Inmune Bio Inc. CEO Raymond Tesi told BioWorld his firm is taking an “oncology-style” approach to Alzheimer’s disease (AD) as the firm tests next-generation tumor necrosis factor (TNF) inhibitor XPro-1595 against neuroinflammation.

It’s working. Shares of the La Jolla-based firm (NASDAQ:INMB) closed at $15.75, up $6.90, or 78%, after the company reported interim findings from a phase Ib experiment that showed XPro-1595 decreased white matter free water, a biomarker measured by magnetic resonance imaging (MRI). XPro-1595 selectively neutralizes the “bad” soluble TNF, implicated in AD pathology, without affecting the “good,” transmembrane TNF or the TNF receptors.

Inmune compared biomarker data obtained from six patients treated with XPro-1595 for 12 weeks with data from 25 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), part of a natural history database. Over a 12-week period, whole brain inflammation increased by 5.1% in the ADNI patients compared to an increase of 1.7% and a decrease of 2.3% in patients treated weekly with 0.3 mg/kg or 1 mg/kg of XPro-1595, respectively.

Detailed analysis of XPro-1595-treated patients turned up a 40.6% reduction in neuroinflammation in the arcuate fasciculus, a major white matter anterior/posterior tract that contains long and short fibers connecting the frontal, parietal and temporal lobes. It’s important for language and short-term memory. The ADNI cohort, by contrast, had a 4.6% increase.

Raymond Tesi, CEO, Inmune

“We do it like it’s a cancer trial,” Tesi said, rather than using outmoded methods pursued by others in the AD space. “They see 100 patients with AD and they say, ‘Come one, come all, I’ll enroll you in my study,’” he said. “If you were developing a drug for breast cancer, you would never do it that way.” Inmune enrolls only AD patients with neuroinflammation, aiming to handle that problem while learning still more about biomarkers. “Almost any expert you ask will grudgingly admit that neuroinflammation is an important part of the pathology,” and will concede that they want an effective drug, he said. “We’ve shown that therapy exists and we just need to get better at it.” Neuroinflammation is “like a junkyard dog,” he said. “It causes many problems in the brain,” which “can’t repair itself if it’s on fire.”

Christopher Barnum, the company’s director of neuroscience, noted that “in order to have cell loss, you must have neuroinflammation. That’s been shown over and over again.” In animal models, treating AD early – when there’s been a loss of connection between neurons but the cells themselves haven’t died – allows for the brain to repair itself. “Whether or not that translates to humans, I don’t know,” he said. “I suspect that it will.” If the disease is more advanced and few neurons are left, treatment “is not going to prove their dementia, because we don’t do resurrections.”

CEO Tesi said the selective-TNF approach is so different from the first-generation, non-selective approach that it’s unfortunate they go by the same name. “I’m not trashing [the first-generation TNFs],” he said. “They are great drugs. They have changed the lives of people with autoimmune diseases, but they are, shall we say, trapped in the treatment of autoimmune diseases because they have side effects.” The company could have targeted other, known indications for TNF inhibitors such as rheumatoid arthritis (RA), psoriasis and irritable bowel disease (IBD), “but quite honestly, why would I? I’d be the ninth drug to market, and that’s before biosimilars show up.” Such compounds are contraindicated in neurological disease, cancer and infection because they block the beneficial transmembrane TNF, he pointed out.

Same drug takes aim at COVID-19

In the late 1990s, after the first-generation TNFs were cleared in IBD and RA, Basel, Switzerland-based Roche Holding AG tried one called lenercept in multiple sclerosis (MS) patients. They got worse. “Everybody was gobsmacked by this because, at the time, people didn’t understand the role of transmembrane TNF,” Tesi said, adding that “through the retrospect-o-scope,” researchers can understand that the cause was likely the blocking of transmembrane TNF. “I can tell you, in a year or two, we’re going to be treating patients with MS, because we have one of the best drugs that we know of that promotes remyelination, which is the holy grail of MS, and it’s a very important part of the pathology of diseases like AD that nobody ever talks about,” he said.

“Our goal is to get this [phase Ib trial in AD] wrapped up by the end of the year,” Tesi said, and the firm will “probably be exploring some additional doses” for the phase II effort, which is expected to start sometime next year. “We don’t want to go sloppily into phase II with the dose, because we believe that AD patients will be on this drug for life,” he said. The average survival in AD is seven years, but XPro-1595 could change the course of the disease, prolonging life, and thereby become sensitive to pricing. “I know what Biogen’s been signaling they’re going to charge for aducanumab, so basically they’re setting the price and we’re going to have to live with it,” he said.

“We believe we’ll be able to do a quality and convincing phase II trial much more quickly than the traditional, shall we say, 18-month trial in AD,” Tesi said. “We now have access to biomarkers and technologies that, quite frankly, weren’t here yesterday.” The precision gained could allow for studies in 200 instead of 800 patients, if the FDA says yes. “It’s their sandbox,” he said. “I’m a big fan of the FDA. If you’re going there with good science and asking the right questions, they get as excited as we do” about a novel approach. “It’s not like we’re the fifteenth drug for erectile dysfunction. We’re talking about a new mechanism of action for the disease of our time.” Formal consultation with the agency will come when more data are in hand. “We’re not quite there yet,” Tesi said. The phase Ib study is being conducted in Australia.

Christopher Barnum, director of neuroscience, Inmune

In AD, the amyloid beta hypothesis has held sway despite repeated failures, mainly out of convention, Barnum said. “It takes a long time to steer the ship. Remember, these folks at the top of the field that have been studying [amyloid] for 40 years – this is their identity. They are extremely resistant and they’re very powerful. It’s just that simple.”

Tesi said the COVID-19 pandemic has “slowed things down” for XPro-1595. Given that the average age of AD patients is 70, which makes them high risk for the virus, doctors have proved “very reluctant to have them come into the hospital or clinic. I thought we were going to dodge the bullet, because the trial is being done in Australia, [which] did a pretty good job of quashing the curve and getting things back to normal, but now Melbourne and Victoria are shut down. You can’t get a trial started in the U.S., U.K. or Australia that’s not a COVID-19 trial,” he said. “We’ve been able to keep this [AD] trial going forward based on the insistence of the patients and the clinical teams.”

Inmune is trying XPro-1595, under the name Quellor, at the phase II stage against COVID-19 as well. Targeted are symptomatic patients not yet on ventilators. “One of the big advantages of our drug is that we target endothelial inflammation, which is the cause of the coagulopathy” seen in the pandemic, Tesi said. “I believe that when they write the history of COVID-19, it’s not going to be a respiratory virus. It’s going to be a virus of the endothelial cell, and it’s the blood clots that cause all the problems.”

Asked about oft-heard predictions that a COVID-19 vaccine will arrive by next year, Tesi said, “We’ll have a vaccine [but] we won’t know whether it works. That’s sleight of hand by the administration. We’re stuck with this virus for another couple of years, unless we start the public health and social behavior that will be necessary to control it.”

Roth analyst Jonathan Aschoff appreciates the setup at Inmune, “the first company to present neuroinflammatory results using MRI of free water to monitor therapeutic effect. We believe that assessing the arcuate fasciculus is highly relevant, given that language problems have been determined to be the most sensitive clinical marker of dementia, AD, and their progression.” Most patients enrolled in the study have either continued dosing in the extension study or are planning to enter extended dosing – an encouraging sign. Aschoff maintained his buy rating on the shares and doubled his price target from $13 to $26.

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