VIDEO: Givosiran cuts acute intermittent porphyria attacks in pivotal trial

Although the study also identified some safety issues with givosiran, an RNA-inhibitor molecule delivered by subcutaneous injection once a month, the increases in liver enzyme levels it produced in some patients as well as decreased renal function did not seem severe or frequent enough to counterbalance the benefits to treated patients, who often have significant comorbidities and adverse effects because of their disease, Manisha Balwani, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Among the 48 patients assigned to the givosiran group, one patient dropped out because of an adverse effect of treatment.

The results put givosiran on track to become the first Food and Drug Administration–approved treatment for acute hepatic porphyria, a set of similar, rare genetic diseases that produce symptoms in about 1 in every 10,000 people, although asymptomatic disease is likely more common (Hepatol Commun. 2019 Feb;3[2]:193-206). The trial outcomes were also notable for the dramatic improvements in life-disrupting symptoms like pain, nausea, and fatigue that many treated patients experienced.

Patients’ lives were “completely transformed” by givosiran treatment, Dr. Balwani said in a video interview. Patients also had a reduced need for analgesics, including opioids, said Dr. Balwani, a medical geneticist at the Icahn School of Medicine at Mount Sinai in New York.

The ENVISION (A Study to Evaluate the Efficacy and Safety of Givosiran [ALN-AS1] in Patients With Acute Hepatic Porphyrias) study randomized 94 patients who were at least 12 years old and diagnosed with an acute hepatic porphyria, and had experienced at least two porphyria attacks during the prior 6 months. The study ran at 36 sites in 18 countries. Enrolled patients averaged about 39 years old, and had been diagnosed with a hepatic porphyria for an average of about 6 years. During the study, patients did not receive hemin (Panhematin) prophylaxis.

 

The study’s primary endpoint was the average annualized rate of porphyria attacks during 6 months of treatment, which was 3.2 attacks in 46 patients evaluable for efficacy on givosiran treatment and 12.5 attacks in 43 patients evaluable for efficacy in the control group, a 74% reduction in attacks with givosiran that was statistically significant, Dr. Balwani reported. The percentage of patients with no attacks during the study was 16% among control patients and 50% among those on givosiran. Future analysis of the study data will attempt to identify the patients with the best responses to givosiran.

Among the full cohort of 94 patients enrolled in the study, 21% of the givosiran-treated patients had a adverse reaction, and 17% had a severe adverse reaction, compared with rates of 9% and 11%, respectively, among controls. Three of the serious adverse reactions were judged related to givosiran treatment: one patient with pyrexia, one with abnormal liver function test results, and one patient who developed chronic kidney disease. A total of two patients in the givosiran group developed chronic kidney disease that warranted elective hospitalization for diagnostic evaluation, and an additional three patients on the drug developed chronic kidney disease that did not require hospitalization. Nausea affected 27% of patients on givosiran and 11% of the control patients. Injection-site reactions occurred in 17% of those on givosiran and in none of the placebo patients. An elevation in the serum level of alanine aminotransferase to more than three times the upper limit of normal of baseline occurred in 15% of the givosiran-treated patients and in 2% of the placebo patients.

Givosiran’s small RNA molecule inhibits production of 5‐aminolevulinic acid synthase 1 (ALAS‐1), the rate-limiting enzyme that drives production of the heme precursor molecules that are pathophysiologic in patients with acute hepatic porphyria.

[email protected]

SOURCE: Balwani M et al. J Hepatol. 2019 April 70(1):e81-2.

Although the study also identified some safety issues with givosiran, an RNA-inhibitor molecule delivered by subcutaneous injection once a month, the increases in liver enzyme levels it produced in some patients as well as decreased renal function did not seem severe or frequent enough to counterbalance the benefits to treated patients, who often have significant comorbidities and adverse effects because of their disease, Manisha Balwani, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Among the 48 patients assigned to the givosiran group, one patient dropped out because of an adverse effect of treatment.

The results put givosiran on track to become the first Food and Drug Administration–approved treatment for acute hepatic porphyria, a set of similar, rare genetic diseases that produce symptoms in about 1 in every 10,000 people, although asymptomatic disease is likely more common (Hepatol Commun. 2019 Feb;3[2]:193-206). The trial outcomes were also notable for the dramatic improvements in life-disrupting symptoms like pain, nausea, and fatigue that many treated patients experienced.

Patients’ lives were “completely transformed” by givosiran treatment, Dr. Balwani said in a video interview. Patients also had a reduced need for analgesics, including opioids, said Dr. Balwani, a medical geneticist at the Icahn School of Medicine at Mount Sinai in New York.

The ENVISION (A Study to Evaluate the Efficacy and Safety of Givosiran [ALN-AS1] in Patients With Acute Hepatic Porphyrias) study randomized 94 patients who were at least 12 years old and diagnosed with an acute hepatic porphyria, and had experienced at least two porphyria attacks during the prior 6 months. The study ran at 36 sites in 18 countries. Enrolled patients averaged about 39 years old, and had been diagnosed with a hepatic porphyria for an average of about 6 years. During the study, patients did not receive hemin (Panhematin) prophylaxis.

 

The study’s primary endpoint was the average annualized rate of porphyria attacks during 6 months of treatment, which was 3.2 attacks in 46 patients evaluable for efficacy on givosiran treatment and 12.5 attacks in 43 patients evaluable for efficacy in the control group, a 74% reduction in attacks with givosiran that was statistically significant, Dr. Balwani reported. The percentage of patients with no attacks during the study was 16% among control patients and 50% among those on givosiran. Future analysis of the study data will attempt to identify the patients with the best responses to givosiran.

Among the full cohort of 94 patients enrolled in the study, 21% of the givosiran-treated patients had a adverse reaction, and 17% had a severe adverse reaction, compared with rates of 9% and 11%, respectively, among controls. Three of the serious adverse reactions were judged related to givosiran treatment: one patient with pyrexia, one with abnormal liver function test results, and one patient who developed chronic kidney disease. A total of two patients in the givosiran group developed chronic kidney disease that warranted elective hospitalization for diagnostic evaluation, and an additional three patients on the drug developed chronic kidney disease that did not require hospitalization. Nausea affected 27% of patients on givosiran and 11% of the control patients. Injection-site reactions occurred in 17% of those on givosiran and in none of the placebo patients. An elevation in the serum level of alanine aminotransferase to more than three times the upper limit of normal of baseline occurred in 15% of the givosiran-treated patients and in 2% of the placebo patients.

Givosiran’s small RNA molecule inhibits production of 5‐aminolevulinic acid synthase 1 (ALAS‐1), the rate-limiting enzyme that drives production of the heme precursor molecules that are pathophysiologic in patients with acute hepatic porphyria.

[email protected]

SOURCE: Balwani M et al. J Hepatol. 2019 April 70(1):e81-2.

Although the study also identified some safety issues with givosiran, an RNA-inhibitor molecule delivered by subcutaneous injection once a month, the increases in liver enzyme levels it produced in some patients as well as decreased renal function did not seem severe or frequent enough to counterbalance the benefits to treated patients, who often have significant comorbidities and adverse effects because of their disease, Manisha Balwani, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Among the 48 patients assigned to the givosiran group, one patient dropped out because of an adverse effect of treatment.

The results put givosiran on track to become the first Food and Drug Administration–approved treatment for acute hepatic porphyria, a set of similar, rare genetic diseases that produce symptoms in about 1 in every 10,000 people, although asymptomatic disease is likely more common (Hepatol Commun. 2019 Feb;3[2]:193-206). The trial outcomes were also notable for the dramatic improvements in life-disrupting symptoms like pain, nausea, and fatigue that many treated patients experienced.

Patients’ lives were “completely transformed” by givosiran treatment, Dr. Balwani said in a video interview. Patients also had a reduced need for analgesics, including opioids, said Dr. Balwani, a medical geneticist at the Icahn School of Medicine at Mount Sinai in New York.

The ENVISION (A Study to Evaluate the Efficacy and Safety of Givosiran [ALN-AS1] in Patients With Acute Hepatic Porphyrias) study randomized 94 patients who were at least 12 years old and diagnosed with an acute hepatic porphyria, and had experienced at least two porphyria attacks during the prior 6 months. The study ran at 36 sites in 18 countries. Enrolled patients averaged about 39 years old, and had been diagnosed with a hepatic porphyria for an average of about 6 years. During the study, patients did not receive hemin (Panhematin) prophylaxis.

 

The study’s primary endpoint was the average annualized rate of porphyria attacks during 6 months of treatment, which was 3.2 attacks in 46 patients evaluable for efficacy on givosiran treatment and 12.5 attacks in 43 patients evaluable for efficacy in the control group, a 74% reduction in attacks with givosiran that was statistically significant, Dr. Balwani reported. The percentage of patients with no attacks during the study was 16% among control patients and 50% among those on givosiran. Future analysis of the study data will attempt to identify the patients with the best responses to givosiran.

Among the full cohort of 94 patients enrolled in the study, 21% of the givosiran-treated patients had a adverse reaction, and 17% had a severe adverse reaction, compared with rates of 9% and 11%, respectively, among controls. Three of the serious adverse reactions were judged related to givosiran treatment: one patient with pyrexia, one with abnormal liver function test results, and one patient who developed chronic kidney disease. A total of two patients in the givosiran group developed chronic kidney disease that warranted elective hospitalization for diagnostic evaluation, and an additional three patients on the drug developed chronic kidney disease that did not require hospitalization. Nausea affected 27% of patients on givosiran and 11% of the control patients. Injection-site reactions occurred in 17% of those on givosiran and in none of the placebo patients. An elevation in the serum level of alanine aminotransferase to more than three times the upper limit of normal of baseline occurred in 15% of the givosiran-treated patients and in 2% of the placebo patients.

Givosiran’s small RNA molecule inhibits production of 5‐aminolevulinic acid synthase 1 (ALAS‐1), the rate-limiting enzyme that drives production of the heme precursor molecules that are pathophysiologic in patients with acute hepatic porphyria.

[email protected]

SOURCE: Balwani M et al. J Hepatol. 2019 April 70(1):e81-2.