From Ashes to Flames: Novel Alzheimer’s Disease Pathways Emerge

Alzheimer's disease (AD) has been one of the most challenging diseases of our times, and currently, there are no therapies that slow or halt the progression of the disease. INmune Bio's Chief Executive Officer, Dr. R.J. Tesi, highlights a unique approach, decreasing neuroinflammation, as a new strategy to slow Alzheimer's disease. 

Moe Alsumidaie: RJ, how will INmune Bio's unique approach challenge the current AD landscape?

RJ Tesi

RJ Tesi: What we are doing at INmune Bio is taking the best practices for clinical development in oncology and apply them to neurology. The failure of the biopharmaceutical industry to get drugs approved in broad disease categories like the central nervous system (CNS) is not because there haven't been suitable therapies but because the traditional approach to clinical trial design has failed. You don't see any oncology companies saying, "I'm doing breast cancer." What they do is take a "slice" of the disease and work on the therapy, and if that works, then the company can expand its footprint in the field.

From an operational point of view, you must closely match the patient's disease with the mechanism of your drug. This is called precision medicine. At INmune Bio, we are focused on precision and biomarker directed medicine. One of our operational challenges has been to educate the clinical sites on how to use these biomarkers. On the one hand, biomarkers make it more difficult to enroll a patient. The pay-off is that you improved the probability of a successful clinical trial. The clinical sites get just as excited about positive results as we do.

MA: That's so interesting because I wrote about how CNS is moving towards oncology-based methodologies. Once you're able to establish those biomarkers, the field will explode with new targeted research, don't you agree?

RT: I agree with you! I always use the AD market as an example. Before aducanumab blew up in March, the field was just sluggish. If you were not doing anti-amyloid therapies, you were not doing anything. Even though previous trials had failed, the focus was still anti-amyloid therapies. The news of aducanumab's failure was the best thing that could have happened to the field because it finally shifted the interest away from amyloid plaques. Experts were forced to look for "other than amyloid" causes underlying the pathology of AD. There are three or four main disease mechanisms that are most interesting; neuroinflammation is the one we are focusing on.

MA: Could you tell me more about the biomarkers that INmune Bio is looking at? 

RT: We are an immunology company focused on the innate immune system and specifically on chronic inflammation. The way I like to describe acute inflammation, in contrast to chronic inflammation, is to think about getting a splinter. Within hours the wound starts to swell up, gets sore, red, and warm. This is acute inflammation with the body trying to protect you from the bacteria in that splinter. When the splinter is expelled, the inflammatory response goes away within hours-literally that fast. 

Chronic inflammation, however, could not be more different. Everybody thinks chronic inflammation is just prolonged acute inflammation, but the biology is completely different. Chronic inflammation is this low level of grumbling inflammation that you can't see, feel, or diagnose. It is associated with cardiovascular disease, neurodegenerative diseases, metabolic disease, and, quite frankly, aging. Many of the diseases of aging are due to chronic inflammation. Now, the beauty of targeting chronic inflammation in conditions like Alzheimer's disease, is that there are more immunologic biomarkers than neurologic biomarkers. This is a classic case where results exceed the sum of the parts. 

We put our money where our mouth is. The AD Phase I trial is unique in that it's an immunology trial in patients with neurologic disease. It is not just a trial in patients with Alzheimer's disease; it's a trial in patients with neuroinflammation who have Alzheimer's disease. 

MA: What endpoints are you focusing on in this trial?RT: Let me tell you first about the inclusion criteria, and then we'll go to the endpoints because one builds on the other. Initially, we just started with a single inflammatory biomarker for inclusion-C reactive protein (CRP). CRP is best known in the cardiovascular world; however, it's now clear that CRP is a measure of chronic inflammation.

Although we started with patients with an elevated CRP, we were concerned that there were a lot of patients who would be slipping through the cracks. We added three additional validated biomarkers of risk for AD. The first is genetic, the presence of the inflammatory gene APOE4. The second is hemoglobin A1c (HgbA1c). There is extensive data that support the correlation between levels of HgbA1c greater than 6% and a higher risk for AD. The third biomarker is the erythrocyte sedimentation rate (ESR) since there is a correlation between abnormally elevated levels of ESR and the increased risk for AD.Beyond CRP, these laboratory values are not traditionally viewed as inflammatory biomarkers. Although a patient only needs one to be enrolled in the study, most have two, seldom three. 

Ultimately, the success of the trial will be measured by the ability of XPro1595 to eliminate neuroinflammation. This is a key point. This Phase I is not designed to impact cognition. The trial is too small and too short for that. We have five buckets of biomarkers to measure efficacy-a decrease in neuroinflammation. The first two are ones everyone uses, tests in blood and cerebrospinal fluid, where we are looking for biomarkers of neurodegeneration, such as neurofilament, amyloid, and tau levels as well as traditional biomarkers of inflammation such as cytokines. The more interesting biomarkers are non-invasive.

MA: Are these established biomarkers or exploratory? Are they acceptable by regulatory authorities?RT: The only approvable endpoint for Alzheimer's disease right now is an improvement or a decrease in the rate of cognitive decline. 

MA: What scales of cognitive decline are you using in this trial?RT: This first trial, it's a three-month trial. That's why it's a neuroinflammation trial. Our endpoints are neuroinflammatory. Here's the hypothesis: if neuroinflammation causes Alzheimer's, and we have a drug candidate that could cure Alzheimer's by targeting neuroinflammation, the first question we have to answer is, "…does our drug candidate get rid of neuroinflammation?" We can do that in three months. Then we can move on to explain the next question, "…if we get rid of neuroinflammation for 12 to 18 months, will that improve cognition?" Both trials are in patients with AD. The first is to determine if we have a drug that eliminates neuroinflammation. The second trial is to determine if we have a drug that treats cognitive decline, the hallmark of this devastating disease. We believe this pas-deux gives us a better chance of success.

We are using several novel biomarkers in the trial. With neuroimaging, we measure white matter free water, which is a biomarker of neuroinflammation. As far as I know, we're the first to use this biomarker prospectively to follow the efficacy of a drug. We also are using a breath test that measures volatile organic compounds that create a "breath signature" for patients with AD. We expect elements of improvement will be the signature's changes because it is a noninvasive test. Arguably, the most relevant biomarkers of neuroinflammation are neuropsychiatric, including depression, sleep disorders, aggression, hallucination, and apathy. We do all those scales, and they are exquisitely sensitive to neuroinflammation. 

The goal of the Phase I trial is to prove that we can get rid of neuroinflammation in a small group of patients. This trial will inform us of the biomarkers and prepare us for a Phase II trial.

MA: That's an interesting approach. You're essentially first validating the neuroinflammatory biomarkers in your Phase I, and then, you're hoping that by reducing neuroinflammation, you might get a response.RT: Exactly. The animal data shows that if you get rid of neuroinflammation, the cognitive decline decreases. Paradoxically, we believe the failure of aducanumab in March really helped the field. By solidifying the belief that anti-amyloid therapeutics are not the "cure" for AD, investors and industry representatives finally said, okay, let us look elsewhere. 

Finally, it is essential to accept there will not be a silver bullet that cures all AD patients-there are multiple causes of dementia. We must try different approaches to treat the disease. Like many complex diseases, Alzheimer's is going to require combination therapy. There'll be some patients where monotherapy is effective. In general, we believe most patients are going to need more than one therapy, also known as combination therapy, for effective treatment.

MA: So when you move into later trials, Phase II trials, and you continue to implement these biomarker collection methodologies, how do you think that'll impact patients? RT: Excellent question. Biomarkers make your clinical trials more accurate, but they can be a hurdle to patient enrollment. That is, patients do not like "invasive" testing. They'll let you draw blood, but as soon as you must do more than that, it becomes problematic. Our goal is ultimately to phase out the invasive strategies and convert them to noninvasive. The other benefit of that is it also allows you to move upstream in your treatment paradigm. In other words, for every disease known to man, the sooner you start to treat it, the better the outcome. Alzheimer's should be no different. You want to begin treating patients the first time they forget their keys, not have to wait until they can't get home one night because they can't remember where they live.

Ultimately, we hope to be able to validate these novel noninvasive biomarkers to allow us to perform better, shorter, and safer clinical trials. At this point, we know that the cognitive scales are the standard for drug approval in AD. In the future, we hope that we can short-circuit that with surrogate endpoints. To come full circle, we looked at the best practices in oncology drug development, and we are applying them to neurology. We're lucky; there are a lot of biomarkers. We're also innovative, and we take some chances.  We believe this will help us get novel therapies to patients faster!
 

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.