ONPATTRO® (patisiran) significantly improved polyneuropathy1

Primary Endpoint: mNIS+71,2

  • Change from baseline at 18 months in modified Neuropathy Impairment Score + 7 (mNIS+7), an objective 304-point assessment of polyneuropathy in hATTR amyloidosis

Change in mNIS+71,a-c

Change in mNIS+7 from baseline at 18 months with ONPATTRO® (patisiran) versus placebo
Change in mNIS+7 from baseline at 18 months with ONPATTRO® (patisiran) versus placebo
 
ONPATTRO
 
Placebo
Improvement in polyneuropathy

Difference at
9 months: -16.0

(ONPATTRO vs Placebo)
95% CI: -20.7, -11.3

Difference at
18 months: -34.0

(ONPATTRO vs Placebo)
95% CI: -39.9, -28.1

p<0.001

aMean mNIS+7 at baseline was 80.9 with ONPATTRO and 74.6 with placebo.1

bBars represent SEM.

cN=number of evaluable patients.

CI=confidence interval; LS=least squares; SEM=standard error of the mean.

  • The progression of polyneuropathy in the placebo arm was consistent with the natural progression of the disease described in previous studies3-5
  • Maintenance of efficacy as measured by mNIS+7 was demonstrated for up to 48 months in 2 OLE studies6
Reversal in neuropathy impairment7

Reversal in neuropathy impairment
from baseline at 18 months7,a,b

Percentage of patients in APOLLO who experienced reversal in neuropathy impairment from baseline at 18 months
56%c
 
4%d
 
 
ONPATTRO
 
Placebo

p<0.001

<0 point change from baseline in mNIS+7e

Adapted from New England Journal of Medicine, Adams D, Gonzalez-Duarte A, O’Riordan WD, et al, “Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis,” 379(1). Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

  • 56% of patients treated with ONPATTRO experienced reversal in neuropathy impairment from baseline7
  • For the 54 ONPATTRO-treated patients who did not experience reversal in neuropathy impairment, progression was slowed compared to the placebo arm (median change of 10 points vs 26 points)7

aOdds ratio: 39.9 (11.0-144.4).7

bPercentages based on mITT population: ONPATTRO (n=148); placebo (n=77).1

c95% CI: 48-64.7

d95% CI: 0-87

eReversal defined as mNIS+7 change from baseline of <0 points.

mITT=modified intention-to-treat.

Primary Endpoint: mNIS+71,2

  • Change from baseline at 18 months in modified Neuropathy Impairment Score + 7 (mNIS+7), an objective 304-point assessment of polyneuropathy in hATTR amyloidosis
  • The progression of polyneuropathy in the placebo arm was consistent with the natural progression of the disease described in previous studies3-5
  • Maintenance of efficacy as measured by mNIS+7 was demonstrated for up to 48 months in 2 OLE studies6

aMean mNIS+7 at baseline was 80.9 with ONPATTRO and 74.6 with placebo.1

bBars represent SEM.

cN=number of evaluable patients.

CI=confidence interval; LS=least squares; SEM=standard error of the mean.

Change in mNIS+71,a-c

Change in mNIS+7 from baseline at 18 months with ONPATTRO® (patisiran) versus placebo
Change in mNIS+7 from baseline at 18 months with ONPATTRO® (patisiran) versus placebo
 
ONPATTRO
 
Placebo
Improvement in polyneuropathy

Difference at
9 months: -16.0

(ONPATTRO vs Placebo)
95% CI: -20.7, -11.3

Difference at
18 months: -34.0

(ONPATTRO vs Placebo)
95% CI: -39.9, -28.1

p<0.001
Reversal in neuropathy impairment7

Reversal in neuropathy impairment
from baseline at 18 months7,a,b

Percentage of patients in APOLLO who experienced reversal in neuropathy impairment from baseline at 18 months
56%c
 
4%d
 
 
ONPATTRO
 
Placebo

p<0.001

<0 point change from baseline in mNIS+7e

  • 56% of patients treated with ONPATTRO experienced reversal in neuropathy impairment from baseline7
  • For the 54 ONPATTRO-treated patients who did not experience reversal in neuropathy impairment, progression was slowed compared to the placebo arm (median change of 10 points vs 26 points)7

Adapted from New England Journal of Medicine, Adams D, Gonzalez-Duarte A, O’Riordan WD, et al, “Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis,” 379(1). Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

aOdds ratio: 39.9 (11.0-144.4).7

bPercentages based on mITT population: ONPATTRO (n=148); placebo (n=77).1

c95% CI: 48-64.7

d95% CI: 0-87

eReversal defined as mNIS+7 change from baseline of <0 points.

mITT=modified intention-to-treat.

Earlier treatment with ONPATTRO substantially reduced polyneuropathy impairment6

Following progression of polyneuropathy over 18 months, patients who received placebo in the APOLLO study and entered into the global OLE study experienced a stabilization in polyneuropathy as measured by mNIS+7 after 24 months of treatment with ONPATTRO.6

Change in mNIS+7 from baseline
in APOLLO and global OLE1,6,a-d

Results from Open-Label Extension study
Results from Open-Label Extension study
 
ONPATTRO
 
Placebo
 
Placebo patients
who received
ONPATTRO in OLE
Improvement in polyneuropathy

a1% of eligible APOLLO patients declined to participate in the global OLE.

bFor APOLLO patients initiating alternative hATTR amyloidosis treatment, mNIS+7 assessments after alternative treatment are missing.

cBars represent SEM (standard error of the mean).

dN=number of evaluable patients.

Earlier treatment with ONPATTRO substantially reduced polyneuropathy impairment6

Following progression of polyneuropathy over 18 months, patients who received placebo in the APOLLO study and entered into the global OLE study experienced a stabilization in polyneuropathy as measured by mNIS+7 after 24 months of treatment with ONPATTRO.6

a1% of eligible APOLLO patients declined to participate in the global OLE.

bFor APOLLO patients initiating alternative hATTR amyloidosis treatment, mNIS+7 assessments after alternative treatment are missing.

cBars represent SEM (standard error of the mean).

dN=number of evaluable patients.

Change in mNIS+7 from baseline
in APOLLO and global OLE1,6,a-d

Results from Open-Label Extension study
Results from Open-Label Extension study
 
ONPATTRO
 
Placebo
 
Placebo patients
who received
ONPATTRO in OLE
Improvement in polyneuropathy
ONPATTRO® (patisiran) significantly improved quality of life1

Key Secondary Endpoint: Norfolk QoL-DN1,8

Change from baseline at 18 months in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) score, a patient-reported assessment that evaluates neuropathy in domains such as physical function, activities of daily living, symptoms, and autonomic neuropathy (score range -4 to 136).

Change in Norfolk QoL-DN score1,a-c

Change in Norfolk QoL-DN score from baseline at 18 months
Change in Norfolk QoL-DN score from baseline at 18 months
 
ONPATTRO
 
Placebo
Improvement in polyneuropathy

Difference at 9 months: -15.0

(ONPATTRO vs Placebo)
95% CI: -19.8, -10.2

Difference at 18 months: -21.1

(ONPATTRO vs Placebo)
95% CI: -27.2, -15.0

p<0.001

aNorfolk QoL-DN scores at baseline were 59.6 with ONPATTRO and 55.5 with placebo.1

bBars represent SEM.

cN=number of evaluable patients.

CI=confidence interval; LS=least squares; SEM=standard error of the mean.

Improvement in quality of life

51% of patients treated with ONPATTRO experienced improvement from baseline in quality of life, compared to 10% of patients treated with placebo.7

Change in Norfolk QoL-DN score1,a-c

Change in Norfolk QoL-DN score from baseline at 18 months
Change in Norfolk QoL-DN score from baseline at 18 months
 
ONPATTRO
 
Placebo
Improvement in polyneuropathy

Difference at 9 months: -15.0

(ONPATTRO vs Placebo)
95% CI: -19.8, -10.2

Difference at 18 months: -21.1

(ONPATTRO vs Placebo)
95% CI: -27.2, -15.0

p<0.001

Key Secondary Endpoint: Norfolk QoL-DN1,8

Change from baseline at 18 months in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) score, a patient-reported assessment that evaluates neuropathy in domains such as physical function, activities of daily living, symptoms, and autonomic neuropathy (score range -4 to 136).

aNorfolk QoL-DN scores at baseline were 59.6 with ONPATTRO and 55.5 with placebo.1

bBars represent SEM.

cN=number of evaluable patients.

CI=confidence interval; LS=least squares; SEM=standard error of the mean.

Improvement in quality of life

51% of patients treated with ONPATTRO experienced improvement from baseline in quality of life, compared to 10% of patients treated with placebo.7

The benefit of ONPATTRO on neuropathy impairment and quality of life was observed across all subgroups,
including age, sex, V30M variant status, previous tetramer stabilizer use, and disease stage.1,7

The benefit of ONPATTRO on neuropathy impairment and quality of life was observed across all subgroups, including age, sex, V30M variant status, previous tetramer stabilizer use, and disease stage.1,7

Improvement in autonomic symptoms7

Autonomic symptoms: COMPASS 312,7

  • COMPASS 31 is a 31-item questionnaire that evaluates autonomic function across 6 domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor (score range 0 to 100)2,9

Change in COMPASS 31 from
baseline at 18 monthsa-d

Change in COMPASS 31 from baseline at 18 months

aCOMPASS 31 at baseline was 30.6 with ONPATTRO and 30.3 with placebo.7

bNumber of patients assessed at 18 months was 136 with ONPATTRO and 53 with placebo.7

cONPATTRO-placebo treatment difference (LS mean): -7.5.10

d95% CI: -11.9, -3.2.10

  • Patients receiving ONPATTRO experienced a significant benefit relative to placebo in reduction of autonomic symptoms
  • In ONPATTRO-treated patients, improvement compared to baseline was seen in orthostatic intolerance and gastrointestinal symptoms, the 2 domains that contribute most to the overall COMPASS 31 score10
    • ONPATTRO-treatment patients were 3 times more likely to report improvement from baseline in severity of orthostatic intolerance than were placebo-treated patients (30% vs 10%, respectively)
    • ONPATTRO-treatment patients were 3.5 times more likely to report improvement from baseline in severity of diarrhea than were placebo-treated patients (18% vs 5%, respectively)

Autonomic symptoms: COMPASS 312,7

  • COMPASS 31 is a 31-item questionnaire that evaluates autonomic function across 6 domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor (score range 0 to 100)2,9
  • Patients receiving ONPATTRO experienced a significant benefit relative to placebo in reduction of autonomic symptoms
  • In ONPATTRO-treated patients, improvement compared to baseline was seen in orthostatic intolerance and gastrointestinal symptoms, the 2 domains that contribute most to the overall COMPASS 31 score10:
    • ONPATTRO-treatment patients were 3 times more likely to report improvement from baseline in severity of orthostatic intolerance than were placebo-treated patients (30% vs 10%, respectively)
    • ONPATTRO-treatment patients were 3.5 times more likely to report improvement from baseline in severity of diarrhea than were placebo-treated patients (18% vs 5%, respectively)

Change in COMPASS 31 from
baseline at 18 monthsa-d

Change in COMPASS 31 from baseline at 18 months

aCOMPASS 31 at baseline was 30.6 with ONPATTRO and 30.3 with placebo.7

bNumber of patients assessed at 18 months was 136 with ONPATTRO and 53 with placebo.7

cONPATTRO-placebo treatment difference (LS mean): -7.5.10

d95% CI: -11.9, -3.2.10

Improvement in ability to perform everyday activities7

Activities of daily living: R-ODS2,7,11

  • R-ODS is a 24-item scale that evaluates limitations on everyday activity (score range 0 to 48)

Change in R-ODS score from
baseline at 18 monthsa-d

Change in R-ODS from baseline at 18 months

aR-ODS scores at baseline were 29.7 with ONPATTRO and 29.8 with placebo.7

bNumber of patients assessed at 18 months was 138 with ONPATTRO and 54 with placebo.7

cONPATTRO-placebo treatment difference (LS mean): 9.0.12

d95% CI: 7.0, 10.9.12

  • Patients receiving ONPATTRO saw a significant benefit relative to placebo in the ability to perform activities of daily living and everyday function

Activities of daily living: R-ODS2,7,11

  • R-ODS is a 24-item scale that evaluates limitations on everyday activity (score range 0 to 48)
  • Patients receiving ONPATTRO saw a significant benefit relative to placebo in the ability to perform activities of daily living and everyday function

aR-ODS scores at baseline were 29.7 with ONPATTRO and 29.8 with placebo.7

bNumber of patients assessed at 18 months was 138 with ONPATTRO and 54 with placebo.7

cONPATTRO-placebo treatment difference (LS mean): 9.0.12

d95% CI: 7.0, 10.9.12

Change in R-ODS score from
baseline at 18 monthsa-d

Change in R-ODS from baseline at 18 months

ONPATTRO improved other key measures of disease burden1,7,a

Increased walking speed

  • Gait speed as measured by 10-meter walk test (10MWT)
  • Gait speed from baseline at 18 months improved in ONPATTRO-treated patients by 0.08 m/sec compared to placebo-treated patients whose speed worsened by -0.24 m/sec (p<0.001)b,c
  • 53% of patients treated with ONPATTRO showed an improvement in gait speed (change >0) at 18 months, compared to 13% of patients treated with placebo

Improved nutritional status

  • ONPATTRO-treated patients maintained a better nutritional status at 18 months compared to placebo-treated patients as demonstrated by a 3.7-unit decrease in modified body mass index (mBMI) vs a 119-unit decrease in the placebo group (p<0.001)d,e
  • A statistical difference in mBMI vs placebo was seen in ONPATTRO-treated patients as early as 3 months

Improved motor strength

  • ONPATTRO-treated patients experienced a 0.1-point increase from baseline at 18 months in Neuropathy Impairment Score-Weakness (NIS-W) compared with the placebo-treated patients whose score increased by 17.9 points (p<0.001)f,g

Improved patient mobility, self-care, usual activities, pain/discomfort, and anxiety/depression13,14,h,i

  • ONPATTRO-treated patients showed improvement at 18 months in these domains of the Euro Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) instrument compared with placebo-treated patients
  • EQ-5D-5L was an exploratory endpoint in the APOLLO study

aAll data are reported as LS mean change from baseline at 18 months.

bONPATTRO-placebo treatment difference (LS mean): 0.31.1

c95% CI: 0.23, 0.39.1

dONPATTRO-placebo treatment difference (LS mean): 116.1

e95% CI: 82, 149.1

fONPATTRO-placebo treatment difference (LS mean): -17.9.15

g95% CI: -22.3, -13.4.15

hONPATTRO-placebo treatment difference (LS mean): 0.212

i95% CI: 0.15, 0.2512

Important Safety Information and Indication

Important Safety Information

Infusion-Related Reactions

Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO® (patisiran). In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

Reduced Serum Vitamin A Levels and Recommended Supplementation

ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

Adverse Reactions

The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).

Indication

ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

For additional information about ONPATTRO, please see the full Prescribing Information.

References:

1. ONPATTRO Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.

2. Adams D, Suhr OB, Dyck PJ, et al. BMC Neurol. 2017;17(1):181.

3. Adams D, Coelho T, Obici L, et al. Neurology. 2015;85(8):675-682.

4. Koike H, Tanaka F, Hashimoto R, et al. J Neurol Neurosurg Psychiatry. 2012;83(2):152-158.

5. Berk JL, Suhr OB, Obici L, et al. JAMA. 2013;310(24):2658-2667.

6. Adams D, Gonzalez-Duarte A, Mauricio E, et al. Poster presented at: European Academy of Neurology, May 23-26, 2020; Virtual Congress.

7. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. N Engl J Med. 2018;379(1):11-21.

8. Vinik EJ, Vinik AI, Paulson JF, et al. J Peripher Nerv Syst. 2014;19:104-119.

9. Sletten DM, Suarez GA, Low PA, et al. Mayo Clin Proc. 2012;87(12):1196-1201.

10. González-Duarte A, Berk JL, Quan D, et al. J Neurol. 2019; 267:703-712.

11. van Nes SI, Vanhoutte EK, van Doorn PA, et al. Neurology. 2011;76(4):337-345.

12. Obici L, Berk JL, González‑Duarte‑A, et al. Amyloid. 2020;27(3):153‑162.

13. Adams D, Gonzalez-Duarte A, O’Riordan W, et al. Slides presented at: American Academy of Neurology; April 25, 2018; Los Angeles, CA.

14. Herdman M, Gudex C, Lloyd A, et al. Qual Life Res. 2011;20(10):1727-1736.

15. Center for Drug Evaluation and Research. NDA 210922—patisiran—cross-discipline team leader review. U.S. Department of Health and Human Services, Food and Drug Administration; 2018.

16. Vinik EJ, Hayes RP, Oglesby A, et al. Diabetes Technol Ther. 2005;7(3):497-508.

17. Berk J, Lin H, Agarwal S, et al. Poster presented at: XVIth International Symposium on Amyloidosis; March 26-29, 2018; Kumamoto, Japan.

18. Suhr O, Danielsson A, Holmgren G, et al. J Intern Med. 1994;235(5):479-485.