TGA approves donanemab for treatment of early Alzheimer's

The Therapeutic Goods Administration (TGA) has granted marketing authorisation for Eli Lilly and Company’s Kisunla (donanemab), an injection to treat mild cognitive impairment and mild dementia due to Alzheimer’s disease. This makes it the first amyloid-targeting therapy for people with Alzheimer’s registered in Australia and the only amyloid plaque-targeting therapy with evidence to support stopping therapy when amyloid plaques are removed, Eli Lilly stated.

Amyloid is a protein produced naturally in the body that can clump together to create amyloid plaques. Donanemab works by inducing antibodies designed to attach to and remove these amyloid plaques from the brain. The drug is given as an intravenous infusion through the arm every four weeks for a maximum of 18 months, and may delay the progression of symptoms in people in the early stages of Alzheimer’s disease.

The registration of donanemab in Australia was based on the TRAILBLAZER-ALZ 2 Phase 3 and TRAILBLAZER-ALZ 6 clinical trial data. The TRAILBLAZER-ALZ 2 study demonstrated that donanemab significantly slowed cognitive and functional decline by up to 35% compared to placebo at 18 months and reduced the risk of progressing to the next clinical stage of disease by 39% over the same period.

“In our TRAILBLAZER-ALZ 2 Phase 3 study, results showed that Kisunla significantly slowed cognitive and functional decline in patients with early symptomatic Alzheimer’s disease, which allowed them more time to do things that mattered most to them like remember information, make meals, manage finances and maintain independence,” said Ilya Yuffa, Executive Vice President and President of Lilly International, Eli Lilly and Company. “As our data showed, the earlier patients are identified, diagnosed and treated with Kisunla, the greater their response to treatment.”

It should be noted that donanemab comes with the possible side effects of brain swelling and bleeding, although the approved dosing schedule is based on TRAILBLAZER-ALZ 6, which demonstrated lower incidence of brain swelling at 24 weeks versus the original dosing schedule. Anyone who has two copies of an Alzheimer’s risk gene called ApoE4 is at a higher risk of brain swelling and bleeding, so patients considering the drug must have genetic testing to check for this gene.

The news comes just days after a study published in the Journal of Medicinal Chemistry presented a new family of candidate compounds for the treatment of Alzheimer’s disease and pain, which have shown promising effects in animal models. Researchers at the University of Barcelona led a multidisciplinary team that designed, synthetised and pharmacologically validated molecules that modulate a therapeutic target which has been little studied: the imidazoline I₂ receptors, which are altered in many diseases without efficient pharmacological treatments.

Imidazole I₂ receptors are located in different organs and have been shown to be involved in multiple physiological processes (analgesia, inflammation, nervous system disorders, etc). Their levels are altered in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and their modulation has been shown to have an impact on pain, so these receptors have been identified as potential drug targets.

The new study saw the researchers develop compounds with high affinity and selectivity towards imidazole I₂ receptors, making them structurally different from those used so far to interact with these receptors. These candidate compounds were tested in preliminary studies in animal models of both neurodegenerative disease and pain, where they were shown to be highly efficient and have no toxic effects.

“A murine model of Alzheimer’s disease treated with one of the new compounds selected has shown an improvement in cognitive and biochemical markers of the disease,” noted Barcelona’s Professor Carmen Escolano. “This compound has also shown analgesic properties in a murine model of pain, with no motor side effects.

“Having molecules that are highly affine and selective for these receptors allows us to describe their pharmacological implication in diseases such as Alzheimer’s and pain and to present drugs that improve their treatment,” Escolano added.

The new compound has a novel mechanism of action, which has been validated by several previous studies. Escolano noted, “Describing novel action mechanisms allows proposing new molecules that … can become, after years of research, new drugs to cure diseases that need therapeutic alternatives. The development of new tools such as those presented in this paper, which allow us to modulate therapeutic targets involved in certain diseases, is the gateway to these new drugs.”

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