PLCγ2

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.

A groundbreaking study has shed new light on the genetic underpinnings of Alzheimer's disease. A groundbreaking study led by experts from Indiana University School of Medicine has shed new light on the genetic underpinnings of Alzheimer's disease. The team's research, rooted in human genetics studies, has unearthed a critical mutation within a key gene operating in the brain's immune cells, potentially elevating the risk of Alzheimer's disease. The research team included several IU investigators within Stark Neurosciences Research Institute -- Gary Landreth, PhD, the Martin Professor of Alzheimer's Research; Bruce Lamb, PhD, executive director of Stark Neuroscience Research Institute; Stephanie Bissel, PhD, assistant professor of genetics; Kwangsik Nho, PhD, associate professor of radiology and imaging sciences; and Adrian Oblak, PhD, assistant professor of radiology and imaging sciences. Their research was recently published in the journal Immunity. Andy Tsai, PhD, a graduate of the Medical Neurosciences Graduate Program, was the driving force behind the research, encompassing his PhD thesis. Tsai, now a postdoctoral fellow at Stanford University Medical School, has significantly contributed to unraveling the mysteries of Alzheimer's disease. The focal point of the investigation revolved around the phospholipase C gamma 2 (PLCG2) gene, intricately entwined within microglia -- central to the brain's immune response. This genetic anomaly, discovered through analysis of the gene's biological workings, showcased the impact of specific rare variants. The study found that the M28L variant heightened the susceptibility to Alzheimer's disease, whereas the P522R variant exhibited a risk-reducing effect. Innovative mouse models of Alzheimer's disease developed by the NIH-funded MODEL-AD Center allowed researchers to substantiate their findings. Immune cells harboring risk-reducing gene variants demonstrated a reduction in amyloid plaques, while those carrying the risk-elevating variants exhibited a surge in plaque accumulation. The study unveiled specific gene clusters orchestrating these alterations in immune cell behavior within microglia. Microglia, often regarded as the brain's first line of defense against infections, toxins and damage, has garnered attention for its significant role in influencing disease susceptibility. "The microglial response affects neurons which then affects the capacity to learn and form new memories," Landreth said. Extensive collaboration within Stark Neurosciences Research Institute enabled a comprehensive evaluation of the gene's implications. This included a comparison between preclinical data from animal models and real-world human data on Alzheimer's disease. "This represents a collaboration that could've only been achieved at Stark," Landreth said. "We used human genetics to investigate and identify a mechanism, and indeed we have." The study's paramount importance lies in explaining the critical role of microglial immune responses and their potential to impact disease risk, positively or negatively. This discovery promises to reshape the understanding of Alzheimer's disease and carve a path toward targeted therapeutics, which is being pursued by the NIH-funded TREAT-AD Center.

A scientific analysis of Alzheimer’s disease/istock, digicomphoto When Eisai and Biogen’s Leqembi (lecanemab) received full approval this month, it was widely viewed as the beginning of a new chapter in Alzheimer’s treatment. But with hurdles still to clear and a marginal efficacy rate, experts say there is still a ways to go in the space—and the next step could involve combination trials. Eisai intends to pair Leqembi with other drugs in its pipeline. Still, it is also open to partnering with other companies to advance treatments for the disease, said Michael Irizarry, the company’s head of Alzheimer’s research. “Our conception of lecanemab is that it would be the backbone anti-amyloid therapy for combination treatments, and that’s the strategy that we’re considering at Eisai,” he told BioSpace. Irizarry said several possible rational combinations exist, including doubling up on the amyloid pathway. “For instance, if there’s a small molecule that can reduce the production of amyloid beta, it might allow you to reduce the dose of antibodies that clear amyloid beta and may allow a better safety profile. “The other approach is to target amyloid and one of the other processes that is ongoing,” he said. Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas agreed that combination therapies are likely the way of the future for Alzheimer’s. “With the approval of Leqembi . . . the stage for combination approaches is set,” he told BioSpace. “So now you can layer on something else on top of Leqembi . . . perhaps you could have a synergistic effect or additive efficacy that you could not achieve with one drug alone.” Tau Combinations The leading theory holds that Alzheimer’s disease is caused by the accumulation of two proteins—amyloid beta and tau—in the brain. So, one potential Leqembi combination is that with a drug targeting tau, Irizarry said. Eisai is developing E2814, an anti-tau antibody intended to prevent the spread of tau seeds within the brain. E2814 is directed against the microtubule-binding region (MTBR) of the tau protein, which Irizarry said is a component of the tau seed believed to drive the trans-neuronal spread of neurofibrillary tangles. The candidate is being tested in a Phase II/III trial that uses lecanemab as the base therapy. Participants in the study—being conducted in concert with Washington University School of Medicine’s Dominantly Inherited Alzheimer Network Trial (DIAN-TU)—are given lecanemab, then randomized after six months to receive either E2814 or placebo. Irizarry said this study design highlights two key points when investigating combination therapies. One is the study population. “At what stage of the disease do you use combinations?” A second consideration is how to sequence therapies and “whether to do full factorial trials or other types of designs,” Irizarry said. For example, in the DIAN-TU trial, “the timing of when we use lecanemab differs based on the stage of disease.” The Alzheimer’s Clinical Trial Consortium (ACTC), funded by the NIH, has announced a platform trial to test multiple tau therapies alone or combined with an anti-amyloid drug. Questions posed by ACTC include when in the course of the disease tau treatment effects can be measured, who to enroll and what effect size correlates with a clinically meaningful response to treatment. Although the ACTC has not stated which anti-amyloid drug it will use in the new trial, the consortium is already collaborating with Eisai on the AHEAD 3-45 trial, which is testing Leqembi in individuals at risk of developing Alzheimer’s due to elevated levels of amyloid. Neurodegeneration and Neuroinflammation Another possible Leqembi combination, Irizarry said, is with a drug directly targeting neurodegeneration. Eisai has two such molecules currently in Phase I. One, E2025, is focused on the nerve growth factor pathway and preventing cholinergic cell loss. A second, E2511 aims to promote recovery and synaptic remodeling of damaged cholinergic neurons and suppress cerebral atrophy caused by neurodegeneration. Irizarry said it “makes sense to combine an amyloid therapeutic with a therapeutic that’s trying to prevent neurodegeneration [because] targeting multiple pathways is a fundamental concept in selecting combinations to get stronger effects.” Another potentially synergistic target is neuroinflammation. Several studies posit that neuroinflammation—particularly microglial dysfunction—plays an important role in the Alzheimer’s disease process. John Hardy, group leader at the U.K. Dementia Research Institute, told BioSpace that this an area ripe for combination trials, with Leqembi and drugs that “increase, in some way, microglial function.” This could include agonists of TREM2 and drugs that mimic PLCG2, he said. TREM2 is necessary for microglial homeostatic maintenance and responses to inflammatory damage in the central nervous system. Variants of the gene underlying this protein are a genetic risk factor for Alzheimer’s disease. PLCG2 is a phospholipase-encoding gene expressed in microglia that has also been linked to the pathology of the disease. Conversely, the P522R variant of PLCG2, which is expressed by microglia, has shown protective effects against developing late-onset Alzheimer’s in mouse studies. Irizarry agreed, saying, “There’s is a lot of interest in therapies that are targeting inflammatory processes, and in particular, microglial function.” He cautioned, however, that if these therapies are combined with a drug like Leqembi that activates microglia—specifically to mediate the clearance of amyloid—“you have to make sure that the way the two drugs work aren’t counteracting themselves.” Early Intervention Alvaro Pascual-Leone, a professor in neurology at Harvard Medical School and medical director at the Wolk Center for Memory Health at Hebrew SeniorLife, said that while Leqembi’s disease-modifying effect “is great, it is not a cure. You’re still going full tilt down the road, just not at 70 miles an hour but at 50.” Pascual-Leone said that anti-amyloid therapies “ought to be a catalyst for change for how we approach dementia care.” Specifically, he said they emphasize “the critical importance of early diagnosis” to determine the root cause of cognitive impairment at an individual level. “In my mind, the early interventions have to seriously consider combination therapeutics,” he said. It doesn’t necessarily have to be a combo with another drug, though, he added. “We know that [anti-amyloid] medications can change the course of disease progression, maybe by 25 to 35%. But we also know that lifestyle modification can change the course of the disease by 40% plus. There is no reason to believe that you cannot have some synergistic effect if you do both.” Pascual-Leone said the next chapter in Alzheimer’s treatment is a more holistic, personalized approach that looks at combination therapies to optimize benefits and reduce risk. Suvannavejh agreed. “There are opportunities to have a better version of Leqembi . . . but I think the real excitement from my perspective is how much combination approaches now can move forward. That is definitely the future.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08. Reporting contributed by Jef Akst.