollment in another clinical study involving an investigational treatment ≤4 weeks or ≤5 published half-lives of the investigational treatment, whichever was longer, before randomization; estimated glomerular filtration rate < 60 mL/minute; receipt of concomitant medications or treatments, including alemtuzumab, total lymphoid irradiation, bone marrow transplant, T-cell vaccination therapy; AQP4-IgG seronegative with a brain magnetic resonance imaging (MRI) abnormality that met diagnostic criteria for multiple sclerosis

Methods

After a screening period (≤ 56 days), eligible participants were randomized (3:1) to receive 300 mg intra­venous inebilizumab or placebo. Intravenous inebilizumab or placebo was administered on days 1 and 15 (total dose of inebilizumab was 600 mg). All patients received oral corticosteroids (prednisone 20 mg per day or equivalent) between days 1 and 14, tapered to day 21. No other use of immunosuppressants was permitted during the randomized controlled period. The randomized controlled period was up to 197 days or until the occurrence of an adjudicated attack.

Treatment was discontinued if patients withdrew consent or if the investigator identified an adverse event that precluded further dosing, including an elevated liver aminotransferase concentration, severe anaphylaxis, a hypersensitivity reaction, an infusion reaction, or neutropenia, or if the patient became pregnant. During the open-label extension period, patients in the inebilizumab group received 300 mg inebilizumab administered on day 1 to maintain B-cell depletion. For those randomly allocated to placebo, 300 mg inebilizumab was administered on open-label days 1 and 15 to establish B-cell depletion. All patients then received open-label 300 mg inebilizumab every 26 weeks.

Duration

Screening: January 6, 2015, to September 24, 2018

Randomized controlled period: 197 days

Open-label extension: 12 months after the last dose

Outcome Measures

Primary outcome: time from day 1 to the onset of an NMOSD attack, on or before day 197

Secondary outcome: worsening of EDSS score from baseline (increase ≥ 2 from baseline of 0, increase ≥ 1 from baseline of 1 to 5, or increase ≥ 0.5 from baseline of ≥ 5.5); change from baseline in low ­contrast visual acuity binocular score (LCVAB); cumulative total number of active MRI lesions; cumulative number of NMOSD ­related inpatient hospitalizations, longer than an overnight stay

Baseline Characteristics

AQP4-IgG-seropositive (n= 213)

Intention-to-treat population (n=230)

Age, years

Female

Race and Ethnicity

American Indian or Alaskan Native

Asian

Black or African American

White

Hispanic or Latino

5 (10%)

8 (15%)

5 (10%)

24 (46%)

15 (29%)

11 (7%)

37 (23%)

14 (9%)

86 (53%)

25 (16%)

5 (9%)

8 (14%)

5 (9%)

28 (50%)

15 (27%)

14 (8%)

39 (22%)

15 (9%)

92 (53%)

28 (16%)

Disease duration, years

Type of most recent attack

Optic neuritis

Myelitis

Brain or brainstem

19 (37%)

32 (62%)

8 (15%)

77 (48%)

94 (58%)

6 (4%)

21 (38%)

34 (61%)

10 (18%)

85 (49%)

99 (57%)

8 (5%)

Previous treatment

Any therapy†

Plasmapheresis

Intravenous immunoglobulin

51 (98%)

26 (50%)

3 (6%)

159 (99%)

58 (36%)

8 (5%)

55 (98%)

27 (48%)

3 (5%)

172 (99%)

67 (39%)

8 (5%)

Baseline gadolinium-enhancing lesions

Baseline EDSS score

†Any previous treatment for neuromyelitis optical, including rescue and maintenance therapy; some patients received more than one maintenance therapy.

Results

Endpoint

NMOSD attack

Placebo

Inebilizumab

Hazard ratio (95% confidence interval [CI])

p-value

n= 52; 22 (42%)

n= 161; 18 (11%)

0.227 (0.121 to 0.423)

< 0.0001

n= 56; 22 (39%)

n= 174; 21 (12%)

0.272 (0.15 to 0.496)

< 0.0001

Worsening in EDSS score from baseline at last visit

Placebo

Inebilizumab

Odds ratio (95% CI)

p-value

n= 52; 18 (35%) 

n= 161; 25 (16%)

0.371 (0.181 to 0.763)

0.007

n= 56; 19 (34%)

n= 174; 27 (16%)

0.37 (0.185 to 0.739)

0.0049

Change in LCVAB score from baseline, least-squares mean ± standard error

Placebo

Inebilizumab

Difference (95% CI)

p-value

n= 52; 0.6 ± 0.999

n= 158; 0.562 ± 0.572

-0.038 (-2.312 to 2.236)

0.97

n= 56; 1.442 ± 1.217

n= 171; 1.576 ± 0.935

0.134 (-2.025 to 2.294)

0.9

Cumulative number of active MRI lesions from baseline

Placebo

Inebilizumab

Rate ratio (95% CI)

p-value

n= 31; 2.3 ± 1.3

n= 74; 1.7 ± 1

0.568 (0.385 to 0.836)

0.0042

n= 32; 2.3 ± 1.3

n= 79; 1.6 ± 1

0.566 (0.387 to 0.828)

0.0034

Cumulative number of NMOSD-related inpatient hospitalizations from baseline

Placebo

Inebilizumab

Rate ratio (95% CI)

p-value

n= 7; 1.4 ± 0.8

n= 8; 1 ± 0

0.258 (0.09 to 0.738)

0.012

n= 8; 1.4 ± 0.7

n= 10; 1 ± 0

0.286 (0.111 to 0.741)

0.01

Adverse Events

Common Adverse Events: nasopharyngitis (AQP4-IgG seropositive placebo 12% vs. AQP4-IgG seropositive inebilizumab 7% vs. as-treated population placebo 11% vs. as-treated population inebilizumab 7%), urinary tract infection (10% vs. 11% vs. 9% vs. 11%), arthralgia (4% vs. 10% vs. 4% vs. 10%), infusion-related reaction (10% vs. 9% vs. 11% vs. 9%), 

Serious Adverse Events: total (10% vs. 4% vs. 9% vs. 5%),  arthralgia (0 vs. 1% vs. 0 vs. 1%), atypical pneumonia (0 vs. 1% vs. 0 vs. 1%), chest pain (2% vs. 0 vs. 2% vs. 0)

Percentage that Discontinued due to Adverse Events: (0 vs. 1% vs. 0 vs. 1%)

Study Author Conclusions

Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD.

InpharmD Researcher Critique

This study has shown the beneficial effects of inebilizumab in reducing NMOSD attacks. Since the study included only 7% AQP4 ­IgG­ seronegative participants, this leaves the efficacy of inebilizumab in AQP4-IgG seronegative patients unable to be determined. Additionally, while inebilizumab did reduce the risk of optic neuritis attacks, the treatment effect did not result in a benefit to low-contrast binocular vision, suggesting inebilizumab might not reduce optic neuritis attack severity or facilitate recovery.

Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder

Design

Phase 3, international, randomized, double-blind, placebo-controlled, parallel-assignment trial

N= 83

Objective

Study Groups

Satralizumab (n= 41)

Placebo (n= 42)

Inclusion Criteria

Adolescents and adults 12-74 years of age who had aquaporin-4 (AQP4-IgG)-seropositive or AQP4-IgG-seronegative neuromyelitis optica or had AQP4-IgG seropositive NMOSD at screening with idiopathic single or recurrent events of longitudinally extensive myelitis (≥ 3 vertebral-segment spinal cord lesions on magnetic resonance imagine), or recurrent or simultaneous optic neuritis in both eyes; experienced at least two relapses in the 2 years before screening with at least one relapse occurring in previous 12 months; Expanded Disability Status Scale (EDSS) score of 0 to 6.5 at screening; doses of permitted baseline treatments stable for 8 weeks before baseline

Exclusion Criteria

Previous treatment with any agent targeting interleukin-6 pathway, alemtuzumab, total body irradiation or bone marrow transplantation at any time; use of eculizumab, belimumab, or multiple sclerosis disease-modifying treatment within 6 months before baseline; use of anti-CD4 agents, cladribine, or mitoxantrone within 2 years before baseline

Methods

Patients were randomized (1:1) to receive either satralizumab, at a dose of 120 mg, or placebo, administered subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter. The double-blind period was planned to end after the occurrence of 26 protocol-defined relapses. Patients who had a relapse that led to treatment with rescue therapy or who had a protocol-defined relapse, as well as patients who remained in the trial when the prespecified number of 26 protocol-defined relapses occurred, were eligible to enter the open-label extension period.

Patients were permitted to continue baseline treatment with stables doses of azathioprine (maximum, 3 mg/kg of body weight per day), mycophenolate mofetil (maximum, 3,000 mg/day), or oral glucocorticoids (maximum, 15 mg of prednisone equivalent/day) during double-blind treatment. Adolescents (patients 12 to 17 years of age) were permitted to continue receiving stable doses of azathioprine or mycophenolate mofetil plus oral glucocorticoids in addition to satralizumab or placebo. Use of anti-CD20 agents, including rituximab, was not permitted during the trial and for 6 months before baseline. Increases in the dose or changes in the baseline treatment were not permitted during the double-blind period; dose decrease was permitted for safety reasons.

Duration

Median treatment duration during double-blind period in satralizumab group: 107.4 weeks

Median treatment duration during double-blind period in placebo group: 32.5 weeks

Median treatment during double-blind and extension periods for patients receiving satralizumab: 143.1 weeks

Outcome Measures

Primary outcome: first protocol-defined relapse

Protocol-defined relapses were new or worsening objective neurologic symptoms with one of the following: an increase of at least 1 on the EDSS from a baseline score of more than 0 [or an increase of ≥ 2 from a baseline score of 0]; an increase of at least 2 on one appropriate symptom-specific functional-system score for the pyramidal system, cerebellar system, brain stem, sensory system, bowel or bladder, or a single eye; an increase of at least 1 on more than one symptom-specific functional-system score with a baseline score of at least 1; or an increase of at least 1 on a symptom-specific functional-system score in a single eye with a baseline score of at least 1.0. Symptoms were required to be attributable to neuromyelitis optica or NMOSD, to persist for more than 24 hours, and to not be attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications. 

Secondary outcomes: change from baseline to week 24 in visual-analogue scale (VAS) score for pain and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score; percentage of patients free from relapse

Baseline Characteristics

Satralizumab (n= 41)

Placebo (n= 42)

Age, years

40.8 ± 16.1

43.4 ± 12

Female

37 (90%)

40 (95%)

Age at clinical presentation, years

Diagnosis

Neuromyelitis optica

NMOSD

33 (80%)

8 (20%)

28 (67%)

14 (33%)

Annualized relapse rate in previous 2 years

Assessment scores

EDSS score§

VAS pain score¶

FACIT-F score•

3.83 ± 1.57

27.6 ± 28.2

34.7 ± 10.5

3.63 ± 1.32

34.6 ± 26.1

33.9 ± 11.3

Treatment at baseline 

Oral glucocorticoids

Azathioprine

Mycophenolate mofetil

Azathioprine plus glucocorticoids

Mycophenolate mofetil plus oral glucocorticoids

17 (41%)

16 (39%)

4 (10%)

3 (7%)

1 (2%)

20 (48%)

13 (31%)

8 (19%)

0

1 (2%)

There were reported to be no significant differences between groups.

§Scores on the EDSS range from 0 (normal neurologic examination) to 10 (death).

¶Scores on the VAS for the assessment of pain range from 0 to 100, with higher scores indicating more pain.

•Scores on the FACIT-F range from 0 to 52, with lower scores indicating more fatigue.

Results

Endpoint

Satralizumab (n= 41)

Placebo (n= 42)

Hazard ratio (95% confidence interval [CI])

p-value

Protocol defined relapse

8 (20%)

18 (43%)

0.38 (0.16 to 0.88)

0.02

Change in VAS pain score

Change in FACIT-F score

0.35 ± 4.52

0.02 ± 2

-3.73 ± 4.12

3.12 ± 1.79

4.08 (-8.44 to 16.61)

-3.1 (-8.38 to 2.18)

0.52

-

Annualized relapse rate (95% CI)

0.11 (0.05 to 0.21)

0.32 (0.19 to 0.51)

0.34 (0.15 to 0.77)

-

In the AQP4-IgG–seropositive subgroup, 3 of 27 patients (11%) receiving satralizumab had a protocol-defined relapse, as compared with 12 of 28 patients (43%) receiving placebo (hazard ratio [HR] 0.21; 95% CI 0.06 to 0.75). In the AQP4-IgG–seronegative subgroup (patients with neuromyelitis optica only), 5 of 14 patients (36%) receiving satralizumab had a protocol-defined relapse, as compared with 6 of 14 patients (43%) receiving placebo (HR 0.66; 95% CI 0.20 to 2.24).

Adverse Events

Common Adverse Events: infection (68% vs. 62%), injection-related reaction (12% vs. 5%)

Serious Adverse Events: total (17% vs. 21%), serious infection (5% vs. 7%), neoplasm (7% vs. 7%)

Percentage that Discontinued due to Adverse Events: A total of 3 patients (7%) in the satralizumab group and 10 (24%) in the placebo group discontinued the trial agent during the double-blind period. All 3 patients (7%) in the satralizumab group discontinued due to adverse events as compared with 5 patients (12%) in the placebo group.

Among the 65 patients who were evaluated in the combined double-blind and open-label extension periods, 6 patients (9%) receiving satralizumab discontinued the trial owing to adverse events.

Study Author Conclusions

Among patients with NMOSD, satralizumab added to immunosuppressant treatment led to a lower risk of relapse than placebo but did not differ from placebo in its effect on pain or fatigue.

InpharmD Researcher Critique

This study had a relatively small sample size and lack of an active comparator. Additionally, the trial could not determine whether there was a difference between the trial groups at specific weeks. Satralizumab may have tolerability issues due to having no difference in effects on pain or fatigue compared to placebo.

Safety and Efficacy of Satralizumab Monotherapy in Neuromyelitis Optica Spectrum Disorder: A Randomised, Double-blind, Multicentre, Placebo-controlled Phase 3 Trial

Design

Phase 3, multicenter, randomized, double-blind, placebo-controlled parallel-group study

N= 95

Objective

To assess the safety and efficacy of satralizumab monotherapy versus placebo in adult patients with NMOSD

Study Groups

Satralizumab (n= 63)

Placebo (n= 32)

Inclusion Criteria

Age 18 to 74 years with either aquaporin-4 (AQP4)-IgG seropositive or seronegative neuromyelitis optica, or AQP4-IgG seropositive NMOSD with either single or recurrent events of longitudinally extensive myelitis (≥ 3 vertebral segment spinal cord MRI lesions) or optic neuritis; clinical evidence of at least one documented attack in the 12 months before screening and a score ≤ 6.5 on the Expanded Disability Status Scale (EDSS)

Exclusion Criteria

Clinical relapse of 30 days or fewer before baseline; any prior treatment with any agent targeting the IL-6 inhibition pathway, alemtuzumab treatment, total body irradiation, or bone marrow transplantation; treatment in the past 6 months with an anti-B-lymphocyte antigen CD20, eculizumab, anti-B lymphocyte stimulator, or any other multiple sclerosis disease-modifying treatment; treatment in the past 2 years with an anti-T-cell surface glycoprotein CD4, cladribine, cyclophosphamide, or mitoxantrone; treatment with any other investigational drug within 3 months prior to baseline. 

Methods

Patients were randomized (2:1) to receive satralizumab 120 mg or placebo subcutaneously at weeks 0, 2, and 4, and every 4 weeks thereafter. Satralizumab was administered on the same dosing schedule during an open-label extension period. Patients who were having a protocol-defined relapse or those who remained in the study when the double-blind period ended without having protocol-defined relapse were eligible to enter the open-label extension period.

Immunosuppressants (e.g., azathioprine, mycophenolate mofetil) were prohibited during the study. Corticosteroids and intravenous immunoglobulin were also prohibited except as rescue therapy; rescue therapy (e.g., pulse intravenous corticosteroids) was permitted for treatment of relapse. Additionally, analgesics were permitted for pain management during the study.

Duration

Aug 5, 2014, and April 2, 2017

Double-blind period: 1.5 years

Outcome Measures

Primary outcome: time to first protocol-defined relapse

Protocol-defined relapses were new or worsening objective neurological symptoms with at least one of the following: increase of 1 or more EDSS points from a baseline EDSS score of more than 0 (or increase of ≥ 2 EDSS points from a baseline EDSS score of 0); increase of 2 or more points on at least one appropriate symptom-specific functional system score for either pyramidal, cerebellar, brainstem, sensory, bowel or bladder, or a single eye; increase of 1 or more points on more than one symptom-specific functional system score with a baseline of at least 1·0; or increase of 1 or more points on a single-eye symptom-specific functional system score with a baseline score of at least 1. Symptoms were required to be attributable to NMOSD, persisting for more than 24 hours, and not attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications.

Secondary outcome: change in Visual Analogue Scale (VAS) pain score and Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score from baseline to week 24, annualized relapse rate

Baseline Characteristics

Satralizumab (n= 63)

Age, years

45.3 ± 12

Age at clinical presentation, years

36.4 ± 10.7

Female

46 (73%)

Race or ethnicity

American Indian or Alaska Native

Asian (non-Japanese)

Black or African American

White

2 (3%)

8 (13%)

13 (21%)

37 (59%)

0

6 (19%)

3 (9%)

27 (69%)

Diagnosis

Neuromyelitis optica

NMOSD

47 (75%)

16 (25%)

24 (75%)

8 (25%)

AQP4-IgG seropositive

41 (65%)

Annualized relapse rate

EDSS score

VAS pain score

FACIT fatigue score

Previous treatment

B-cell-depleting therapy

Immunosuppressants or other

Disease duration, weeks

8 (13%)

55 (87%)

317.8 ± 340.9

4 (13%)

28 (88%)

214.7 ± 201.3

Results

Endpoint

Satralizumab (n= 63)

Placebo (n= 32)

Protocol defined relapse

19 (30%)

16 (50%

0.45 (0.23 to 0.89)

0.18

Difference (95% CI)

Change from baseline at week 24 (95% CI)

VAS pain score

FACIT fatigue score

-2.74 (-11.2 to 5.73)

5.71 (2.51 to 8.91)

-5.95 (-15.55 to 3.65)

3.6 (-0.01 to 7.22)

3.21 (-5.0.9 to 11.52)

2.11 (-1.02 to 5.22)

0.44

-

Annualized relapse rate (95% CI)

0.17 (0.1 to 0.26)

0.41 (0.24 to 0.67)

0.41 (0.21 to 0.79)

-

In the AQP4-IgG seropositive subgroup, nine (22%) of 41 patients receiving satralizumab versus 13 (57%) of 23 receiving placebo experienced a protocol-defined relapse (hazard ratio [HR] 0.26; 95% Cl 0.11 to 0.63). In the AQP4-IgG seronegative subgroup, ten (46%) of 22 patients receiving satralizumab experienced a protocol-defined relapse versus three (33%) of nine patients receiving placebo (HR 1.19; 95% CI 0.30 to 4.78).

Adverse Events

Common Adverse Events: infections (54% vs. 44%), injection-related reactions (13% vs. 16%)

Serious Adverse Events: total (19% vs. 16%), serious infections (10% vs. 9%)

Percentage that Discontinued due to Adverse Events: One patient in the satralizumab group discontinued due to a severe event of pneumonia.

Study Author Conclusions

Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favorable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD.

InpharmD Researcher Critique