Meeting NewsPerspective

Novel RNA interference agents improve lipid profiles in healthy volunteers

Christie M. Ballantyne

PHILADELPHIA — Two novel RNA interference agents, one targeting apolipoprotein C-III and one targeting angiopoietin-like protein 3, improved various lipid parameters in early studies with healthy volunteers, according to new data presented at the American Heart Association Scientific Sessions.

One agent targeting apolipoprotein C-III (ARO-APOC3, Arrowhead) was associated with reductions in serum APOC3 and improvements in other lipids, while another agent targeting ANGPTL3 (ARO-ANG3, Arrowhead Pharmaceuticals) was associated with reductions in ANGPTL3 and improvements in other lipids, researchers reported.

Targeting APOC3

Genetic studies identified loss of function of APOC3 as associated with lower triglycerides and improved CVD outcomes, and APOC3 is synthesized in hepatocytes, making it a good target for an RNA interference agent, Christie M. Ballantyne MD, professor of medicine at Baylor College of Medicine, said during a press conference.

ARO-APOC3 is “designed to induce deep and durable gene-specific silencing while avoiding off-target effects,” he said. Its initial application would be in patients with familial chylomicronemia syndrome, who have severely elevated triglycerides leading to pancreatitis, and who have not benefited from standard triglyceride-lowering therapies, he said.

“There has already been an antisense oligonucleotide approach (volanesorsen, Akcea) which showed efficacy for lowering triglycerides in severe hyperlipidemia, but unfortunately, due to the adverse event profile in both toxicity and compliance, the FDA did not approve that therapy,” Ballantyne said during the press conference.

For the phase 1 clinical study, researchers assigned 40 healthy volunteers (mean age, 36 years; 70% men) to receive one dose of placebo or ARO-APOC3 in doses ranging from 10 mg to 100 mg.

There were no serious or severe adverse events, and eight participants had mild injection site reactions, Ballantyne said. One participant had transient elevation of alanine aminotransferase, which normalized by day 113.

At 16 weeks, mean maximum reduction in serum APOC3 in those assigned ARO-APOC3 ranged from 72% in those with the 10 mg dose to 94% in those with the 100 mg dose (P < .0001 for both), and the reductions were maintained at the end of the study, Ballantyne said.

Mean maximum reduction in serum triglycerides after a single dose ranged from 53% in those with the 10 mg dose (P = .002) to 64% in those with the 100 mg dose (P = .0001), and mean maximum reduction in serum VLDL ranged from 53% in those with the 10 mg dose (P = .0005) to 68% in those with the 50 mg dose (P < .0001), he said, noting these reductions were also maintained at the end of the study.

Mean maximum reduction in serum LDL ranged from 12% with the 25 mg dose (P = .03) to 25% with the 10 mg dose (P = .0004) and mean maximum increase in serum HDL ranged from 30% with the 10 mg dose (P = .0006) to 69% with the 100 mg dose (P < .0001), he said, noting the HDL increase was maintained at the end of the study.

“RNA interference leads to reductions in APOC3, even at the low dose of 10 to 25 mg,” Ballantyne said at the press conference. “There was quite a robust response and a favorable safety profile.”

If the therapy can be given infrequently because one dose sustains improvements for a long time, that may help with patient adherence, Ballantyne said.

“You can miss a week of your statin and it’s not that big of a deal,” he said. “If you miss your triglyceride therapy for a week or two and you have severe high triglycerides, you can end up in the hospital with pancreatitis. It’s very unforgiving for lifestyle and adherence to medications. So, it’s beneficial to have a therapy that would have sustained reductions.”

Targeting ANGPTL3

Gerald F. Watts

Gerald F. Watts, DSc, PhD, DM, FRCP, FRACP, senior academic in the School of Medicine and Pharmacology at the University of Western Australia, said during the press conference that genetic studies have also documented that loss of function in ANGPTL3 confers reductions in lipid levels and improved CVD outcomes, and ANGPTL3 is also a good target for RNA interference because it is synthesized in hepatocytes.

For the phase 1 clinical study, the researchers assigned 40 healthy volunteers (mean age, 36 years; 50% men) to receive placebo or doses of ARO-ANG3 ranging from 35 mg to 300 mg.

At 16 weeks, mean maximum reduction in ANGPTL3 in those assigned ARO-ANG3 ranged from 55% in those with the 35 mg dose to 83% in those with the 300 mg dose (P < .0001 for both), and the reductions were maintained at the end of the study, Watts said.

Mean maximum reduction in triglycerides ranged from 31% in those with the 35 mg dose (P = .06) to 66% in those with the 200 mg dose (P = .0002), and mean maximum reduction in VLDL ranged from 30% in those with the 35 mg dose (P = .006) to 65% in those with the 200 mg dose (P < .0001), he said. These reductions were also maintained at the end of the study for the 200 mg and 300 mg doses.

Mean maximum LDL reductions ranged from 9% with the 200 mg dose (P = .4) to 30% with the 300 mg dose (P = .0004). The highest reduction maintained at week 16 was 28% for the 100 mg dose, and the 200 mg group may have been an outlier because it had the two participants with the highest triglyceride levels in the cohort, he said.

Mean maximum HDL was reduced from 8% with the 35 mg dose (P = .02) to 26% with the 300 mg dose (P < .0001), he said.

There were no serious adverse events or study dropouts, nor any abnormalities in platelet counts or renal biochemistry. One mild injection site reaction was reported and two participants, one in each treatment group, had elevation of transient alanine aminotransferase, Watts said, noting the one from the therapy group was taking an herbal supplement known to cause liver toxicity.

“ANGPTL3 inhibition is potentially a new mechanism for potentially addressing residual risk of CVD in patients with dyslipidemias,” Watts said at the press conference. “Multi-dose studies in patients with nonalcoholic fatty liver disease, hyperlipidemia despite statin therapy, familial hypercholesterolemia and severe hypertriglyceridemia are underway.”

Brave new world

Daniel J. Rader

“We are in a brave new world of RNAi therapeutics,” Daniel J. Rader, MD, chair of the department of genetics, chief of the division of translational medicine and human genetics and the Seymour-Gray Professor of Molecular Medicine at the University of Pennsylvania Perelman School of Medicine, said during a discussion of the findings. “It’s similar to, but mechanistically different from, antisense oligonucleotides. The same molecule can go around and destroy multiple aspects of the RNA in a way that provides substantial longevity in terms of their duration of effect.”

Lowering elevated triglycerides is an unmet need, and the APOC3 and ANGPTL3 genes inhibit the lipoprotein lipase pathway “and are great new targets that have come out of human genetics,” Rader said.

The stable reductions out to 16 weeks “are quite remarkable,” he said. “It will be interesting to figure out which of these will do better in the long run. The agent targeting ANGPTL3 lowers LDL more but also lowers HDL. APOC3 is also made in the intestine, which is not targeted, while ANGPTL3 is largely liver-derived. We also need to learn how frequently these will need to be dosed. And we need to know how these will compare to other approaches to these targets, including antibodies and antisense oligonucleotides. It’s going to be an interesting next several years.” – by Erik Swain

References:

Ballantyne CM, et al.

Watts GF, et al. Late Breaking Science VI: New Frontiers in Lipid Therapy. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Disclosures: The studies were funded by Arrowhead Pharmaceuticals. Ballantyne reports he has financial ties with Abbott Diagnostics, Akcea, Amarin, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Denka Seiken, Esperion, Intercept, Janssen, Matinas BioPharma, Merck, Novartis, Novo Nordisk, Regeneron, Roche and Sanofi Synthelabo, and that he is named on a patent filed by his institution and Roche. Watts reports no relevant financial disclosures. Rader reports he holds equity in Vascular Strategies, received honoraria from Alnylam, Novartis, Pfizer and Verve and is an unpaid advisor to the FH Foundation.

Christie M. Ballantyne

PHILADELPHIA — Two novel RNA interference agents, one targeting apolipoprotein C-III and one targeting angiopoietin-like protein 3, improved various lipid parameters in early studies with healthy volunteers, according to new data presented at the American Heart Association Scientific Sessions.

One agent targeting apolipoprotein C-III (ARO-APOC3, Arrowhead) was associated with reductions in serum APOC3 and improvements in other lipids, while another agent targeting ANGPTL3 (ARO-ANG3, Arrowhead Pharmaceuticals) was associated with reductions in ANGPTL3 and improvements in other lipids, researchers reported.

Targeting APOC3

Genetic studies identified loss of function of APOC3 as associated with lower triglycerides and improved CVD outcomes, and APOC3 is synthesized in hepatocytes, making it a good target for an RNA interference agent, Christie M. Ballantyne MD, professor of medicine at Baylor College of Medicine, said during a press conference.

ARO-APOC3 is “designed to induce deep and durable gene-specific silencing while avoiding off-target effects,” he said. Its initial application would be in patients with familial chylomicronemia syndrome, who have severely elevated triglycerides leading to pancreatitis, and who have not benefited from standard triglyceride-lowering therapies, he said.

“There has already been an antisense oligonucleotide approach (volanesorsen, Akcea) which showed efficacy for lowering triglycerides in severe hyperlipidemia, but unfortunately, due to the adverse event profile in both toxicity and compliance, the FDA did not approve that therapy,” Ballantyne said during the press conference.

For the phase 1 clinical study, researchers assigned 40 healthy volunteers (mean age, 36 years; 70% men) to receive one dose of placebo or ARO-APOC3 in doses ranging from 10 mg to 100 mg.

There were no serious or severe adverse events, and eight participants had mild injection site reactions, Ballantyne said. One participant had transient elevation of alanine aminotransferase, which normalized by day 113.

At 16 weeks, mean maximum reduction in serum APOC3 in those assigned ARO-APOC3 ranged from 72% in those with the 10 mg dose to 94% in those with the 100 mg dose (P < .0001 for both), and the reductions were maintained at the end of the study, Ballantyne said.

Mean maximum reduction in serum triglycerides after a single dose ranged from 53% in those with the 10 mg dose (P = .002) to 64% in those with the 100 mg dose (P = .0001), and mean maximum reduction in serum VLDL ranged from 53% in those with the 10 mg dose (P = .0005) to 68% in those with the 50 mg dose (P < .0001), he said, noting these reductions were also maintained at the end of the study.

PAGE BREAK

Mean maximum reduction in serum LDL ranged from 12% with the 25 mg dose (P = .03) to 25% with the 10 mg dose (P = .0004) and mean maximum increase in serum HDL ranged from 30% with the 10 mg dose (P = .0006) to 69% with the 100 mg dose (P < .0001), he said, noting the HDL increase was maintained at the end of the study.

“RNA interference leads to reductions in APOC3, even at the low dose of 10 to 25 mg,” Ballantyne said at the press conference. “There was quite a robust response and a favorable safety profile.”

If the therapy can be given infrequently because one dose sustains improvements for a long time, that may help with patient adherence, Ballantyne said.

“You can miss a week of your statin and it’s not that big of a deal,” he said. “If you miss your triglyceride therapy for a week or two and you have severe high triglycerides, you can end up in the hospital with pancreatitis. It’s very unforgiving for lifestyle and adherence to medications. So, it’s beneficial to have a therapy that would have sustained reductions.”

Targeting ANGPTL3

Gerald F. Watts

Gerald F. Watts, DSc, PhD, DM, FRCP, FRACP, senior academic in the School of Medicine and Pharmacology at the University of Western Australia, said during the press conference that genetic studies have also documented that loss of function in ANGPTL3 confers reductions in lipid levels and improved CVD outcomes, and ANGPTL3 is also a good target for RNA interference because it is synthesized in hepatocytes.

For the phase 1 clinical study, the researchers assigned 40 healthy volunteers (mean age, 36 years; 50% men) to receive placebo or doses of ARO-ANG3 ranging from 35 mg to 300 mg.

At 16 weeks, mean maximum reduction in ANGPTL3 in those assigned ARO-ANG3 ranged from 55% in those with the 35 mg dose to 83% in those with the 300 mg dose (P < .0001 for both), and the reductions were maintained at the end of the study, Watts said.

Mean maximum reduction in triglycerides ranged from 31% in those with the 35 mg dose (P = .06) to 66% in those with the 200 mg dose (P = .0002), and mean maximum reduction in VLDL ranged from 30% in those with the 35 mg dose (P = .006) to 65% in those with the 200 mg dose (P < .0001), he said. These reductions were also maintained at the end of the study for the 200 mg and 300 mg doses.

PAGE BREAK

Mean maximum LDL reductions ranged from 9% with the 200 mg dose (P = .4) to 30% with the 300 mg dose (P = .0004). The highest reduction maintained at week 16 was 28% for the 100 mg dose, and the 200 mg group may have been an outlier because it had the two participants with the highest triglyceride levels in the cohort, he said.

Mean maximum HDL was reduced from 8% with the 35 mg dose (P = .02) to 26% with the 300 mg dose (P < .0001), he said.

There were no serious adverse events or study dropouts, nor any abnormalities in platelet counts or renal biochemistry. One mild injection site reaction was reported and two participants, one in each treatment group, had elevation of transient alanine aminotransferase, Watts said, noting the one from the therapy group was taking an herbal supplement known to cause liver toxicity.

“ANGPTL3 inhibition is potentially a new mechanism for potentially addressing residual risk of CVD in patients with dyslipidemias,” Watts said at the press conference. “Multi-dose studies in patients with nonalcoholic fatty liver disease, hyperlipidemia despite statin therapy, familial hypercholesterolemia and severe hypertriglyceridemia are underway.”

Brave new world

Daniel J. Rader

“We are in a brave new world of RNAi therapeutics,” Daniel J. Rader, MD, chair of the department of genetics, chief of the division of translational medicine and human genetics and the Seymour-Gray Professor of Molecular Medicine at the University of Pennsylvania Perelman School of Medicine, said during a discussion of the findings. “It’s similar to, but mechanistically different from, antisense oligonucleotides. The same molecule can go around and destroy multiple aspects of the RNA in a way that provides substantial longevity in terms of their duration of effect.”

Lowering elevated triglycerides is an unmet need, and the APOC3 and ANGPTL3 genes inhibit the lipoprotein lipase pathway “and are great new targets that have come out of human genetics,” Rader said.

The stable reductions out to 16 weeks “are quite remarkable,” he said. “It will be interesting to figure out which of these will do better in the long run. The agent targeting ANGPTL3 lowers LDL more but also lowers HDL. APOC3 is also made in the intestine, which is not targeted, while ANGPTL3 is largely liver-derived. We also need to learn how frequently these will need to be dosed. And we need to know how these will compare to other approaches to these targets, including antibodies and antisense oligonucleotides. It’s going to be an interesting next several years.” – by Erik Swain

References:

Ballantyne CM, et al.

Watts GF, et al. Late Breaking Science VI: New Frontiers in Lipid Therapy. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Disclosures: The studies were funded by Arrowhead Pharmaceuticals. Ballantyne reports he has financial ties with Abbott Diagnostics, Akcea, Amarin, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Denka Seiken, Esperion, Intercept, Janssen, Matinas BioPharma, Merck, Novartis, Novo Nordisk, Regeneron, Roche and Sanofi Synthelabo, and that he is named on a patent filed by his institution and Roche. Watts reports no relevant financial disclosures. Rader reports he holds equity in Vascular Strategies, received honoraria from Alnylam, Novartis, Pfizer and Verve and is an unpaid advisor to the FH Foundation.

    Perspective
    Jennifer G. Robinson

    Jennifer G. Robinson

    The brilliance of these compounds is that there is a very focused target in a very focused organ. If the action is just in the liver, off-target effects due to the drug should be limited, and the safety should be better. We are on the cusp of a revolution in genetics and precision medicine. Maybe for one patient, APOC3 is the best thing to inhibit, but for another, it is something else.

    However, the devil is in the details about how we are going to pay to get there. We are all wrestling with this. Ultimately, it will come down to price and resources. We only have so much money we are willing to pay for health care. What is the best use of that money to maximize the outcomes?

    • Jennifer G. Robinson, MD, MPH
    • Professor of Medicine and Epidemiology
      University of Iowa Carver School of Medicine
      Director, Preventive Intervention Center
      University of Iowa College of Public Health

    Disclosures: Robinson reports she received honoraria from Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron and Sanofi and research grants from Acasti, Amarin, Amgen, AstraZeneca, Eisai, Esperion, Merck, Regeneron, Sanofi and Takeda.

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