Cardiovascular disease kills nearly 18 million people every year worldwide—nearly twice as many as cancer. Yet while the past two decades have seen a flurry of hot new oncology drugs and cancer-focused startups enter the arena, the same can’t be said for heart medicines, despite a wealth of new knowledge about how disease affects this organ.
“If you look at the pace of innovation over the last 15 to 20 years, it’s been very limited,” Bitterroot Bio CEO Pavan Cheruvu, M.D., told Fierce Biotech in an interview. “You’ve had basically the same kinds of approaches being tried over and over again. Although the targets have evolved, we’re still trying to lower LDL cholesterol, we’re still delivering antiplatelet agents.”
Bitterroot Bio aims to change that. The Palo Alto-based company officially emerged from stealth mode on June 7 following the close of a whopping $145 million series A, which it claimed is the largest-ever investment for a preclinical CVD-focused biotech. The round was led by ARCH Venture Partners and Deerfield Management with support from Google Ventures, Koch Disruptive Technologies and others.
“That total amount really was the result of a lot of discussion between our board [and] our management team trying to determine the right amount of capital to get this company started,” Cheruvu explained. “Cardiovascular disease is not for the faint of heart—there’s a long, arduous journey ahead for any company that’s pursuing CV indication.”
The funds will go toward homing in on a fresh treatment angle for the disease, one that’s taken straight from the oncology and autoimmune playbook: immunotherapies, starting with a drug for atherosclerosis.
“Our view is that there’s been an enormous leap in our understanding of the root cause of many forms of cardiovascular disease and that those root causes are linked to pathways of inflammation and the immune response,” Cheruvu said. “We see a real opportunity here to build a world leader in what we call cardio-immunology, where we would take well-validated and characterized approaches that have been tried in other areas and apply them to great effect, we hope, in the cardiovascular domain for the first time.”
From 'don’t-eat-me' into 'do-eat-me'
Behind Bitterroot are co-founders Nicholas Leeper, M.D., and Irving Weissman, M.D., a Stanford cardiologist and stem cell biologist, respectively. The fledgling company is something of an encore for the pair: they previously founded Forty Seven, an immuno-oncology biotech acquired in 2020 by Gilead for just under $5 billion. The same pathways targeted by Forty Seven will be the focus at Bitterroot, but initially for CVD instead of cancer.
“This really all comes from maybe a decade’s worth of work at Stanford,” Leeper said in an interview. “We’ve been very focused on moving beyond the traditional risk pathways and have intentionally ignored things that go after the usual suspects, if you will, like blood pressure, cholesterol and insulin resistance.”
Unbiased high-throughput genetics screenings conducted by Leeper’s lab at Stanford showed that most of the heritable components of CVD are linked not to hypertension or low-density lipoprotein (LDL) levels, but to the immune system. They found that dysregulated inflammatory pathways in the blood vessel wall prevent efferocytosis, a process by which immune cells called macrophages dispose of diseased or dead cells.
Normally, these dying cells give off signals that tell macrophages to eat them—but, on account of the deranged pathways, they give off “don’t eat me” signals instead, Leeper explained. The cells build up in the blood vessels as plaque.
“You have a scenario where the garbage man doesn’t realize there’s garbage that needs to be taken out,” Leeper said.
The culprit behind the “don’t eat me” signal is a molecule called CD47, which is activated by inflammation. Work in mice by Leeper and Weissman’s teams has shown that blocking signaling pathways involving CD47 and the protein SIRP-alpha, also known as the CD47/SIRP-alpha axis, could turn off the signal and render the diseased cells edible to macrophages once again.
CD47 was also the target of Forty Seven’s antibody magrolimab. Back when the company was conducting its first-in-human trials, they saw that the drug didn’t just shrink patients’ tumors—it also lowered inflammation in their blood vessels and improved metabolic activity in their carotid arteries.
Now, the team is leveraging this activity for Bitterroot’s first asset, a complex protein biologic called BRB-002 that’s indicated for atherosclerosis. In mice, the drug was able not only to prevent plaques from progressing, but actually melted them away, Leeper said.
“That’s really the holy grail for cardiovascular scientists,” he added.
BRB-002 and beyond
BRB-002 differs from its oncology predecessors in a few key ways. First, it’s formulated in a way that mitigates the likelihood of the adverse effects seen with other CD47-targeting drugs. Second, it’s purified to a higher degree, giving it a much higher affinity for CD47 targets and, thus, a lower required dose. That’s compounded by the fact that it only needs to get into the vascular wall, not penetrate a tumor, so less of the drug is necessary to see results in atherosclerosis.
“For all those reasons, we have a highly-refined molecule that also has these favorable properties that make it very safe for people and delivers a very high level of efficacy,” said Bitterroot's Chief Medical Officer Craig Basson, M.D., Ph.D.
BRB-002 is currently progressing through IND-enabling studies. The company has efficacy and safety data from mice, rats and non-human primates, with plans to get the drug into the clinic within the next calendar year. The series A funding will be enough to get it through phase 1 and likely proof-of-concept phase 2a clinical trials, Cheruvu said.
“We think that will be very important validation of our program,” he added.
Beyond that, Bitterroot has a few possibilities in play. The company is both investing in in-house R&D and exploring acquiring new assets from elsewhere in the cardiovascular ecosystem. And it’s already looking at the pipeline-in-a-product potential of BRB-002, with one undisclosed “orphan-like” indication under investigation.
“We believe that targeting CD47 might have benefits not just in atherosclerosis, but in other inflammation-driven cardiovascular diseases as well,” the CEO said.