Kallikrein Inhibitor STAR-0215 Has Long-lasting Effect in Monkeys

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by Steve Bryson, PhD |

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STAR-0215, an investigational therapy to prevent swelling attacks in people with hereditary angioedema (HAE), rapidly and durably suppressed the enzyme kallikrein, supporting a once every three months or longer dosing in humans, according to new preclinical data.

The data was recently presented in a flash talk titled, “STAR-0215, a Long-Acting Monoclonal Antibody Plasma Kallikrein Inhibitor in Development for Treatment of HAE, Demonstrated Sustained Functional Inhibition in Subcutaneously Dosed Cynomolgus Monkeys,” at the European Academy of Allergy and Immunology 2022 Hybrid Congress in Prague, the Czech Republic.

The potential therapy’s mechanism of action is similar to that of the approved HAE medicine Takhzyro (lanadelumab), marketed by Takeda, which is given via subcutaneous (under-the-skin) injection, usually once every two weeks.

Building on these and other preclinical data, Astria Therapeutics, the therapy’s developer, hopes to soon launch a Phase 1a study to test STAR-0215 in healthy human volunteers.

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“These new preclinical results continue to support that STAR-0215 is a novel, potent, and selective inhibitor of plasma kallikrein, and demonstrate the potential for STAR-0215 to be dosed once every 3 months or longer,” Andy Nichols, PhD, chief scientific officer at Astria, said in a press release.

STAR-0215 is an antibody-based therapy designed to block the activity of the enzyme kallikrein. In HAE, this enzyme is abnormally active and leads to the excessive production of bradykinin, a pro-inflammatory molecule that stimulates swelling. STAR-0215 seeks to lower bradykinin levels and prevent swelling attacks by suppressing kallikrein activity.

Previously reported preclinical data showed STAR-0215 was about 10 times more potent than Takhzyro at blocking 90% of the enzyme’s activity — a level estimated to reduce attacks and maximize the time without attacks. Also, studies demonstrated STAR-0215’s mean half-life in the bloodstream was markedly more prolonged than Takhzyro’s.

Half-life is the time it takes for a compound level to drop to half after it’s been administered. The longer the half-life, the longer a compound will remain active in the body.

The new preclinical findings are based on tests conducted in cynomolgus (macaque) monkeys, a nonhuman primate model.

The animals received 10, 30, or 100 mg/kg of STAR-0215 every 15 days. Blood samples were collected before and after injection to assess its pharmacological properties. Kallikrein activity was assessed by measuring the levels of cleaved high molecular weight kininogen (cHMWK), a protein produced alongside bradykinin.

Blood tests showed STAR-0215 peaked in the bloodstream after about 72 hours (three days) and reached maximum levels in a dose-dependent manner, which were sustained over 43 days (1.4 months).

Before dosing, cHMWK levels were at 67%. Following treatment with STAR-0215, cHMWK levels dropped in a dose-dependent manner: after 10 mg/kg, cHMWK dropped to 17%, after 30 mg/kg to 10%, and at the highest dose of 100 mg/kg, cHMWK decreased to 6%. No reduction in HMWK cleavage was seen in control animals.

HMWK cleavage was rapidly blocked after treatment, with cHMWK levels dropping to 9% one day following the administration of the highest dose, which was sustained for 43 days. According to Astria, these levels were maintained throughout the 84-day dose-free extended portion of the study.

The goal of the planned Phase 1a trial is to confirm these preclinical results after giving several doses of STAR-0215 to healthy volunteers.

“We expect to advance STAR-0215 into the clinic this year with our Phase 1a trial in healthy volunteers, which would bring us another step closer to our goal of developing the most patient-friendly treatment for HAE,” Nichols said.