Susan Catalano, founder and CSO of Cognition Therapeutics, says new data supports the notion that the Pittsburgh biotech’s lead drug targets a key aspect of Alzheimer’s pathology.
Susan Catalano, founder and chief science officer of Cognition, trained in neurobiology, working on synaptic plasticity and mechanisms of learning and memory. She did her doctorate at UC Irvine, and a postdoc with renowned neuroscientist Carla Schatz PhD at UC Berkeley. She moved to Caltech and worked with another famous neuroscientist, Mary Kennedy, PhD, “before going to the dark side” and starting at Roche Palo Alto.
After a stint working outside the area of neurobiology, she joined Acumen Pharmaceuticals and then co-founded Cognition in 2007 in the Bay Area before relocating the company to Pittsburgh. The company is still small, with 22 employees, but has attracted significant government funding and is pushing forward in the clinic with a promising small-molecule drug for Alzheimer’s disease. Cognition is also making important strides in understanding the genetics of the disease, information that reinforces and refines its therapeutic rationale.
Kevin Davies asked Catalano to talk about Cognition’s clinical progress and the underlying rationale for its Alzheimer’s drug program. (This interview has been lightly edited for length and clarity.)
GEN Edge: What was behind your move to Pittsburgh?
Catalano: The Bay Area is certainly a hotbed. But we’re operating a company for about a quarter of the price. Pittsburgh is a great neuroscience town. They have a historically very high focus of neuroscience faculty at the university so we’ve been able to build a company, staff it, and grow it.
The economic development agencies in Pennsylvania, which include the Ben Franklin system: our local chapter here in Pittsburgh is called Innovation Works and Rich Lunak and the team were instrumental in rolling out the red carpet to us. We also had the support of John Manzetti and the Pittsburgh Life Sciences Greenhouse. So starting Cognition here and incubating it was really seamless.
GEN Edge: Is Alzheimer’s disease your sole focus?
Catalano: It’s part of a wider area of therapeutic interest. The company has been focused on Alzheimer’s disease for a while, but we’ve recently added additional indications that leverage what we’ve learned about our target to other disease areas where there’s a lot of unmet medical need.
GEN Edge: What is currently in the clinic or heading that way?
Catalano: Our lead drug candidate is CT1812, currently in four phase II clinical trials with a fifth about to start. These are studies where we are looking at the clinical pharmacology to understand the drug’s mechanism of action and its impact on disease. These trials are all being done in patients with mild-to-moderate Alzheimer’s disease, with the exception of the one that’s going to start [in 2021].
We announced the results of the first set of 24 patients to be dosed with the drug for six months [in the SHINE study] last July at the Alzheimer’s Association conference (AAIC).
GEN Edge: Is the hope for this drug to slow the course of the disease or to actually reverse the pathogenesis of the disease?
Catalano: We believe this is a disease-modifying therapeutic that will have a very broad and profound impact on Alzheimer’s disease progression. It works by reducing Aβ [amyloid beta] oligomer binding affinity. CT1812 is literally the only drug candidate in clinical development that can destabilize the binding pocket where Aβ oligomers bind on synapses on neurons and create all of the downstream damage and memory failure that we see in Alzheimer’s disease. The drug binds to sigma-2 receptors receptors, allosterically modulates them, which in turn modulates the receptors that oligomers bind to, causing an increase in the off rate of oligomers as a result of this destabilized binding pocket.
GEN Edge: You are firm believers in the amyloid hypothesis then?
Catalano: We are indeed. We think there’s pretty overwhelming evidence that supports that. Not only the very well-known risk genes that result in early onset inherited disease but also in sporadic disease and of course with this very profound protective mutation (in the amyloid precursor protein APP gene] that was discovered back in 2012.
GEN Edge: You wouldn’t have been able to advance this drug into Phase II without some pretty impressive preclinical data. What was the most impressive animal model data that got the drug into the clinic?
Catalano: We’ve been able to use three separate methods to actually demonstrate that the drug increases the off rate of the Aβ oligomer—this pathological ligand that’s only there in the disease. We looked with mature primary neurons in the dish. We looked with Alzheimer’s patient post-mortem tissue sections. We also looked in the brains of living mice. In all cases, we observed an increase in the off rate of Aβ oligomers, in some cases after a single dose of drug.
In the case of the patient tissue sections, this is what we classically refer to in the industry as an ex vivo binding experiment. You’re not adding anything to the tissue sections, you’re just putting solution on top of them as they sit on the slide that contain identical volumes with ascending concentrations of drug. Then you look to see what’s left in the tissue and what’s extracted out of the tissue in the supernatant. We saw less oligomer in the tissue section around the plaques in AD patient brains and an increase in oligomers in the supernatant that was dose-dependent.
GEN Edge: Are you doing this by yourself or have you partnered with anybody?
Catalano: We’ve been fortunate to have enormous amounts of support from the National Institute on Aging (NIA). I think they recognize the necessity for very novel approaches even to traditional targets in Alzheimer’s disease. We are the only sigma 2 allosteric antagonist in the clinic for any indication, and we’re the only one pursuing this Aβ oligomer displacement mechanism in Alzheimer’s disease.
NIA has supported the entire clinical development of this drug—close to $120 million in grant funding, the majority of that being clinical. Last June, we announced that we had received a $75.8 million award from NIA to support a 540-patient efficacy study that we’re about to launch in collaboration with the ACTC. That was the largest grant they’ve ever given to a single drug company.
GEN Edge: Have you settled on the dosage? How is the drug administered?
Catalano: This is a once daily oral medication. We’ll be testing two doses versus placebo. All of our clinical trials have been double-blind placebo controlled.
GEN Edge: Let’s talk about the genetics of Alzheimer’s. How important is it to understand the genetics and how much of an influence is this understanding in terms of guiding your therapeutic course?
Catalano: We think that genetics is the guiding light as you might imagine. What gets lost in the rather dramatic sets of clinical failures that we’ve had in Alzheimer’s disease is the genetics.
In Alzheimer’s disease, when you simply look at the risk genes or the causative genes, all roads lead to Aβ. The vast majority of mutations that cause the early-onset form lead to a single phenotype—an increase in the concentration or the ratio of this longer, more aggregation-prone form of the Aβ protein. When we finally discovered the first robust protective mutation that has strong functional evidence, as well as epidemiological evidence of its impact, it was also a mutation in the Aβ sequence.
In every other neurodegenerative disease that you would look at, there are 2, 3, sometimes multiple genes mutations that could lead to an early onset form the disease that’s indistinguishable from the sporadic form. That’s not the case in Alzheimer’s disease. Alzheimer’s is unique. All roads really did lead to Aβ.
GEN Edge: You’ve got a new study in the Journal of Neurochemistry about a mutation called A673T first discovered in the Icelandic population. It’s arguably the strongest protective AD mutation discovered to date. What is the significance of this new finding?
Catalano: Collaborators at Genentech and Iceland’s DeCode Genetics discovered this mutation [in the APP gene] by genotyping everybody. It’s also position 2 in Aβ. This mutation is actually quite rare—in the first publication there were only about 41 folks who had it, and all but three were heterozygotes. Since then it’s been found in other Scandinavian populations at low frequency, but the folks who carry it — even the folks who are heterozygous for it—have a four-fold lower incidence of Alzheimer’s disease and age-related cognitive decline. So, it’s profoundly protective in a way that a lot of the other putative protective genes that have been identified really can’t demonstrate.
Many people have studied this mutation since it was discovered in 2012. Scientists have looked at the rate of fibrilization: the morphology of those fibrils. We wanted to look at the oligomeric form of that protein. Aβ is an intrinsically disordered protein. It takes a variety of shapes—it’s never a nice well-folded globular form. So we have the monomer; an infinite polymer known as a fibril that looks like a zipper; and we have a globular intermediate known as an oligomer—probably the best analogy of this is a Medusa’s head—with a hydrophobic central core that self assembles and then these floppy N termini around the outside of that central core.
The oligomers are the focus of most AD research for the past decade for one simple reason—the oligomers are the most toxic form of the protein. The reason for this toxicity is they behave like ligands. They bind to a single receptor site on neuronal synapses. When they’re bound, they trigger a variety of downstream changes that include memory failure—the inability to encode new memories. This is a very prominent feature of Alzheimer’s disease.
It’s this pathological ligand that everyone’s been studying for the past decade. It’s challenging to study because it’s intrinsically disordered, you can isolate it from patient brain or you can make it in the dish by taking peptide and allowing it to self-assemble and using experimental systems to measure toxicity.
That’s what we did. We chose a method of making these synthetic oligomers that is most physiologically relevant, a method pioneered by Bill Klein years ago. Using this method to make the oligomers we looked at wild-type and mutation containing oligomer side by side. We found that mutation-containing oligomers are less likely to form in the first place (by about half).
What was really surprising was when we took the wild-type oligomers and the protective mutation-containing oligomers and we put them on neurons and looked at the binding, (which is how the toxicity is actually happening), we found that the mutant oligomers bound with fourfold lower affinity. We had no idea that we would see this profound fourfold lower affinity.
When you add all this up, the predominant effect of this protective mutation is to lower the binding affinity of this pathological ligand. That was unexpected, and to us it was significant because our drug reduces affinity—lowers the ability of the oligomers to bind to this receptor at synapses in the brain.
GEN Edge: This reinforces what Decode and others had observed from the genetics, you’ve now got solid experimental proof that really backs up the genetic findings. Does that have any direct bearing on your ongoing clinical trials?
Catalano: This is a very important genetic validation of the approach that we’re taking. It was truly unexpected. It also points us in directions for looking at target engagement within those clinical trials in a fresh way. It’s going to be important to look at the movement of these oligomers — to look at the total equilibrium of Aβ in all three of its structural forms.
GEN Edge: Your lead drug candidate is in phase II trials. Might there be ways to further improve the specificity, reduce the toxicity of this small molecule?
Catalano: Like any drug discovery company, we do look for more effective forms of the molecule. We think CT1812 will be an effective therapeutic, but there’s always strategies that you can engage in to pursue follow-on molecules in the pipeline.
GEN Edge: What does the future hold for Cognition?
Catalano: We recently announced the results from the first group of mild-to-moderate Alzheimer’s patients that were treated with the drug once daily for six months, the SHINE trial, reported back in July. These 24 patients showed a trend for improvement in their cognitive scores compared to placebo-treated patients, meaning they had a slower decline than placebos were exhibiting.
In terms of biomarker evidence, we observed significantly reduced Aβ in drug-treated patient’s CSF [cerebrospinal fluid] compared to the placebo patients.
We have evidence of slowed cognitive decline and evidence of an impact on the Aβ biology in Alzheimer’s as well. This was something that the secretase inhibitors were hoping to achieve. We know that it’s very preliminary—this is a very small number of patients; it is not adequately powered for cognitive outcomes—but it’s encouraging and supportive of further development.
Next year, we’re going to get the results from two additional cohorts of patients where we’re planning to look at the cognitive score as well as the protein expression in these patients and a lot of imaging parameters, including the first ever clinical trial (SPARC) to look at synaptic density using a very exciting new PET tracer UCB-J that measures the synaptic protein SV2A. This is the world’s first trial to look at how synaptic density measured with this PET tracer changes longitudinally in Alzheimer’s patients.
This PET tracer was developed by Richard Carson and Chris van Dyck at Yale, who reported a hypo-intensity in the hippocampus using this PET (positron emission tomography) tracer in living Alzheimer’s patients—very different from what they saw in normal patients.
A tracer that allows us to measure synaptic density is groundbreaking and it would impact all of neurology. We’re excited to see the outcome from this trial. The first half of next year is going to be a very big year for Cognition.
GEN Edge: It’s my impression that several big pharma companies have pulled out of the neuroscience field because it’s just too difficult. Have you seen competitors drop out because they found trying to try to drug a disease like Alzheimer’s is just too complicated?
Catalano: No question about it. There have been a lot of failures and several large pharma companies discontinued their programs. Ironically and unfortunately this presents an opportunity for the therapeutic approaches that remain. Science marches on and our understanding of the disease progresses and we remain hopeful that that science will be reflected in therapeutics that are going to be more effective. We think that CT1812 will be one of them.
Ultimately, we expect Alzheimer’s to be treated like other chronic diseases with polypharmacology—therapeutics that are effective anti-inflammatories, therapeutics that effectively address tau build up in a patient brains, are combined with anti-amyloid approaches. But you’re going to have to address the Aβ oligomer pathology that sets the whole thing in motion and keeps it in motion. Otherwise, you’re, you’re not going to be able to fundamentally halt disease progression.
GEN Edge: So CT1812 Is perhaps part of a cocktail down the road where different drugs are tackling different elements of the pathology?
Catalano: That’s exactly right, Kevin. These poor patients and their families really need a breakthrough.