aptaTargets’ First-in-Human Data Shows Efficacy of Aptamers in Stroke


Madrid-based aptaTargets S.L. announced data from its first-in-human trial using its ApTOLL aptamer to protect patients against the deleterious effects of acute ischemic stroke.

Speaking at TIDES Digital Week, Marcarena Hernández-Jiménez, Ph.D., chief scientific officer, said, “ApTOLL is a confirmed anti-inflammatory drug with an excellent safety profile.” Data to date is promising for eventual use in treating ischemic stroke and other diseases, possibly including myocardial infarction, multiple sclerosis, and hemorrhagic stroke.

Phase Ia/IIb trials are underway now to assess the safety of administering ApTOLL with endovascular therapy in acute ischemic stroke patients who are candidates for reperfusion therapies. The Phase Ib portion of the trial will focus on safety, and the Phase IIa portion will focus on efficacy.

ApTOLL is an aptamer designed to block TLR4, which is a critical receptor involved in the inflammatory response for multiple diseases.

“In stroke and other diseases there is a dual inflammatory response characterized by two peaks in inflammation. One occurs just after the occlusion of the artery and is involved in tissue damage,” Hernández-Jiménez explained. The other response is involved later, and reduces the potentially harmful proinflammatory response.

Once a stroke occurs, there is a cascade of DAMPS, TLR4, and NFkB and leukocyte infiltration begins, causing tissue damage. IL1, IL-6, and TNFα, are part of the cytokine cascade and activate the immune system. In this cascade, “ApTOLL targets one of the most upstream receptor,” she said. “The aim is to block the (initial) inflammatory response.

“Because aptamers have a short half-life, we can use them to block the first part of the inflammatory response without blocking the second, good part of the inflammation,” Hernández-Jiménez continued. “When ApTOLL is administered soon after a stroke patient is hospitalized, it lets us reach the part of the tissue where blood flow was stopped,” Hernández-Jiménez added.

As a benefit, they are non-immunogenic. Additional advantages include specific recognition, stable binding, chemical synthesis and the ability to be lyophilized for a power formulation.

In preclinical studies, ApTOLL dramatically reduced the release of proinflammatory cytokines across all animal models. For example, the stroke model for mice showed a 40% reduction in IL-6, 33% reduction in IL-12, and25% reduction in INFy.

In the myocardial infarction (MI) model in pigs, there was 100% reduction in INFy, 92% in IL-1ß, and 47% in IL-6. The MI model in mice showed a 70% reduction in Tir4, 60% reduction in Nfkb1, and 60% reduction in Sele. Additionally, the microglia assessment in mice showed a 33% reduction in IL-12 at 20 days.

ApTOLL ‘s protective effects lasted at least 12 hours – the duration of follow-up for that particular study. Protection was in mice and rats ranged from 35 to 66%, with functionality returned to the tissue within seven days. In pigs, administration of ApTOLL reduced the infarct area significantly, and the myocardial tissue was functional when tested on day seven. 

In hemorrhagic stroke, “ApTOLL reduces more than 20% of the hemorrhagic volume in the ICH (intracerebral hemorrhage) model,” Hernández-Jiménez said.

Importantly, ApTOLL showed no off-target or drug-to-drug interactions and animals, Human data has been similarly encouraging and suggests it may be effectively combined with other drugs.

There is a notable need for an early, protective, intervention for stroke patients. When a stroke happens, excitotoxity occurs almost immediately, followed by inflammation and, eventually, apoptosis. “Even among patients with successful recanalization, penumbra loss can still account for up to 50% of brain damage,” Hernández-Jiménez told the TIDES audience.

Currently, only two other therapies are on the market administration soon after a stroke. Meanwhile, the incidence of stroke – both ischemic and hemorrhagic – in the U.S. and Canada is 100 to 150 per 100,000. In China and Russa, the incidence is 200 to 250. The incidence rate peaks in some of the Baltic countries, at 300 to 350 per 100,000. Incidence is lowest – typically below 100 per 100,000 people – in Latin America, Africa, the Middle East and Australia. In 83% of the cases, the strokes are ischemic.

In developing ApTOLL, AptaTargets has had to transition its mindset from an academia setting to a commercial setting. “That was one of the first challenges we faced at the begnning of the project,” she said. “That was difficult, but exciting.”

The other key challenge was the community’s unfamiliarity with aptamers. “The regulatory agencies weren’t familiar with them, and people mistrusted them,” she recalled. That’s changing as more and more data is disseminated.

Moving forward, she said, “It’s most important to demonstrate efficacy in patients.”

Although acute ischemic stroke is the initial indication, Hernández-Jiménez  said the company also is working on additional indications in preclinical work. It may, she suggested, lead to some very interesting possiblities in the future.

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