TREM2

Blockage of arterial blood vessels caused by atherosclerosis is largely responsible for heart attacks and strokes, which are the most common causes of death worldwide. The complex mechanisms that lead to pathological changes in the arteries are not yet fully understood. An international research team has now made important progress in understanding this disease and identified potential new approaches for early detection and therapy. Blockage of arterial blood vessels caused by atherosclerosis is largely responsible for heart attacks and strokes, which are the most common causes of death worldwide. The complex mechanisms that lead to pathological changes in the arteries are not yet fully understood. An international research team led by the Medical University of Vienna and the University Hospital of Würzburg has now made important progress in understanding this disease and identified potential new approaches for early detection and therapy. The results of the study were recently published in the scientific journal Nature Cardiovascular Research. Researchers already know that specialised cells called macrophages are central to the development of atherosclerosis. These cells play a critical role in the formation of so-called plaques, which narrow or block the arteries and can lead to dangerous complications -- above all heart attacks and strokes. However, the exact mechanisms of how macrophages function in this process are not yet fully understood. In the search for the solution to this puzzle, Christoph Binder and Florentina Porsch from MedUni Vienna's Department of Laboratory Medicine, in collaboration with Clément Cochain, Alma Zernecke and Marie Piollet from the University Hospital of Würzburg, took a closer look at the protein TREM2. TREM2 (TREM = Triggering Receptor Expressed on Myeloid Cells) controls the activity of macrophages and therefore has a potential influence on the development of atherosclerosis. The study results indicate that TREM2 plays an important role in the formation of unstable plaques, which are particularly susceptible to rupture and thus increase the risk of heart attacks and strokes. By regulating the survival of so-called foam cells, which are particularly common in atherosclerotic plaques, and by promoting the degradation and removal of damaged or dying cells, TREM2 helps to limit the formation of these dangerous plaques. Important insight into complex mechanisms The evidence obtained in the study that the treatment of mice prone to atherosclerosis with a specific antibody against TREM2 was able to reduce the formation of these unstable plaques is particularly promising. TREM2 thus emerges as a new therapeutic target for stabilising plaques, which could prevent heart attacks and strokes. In addition, the researchers were able to establish a link between a soluble form of this protein ("sTREM2") and the progression of atherosclerosis. TREM2 could therefore not only enable new approaches for the treatment of the disease but also serve as a potential biomarker for early detection. "Our results provide an important insight into the complex mechanisms of atherosclerosis and open up new avenues for the development of effective therapies," the researchers summarise the relevance of their work in the run-up to further studies.

Pictured: A MRI brain scan background, magnetic using blue tones/iStock, DedMityay After decades of frustration and flops, the Alzheimer’s disease market is on the cusp of offering two disease-modifying treatments. Biogen and Eisai’s Leqembi earned full approval last July and an FDA stamp on Eli Lilly’s donanemab could come any day now—after the company advised to expect a decision before the end of 2023. The anti-amyloid space endured a rocky start after Aduhelm’s history-making but controversial approval in 2021. Biogen has since made the decision to discontinue sales of the embattled therapy and terminate the post-approval study. Now, several other companies are looking to push their investigational drugs to market. “We’re still in very early days of Alzheimer’s disease treatment,” said Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. Many of the candidates currently in development target a specific piece of the Alzheimer’s puzzle, such as triggering receptor expressed on myeloid cells 2 (TREM2) and the hepatocyte growth factor (HGF) system. Suvannavejh told BioSpace that he believes a combination approach—like the ones seen in cancer treatment—is where the space is ultimately headed. Here are five Alzheimer’s assets with data readouts Suvannavejh is excited about in 2024: 1. Alector/AbbVie’s AL002 Alector Therapeutics’ monoclonal antibody, AL002, has a novel target—TREM2. Impairments to this receptor’s functionality is believed to lead to Alzheimer’s disease and other forms of dementia, according to the company’s website. AL002 activates TREM2 signaling to improve cell survival and activity. The infused antibody is currently in Phase II testing, with a data readout slated for the fourth quarter of 2024 that will determine the future of the program, Suvannavejh said. AbbVie has full opt-in rights to Phase III development if the results are sufficiently compelling. 2. Athira Pharma’s fosgonimeton According to Athira, this potential first-in-class therapy is designed to modulate the HGF system to activate neuroprotective and anti-inflammatory pathways in the central nervous system. Fosgonimeton flopped in a Phase II trial in December for Parkinson’s disease dementia or dementia with Lewy bodies. However, once Athira shrunk the scope to five patients in the modified intent-to-treat population, it saw a statistically significant improvement in cognitive score. Athira has now completed enrollment in a Phase II/III trial for mild-to-moderate Alzheimer’s, with a topline data readout expected in the second half of this year. Suvannavejh said he finds fosgonimeton “intriguing,” despite the controversial data so far collected, adding that HGF is a unique drug target that could potentially improve neuron function and be used in combination with an anti-amyloid or anti-tau therapy. 3. Alzheon’s ALZ-801 The first oral disease-modifying treatment for Alzheimer’s could come from the labs of Framingham, Mass.–based Alzheon. ALZ-801 is designed to prevent the formation of amyloid oligomers, the toxic amyloid species that eventually form plaques. It is being tested in patients with at least one copy of the APOE4 gene variant as these individuals tend to have a higher buildup of amyloid-beta in the brain. Topline results from an ongoing Phase II trial showed that after two years, ALZ-801 preserved the hippocampus without increasing the risk of ARIA, a side effect sometimes seen with anti-amyloid therapies like Leqembi and donanemab. ALZ-801 is now in Phase III testing, with a readout expected around the middle of the year, Suvannavejh noted. While Alzheon is a private company at this point, Suvannavejh believes a positive data readout will lead to either a deal with a larger company or possibly an IPO. 4. Prothena’s PRX012 Holding the FDA’s Fast Track designation, Prothena’s next-generation anti-amyloid antibody carries best-in-class potential, Suvannavejh said. PRX012’s key differentiator: it’s delivered subcutaneously, as opposed to intravenously like Leqembi and donanemab. Although the candidate is only in Phase I trials, Suvannavejh said investor interest was clear last year and resulted in a stock bump driven by the convenient formulation, efficacy and possibility of avoiding ARIA. But clinical readouts have been delayed, somewhat dampening excitement, Suvannavejh noted. In a January press release, Prothena reported that the ongoing Phase I trial “continues as planned,” with an update expected this year. 5. Axsome Therapeutics AXS-05 Unlike the other drugs on this list, this candidate is not a disease-modifying treatment but a symptom-treating one. Axsome has repurposed a drug currently on the market as an antidepressant and is testing it against Alzheimer’s disease-related agitation. According to Axsome’s website, agitation is reported in about 70% of people living with Alzheimer’s and is associated with decreased functioning, earlier nursing home placement and increased mortality. Already riding high on positive Phase II and Phase III data, Axsome’s second pivotal Phase III study is expected to read out in the second quarter of 2024, Suvannavejh noted. While Otsuka and Lundbeck gained approval for Rexulti last year for Alzheimer’s agitation, the drug comes with a black box warning for elderly patients with dementia-related psychosis. Suvannavejh said that if Axsome is successful, it would be the only drug on the market indicated for AD agitation without such a warning. As of January 2023, there were 187 trials assessing 141 drugs for Alzheimer’s disease. With these readouts and more anticipated in 2024, the stage is set for additional, compelling options for Alzheimer’s patients. “This is, in my opinion, a really exciting place for innovation and Alzheimer’s disease,” Suvannavejh said. Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.

Pictured: Flames attacking a brain/Nicole Bean for BioSpace Alois Alzheimer recognized more than a century ago the role of neuroinflammation in the development of the disease that would bear his name. “If you actually go back to his original drawings, he was drawing the cells, which today we know are microglia,” immune cells of the brain, said Bruce Lamb, executive director of the Paul and Carole Stark Neurosciences Research Institute at Indiana University School of Medicine and co-founder of Monument Biosciences, which is exploring neuroinflammation-targeted Alzheimer’s treatments. “So, he recognized way back, 120 years ago, that these cells were there” and that they could be playing a role in the disease process. Several studies have established a link between neuroinflammation and Alzheimer’s disease, and the culprit indeed appears to be microglia. “I think it’s very clear that, at least the minute amyloid is deposited in the brain and maybe even before, there’s a microglial response,” Lamb told BioSpace. And it’s this immune response that could be causing problems with neuronal function. Lamb said that over the last decade and a half, there has been a renewed interest in the role of microglia in Alzheimer’s, spurred in part by discoveries in the genetics of late-onset Alzheimer’s disease. Genome-wide association studies and the identification of rare mutations that occur in families have led to a list of Alzheimer’s-associated genes, and most of these are expressed in microglia, Lamb said. Meanwhile, transcriptomics, proteomics and metabolomics data from human cases and controls have revealed similar findings, he added. “A lot of the networks and pathways that are disturbed, especially in late-onset Alzheimer’s disease, are in these inflammatory networks.” Targeting TREM2 and More Working under the hypothesis that neuroinflammation contributes to the Alzheimer’s disease process, biotech companies are exploring different targets. Vigil Neuroscience is developing a candidate based on the role of TREM2-mediated microglial dysregulation in the disease process. Also targeting TREM2 is Alector Therapeutics, which describes its strategy as immuno-neurology. TREM2 is expressed on microglia in the brain, but it is really only expressed in response to amyloid deposits, Lamb explained. There is a signaling cascade downstream of TREM2 within the microglia, “and a lot of the other genes that are implicated in Alzheimer’s disease are also in microglia downstream of TREM2,” he said. At his own company, Lamb added, the team is initially targeting the PLCG2 and INPP5D genes, both of which are downstream of TREM2 and also have genetic associations with Alzheimer’s disease. Boston–based Cerevance is targeting a different gene, KCNK13, which is specific to and upregulated in the microglia. While others are also going after the NOD-like receptor protein 3 (NLRP3) inflammasome, Cerevance is looking to regulate inflammation only in the central nervous system, leaving peripheral immune cells ready and able to fight opportunistic infections, said CEO Craig Thompson. This is particularly important in Alzheimer’s, he added, because the patients tend to be older and frail. “Our thought was, is there a way to damped down the inflammation on the inflammasome but still [leave] other aspects of the NLRP3 that are helpful for normal immune system functioning?” In preclinical models, the company’s KCNK13-targeting asset, CVN293, had minimal impact on the peripheral immune system while reducing neuroinflammation in the brain, Thompson explained. Cerevance has shown that “we can tamp down the inflammation response, or the inflammasome, but keep all the other surveillance and other aspects of microglia still functioning as they should.” The company is now conducting a Phase I study of CVN293, with topline data expected in the second quarter of 2024. In Ohio, biotech NeuroTherapia was co-founded by anesthesiologist Mohamed Naguib, who found that microglia upregulated the cannabinoid type 2 (CB2) receptor, CEO Tony Giordano relayed in an interview with BioSpace. Naguib further found that “CB2 agonists were able to shift the microglia . . . from a proinflammatory phenotype to an anti-inflammatory phenotype,” which improved amyloid clearance and neuronal function in preclinical models, Giordano said. NeuroTherapia is developing a CB2 receptor agonist for Alzheimer’s disease called NTRX-07, which Giordano expects to enter Phase II trials in the third quarter of this year. “We believe that it’s the continued activation of the microglia and the production of the proinflammatory cytokines that starts to interfere with synaptic transmission and neuronal function,” Giordano explained. “Fortunately, it appears that if you can stop that activity, you’re going to get improvement in neuronal function.” A Multipronged Attack Ultimately, Giordano and Thompson agreed that treating Alzheimer’s disease will require a multifaceted attack. “Alzheimer’s is a very, very complex disease, and you’re not going to treat it with a single agent,” Giordano said. “It’s likely that you’re going to put together a cocktail and we really believe that neuroinflammatory inhibitors are going to be a part of that cocktail.” Thompson called Alzheimer’s “more of a constellation of diseases” and said that tackling it from multiple approaches will be “really important.” He teased that Cerevance is also looking at other approaches with some of its earlier compounds. While he wouldn’t reveal the targets, he said that, like KCNK13, “they’re very novel approaches.” Lamb added that anti-amyloid antibodies, including Eisai and Biogen’s Leqembi, appear to be working primarily through the microglia. “The microglia have these FC receptors which bind to the antibodies and then can actually remove amyloid from the brain,” he said. Amyloid-related imaging abnormalities (ARIA) has been the primary smudge on the surface of drugs like Leqembi and Eli Lilly’s donanemab. Lamb explained that this side effect is thought to be an inflammatory process. “We think it’s amyloid binding to blood vessels where there’s amyloid and that that is actually recruiting immune cells and leading to where there’s an immune dysfunction.” Accordingly, he said, there is a lot of interest in combination therapies with monoclonal antibodies and drugs targeting microglia “to either improve the removal of amyloid, or even better, prevent some of these side effects that are seen with these antibodies.” When asked which approach is most likely to lead to the next Alzheimer’s breakthrough, Lamb acknowledged he is biased, but said, “I certainly think the immune pathways . . . are near the front of that sort of discussion.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.