The world’s best-selling anticoagulants are typically prescribed for use once or twice daily, depending on their indication and dosage. Anthos Therapeutics, a Cambridge, MA, startup launched with $250 million and two big-name partners two years ago, aims to disrupt the market for blood thinners with a therapeutic intended for use every 30 days.
Researchers for Anthos and clinical partners recently published and presented final positive Phase II data for its anticoagulant candidate, the fully human monoclonal antibody abelacimab, from the ANT-005 trial (EudraCT number 2019-003756-37), which evaluated 412 patients undergoing elective total knee arthroplasty.
A single dose of abelacimab administered after elective total knee arthroplasty reduced the rate of venous thromboembolism (VTE) by ~80% compared to Lovenox® (enoxaparin), a low molecular weight heparin marketed by Sanofi.
The dose ranging study’s primary composite efficacy outcome—which included deep vein thrombosis detected by venography of the operated leg and documented symptomatic VTE events—took place in 4% (4 of 98) of patients treated with the 150-mg dosage of abelacimab; 5% (5 of 99) of 75 mg patients; and 13% (13 of 102) of patients in the 30-mg dosage group, compared with 22% patients treated with enoxaparin.
As a result, the 75-mg and 150-mg abelacimab regimens were both statistically superior to enoxaparin, while the 30-mg dose was deemed “non-inferior.”
Also encouraging, say Anthos and researchers: None of the 99 patients in the 150-mg abelacimab group reported bleeding—as did none in the enoxaparin group—while bleeding occurred in just 2% of patients (2 of 104) in the 75-mg group and 2% (2 of 102) in the 30-mg group.
The only bleeding instance classified as major was a 75-mg patient who showed clinically relevant bleeding on day 6, followed six days later by a joint infection and hemarthrosis on day 12 that led to surgical drainage and was reclassified as major bleeding. Data from the study was published in the New England Journal of Medicine, and presented at the International Society of Thrombosis and Haemostasis (ISTH) 2021 Congress.
“We got that marked reduction without a significant increase in bleeding,” Jeffrey Weitz, MD, professor at McMaster University in Hamilton, Ontario, Canada, and corresponding author of the NEJM study, told GEN Edge. “Typically, what happens with anticoagulants is that, as you increase the dose, you get better efficacy, but you also pay a price with more bleeding. Here we have dramatically better efficacy without an increase in bleeding.”
Uncoupling thrombosis, hemostasis
Through abelacimab, Weitz said, Anthos aims to achieve effective protection from thromboembolic events with a reduced risk of clinically significant bleeding. A study just published in Journal of the American College of Cardiology by Weitz and colleagues hypothesizes that Factor XI plays an important role in the development of pathological thrombosis but only a minimal role in physiological hemostasis. By inhibiting Factor XI, the researchers wrote—and Anthos reasons—the two pathways can be uncoupled. This is in contrast with warfarin or DOACs, which affect coagulation factors that act on both hemostasis and thrombosis.
“A safer class of anticoagulants would provide opportunities for treatment of a wider range of patients, including those at high risk for bleeding,” the researchers wrote.
Weitz said the positive results will help validate abelacimab’s mechanism of action compared with existing anticoagulants. Together with the monthly dosing schedule, Anthos expects to position its antibody competitively against rivals. According to a report published last month by Research and Markets, the global anticoagulants market is estimated to grow from $28.6 billion this year to $41.87 billion by 2026—a compound annual growth rate of 7.9%.
While warfarin (sold in branded and generic versions) blocks vitamin K from making clotting factors, three of the best-selling anticoagulants are blockbuster direct-acting oral anticoagulants (DOACs) that work by inhibiting Factor Xa. Those blockbusters are Eliquis® (apixaban), co-marketed by Bristol-Myers Squibb and Pfizer; Xarelto® (rivaroxaban), co-marketed by Johnson & Johnson’s Janssen Biotechnology and Bayer; and Daiichi Sankyo’s Savaysa® (edoxaban)—marketed as Lixiana in Europe and Japan.
Eliquis led the anticoagulant category in 2020 sales with $14.12 billion—$9.17 billion from BMS and $4.95 billion from Pfizer. Next-highest was Xarelto with $7.71 billion in sales—$2.34 billion from J&J and €4.51 billion ($5.36 billion) from Bayer. Savaysa racked up ¥165.9 billion ($1.52 billion) in 2020 sales.
Two other anticoagulant blockbusters use different mechanisms of action: Boehringer Ingelheim’s Pradaxa—(dabigatran etexilate), a direct thrombin inhibitor, generated €1.49 billion ($1.77 billion) in sales last year, while Sanofi’s Lovenox finished 2020 with €1.35 billion ($1.6 billion).
Unlike all five branded blockbusters and warfarin, abelacimab is designed to work by targeting both the inactive zymogen Factor XI and its active form, Factor XIa, resulting in Factor XI suppression that lasts up to 30 days after a single intravenous or subcutaneous dose.
“Once it binds to factor XI, it blocks it in this inactive precursor conformation, so that it can’t be activated by either factor XIIa or by thrombin. Essentially, it paralyzes factor XI and prevents it from getting activated,” Weitz said.
Eliquis and Xarelto, he acknowledged, have fewer drug-drug interactions than warfarin or other vitamin K antagonists.
Dialing Out drug-drug Interactions
“As an antibody, abelacimab dials out those drug-drug interactions. Plus, abelacimab is not cleared by the kidney, so you don’t have to worry about accumulation in patients with severe renal impairment the way you do with Xarelto or with Eliquis,” Weitz said. “There are some distinct advantages of abelacimab over existing anticoagulants. And if it is at least as effective and safer, well then, you have it all.”
Also targeting Factor XI is Ionis Pharmaceuticals, which is partnering with Bayer to develop a ligand-conjugated (LICA) antisense oligonucleotide, now in Phase II development, IONIS-FXI-LRx.
Weitz said abelacimab essentially works much like an antisense oligonucleotide that knocks down the levels of factor XI by reducing the synthesis of factor XI, rendering it inactive.
“The advantage of this over the antisense oligonucleotide is that you can give abelacimab intravenously or subcutaneously and get an almost immediate effect,” Weitz said.
Bayer is also targeting Factor XIa with its Phase II monoclonal antibody candidate osocimab (formerly BAY 1213790), in development for thrombosis prevention in end-stage renal disease.
However, in the NEJM study, the Anthos researchers referenced a 2020 JAMA study showing that osocimab showed superiority to Lovenox only when administered preoperatively, while only noninferior to Lovenox in preventing VTE after total knee arthroplasty: “Therefore, whether postoperative factor XI inhibition is as effective as preoperative inhibition remains unknown.”
Another Bayer candidate designed to inhibit Factor Xia is the Phase II asundexian, which is in development for stroke prevention in atrial fibrillation, 2nd-line stroke prevention, and major adverse cardiac events prevention. It joins BMS’ Phase II candidate milvexian (formerly BMS-986209) and a preclinical candidate, both in development for thrombotic disorders; and Ono Pharmaceutical’s ONO-7684.
Oral Once-Daily Data
Last January, researchers with Ono and a clinical partner published positive data in the British Journal of Clinical Pharmacology from its Phase I first-in-human trial (NCT03919890): In patients fed before receiving the drug, the researchers reported, the half-life of ONO-7684 ranged from 22.1 to 27.9 hours, “supporting once daily oral dosing.”
Development plans for abelacimab emerged after Blackstone Life Sciences partnered with Novartis to launch Anthos in February 2019. Blackstone provided $250 million, while Novartis licensed to Anthos abelacimab and retains a minority equity interest in the startup.
Novartis co-discovered abelacimab (originally named MAA868) with MorphoSys after the companies launched a collaboration in 2004 to discover and develop antibody-based drugs for unmet medical need across a variety of diseases, using MorphoSys’ HuCAL (Human Combinatorial Antibody Library) GOLD® in vitro antibody generation platform.
In 2018, Novartis registered a pair of Phase II studies on ClinicalTrials.gov assessing abelacimab—one in patients following total knee replacement, the other in atrial fibrillation patients. However, both studies (NCT03398434 and NCT03393481) were canceled before any patients were recruited.
Blackstone Life Sciences is the life-sci investing entity of The Blackstone Group, which has $119 billion in corporate private equity assets under management, with $35 billion in capital available to invest.
Since its launch, Anthos has grown its headcount to 10 people, with no expectation of expanding that significantly due to its hybrid externalized model.
Weitz said Anthos’ ANT-005 trial is one of three Phase II studies the company has been conducting for abelacimab
A much larger study, ANT-006 (AZALEA-TIMI 71; NCT04755283), is assessing abelacimab head-to-head with Xarelto in 1,200 patients with atrial fibrillation, with the aim of assessing the effects of long-term once-monthly subcutaneous administration of abelacimab for stroke prevention. That trial has an estimated primary completion date of January 2023. Weitz is a member of the steering committee for ANT-006 and other upcoming studies of abelacimab.
In December, 2020, researchers from Anthos and clinical partners finished the first Phase II study (NCT04213807), a randomized, placebo-controlled, multiple ascending dose-ranging study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) effects of abelacimab.
“The efficacy findings announced [in the ANT-005 trial] represent the first major milestone in our development plans for abelacimab,” Anthos CEO John Glasspool stated last month.
