caspase 9

Paris (France), April 25, 2024 – PEP-Therapy, a clinical-stage biotechnology company developing first-in-class peptides as targeted therapies in oncology, and Institut Curie, France’s leading cancer center, today announced the dosing of the first patients in a Phase Ib clinical trial evaluating PEP-Therapy’s lead candidate, PEP-010, based on highly encouraging Phase Ia results. This second part ot the Phase I study is evaluating PEP-010 in combination with chemotherapy (paclitaxel or gemcitabine), in advanced or metastatic ovarian cancer (OC) and in metastatic pancreatic ductal adenocarcinoma (PDAC), two indications with high unmet medical need. PEP-010 is a first-in-class bifunctional therapeutic peptide that penetrates cells and specifically disrupts the interaction between Caspase-9 and PP2A, leading to the inhibition of key pathological mechanisms, without altering physiological mechanisms. PEP-010 is a pro-apoptotic agent which has demonstrated a good safety and tolerability pro first signals of efficacy in the CLEVer-PEPtide Phase Ia dose escalation clinical trial. The two-cohort, open-label, non-controlled, multicenter Phase Ib program will evaluate the safety and tolerability, complete or assess the pharmacokinetics, and evaluate the anti-tumor activity of intravenous PEP-010 when administered in combination with paclitaxel or gemcitabine. The first cohort (expansion cohort) will evaluate the efficacy of PEP-010 at the recommended Phase II dose (RP2D) in combination with paclitaxel in patients with metastatic PDAC. The second cohort (dose escalation) will determine the maximum tolerated dose (MTD) and the RP2D of PEP-010 when administered in combination with gemcitabine in patients with metastatic PDAC or advanced or metastatic OC. Target enrollment is up to 53 patients. Four sites in France are currently recruiting: Institut Curie, Gustave Roussy, Centre François Baclesse and Institut de Cancérologie de l'Ouest. “We are thrilled to see the first patients dosed in this Phase Ib trial. PEP-010 represents a potentially safer and effective new option for patients with few therapeutic alternatives. I am delighted to work with our clinical team and the different centers to determine if PEP-010, when combined with chemotherapies, can provide therapeutic benefits for patients.” said Pr. Christophe Le Tourneau, Medical Oncologist at Institut Curie, Head of the Department of Drug Development and Innovation (D3i), and Principal Investigator of the CLEVer-PEPtide trial. Antoine Prestat, CEO and co-founder of PEP-Therapy added: “We are delighted with the start of our Phase Ib trial, and we are grateful for the support of the participating cancer centers which has enabled this important new milestone for our company. This study reflects our commitment to provide a new treatment that addresses unmet medical needs and improve patient outcomes in combination with the standard-of-care. Reactivating apoptosis of cancer cells using peptide technology represents a promising and innovative therapeutic modality. We look forward to confirming the potential of PEP-010 in this Phase Ib trial." Encouraging data from the Phase Ia study were presented at the AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics 2023 confirming the safety of PEP-010 with encouraging preliminary signals of antitumoral activity in 13 patients who experienced partial response or stable disease, including 2 confirmed partial responses in combination with paclitaxel in ovarian and pancreatic cancers, along with a good safety pro patients with recurrent and/or metastatic solid cancers. XXX About PEP-010 PEP-010 is a first-in-class bifunctional peptide that penetrates cells and specifically disrupts the interaction between Caspase-9 and PP2A, two key proteins involved in the apoptotic pathway. PP2A and Caspase-9, when released, restore normal apoptosis in cancer cells. PEP-010 is currently evaluated in a Phase Ia/b clinical trial. About CLEVer-PEPtide trial CLEVer-PEPtide is a Phase Ia/b, open-label, non-controlled, multicenter clinical study (NCT 04733027). It is a first-in-human dose escalation and expansion study that is expected to enroll up to 87 patients to evaluate the safety, pharmacokinetics and preliminary antitumor activity of intravenous PEP-010, administered as single agent and in combination with paclitaxel or with gemcitabine in patients with recurrent and/or metastatic solid cancer. In Phase Ia, results obtained on 34 patients showed good safety pro PEP-010 in monotherapy, the Recommended Phase 2 Dose (RP2D) being the highest dose level tested. In combination with paclitaxel, preliminary antitumor activity (4 confirmed Partial Responses) was observed, including in OC and PDAC patients. The clinical development continues with a Phase Ib focusing on two indications, advanced/metastatic OC and PDAC. A new combination of PEP-010 with a standard-of-care in these two indications, gemcitabine, will also be evaluated. PEP-010 clinical development is conducted in partnership with two leading European cancer centers, Institut Curie and Gustave Roussy, and also recruiting at Centre François Baclesse and Institut de Cancérologie de l'Ouest. CLEVer-PEPtide is led by Professor Christophe Le Tourneau, Medical Oncologist at Institut Curie, Head of the Department of Drug Development and Innovation (D3i), and Principal Investigator of the trial. About PEP-Therapy PEP-Therapy is a Paris-based clinical-stage biotechnology company developing first-in-class peptides as targeted therapies in oncology. PEP-010, lead drug candidate, is a pro-apoptotic agent currently evaluated in a Phase Ia/b clinical trial. The company also develops a pipeline of peptide-based products in oncology. Founded in 2014, PEP-Therapy builds on research from Sorbonne University and Institut Curie, and is backed by international investors: Seventure Partners (Quadrivium 1 Seed Fund), CapHorn, i&i Prague, Italian Angels for Growth (IAG), Doorway, Magna Capital Partners (MCP), Business Angels des Grandes Ecoles (BADGE), and Jérôme Majoie (former Managing Director of Laboratoires Fournier affiliates (USA, UK, Sweden, Japan), CEO of La Fondation Fournier-Majoie). For more information, please visit . About Institut Curie Institut Curie, France’s leading cancer center, combines an internationally-renowned research center with a cutting-edge hospital group, treating all types of cancer, including the rarest. Founded in 1909 by Marie Curie, Institut Curie has 3 sites (Paris, Saint-Cloud and Orsay) with over 3,700 researchers, physicians and health professionals working on its 3 missions: treatment, research and teaching. A private foundation with public utility status, Institut Curie is authorized to accept donations and bequests, and thanks to the support of its donors, is able to accelerate discoveries and improve patient treatment and quality of life. To find out more: Twitter, Facebook, LinkedIn, Instagram Institut Curie has been a certified “Carnot Curie Cancer Institute” since 2011. The Carnot certification is a recognition of excellence awarded to academic research organizations whose quality and involvement in partnership-based research have been demonstrated. Curie Cancer offers industrial partners the opportunity to implement research collaborations utilizing the expertise of Institut Curie’s research teams to develop innovative therapeutic solutions for cancer, from therapeutic target to clinical approval. Curie Cancer is a member of the Carnot FINDMED network, a group of thirteen Carnot institutes, to facilitate access to their technological platforms and to their innovations for very small and medium-sized companies in the pharmaceutical industry. Find out more: - Contacts PEP-Therapy Antoine Prestat, CEO & co-founder hello.pep@pep-therapy.com ATCG Partners Marie Puvieux PEP-Therapy@atcg-partners.com +33 6 10 54 36 72 Institut Curie Elsa Champion, Press Relations Officer elsa.champion@curie.fr + 33 7 64 43 09 28 Attachment PR in English

A new study in mice suggests experimental eye drops may be more effective than injections for treatment of retinal vein occlusion, a major cause of blindness. A new study suggests that eye drops developed by Columbia University researchers could be a more effective-and comfortable-therapy for a common eye disease currently treated with injections into the eye. Retinal vein occlusion (RVO), an eye disease that affects up to 2% of people over age 40, occurs when a vein in the eye's retina becomes blocked, leading to swelling in the eye, inflammation, damage to the retina, and vision loss. Standard therapy involves injecting into the eye a vascular endothelial growth factor inhibitor (anti-VEGF) that reduces swelling. The therapy can improve vision but patients with significant retinal damage due to impaired blood flow often have poor outcomes. "Anti-VEGF therapy has helped a lot of people with RVO, but the fear factor -- having to get a needle in the eye -- causes many people to delay treatment, which can lead to retinal damage," says Carol M. Troy, MD, PhD, professor of pathology & cell biology and of neurology at Columbia University Vagelos College of Physicians and Surgeons. "There's an opportunity to help more people with this disease that is a leading cause of blindness worldwide." The study found that an experimental eye drop treatment was twice as effective as the standard injection therapy at reducing swelling and improving blood flow within the retina of mice with RVO. The eye drops also prevented neurons (photoreceptors) in the retina from deteriorating and preserved visual function over time, whereas the standard injections had no effect on either. Eye drops target 'death enzyme' The eye drops contain an experimental drug that blocks caspase-9, an enzyme that triggers cell death, and was found by Troy's lab to be overactive in blood vessels injured by RVO. "We think the eye drops improve the health of blood vessels in the retina, which then decreases the toxic signaling that damages the retina's neurons and leads to vision loss," says Maria I. Avrutsky, PhD, the study's first author who conducted the research as a postdoc in the Troy lab. Future studies are aimed at preparing to test the eye drops in human clinical trials and identifying additional therapeutic targets. "Finding the root cause of RVO is the holy grail, but if we can at least provide better symptomatic relief that doesn't distress patients, it would be a really good start," Troy says. More information The study, "Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion," was published online in Frontiers of Neuroscience. All authors: Maria I. Avrutsky (Columbia, now at Character Biosciences), Claire W. Chen (Columbia), Jacqueline M. Lawson (Columbia), Scott J. Snipas (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA) Guy S. Salvesen (Sanford Burnham Prebys), and Carol M. Troy (Columbia). The study was supported by a sponsored research agreement with Opera Therapeutics and grants from the National Institutes of Health (R01NS091333 and T32EY013933) and the Department of Defense Army/Air Force. Carol Troy and Maria Avrutsky are inventors on patent applications filed by Columbia University related to the therapeutic use of caspase-9 inhibitors. Maria Avrutsky received consulting income from Opera Therapeutics.

THURSDAY, April 6, 2023 -- Chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells (GD2-CAR T cells) are feasible and safe for children with heavily pretreated neuroblastoma, according to a study published in the April 6 issue of the New England Journal of Medicine . Francesca Del Bufalo, M.D., from IRCCS Ospedale Pediatrico Bambino Gesù in Rome, and colleagues conducted a phase 1/2 clinical trial involving 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and one with a complete response at the end of first-line therapy) who received GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). The researchers observed no failure to generate GD2-CART01. In the phase 1 part of the trial, three dose levels were tested (3-, 6-, and 10x10 6 CAR-positive T cells/kg body weight), with no dose-limiting toxic effects reported. For the phase 2 part of the trial, the recommended dose was 10x10 6 CAR-positive T cells/kg. In 74 percent of patients, cytokine release syndrome occurred and was mild in all but one patient. The suicide gene was activated in one patient, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo; up to 30 months after infusion, they were detectable in peripheral blood in 26 of 27 patients. Overall response was 63 percent, with nine and eight patients having a complete and partial response, respectively. Three-year overall survival and event-free survival were 60 and 36 percent, respectively, among children receiving the recommended dose. "GD2-CART01 may induce sustained eradication of disease in a proportion of patients with relapsed or refractory neuroblastoma," the authors write. Bellicum Pharmaceuticals donated rimiducid for the trial. Abstract/Full Text (subscription or payment may be required) Editorial (subscription or payment may be required) Posted April 2023