Amendment 1 - The primary purpose for this protocol amendment is to clarify that based on review of data from the ongoing ALN-AS1-001 study, the Safety Review Committee (SRC) has determined the study starting dose and dosing regimen for administration in study ALN-AS1-002 is to be 5.0 mg/kg administered every 3 months. Additionally, minor changes were made to schedules of assessment to increase consistency and clarity.

Amendment 2 - The primary purpose of this amendment is to implement additional safety monitoring; specifically to require lipase monitoring and review of recent clinical laboratory results prior to dosing. These changes are being made in accordance with the study's Safety Review Committee recommendation pursuant to an unlikely related SAE of hemorrhagic pancreatitis with fatal outcome. Additionally, out of date text describing the nonclinical and clinical experience with ALN-AS1 has been removed and replaced with a reference to the current Investigator's Brochure, which has been updated to include a description of the aforementioned unlikely related fatal SAE.

Amendment 3 - The purpose of this amendment is to update the risk-benefit assessment of the study protocol to align with the current Investigator's Brochure, to add regular monitoring of prothrombin time (PT), International Normalized Ratio (INR), and c-reactive protein (CRP), and to clarify the timing of the review of clinical laboratory assessments prior to scheduled dosing.

Amendment 4 - This protocol is being amended to update the electrocardiogram (ECG) assessments to obtain triplicate 12-lead ECGs using central equipment and paired with plasma PK at times corresponding to nominal maximum concentration (Cmax). Also, Schedule of Assessments footnotes and related text were updated to define the visit range in which previously noted predose interpretation of hematology, coagulation, and chemistry test results are required.

Amendment 5 - The purpose of the amendment is to: Include clinical data on a single case of anaphylactic reaction, information regarding the potential risk for anaphylactic reactions, and provide updated guidance for dosing and monitoring. The event of anaphylactic reaction was previously reported to applicable regulatory authorities and Institutional Review Boards/Ethics Committees. Benefit-Risk Assessment modified to align with potential risks in the Investigator’s Brochure. Information on reproductive health moved to Contraceptive Requirements and cytochrome P450 (CYP) inhibition moved to Concomitant Medications. Update guidance and procedures on patient withdrawal from study. Schedule of Assessments footnotes were updated to: Update end of study visit, early termination visit, and safety follow-up visit timing and assessments. Clarify clinical laboratory testing required prior to dosing. Clarify timing of ECG assessments for patients administered ≤ 2.5 mg/kg and >2.5 mg/kg ALN-AS1 provide the following clarifications: o patient withdrawal details regarding subsequent visits and data collection o definition of sexual abstinence o contraception with an intrauterine hormone-releasing system also requires use of a barrier method

Amendment 6 - The primary purpose for this protocol amendment is to provide updated information from a recently completed drug-drug interaction study (ALN-AS1-004) performed in acute intermittent porphyria (AIP) patients who are asymptomatic high excreters in the concomitant medications section. The results of the study indicated that ALN-AS1 treatment resulted in moderate reduction in CYP1A2 and CYP2D6 activity, weak reduction in CYP3A4 and CYP2C19 activity, and no change in the activity of CYP2C9. This amendment also extends the treatment period to 48 months to continue the study until ALN-AS1 is anticipated to be commercially available in the countries where the study sites are located. Additional updates are being implemented as noted below: clarification that patients may continue to receive ALN-AS1 until it is commercially available in the patient’s territory, addition of guidance for serious breaches of protocol, and deletion of Section 11.3, List of Sensitive CYP3A substrates and those with a Narrow Therapeutic Range.

Amendment 7 - The purpose of this protocol amendment is to incorporate Urgent Safety Measures (USMs) that were communicated to investigators in a Dear Investigator Letter to assure the safety of study participants while minimizing risks to study integrity amid the COVID-19 pandemic. These changes are in line with guidance from both the European Medicines Agency and the United States Food and Drug Administration on the conduct of clinical trials during the COVID-19 pandemic.

Amendment 8 - The purpose of this protocol amendment is to recommend testing of blood homocysteine levels. In addition, it is recommended that patients with increased blood homocysteine levels receive a supplement containing vitamin B6. These recommendations are being made because during ALN-AS1 treatment, increases in blood homocysteine levels have been observed compared to levels before ALN-AS1 treatment. Thus, monitoring for changes in blood homocysteine levels during treatment with ALN-AS1 has been incorporated into the protocol. Blood homocysteine levels may also be increased in patients with acute hepatic porphyria (AHP), vitamin deficiencies, or chronic kidney disease. The clinical relevance of the elevations in blood homocysteine during ALN-AS1 treatment is unknown.