Using a new pathway to better understand and reduce the impact of neurodegenerative and autoimmune diseases
CEO: Douglas Love
Based: South San Francisco, CA
Clinical focus: Alzheimer’s, Huntington’s, glaucoma, autoimmune disorders
The scoop: This preclinical biotech, led by Genentech and Elan veteran Doug Love, is looking to bring its pipeline of classical complement pathway inhibitor antibodies into the clinic starting next year as a bold new way of treating a host of central nervous disorders, as well as autoimmune and ophthalmic conditions. Annexon's two lead candidates, ANX005 for serious CNS and autoimmune disorders and ANX007 for ophthalmic disorders, both inhibit a protein known as C1q, which is the initiating molecule of the classical pathway, and blocks the complement activation involved in neurodegeneration.
What makes Annexon Biosciences Fierce: You can’t help but admire a biotech that will go after a condition like Alzheimer’s, which has seen a 99% failure rate in the lab over the past decade. Love, Annexon’s CEO since 2014, said there is a natural sense of trepidation over targeting Alzheimer’s given how well he knows some of these failures, but he is certain that his biotech’s approach will prevail.
Whereas most current Big Pharma and biotech research on the area is focused on clearing tau or amyloid from the brain in Alzheimer’s patients (and results have been patchy at best), Annexon is looking to halt synaptic degeneration, rather than clearing out tangles and plaques from the brain once the memory-robbing disease has taken hold.
The focus is on the protein C1q, which mediates synaptic removal--including that of functioning and healthy synapses, which is one of the first events in the onset of neurodegenerative disease.
The classical complement pathway, with its initiating molecule C1q, is thought to lead to the loss of nerve connections, inflammation and neuronal death.
Love explains: “We are the first-in-kind in pursuing the classical complement pathway and what’s unique about our approach is that it is based on the science founded around 10 years ago by Dr. Ben Barres [who is chair of neurobiology at Stanford University], so we are the discoverers of the approach. And what we discovered was that the classical pathway’s appropriate function in early development is to rid the body of weak or dying synapses from when we are born.
“So, it triggers a cascade of events which then allows us to move forward in life; they allow our neurons and synapses to go forth and conquer, which is great. Then Dr. Barres went on to discover that the initiating molecule of this pathway, C1q, actually accumulates on synapses as we age. And that’s in all of us, not just those with dementia or other disorders. That was a very significant discovery because age is the number one risk factor for neurodegeneration, so the thought originally was that this could be a common mechanism by which the body actually targets synapses and causes their removal. Dr. Barres went on to research this in a host of neurodegenerative diseases, originally starting in the eye with glaucoma, and then moved on to Alzheimer’s and Huntington’s disease.”
Love says that Dr. Barres found that at the earliest onset of these diseases, C1q is triggered, which causes the removal of synapses and degeneration of neurons, including neuroinflammation. All of this pointed to the conclusion that this could be the pathway by which functioning synapses are lost, which exacerbates a host of neurodegeneration disorders.
“We formed the company around that idea 5 years ago and are continuing on with preclinical studies. So far, early data used across a number of these types of neurodegenerative disorders has shown consistently, regardless of which specific disorder we look at, in our animal models that when the disease starts, C1q is triggered, the classical cascade has been amplified, and causes the removal of healthy, functioning synapses.
“So when we inhibit this using ANX005 and ANX007 at any point of the disease process, we can show that we are protecting synapses against neuronal degradation. We can also improve survival rates in mice with other conditions, so we’re highly excited by these data.”
Love adds that it’s important to note the biotech is not seeking to stop the underlying cause of these diseases. He points to the 99% failure rate in Alzheimer’s and says everyone asks him “why do you think you’re different?” “Well, we’re not targeting the underlying disease, we’re actually targeting the mechanism that causes the removal of neurons, synapses and causes damage,” he says. “So, we think it’s a completely novel and different approach than what’s been going on in other labs.”
The biotech is also working on using smart biomarker “breadcrumbs” to measure neuroinflammation as a way to assess its candidates and get early reads on the data. “This is similar to the processes used in cancer around a decade ago, where we started to use diagnostics to pinpoint which patients would respond to certain drugs that targeted specific mutations,” Love says. "That’s the kind of paradigm we want to create with our biomarkers.”
After securing a $44 million Series B in the summer, Love says that the two C1q compounds ANX005 and ANX007 will be entering the clinic starting next year for a host of CNS and autoimmune disorders, and that the company has enough cash to see it through to Phase II. Until then, science is the only thing on his mind.
Investors: NEA, Correlation Ventures, Novartis Venture Fund, Clarus Ventures and Satter Investment Management