CaMKII

‘Undruggable’ targets aren’t just in oncology. Cardurion Pharmaceuticals is hoping to become the first to successfully develop a treatment for a genetic heart condition that researchers have been studying for decades. The startup is working on a rare heart disease known as catecholaminergic polymorphic ventricular tachycardia — CPVT for short — that can lead to abnormal heart rhythms and is estimated to impact one in 10,000 people. To do so, it’s using a CaMKII inhibitor and has become the first to put such a drug into human studies. It’s not an easy target. CaMKII is a protein kinase that is involved in both heart function and human memory — meaning that any drug going after it has to be extra precise. Cardurion CEO Peter Lawrence told Endpoints News that big pharma companies they are in contact with “were really intrigued by the fact we were able to get into human clinical testing with the CaMKII inhibitor because other major pharmas and biotechs have tried for a very long time — and it was hard to do.” Cardurion’s plan to develop the next generation of heart disease treatments involves a mix of internal research and external hunting. Founded by cardiologist and seasoned industry executive Michael Mendelsohn, who previously led cardiovascular research at Merck Research Laboratories, Cardurion launched in 2017 through a partnership deal with Takeda. As part of that partnership, a cardiovascular research team from Takeda’s site in Shonan, Japan turned into Cardurion’s drug discovery unit. Along with its CaMKII inhibitor, the Massachusetts-based company has clinical trials for heart failure studying two PDE9 inhibitors, one of which was a failed blood disorder treatment that Cardurion is looking to revive. In May, the company touted biomarker results from its Phase 2 study of one of those inhibitors. The company declined to disclose exactly how much money it has raised, beyond saying it’s somewhere north of $500 million. That includes a $260 million Series B that Cardurion announced in July and part of a $300 million commitment from Bain. “What we do is translate our expertise in cardiovascular signaling pathways into therapeutics for our patients. That is the scientific thesis that undergirds everything that we do,” Lawrence said. “We are constantly thinking about what could be attractive targets to pursue in various diseases. And we don’t talk a lot about what we’re looking at, because it’s proprietary, but it is no different than oncology.” Key backers: Ascenta Capital, Blue Owl Capital, Delos Capital, Digitalis Ventures, Farallon Capital Management, Fidelity Management, GV, Millennium Management, New Enterprise Associates, The Invus Group, Bain Capital Life Sciences and Bain Capital Private Equity, Polaris Partners, Takeda Pharmaceuticals Find the full list of 2024 Endpoints 11 winners here .

Cardurion also plans to use the funding to expand the indications outlined for the two candidates and acquire additional assets for treating cardiovascular disorders. Image Credit: VectorMine / Shutterstock. US-based cardiology biotech Cardurion Pharmaceuticals has raised $260m in Series B financing to advance its drug pipeline. The proceeds will fund the late-stage trials for two of the company’s lead candidates, CRD-750, a phosphodiesterase 9 (PDE9) inhibitor for heart failure; and CRD-4730, a calmodulin-dependent protein kinase II (CaMKII) inhibitor for treating catecholaminergic polymorphic ventricular tachycardia. Both therapies are being evaluated in Phase II trials. The company also plans to use the fund to expand the number of indications being explored for the two candidates and acquire additional assets for treating cardiovascular disorders. The investors in the Series B round included Bain Capital, Ascenta Capital, and other US-based investment companies. CRD-750 is being evaluated in two Phase II trials (NCT06215586 and NCT06215911) to treat two types of heart failure – heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Both placebo-controlled trials are currently recruiting patients across multiple locations in the US and Canada. In May, the company presented positive data for another PDE9 inhibitor, CRD-740, in patients with heart failure. The CARDINAL-HF Phase IIa trial (NCT05409183) met its primary endpoint in patients with HFrEF by demonstrating a statistically significant median increase in plasma cyclic guanosine monophosphate (cGMP). See Also: Sumitomo Pharma’s DSP-5336 gains FDA fast track for AML AstraZeneca completes Amolyt Pharma acquisition CRD-4730 is being evaluated in a Phase II trial (NCT06005428) as a treatment for catecholaminergic polymorphic ventricular tachycardia—a rare genetic arrhythmic disease. The company also plans to develop CaMKII inhibitors to target additional cardiovascular indications. There has been an increased interest in developing novel cardiovascular therapies in recent months. In February, Novo Nordisk agreed to pay up to $1.46bn to license multiple molecular glue degraders for treating cardiometabolic disorders and rare diseases from Neomorph. As part of the agreement, Neomorph would bear discovery and preclinical research responsibilities while Novo Nordisk would have exclusive rights to further clinical development and commercialisation. Another approach that has emerged as a promising treatment in the cardiovascular space is drugs targeting the glucagon-like peptide-1 (GLP-1) receptor. Last year, Novo Nordisk reported that its GLP-1 therapy Wegovy (semaglutide) reduced the incidence of cardiovascular events in obese and overweight patients by 20% compared to placebo.

“People see cardio as not just the province of Big Pharma anymore,” Cardurion CEO Peter Lawrence told Fierce Biotech in an interview. Cardurion Pharmaceuticals was made flush in 2021 thanks to a $300 million investment from Bain Capital. Now, the biotech is looking to challenge the statin-dominated cardiovascular status quo with a $260 million series B fundraising round. Bain also participated in this latest raise, which was led by Ascenta Capital. Other new investors include NEA, GV, Fidelity Management & Research Company, Millennium Management, Farallon Capital Management, Invus, Blue Owl Healthcare Opportunities, Delos Capital and Digitalis Ventures. Cardurion was founded by Michael Mendelsohn, M.D., a physician-scientist and previous global head of cardiovascular research at Merck, to develop new therapies for heart failure and other cardiovascular diseases. After forming a collaboration with Takeda in 2017, the biotech emerged with lab space, development resources and licenses to a bunch of Takeda assets. CEO Peter Lawrence, who joined in 2020, credits Cardurion’s success over subsequent years despite a tough market to general excitement about cardiovascular diseases and specific enthusiasm for Cardurion’s first-in-class drugs. “People see cardio as not just the province of Big Pharma anymore,” Lawrence told Fierce Biotech in an interview. “We have two clinical stage assets, three ongoing proof of concept trials, any one of which, if successful, could be somewhat transformational for a patient population.” Cardurion plans to harness the fresh funds to support later-stage clinical trials of its two leading drug candidates, a phosphodiesterase-9 (PDE9) inhibitor called CRD-750 and a calcium–calmodulin-dependent protein kinase II (CaMKII) inhibitor called CRD-4730, both of which are currently in phase 2 clinical trials. CRD-750 is being tested for both types of heart failure: heart failure with preserved ejection fraction, and heart failure with reduced ejection fraction. More than six million adults in the U.S. have heart failure, and heart disease is the leading cause of death in the nation. When the heart is stressed, it depends on a messenger molecule called cyclic guanosine monophosphate (cGMP) to regulate its response. PDE9 plays a role by breaking down cGMP so it isn’t overabundant, but in heart failure, this can lead to a lack of the needed cGMP for the heart to respond to stress. CRD-750 binds to PDE9 and prevents it from breaking down cGMP, which Cardurion thinks will allow the signaling molecule to build up and alleviate heart failure symptoms. “At each step of the way, preclinically and then clinically, the hypothesis has held,” Lawrence said. He believes CRD-750 has the potential to become the standard of care for heart failure. CRD-4730 is being tested for a rare genetic disease called catecholaminergic polymorphic ventricular tachycardia, which causes heart arrhythmia. Cardurion also plans to expand its CaMKII inhibitors into other, more common cardiovascular diseases. “Big Pharma has been trying to get CaMKII inhibitors in the clinic for almost two decades,” Lawrence said. “This is actually the first-ever CaMKII inhibitor that's been taken into human clinical testing.” In addition to furthering its own drugs, Cardurion plans to use series B funds to pursue and purchase other assets. The biotech is currently eyeing one or two preclinical targets that have shown great potential, Lawrence said, and he thinks Cardurion’s robust M&A strategy helped make the company enticing to investors. “It's a high bar because we have great internal assets,” the CEO said. “But if we see something that we love, targets that we think are going to be important, we're going to try and figure out a way to bring them in and get going on them.” Lawrence has been on the other side of the dealmaking table, too; he oversaw the $2.7 billion sale of oncology biotech ArQule to Merck & Co. in 2020. While Cardurion is interested in partnering with Big Pharma, he said, his focus is on pumping up the biotech’s independence. “Having been in and around M&A for 30 years, I think you can never build to [acquisition],” Lawrence said. “We're building the company to have a long gestation.”