Givosiran clinical trial results
| . | Phase 1/2 . | Phase 3 double-blind period . | OLE, 36 months . |
|---|---|---|---|
| Dates | 6 May 2015-6 September 2017 | 16 November 2017-31 January 2019 | Through 3 May 2021 |
| Patient number | 17 AIP patients with recurrent attacks (Parts A and B), 23 AIP patients without recurrent attacks (Part C) | 94 AHP patients with recurrent attacks | 93 AHP patients enrolled 14 discontinued 79 completed |
| Gender | 78% female, parts A/B; 88% female, part C | 89% female | 89% female |
| Age (years) | Median 47 (range, 30-64), parts A/B; 36 (21-59), part C on givosiran | 39.0 ± 11.4 (mean, SD) for AIP patients | Median, 37.5 (range, 19-65) |
| AHP types | All AIP | 89 AIP, 1 HCP, 2 VP, 2 no identified mutation | 89 AIP, 4 other AHP |
| Previous hemin prophylaxis | 46% of patients on givosiran in part C | 40% | 40% |
| Attack rate decrease (%) | 79% reduction in median attack rate for recurrent attack patients | 74% and 90% reduction in the mean and median AAR, respectively | 92% reduction in median AAR for placebo crossover group. Median AAR 0.4 across both placebo crossover and continuous givosiran groups. |
| Urinary PBG decrease (%) | Maximum reduction 96%, dose dependent | 91% decrease in median urinary PBG | Sustained improvement |
| Urinary ALA decrease (%) | Maximum reduction 91%, dose dependent | 86% decrease in median urinary ALA | Sustained improvement |
| Quality of life | Not reported | Improved | Sustained improvement |
| Liver adverse events | No clinically significant changes in laboratory measures | ALT level of more than 3 × ULN in 15% of givosiran group and 2% of placebo, to 9.9 × ULN in one patient leading to discontinuation. ALT later normalized in all patients. | 11% of patients had elevated ALT levels >3 × ULN, generally ~3-6 months with resolution over time. |
| Kidney adverse events | No clinically significant changes in laboratory measures | Abnormal renal function in 15% of givosiran group and 7% of placebo | <25% of patients had renal adverse events, with small initial decreases in renal function stabilizing over time. |
| Other adverse events | Nasopharyngitis, abdominal pain, diarrhea, and injection site reaction, but similar incidence among treatment groups. One patient on givosiran died of hemorrhagic pancreatitis. | Adverse events reported more commonly than placebo included nausea, injection site reactions, chronic kidney disease, rash, increased ALT, and fatigue. | The most frequent adverse events were injection site reactions and nausea. Sixteen percent of patients experienced elevated homocysteine levels. Four patients discontinued therapy due to treatment-related adverse events that included injection site reaction, elevated homocysteine level, pancreatitis, drug hypersensitivity, and abnormal liver biochemistries. |
| . | Phase 1/2 . | Phase 3 double-blind period . | OLE, 36 months . |
|---|---|---|---|
| Dates | 6 May 2015-6 September 2017 | 16 November 2017-31 January 2019 | Through 3 May 2021 |
| Patient number | 17 AIP patients with recurrent attacks (Parts A and B), 23 AIP patients without recurrent attacks (Part C) | 94 AHP patients with recurrent attacks | 93 AHP patients enrolled 14 discontinued 79 completed |
| Gender | 78% female, parts A/B; 88% female, part C | 89% female | 89% female |
| Age (years) | Median 47 (range, 30-64), parts A/B; 36 (21-59), part C on givosiran | 39.0 ± 11.4 (mean, SD) for AIP patients | Median, 37.5 (range, 19-65) |
| AHP types | All AIP | 89 AIP, 1 HCP, 2 VP, 2 no identified mutation | 89 AIP, 4 other AHP |
| Previous hemin prophylaxis | 46% of patients on givosiran in part C | 40% | 40% |
| Attack rate decrease (%) | 79% reduction in median attack rate for recurrent attack patients | 74% and 90% reduction in the mean and median AAR, respectively | 92% reduction in median AAR for placebo crossover group. Median AAR 0.4 across both placebo crossover and continuous givosiran groups. |
| Urinary PBG decrease (%) | Maximum reduction 96%, dose dependent | 91% decrease in median urinary PBG | Sustained improvement |
| Urinary ALA decrease (%) | Maximum reduction 91%, dose dependent | 86% decrease in median urinary ALA | Sustained improvement |
| Quality of life | Not reported | Improved | Sustained improvement |
| Liver adverse events | No clinically significant changes in laboratory measures | ALT level of more than 3 × ULN in 15% of givosiran group and 2% of placebo, to 9.9 × ULN in one patient leading to discontinuation. ALT later normalized in all patients. | 11% of patients had elevated ALT levels >3 × ULN, generally ~3-6 months with resolution over time. |
| Kidney adverse events | No clinically significant changes in laboratory measures | Abnormal renal function in 15% of givosiran group and 7% of placebo | <25% of patients had renal adverse events, with small initial decreases in renal function stabilizing over time. |
| Other adverse events | Nasopharyngitis, abdominal pain, diarrhea, and injection site reaction, but similar incidence among treatment groups. One patient on givosiran died of hemorrhagic pancreatitis. | Adverse events reported more commonly than placebo included nausea, injection site reactions, chronic kidney disease, rash, increased ALT, and fatigue. | The most frequent adverse events were injection site reactions and nausea. Sixteen percent of patients experienced elevated homocysteine levels. Four patients discontinued therapy due to treatment-related adverse events that included injection site reaction, elevated homocysteine level, pancreatitis, drug hypersensitivity, and abnormal liver biochemistries. |
AAR, annualized attack rate; AHP, acute hepatic porphyria; AIP, acute intermittent porphyria; ALA, d-aminolevulinic acid; ALT, alanine aminotransferase; PBG, porphobilinogen; SD, standard deviation; ULN, upper limit of normal.