CRHR2

PARIS, France I September 07, 2023 I Corteria Pharmaceuticals (“Corteria”), a biopharmaceutical company specialized in the development of transformative therapies for unaddressed heart failure subpopulations, today announced an oversubscribed €65M ($71M ) Series A co-led by US investment firm OrbiMed and EU-based leading investment firm Jeito Capital, with the participation of all existing seed investors (Kurma Partners, Fountain Healthcare Partners, V-Bio Ventures, Invivo Capital, Omnes Capital). As a result, Erez Chimovits from OrbiMed and Andreas Wallnoefer from Jeito Capital will join the board of Directors of Corteria. The funding will be used to advance Corteria’s cardiovascular pipeline into the clinic. Heart failure is a serious disease with a prevalence of more than 60 million patients globally and still growing. Corteria’s innovative approach is centered on selecting therapeutic targets involved in the worsening and acute forms of human heart failure, as well as a stratification strategy to identify specific subgroups that are most likely to benefit from the treatments. These forms of heart failure are widespread, life-threatening, and not directly addressed by the current standards of care. Corteria was founded in 2021 by Sanofi’s former head of cardiovascular research, Philip Janiak, and Marie-Laure Ozoux, former cardiovascular project leader at Sanofi, around two cardiovascular programs in-licensed from Sanofi. Since then, Corteria’s pipeline has expanded rapidly and comprises today three first-in-class therapies that are highly differentiated as they produce multi-organ benefits, acting on the kidneys, the heart, and the vessels: The lead asset for Worsening Heart Failure is expected to enter the clinic in early 2024. “This financing marks a major milestone in our mission to bring therapies to heart failure subpopulations with high unmet needs,” said Philip Janiak, Founder and President of Corteria Pharmaceuticals. We are extremely grateful to Jeito and OrbiMed as our new investors for their trust in our science and team and to our existing investors for their support and commitment since inception. We are looking forward to working all together to develop next generation transformative therapeutics.” Andreas Wallnoefer, Partner at Jeito Capital, said: “Despite current treatments, heart failure is a progressing disease that impacts severely the lives of many patients and remains one of the leading causes of mortality worldwide. Corteria focuses on translating important therapeutic innovation in cardiology into clinical practice. Our investment in Corteria reflects Jeito’s commitment to address significant unmet needs in the realm of cardiology. We are excited to join forces with Corteria’s dedicated team to develop a portfolio of medicines with important clinical benefit for patients.” “We are proud to have been involved with Corteria since its early days and impressed with the progress made to date. The company is now at a turning point of entering the clinic with its lead asset early next year and validating its unique positioning in well-defined heart failure subpopulations with high unmet medical needs. Kurma Partners is pleased to continue supporting the company during this key step that we hope will bring transformative clinical outcome for patients,” said Thierry Laugel, Managing Partner at Kurma Partners, and Chairman of the board of Corteria. About OrbiMed OrbiMed is a healthcare investment firm, with over $17 billion in assets under management. OrbiMed invests globally across the healthcare industry through a range of private equity funds, public equity funds, and royalty/credit funds. OrbiMed’s team of over 100 professionals is based in New York City, San Francisco, Shanghai, Hong Kong, Mumbai, Herzliya, and other key global markets. www.orbimed.com About Jeito Capital Jeito Capital is a global leading Private Equity company with a patient benefit driven approach that finances and accelerates the development and growth of ground-breaking medical innovation. Jeito empowers and supports managers through its expert, integrated, multi-talented team and through the investment of significant capital to ensure the growth of companies, building market leaders in their respective therapeutic areas with accelerated patients’ access globally, especially in Europe and the United States. Jeito Capital has €534 million under management and a rapidly growing portfolio of investments. Jeito Capital is based in Paris with a presence in Europe and the United States. For more information, please visit www.jeito.life or follow @Jeito_life on Twitter LinkedIn About Corteria Pharmaceuticals Founded in 2021, Corteria Pharmaceuticals is a privately held biopharmaceutical company developing first-in-class drugs in heart failure subpopulations. Despite some improvements in the management of this serious disease, the prevalence of heart failure keeps increasing with more than 60 million patients worldwide. Corteria’s strategy involves innovative patient stratification and target selection based on human evidence and a better understanding of disease biology in patients with a focus on worsening and acute heart failure and right heart failure. More information available at: www.corteriapharma.com Applying a 1.0886 EUR/USD exchange rate as of 30 August 2023 (Banque de France) rounded to $71M CRF2 peptide agonist and AVP neutralizing monoclonal antibody programs Corticotropin-releasing hormone receptor 2 SOURCE: Corteria Pharmaceuticals

Cortene President and CEO Gerard Pereira/Courtesy Cortene Inc. As with any hard-fought battle, it is becoming clear that many survivors of COVID-19 are returning from the trenches with a chronic condition known as Long Covid. On October 6, the World Health Organization published a formal definition of the illness, which it refers to as “post Covid-19 condition.” The therapeutic market for Long Covid will undoubtedly be substantial, and one Burlingame, CA-based biopharma company, may have a head start. Cortene Inc. is developing CT38, a proprietary peptide agonist selective for Corticotropin-Releasing Factor Receptor Type 2 (CRFR2), one of two receptors, or pathways, that control serotonin in the limbic system and cord. In response to any threat to homeostasis, corticotropin-releasing factor (CRF) acts via CRFR1 and CRFR2 to control serotonin. When the threat subsides, these receptors return to their normal configuration – unless permanently upregulated by an intense or prolonged threat. This then dysregulates serotonin, leading to the shared symptoms of many chronic diseases. CT38 is being studied in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), as well as in fibromyalgia and chronic Lyme disease. Fatigue is commonly understood as the most prevalent symptom of Long Covid – which comes alongside other symptoms that mirror CFS, such as sleep and cognitive issues, depression and anxiety. Cortene believes that enigmatic diseases such as long Covid, fibromyalgia, Multiple Chemical Sensitivities and PTSD all share a common mechanism, where the specific symptoms relate to different sets of neurons that are affected by a triggering insult (e.g. COVID-19), genetics, life history and gender (women are more susceptible). Cortene narrows the dysregulation down even further, attributing specific responses – or symptoms – to individual neurons. Gerard Pereira, Cortene’s president and CEO, offered an example. “For instance, a particular neuron going in the preoptic area of the anterior hypothalamus is associated with thermoregulation. If its signal is stronger than normal, your body will cool. If its signal is weaker than normal, your body will warm,” he told BioSpace. "With CRFR2 upregulated, cooling/warming behavior is inappropriate." We've laid out a pathway in the brain, and we've provided the first preliminary evidence that this pathway, in fact, generates all the various symptoms of chronic disease,” Pereira continued. He explained that this is the reason why the same sets of symptoms appear to be consistent across the chronic disease spectrum – symptoms such as brain fog, dizziness, orthostatic intolerance (an abnormal response to being upright) and fatigue. While the conventional approach would be to block the overactive pathway, Cortene’s strategy is counterintuitive. During the past forty years, scientists have identified pathways that are either overactive or underactive. They have then endeavored to block or stimulate these pathways. “The problem with this logic is that the body, and especially the brain, is dynamic, not static,” Pereira said. Thus, the idea of putting in a fixed dose of a blocker or stimulant is flawed because it will not account for real-time changes. Cortene’s approach seeks to overstimulate CRFR2, causing it to downregulate without the need for chronic treatment. And so far, the theory looks promising. In a proof-of-concept trial dubbed InTiME, Cortene infused 14 ME/CFS patients with CT38, at one of four infusion rates for a maximum of 10.5 hours, in 14 ME/CFS patients. The drug was associated with a significant reduction in mean 28-day total daily symptom score (TDSS), which aggregated 13 patient-reported, daily symptom scores. The 0.03 μg/kg/h infusion rate seemed to be the sweet spot, as patients achieved a 26% improvement in TDSS –effects Pereira said are still evident after two years. Cortene recently published a peer-reviewed paper with full results of this study in Frontiers in Systems Neuroscience. Dr. James Baraniuk, M.D., professor of medicine in the Neuroscience program at Georgetown University, was one of these peer reviewers. He offered further insight into the CRFR2 pathway (also referred to as the CRHR2 receptor) “Once the CRHR2 receptor gets switched on, it's as if it is permanently switched on. When that happens, it has downstream effects on the limbic system and serotonin system.” Then, any stressor the person is exposed to – including exercise, heat or bright lights – is interpreted as being a major stressor. Other potential stressors are mental trauma, physical trauma, viruses and toxins. While expressing cautious optimism about the potential of the approach, Baraniuk stated that this particular study had a number of limitations, including a small patient sample. “Some of the subjects had adverse events like fast heartbeat, low blood pressure,” he said, adding that these effects were easy to treat at the time of the infusion, but that “fatigue and cognitive problems” also occurred. “The problem is with the variation in any CFS, you have good days and bad days, so some of the adverse events they had could be just the normal variation of this disease.” Baraniuk noted that the 26% symptomatic improvement, measured at 28 days as opposed to immediately following the infusion, was significant. “Let’s put it into perspective,” he said. “There’s no treatment for ME/CFS, and they gave one infusion of the drug, and then 28 days later, people had a continuing beneficial effect. So that is very encouraging to suggest that they should definitely do more studies to understand and prove that the symptoms are getting better.” Baraniuk indicated that the right dose could be the most difficult for Cortene to determine, as it is typical to have a U-shaped dose response curve in the brain. In dose ranging studies, “what they found was a Goldilocks effect. If you gave too much drug, you could end up with adverse events. If you gave too little, you had no effect. They had to get it just right.” Next up, Pereira said Cortene will endeavor to raise a Series A venture round to further the research and test the drug in a larger trial. “These ideas are not that difficult, but they are different. Nobody's thought of an organic change in the brain as the nexus for chronic disease,” he said, “But the flip side of that is no chronic disease has been cured either.”

BURLINGAME, Calif., Sept. 2, 2021 /PRNewswire/ -- Cortene Inc. announces publication of its InTiME clinical trial in which a short subcutaneous infusion of its experimental drug, CT38, achieved sustained symptom improvement in ME/CFS. The company intends to test CT38 in Long Covid, the post-acute stage of COVID-19 infection, which is considered by many to be the latest trigger for ME/CFS. Cortene believes the CRFR2 pathway is upregulated and therefore overactive, leading to the wide variety of symptoms in ME/CFS. "The conventional approach would be to block the overactive pathway," said Sanjay Chanda, PhD, Cortene's Chief Development Officer. "Instead, our counterintuitive approach seeks to overstimulate CRFR2, causing it to downregulate, without the need for chronic treatment." CT38 was subcutaneously infused at one of four infusion rates for a maximum of 10.5 hours, in 14 ME/CFS patients. CT38 treatment was safe and generally well-tolerated. It was associated with significant reduction in mean 28-day, total daily symptom score (TDSS), which aggregated 13 patient-reported, daily symptom scores. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by 26% (p < 0.01, n = 7). "Infusing CT38 is known to cause temporary cardiovascular changes and InTiME revealed that patients were significantly more sensitive to these changes than healthy subjects from a previous safety study," said Hunter Gillies, MD, InTiME's medical monitor. "These data support there being a pathological hypersensitivity in the CRFR2 pathway. Given that InTiME showed i) dose-dependent improvements in TDSS; and ii) additional infusions provide additional benefit, the next trial should test CT38 using longer or additional infusions. While infusion rates are somewhat limited by tolerability, it is total exposure at low rates that appears to drive symptom improvement." "The persistent improvement in symptoms over weeks using a limited exposure is encouraging. Many patients are still showing signs of improvement almost 2 years after treatment," said Lucinda Bateman, MD, founder and Medical Director of the Bateman Horne Center, scientific advisor to Cortene, and the Principal Investigator of the InTiME study. "In fact, a few patients expressed a desire for 'just a little bit more drug'." Full details of the trial have been peer reviewed and published in Frontiers in Systems Neuroscience, Acute corticotropin-releasing factor receptor type 2 agonism results in sustained symptom improvement in myalgic encephalomyelitis / chronic fatigue syndrome. The publication explains how the CRFR2 pathway controls homeostasis (maintaining biological system stability), how this pathway can become disrupted at the neuronal level leading to the individual symptoms of ME/CFS and how these same symptoms manifest in many other chronic diseases. Cortene plans to conduct additional trials in patients with ME/CFS and other diseases with similar symptoms using well-tolerated infusion rates and greater total exposure. To view the full publication, please visit . About ME/CFS ME/CFS is an unexplained, life-long disease, usually triggered by infection, physical/mental trauma, or chemical exposure. Symptoms include diminished physical capacity, pain, sleep issues, cognitive impairment, orthostatic intolerance, among many others, which worsen with innocuous stimulation (referred to as post-exertional malaise) and are not improved by sleep. ME/CFS afflicts 3 million Americans. There are no approved therapeutics and quality of life is worse than in most chronic diseases. About InTiME InTiME was a proof-of-concept, single-site, open-label interventional trial, with patients blind as to dose, to investigate the safety and efficacy of CT38 in ME/CFS patients. Efficacy was assessed by a variety of endpoints, including patient-reported daily symptoms scores for each of 13 symptoms, general health (via SF-36), and continuous Fitbit™ monitoring. The primary endpoint was the change in the mean total daily symptom score over the 28-day periods immediately prior to the first treatment (pre-treatment) and immediately prior to exit from the trial (post-treatment).