APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis

• patisiran (ALN-TTR02) (Drug): administered by intravenous (IV) infusion
• Sterile Normal Saline (0.9% NaCl) (Drug): administered by intravenous (IV) infusion

Primary outcomes

• Modified Neuropathy Impairment Score +7 (mNIS+7) [18mo]: The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mNIS+7 at 18 months. The mNIS+7 is a composite score that quantitates motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome.

Secondary outcomes

• Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire [18mo]: The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in Norfolk QoL-DN at 18 months. The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.
• Neurological Impairment Score-Weakness (NIS-W) Score [18mo]: The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in NIS-W at 18 months. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome.
• Rasch-built Overall Disability Scale (R-ODS) Score [18mo]: The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in R-ODS score at 18 months. The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in patients. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome.
• Timed 10-meter Walk Test (10-MWT, Gait Speed) [18mo]: The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in 10-MWT at 18 months. Ability to ambulate (gait speed) was assessed through the 10-meter walk test (10-MWT). The walk had to be completed without assistance from another person; ambulatory aids such as canes and walkers were permitted.
• Modified Body Mass Index (mBMI) [18mo]: The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mBMI at 18 months. The nutritional status of patients was evaluated using the mBMI; calculated as the product of BMI (weight in kilograms divided by the square of height in meters) and serum albumin (g/L).
• Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31]) [18mo]: The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in COMPASS 31 at 18 months. The COMPASS 31 is a measure of autonomic neuropathy symptoms. The questions evaluated 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome.

Sex: All, ages: 18 Years to 85 Years

Inclusion Criteria:

* Male or female of 18 to 85 years of age (inclusive);
* Have a diagnosis of FAP
* Neuropathy Impairment Score requirement of 5-130
* Meet Karnofsky performance status requirements
* Have adequate complete blood counts and liver function tests
* Have adequate cardiac function
* Have negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV)

Exclusion Criteria:

* Had a prior liver transplant or is planned to undergo liver transplant during the study period;
* Has untreated hypo- or hyperthyroidism;
* Has known human immunodeficiency virus (HIV) infection;
* Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated;
* Recently received an investigational agent or device
* Is currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid

Participant flow

Outcome results

• Modified Neuropathy Impairment Score +7 (mNIS+7) (Primary), Least squares mean, score on a scale: Patisiran (ALN-TTR02) -6.03 +/- 1.739; Placebo 27.96 +/- 2.602 (p <0.0000001)
• Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire (Secondary), Least squares mean, score on a scale: Patisiran (ALN-TTR02) -6.7 +/- 1.77; Placebo 14.4 +/- 2.73 (p <0.0000001)
• Neurological Impairment Score-Weakness (NIS-W) Score (Secondary), Least squares mean, score on a scale: Patisiran (ALN-TTR02) 0.05 +/- 1.306; Placebo 17.93 +/- 1.959 (p <0.0000001)
• Rasch-built Overall Disability Scale (R-ODS) Score (Secondary), Least squares mean, score on a scale: Patisiran (ALN-TTR02) 0.0 +/- 0.59; Placebo -8.9 +/- 0.88 (p <0.0000001)
• Timed 10-meter Walk Test (10-MWT, Gait Speed) (Secondary), Least squares mean, m/sec: Patisiran (ALN-TTR02) 0.077 +/- 0.0242; Placebo -0.235 +/- 0.0358 (p <0.0000001)
• Modified Body Mass Index (mBMI) (Secondary), Least squares mean, kg/m^2 × albumin g/L: Patisiran (ALN-TTR02) -3.7 +/- 9.57; Placebo -119.4 +/- 14.51 (p <0.0000001)
• Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31]) (Secondary), Least squares mean, score on a scale: Patisiran (ALN-TTR02) -5.29 +/- 1.300; Placebo 2.24 +/- 1.940 (p 0.0008)

Adverse events

Time frame: All Adverse Events (AEs) that occurred from start of study drug administration through End of Study (Day 567), or Follow-up (Day 602) if patient did not enter open-label extension study. AEs for patients with Rapid Disease Progression at Month 9 who stopped dosing were collected through Day 294 (42 days after last dose).

Serious adverse events by term

68 more terms not shown.

Other adverse events by term

• Results publication: Lin KP, Yang CC, Lee YC, Lee MJ, Vest J, Sweetser MT, White MT, Badri P, Hsieh ST, Chao CC. Patisiran, an RNAi therapeutic for hereditary transthyretin-mediated amyloidosis: Sub-analysis in Taiwanese patients from the APOLLO study. J Formos Med Assoc. 2024 Sep;123(9):975-984. doi: 10.1016/j.jfma.2024.03.008. Epub 2024 Mar 27. PMID 38548524
• Results publication: Quan D, Obici L, Berk JL, Ando Y, Aldinc E, White MT, Adams D. Impact of baseline polyneuropathy severity on patisiran treatment outcomes in the APOLLO trial. Amyloid. 2023 Mar;30(1):49-58. doi: 10.1080/13506129.2022.2118043. Epub 2022 Sep 18. PMID 36120830
• Results publication: Zhang X, Goel V, Attarwala H, Sweetser MT, Clausen VA, Robbie GJ. Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis. J Clin Pharmacol. 2020 Jan;60(1):37-49. doi: 10.1002/jcph.1480. Epub 2019 Jul 19. PMID 31322739
• Results publication: Minamisawa M, Claggett B, Adams D, Kristen AV, Merlini G, Slama MS, Dispenzieri A, Shah AM, Falk RH, Karsten V, Sweetser MT, Chen J, Riese R, Vest J, Solomon SD. Association of Patisiran, an RNA Interference Therapeutic, With Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis: The APOLLO Study. JAMA Cardiol. 2019 May 1;4(5):466-472. doi: 10.1001/jamacardio.2019.0849. PMID 30878017
• Results publication: Solomon SD, Adams D, Kristen A, Grogan M, Gonzalez-Duarte A, Maurer MS, Merlini G, Damy T, Slama MS, Brannagan TH 3rd, Dispenzieri A, Berk JL, Shah AM, Garg P, Vaishnaw A, Karsten V, Chen J, Gollob J, Vest J, Suhr O. Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis. Circulation. 2019 Jan 22;139(4):431-443. doi: 10.1161/CIRCULATIONAHA.118.035831. PMID 30586695
• Results publication: Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP, Vita G, Attarian S, Plante-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH 3rd, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153. PMID 29972753
• Results publication: Adams D, Suhr OB, Dyck PJ, Litchy WJ, Leahy RG, Chen J, Gollob J, Coelho T. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017 Sep 11;17(1):181. doi: 10.1186/s12883-017-0948-5. PMID 28893208

• Study Protocol (PDF, 2015-09-08)
• Statistical Analysis Plan (PDF, 2017-08-23)

• Jared Gollob, Study director, Alnylam Pharmaceuticals