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Drug Trials Snapshots: ULTOMIRIS

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the ULTOMIRIS Package Insert for complete information.

ULTOMIRIS (ravulizumab-cwvz)
ul-toe-meer'-is
Alexion Pharmaceuticals, Inc
Approval date: December 21, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ULTOMIRIS is a drug used to treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH).

PNH is a rare, life-threatening disease in which the bone marrow does not produce enough blood cells and red blood cells break apart prematurely (called hemolysis).

How is this drug used?

ULTOMIRIS is given by a healthcare provider directly into the bloodstream through a needle in the vein (known as an intravenous or IV infusion). Two weeks after the first dose, ULTOMIRIS is given every eight weeks. The dose is based on the patient’s weight.

It takes about two hours to receive an ULTOMIRIS infusion.

What are the benefits of this drug?

Two trials compared the need for blood transfusions and evidence of hemolysis between ULTOMIRIS and eculizumab (a drug used to treat PNH). The trials cannot show whether one treatment is better than the other, but patients treated with ULTOMIRIS achieved results that were as good as those in patients treated with eculizumab.

What are the benefits of this drug (results of trials used to assess efficacy)?

The tables below summarize efficacy results for the evaluated patients in Trials 1 and 2. The primary outcome in Trial 1 was transfusion avoidance and hemolysis as directly measured by lactate dehydrogenase-normalization (LDH-N). The primary outcome in Trial 2 was hemolysis as directly measured by LDH-N.

Table 2. Efficacy Results in the Complement-Inhibitor Naïve Patients-Trial 1

 

ULTOMIRIS
(N=125)

Eculizumab
(N=121)

Statistic for Comparison

Treatment Effect
(95% CI)

Transfusion   avoidance rate

73.6%

66.1%

Difference in rate

6.8
(-4.66, 18.14)

LDH normalization

53.6%

49.4%

Odds ratio

1.19
(0.80, 1.77)

Note: LDH = lactate dehydrogenase; CI = confidence interval

For the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI.

ULTOMIRIS Prescribing Information

Table 3. Efficacy Results in the Eculizumab-Experienced Patients with PNH-Trial 2

 

ULTOMIRIS
n = 97

Eculizumab
n = 98

Statistic for Comparison

Treatment Effect
(95% CI)

LDH Percent change

-0.82%

8.4%

Difference in % change from baseline

9.2
(-0.42, 18.8)

Transfusion avoidance

87.6 %

82.7%

Difference in rate

5.5
(-4.3, 15.7)

Note: CI = confidence interval

ULTOMIRIS Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: ULTOMIRIS worked similarly in men and women
  • Race: ULTOMIRIS worked similarly among White and Asian patients. The number of patients in other races was limited; therefore, differences in how well the drug worked among other races could not be determined.
  • Age: ULTOMIRIS worked similarly in patients younger and older than 65 years.

Were there any differences in how well the drug worked in clinical trials among sex, race and age groups?

The tables below summarize efficacy results by sex, race and age. The majority of patients were White and Asian, and the number of patients in all other races was limited. Therefore, racial subgroup differences were investigated between Whites, Asians and all other races.

Table 4. Number (%) of Patients Achieving Transfusion Avoidance in Complement-Inhibitor Naïve Patients-Trial 1

 

 Demographic Parameter

ULTOMIRIS
(N=125)
% (n/N)

Eculizumab
(N=121)
% (n/N)

Treatment Effect
(ULTOMIRIS-Eculizumab)
Diff (95% CI)

Sex

     Male

75.4 (49/65)

73.9 (51/69)

1.5 (-15.60, 18.40)

     Female

71.7 (43/60)

55.8 (29/52)

15.9 (-2.72, 33.69)

Race

    White

79.1 (34/43)

68.6 (35/51)

10.4 (-9.79, 30.17)

     Asian

69.4 (50/72)

59.6 (34/57)

9.8 (-7.60, 26.70)

     Other

80.0 (8/10)

84.6 (11/13)

-4.6 (-44.17, 35.23)

Age at First Infusion

     18-65 years

76.6 (85/111)

70.9 (73/103)

5.7 (-7.75, 18.99)

     > 65 years

50.0 (7/14)

38.9 (7/18)

11.1 (-24.19, 44.56)

CI=confidence interval

FDA Review

Table 5. Patients Achieving LDH Normalization in Complement-Inhibitor Naïve Patients-Trial 1

 Demographic Parameter

ULTOMIRIS
(N=125)

Eculizumab
(N=121)

ULTOMIRIS Versus Eculizumab
OR (95% CI)

Sex

     Male

57.0%

43.3%

1.74 (0.99, 3.04)

     Female

47.6%

58.0%

0.66 (0.36, 1.19)

Race

     White

42.1%

42.1%

1.0 (0.51, 1.98)

     Asian

59.7%

60.0%

0.99 (0.56, 1.73)

     Other

55.7%

26.0%

3.58 (0.80, 16.01)

Age at First Infusion

    18-65 years

55.1%

50.1%

1.23 (0.80, 1.88)

     > 65 years

46.3%

49.6%

0.88 (0.28, 2.76)

Note: LDH = lactate dehydrogenase; OR=odds ratio

FDA Review

Table 6. LDH Percent Change in Eculizumab-Experienced Patients-Trial 2

 Demographic Parameter

ULTOMIRIS
(N=97)

Eculizumab
(N=98)

Treatment Effect
(ULTOMIRIS-Eculizumab)
Diff (95% CI)

Sex

     Male

5.62

7.24

1.62 (-17.61, 20.85)

     Female

-3.81

3.96

7.77 (0.08, 15.45)

Race

     White

-0.78

7.91

8.69 (-0.83, 18.20)

     Asian

2.50

6.61

4.11 (-3.82, 12.04)

     Other

-5.25

-3.23

2.02 (-8.30, 12.35)

Age at First Infusion

     18-65 years

-0.09

10.29

10.38 (-0.53, 21.30)

      > 65 years

-3.77

1.37

5.13 (-4.89, 15.15)

Note: LDH = lactate dehydrogenase

FDA Review

Table 7. Number (%) of Patients Achieving Transfusion Avoidance in Eculizumab-Experienced Patients-Trial 2

 

 Demographic Parameter

ULTOMIRIS
(N=97)
% (n/N)

Eculizumab
(N=98)
% (n/N)

Treatment Effect
(ULTOMIRIS-Eculizumab)
Diff (95% CI)

Sex

     Male

92.0 (46/50)

89.6 (43/48)

2.4 (-17.19, 22.50)

     Female

83.0 (39/47)

76.0 (38/50)

7.0 (-13.24, 26.61)

Race

     White

88.0 (44/50)

83.6 (51/61)

4.4 (-14.29, 22.73)

     Asian

82.6 (19/23)

78.9 (15/19)

3.7 (-26.59, 32.78)

     Other

91.7 (22/24)

83.3 (15/18)

8.3 (-22.59, 38.14)

Age at First Infusion

     18-65 years

89.4 (76/85)

84.5 (71/84)

4.9 (-10.31, 19.62)

     > 65 years

75.0 (9/12)

71.4 (10/14)

3.6 (-33.91, 40.68)

FDA Review

What are the possible side effects?

ULTOMIRIS may increase the chance of getting serious and life-threatening infections including meningococcal infection (a bacterial infection of the brain and spinal cord). ULTOMIRIS can also cause serious infusion reactions.

The most common side effects of ULTOMIRIS are upper respiratory infection and headache.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions in patients with PNH in the combined trials.

Table 8. Adverse Reactions Reported In 5% or More of ULTOMIRIS Treated Patients in Complement Inhibitor Naïve and Eculizumab-Experienced Patients with PNH

Body System
Adverse Reaction

Number of Patients

ULTOMIRIS
(n=222)
n (%)

Eculizumab
(n=219)
n (%)

Gastrointestinal disorders

     Diarrhea

19 (9)

12 (5)

     Nausea

19 (9)

19 (9)

     Abdominal pain

13 (6)

16 (7)

General Disorders and Administration Site Conditions

     Pyrexia

15 (7)

18 (8)

Infections and Infestations

     Upper respiratory tract infectiona

86 (39)

86 (39)

Musculoskeletal and Connective Tissue Disorders

    Pain in extremity

14 (6)

11 (5)

    Arthralgia

11 (5)

12 (5)

Nervous System Disorders

     Headache

71 (32)

57 (26)

     Dizziness

12 (5)

14 (6)

a Grouped term includes: Nasopharyngitis, Upper respiratory tract infection, Oropharyngeal pain, Viral upper respiratory tract infection, Rhinitis, Respiratory tract infection, Rhinorrhoea, Pharyngitis, and Upper respiratory tract inflammation

ULTOMIRIS Prescribing Information

Were there any differences in side effects among sex, race and age?

  • Sex: The occurrence of side effects was similar among men and women.
  • Race: The occurrence of side effects was similar among White and Asian patients. The number of patients in other races was limited; therefore, differences in how well the drug worked could not be determined.
  • Age: The occurrence of side effects was similar in patients younger and older than 65 years.

The table below summarizes the occurrence of the most common adverse reaction, upper respiratory tract infection, by subgroup.

Table 9. Subgroup Analysis of Upper Respiratory Tract Infection (safety population)

Demographic Characteristic

ULTOMIRIS
n/N (%)

Eculizumab
n/N (%)

Sex

  Men

47/115 (41.6)

40/117 (34.2)

  Women

39/107 (36.4)

46/102 (45.1)

Race

   White

35/93 (37.6)

42/112 (37.5)

   Black or African American

2/7 (28.6)

1/7 (14.3)

   Asian

39/100 (39.0)

34/76 (44.7)

   Other

10/26 (38.5)

9/23 (39.1)

Age Group

   18 -  65 years

80/194 (41.2)

71/185 (38.4)

    > 65 years

6/28 (21.4)

15/34 (44.1)

Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved ULTOMIRIS based on evidence from two clinical trials (Trial 1/NCT02946463 and Trial 2/NCT03056040 of 441 adult patients with paroxysmal nocturnal hemoglobinuria (PNH). The trials were conducted in Asia, Canada, Europe, Latin America, and the United States.

Figure 1 summarizes how many men and women were in the clinical trials used to evaluate PNH.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many males and females were in the clinical trials. In total, 232 (53%) males and 209 (47%) females participated in the clinical trial.

FDA Review

Figure 2 summarizes the percentage of patients by race in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the clinical trial. In total, 205 (47%) White, 14 (3%) Black or African American, and 171 (39%) Asian and 51 (11%) Other patients participated in the clinical trials.

*Other includes American Indian or Alaska Native

FDA Review

Table 1. Demographics of Combined Clinical Trials by Race

Race

Number of Patients

Percentage of Patients

White

205

47%

Black or African American

14

3%

Asian

171

39%

American Indian or Alaska Native

2

less than 1%

Other

49

11%

FDA Review

Figure 3 summarizes the percentage of patients by age in the clinical trials.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were enrolled in the clinical trials. In total, 379 patients (86%) were less than 65 years old, and 62 patients (14%) were 65 years and older.

Clinical Trial Data

Who participated in the trials?

The table below summarizes the demographics of the patients in the combined clinical trials.

Table 10. Baseline Demographics of the Combined Clinical Trials

 

Trial 1

Trial 2

 

 

Demographic Characteristic

ULTOMIRIS
(N = 125)

Eculizumab
(N = 121)

ULTOMIRIS
(N = 97)

Eculizumab
(N = 98)

Total
(N = 441)

Sex, n (%)

     Male

65 (52.0)

69 (57.0)

50 (51.5)

48 (49.0)

232 (52.6)

     Female

60 (48.0)

52 (43.0)

47 (48.5)

50 (51.0)

209 (47.4)

Race, n (%)

      White

43 (34.4)

51 (42.1)

50 (51.5)

61 (62.2)

205 (46.5)

       Black or African American

2 (1.6)

4 (3.3)

5 (5.2)

3 (3.1)

14 (3.2)

       Asian

72 (57.6)

57 (47.1)

23 (23.7)

19 (19.4)

171 (38.8)

       American Indian or Alaska Native

1 (0.8)

1 (0.8)

0 (0)

0 (0)

2 (0.4)

       Other

7 (5.6)

8 (6.6)

19 (19.6)

15 (15.3)

49 (11.1)

Age Group (years), n (%)

        < 65 years

110 (88.0)

102 (84.3)

84 (86.6)

83 (84.7)

379 (85.9)

         > 65 years

15 (12.0)

19 (15.7)

13 (13.4)

15 (15.3)

62 (14.1)

     Mean (SD)

44.8 (15.16)

46.2 (16.24)

46.6 (14.41)

48.8 (13.97)

46.6 (14.95)

     Median

43.0

45.0

45.0

49.0

45.0

     Min, max

18, 83

18, 86

18, 79

23, 77

18, 86

Ethnicity, n (%)

     Not Hispanic

116 (92.8)

102 (84.3)

76 (78.4)

77 (78.6)

371 (84.1)

     Hispanic

5 (4.0)

13 (10.7)

3 (3.1)

4 (4.1)

25 (5.7)

     Not reported

2 (1.6)

4 (3.3)

15 (15.5)

17 (17.3)

38 (8.6)

     Missing/unknown

2 (1.6)

2 (1.7)

3 (3.1)

0 (0)

7 (1.6)

Region, n (%)

     Asia

67 (53.6)

57 (47.1)

23 (23.7)

20 (20.4)

167 (37.9)

     Canada

2 (1.6)

2 (1.7)

6 (6.2)

4 (4.1)

14 (3.2)

     Europe

44 (35.2)

47 (38.8)

62 (63.9)

66 (67.3)

219 (49.6)

     Latin America

9 (7.2)

13 (10.7)

0 (0)

0 (0)

22 (5.0)

     United States

3 (2.4)

2 (1.7)

6 (6.2)

8 (8.2)

19 (4.3)

Clinical Trial Data

How were the trials designed?

The benefit and side effects of ULTOMIRIS were evaluated in two clinical trials in adult patients with PNH. Patients in both trials were vaccinated or received treatment to prevent meningococcal infection.

Trial 1 enrolled adult patients 18 to 83 years old who had not been treated for PNH previously and had an ongoing destruction of blood cells. Patients were randomized to receive either ULTOMIRIS or eculizumab intravenously for a total of 26 weeks of treatment. The benefit of ULTOMIRIS was assessed based on the percentage of patients who did not need a blood transfusion and who experienced a decrease in the destruction of red blood cells.

Trial 2 enrolled adult patients 18 to 79 years old who had been treated for PNH previously with eculizumab. Patients were randomized to receive either ULTOMIRIS or eculizumab intravenously for a total of 26 weeks of treatment. The benefit of ULTOMIRIS was assessed based on the percentage of patients who experienced a decrease in the destruction of red blood cells.

How were the trials designed?

The efficacy and safety of ULTOMIRIS were evaluated in two open-label, randomized, active-controlled, non-inferiority trials. Trial 1 enrolled patients aged 18 to 83 years of age with PNH who were complement inhibitor naïve and had active hemolysis. Trial 2 enrolled patients aged 18 to 79 years of age with PNH who were PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months. All patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

In both trials, patients were randomized to receive ULTOMIRIS or eculizumab intravenously in accordance with the weight-based dosing. All patients randomized to ULTOMIRIS received an initial loading dose, followed by maintenance doses once every eight weeks for 3 doses (a total of 26 weeks of treatment). All patients randomized to eculizumab received eculizumab on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for a total of 26 weeks of treatment.

The co-primary efficacy endpoint was transfusion avoidance and hemolysis as directly measured by LDH-N in Trial 1. The primary efficacy endpoint was hemolysis as directly measured by LDH-N in Trial 2.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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