Givosiran: Timing of Dosing

Givosiran: Timing of Dosing

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The full Prescribing Information for GIVLAARI® (givosiran) is provided here. Alnylam Pharmaceuticals does not recommend the use of its products in any manner that is inconsistent with the approved Prescribing Information. This resource may contain information that is not in the approved Prescribing Information.

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INDEX

Label Information – Clinical Data – Abbreviations – References

Givlaari prescribing information – Relevant content

For relevant labeling information, please refer to the following section(s) of the Prescribing Information:1

• DOSAGE AND ADMINISTRATION Section 2.1 Recommended Dosage

Clinical Data

Study Design

The Phase 1 study of givosiran was a multicenter, randomized, placebo-controlled, 3-part study (n=23 in Parts A and B; n=17 in Part C) designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of givosiran. The clinical activity of givosiran was also explored in Part C. Parts A and B were single-blind trials of single ascending and multiple ascending dose phases, respectively, in patients with AIP who were CHEs (defined as having a urinary porphobilinogen level >4 mmol/mol creatinine at screening and no attacks in the 6 months before baseline).2

Part C was a multidose, double-blind study in which patients with AIP were followed during a run-in period of 4 to 24 weeks. These patients had to have ≥1 attack prior to randomization, in addition to ≥2 attacks within the 6 months before the run-in period; or receive scheduled hemin prophylaxis at the start of the run-in period as needed. The 17 AIP patients were divided into 5 cohorts and were randomly assigned in a 3:1 ratio to receive givosiran (2.5 or 5.0 mg/kg) at quarterly or monthly intervals or placebo for 12 weeks (13 patients were assigned to receive givosiran and 4 to receive placebo). Patients were followed for an additional 12 weeks after the last injection.2

Pharmacodynamics

In Part C, in each of the four givosiran-treated cohorts (2.5 mg/kg quarterly for two doses, 2.5 mg/kg monthly for four doses, 5.0 mg/kg quarterly for two doses, or 5.0 mg/kg monthly for four doses), reduction of ALAS1 mRNA from baseline was seen with maximal reductions of 49 (±3%), 67 (±3%), 53 (±7%), and 74 (±6%), respectively. Reduction in ALAS1 mRNA was accompanied by a lowering of urinary ALA and PBG with a mean maximum reduction of >90% compared to baseline observed in both monthly doses. The monthly dosing regimens led to sustained urinary ALA and PBG reductions and lower peak-to-trough fluctuations when compared to the quarterly dosing regimen. There was no observed difference in reduction of urinary ALA or PBG with the increased monthly dose regimen (2.5 mg/kg versus 5.0 mg/kg).2

Exploratory Clinical Outcomes

The mean AAR was evaluated in Part C as an exploratory endpoint and is shown in Figure 1. Attacks were defined as those leading to hospitalization, urgent healthcare visits, or the use of intravenous hemin at home. The mean AAR during the treatment period of Part C was 7.2 for all givosiran-treated groups, compared to 16.7 in the placebo group (a 57% difference). The mean AAR was further reduced when only the 2.5 and 5.0 mg/kg monthly givosiran dosing groups were compared to placebo (83% and 75% reduction, respectively). Though a statistical analysis was not conducted, patients who received monthly givosiran at either dose had a lower mean AAR than patients who received either quarterly givosiran dose (Figure 1).2

Figure 1. Mean AAR.2

The annualized number of hemin doses was also evaluated between treatment groups in Part C and is shown in Figure 2. Patients treated with givosiran across all groups in Part C had a mean annualized number of hemin doses of 12.1 versus 23.4 for the placebo group (a 48% reduction). When comparing the run-in period to the treatment period, givosiran treatment reduced the annualized hemin doses by a mean of 64% across all groups as compared to a 34% mean reduction in the placebo group. Though a statistical analysis was not conducted, patients who received monthly givosiran at either dose had lower mean annualized number of hemin doses than patients who received either quarterly givosiran dose (Figure 2).2

Figure 2. Mean Annualized Number of Hemin Doses.2

Safety

Most AEs in the Phase 1 Study were mild or moderate, occurred at similar rates across the treatment groups, and had no clear relationship to givosiran dosing. The most common AEs across all 3 parts of the study were abdominal pain, nausea, diarrhea, and nasopharyngitis. Injection-site reactions were reported in 6 patients who received givosiran (18%) and in no patients who received placebo.2 Eight SAEs occurred in 6 patients who received givosiran and none who received placebo, including abdominal pain (2 patients) and spontaneous abortion, influenza A infection, functional gastrointestinal disorder, staphylococcal bacteremia, auditory hallucination, and fatal hemorrhagic pancreatitis (1 patient each). All SAEs were assessed as unlikely to be related to givosiran treatment by the investigating physician.2,3

Abbreviations

AAR = annualized attack rate; AE = adverse event; AIP = acute intermittent porphyria; ALA = aminolevulinic acid;
ALAS1 = aminolevulinic acid synthase 1; CHE = chronic high excreter; PBG = porphobilinogen; SAE = serious adverse event.

Updated 25 Oct 2024

References

1.  GIVLAARI (givosiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.

2.  Sardh E, Harper P, Balwani M, et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380(6):549-558. doi:10.1056/NEJMoa1807838

3.  Supplement to: Sardh E, Harper P, Balwani M, et al. Phase 1 trial of an RNA interference therapy for acute intermittent Porphyria. N Engl J Med. 2019;380(6):549-558. doi:10.1056/NEJMoa1807838