IL-1RA

NEW YORK, March 13, 2024 /PRNewswire/ -- A certain variant of a key anti-inflammatory gene protects men under age 75 from severe illness and death when hospitalized from Covid-19, a genetic analysis of their blood shows. According to the study authors, the protective gene in question, an interleukin-1 receptor antagonist (IL1RN) variant, appears to tamp down inflammation. Inflammation is the body's normal reaction to infection, but when unchecked, inflammation can go too far and damage tissues as part of many diseases, including in severe cases of infection with the pandemic virus SARS-CoV-2. Published as a "major article" in The Journal of Infectious Diseases online March 13, the study showed that 124 men between the ages of 19 and 74 who possessed the IL1RN variant, called rs419598, were less likely to become severely ill after hospitalization for Covid-19, and 80% less likely to die from the disease. IL1RN is expressed naturally in the body. Different types of interleukin genes are known to dial inflammation up or down in the context of arthritis, and researchers say the results of the current study suggest that a similar dynamic influences the interleukin-1-related inflammation seen in Covid-19 patients. The findings, from researchers at NYU Grossman School of Medicine, stand out because historically more men than women are known to die from Covid-19, and the IL1RN rs419598 variant appears to selectively protect only men up to age 74, but not beyond that as age-related chronic illnesses unfold. The research team used sequencing technologies for the study to determine the presence of specific genes or variations in the letter code that makes up genes in blood samples from 2,589 men and women hospitalized for Covid-19 at NYU Langone's Tisch Hospital in Manhattan from March 2020 to March 2021. More than half of the men and women in the study were older than age 60 and obese, factors that are known to increase the risk of death from the viral infection. Overall, more men than women (240 men, at 60.5%; and 157 women, at 39.5%) died from their disease, with women 20% less likely to die than men. "Our study results show that among hospitalized patients, while women are still overall less likely than men to die from Covid-19, those men age 74 and younger who possess the IL1RN gene variant rs419598 are much less likely to suffer the severe inflammation tied to SARS-CoV-2 infection and less likely to die from the disease," said study colead investigator and molecular biologist Mukundan Attur, PhD. Attur is an associate professor in the Department of Medicine at NYU Langone Health. Among the study's other findings was that average blood levels of the anti-inflammatory protein IL-1Ra, coded by IL1RN, were 14 times higher in 181 hospitalized men than in healthy male study controls from the general population, and 10 times as high in 178 hospitalized women than in healthy females. However, researchers say the increased levels of IL-1Ra in women did not result in any statistically significant reductions in death. "Our analysis offers substantial evidence of the biological link between the severe inflammation seen in SARS-CoV-2 and that which occurs in rheumatoid arthritis," said study senior investigator Steven Abramson, MD, the Frederick H. King Professor of Internal Medicine at NYU Langone. Abramson, a rheumatologist who also serves as chair of the Department of Medicine and chief academic officer at NYU Langone, says previous research has shown that such rheumatoid inflammation is lower in people who possessed one of the three IL1RN variants analyzed in the study. More importantly, Abramson says, the new research suggests that restraining the interleukin-1 biological pathway, which is in part tamped down by the anti-inflammatory protein IL-1Ra, could help prevent the severe inflammation seen in SARS-CoV-2 infection. Further research, he says, is warranted into whether IL-1-inhibiting therapies, such as the IL1 receptor antagonists anakinra, canakinumab, and rilonacept, are effective against Covid infection. Abramson already has plans to investigate if the IL-1 pathway plays a role in long Covid, when people experience new or lingering symptoms, such as fatigue and "brain fog," months after recuperating from their initial infection. Abramson points out that the new study adds to the growing scientific evidence about the biological factors that contribute to gender differences seen in deaths from Covid-19, which are known to vary widely across the United States. Funding support for this study was provided by National Institutes of Health grants P30CA016087 and R21AR078466. Besides Abramson and Attur, other NYU Langone researchers involved in this study are co-lead investigators Christopher Petrilli, MD, and Samrachana Adhikari, PhD, and study co-investigators Eduardo Iturrate, MD; Xiyue Li, MS; Stephanie Tuminello, MPH; Nan Hu, MS; Aravinda Chakravarti, PhD; and David Beck, MD, PhD. STUDY LINK: Media Inquiries: David March 212-404-3528 [email protected] SOURCE NYU Langone Health System

-- PCRX-201 is the first gene therapy product candidate to receive RMAT designation for osteoarthritis -- -- Designation supported by encouraging preliminary data from 72-patient Phase 1 study -- -- 52-Week Data Accepted for Presentation at OARSI 2024 and 104-week data to be submitted for presentation later this year -- TAMPA, Fla., March 13, 2024 (GLOBE NEWSWIRE) -- Pacira BioSciences, Inc. (Nasdaq: PCRX), the industry leader in its commitment to non-opioid pain management and regenerative health solutions, today announced that the U.S. Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to PCRX-201 (enekinragene inzadenovec), the company’s novel, intra-articular helper-dependent adenovirus (HDAd) gene therapy product candidate that codes for interleukin-1 receptor antagonist (IL-1Ra), for the treatment of osteoarthritis of the knee. “We are honored to receive FDA’s first-ever RMAT designation for a gene therapy product candidate in osteoarthritis," said Frank D. Lee, chief executive officer of Pacira BioSciences, Inc. “We continue to be encouraged by the preliminary clinical findings supporting PCRX-201 as a potential disease-modifying therapy for osteoarthritis, and we look forward to presenting additional follow-up data later this year.” The company’s RMAT application was supported by the preliminary safety and efficacy findings from a Phase 1 open-label, proof-of-concept, single ascending dose trial that enrolled 72 patients in two three-dose cohorts: a co-administered intra-articular steroid cohort and a cohort that did not receive a steroid. PCRX-201 was well tolerated, with efficacy observed through at least 52 weeks at all doses and cohorts. The highest level of efficacy was achieved in the co-administered steroid group, which showed a greater percentage of patients with at least a 50% improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness scores, as well as a meaningful improvement in (Knee Injury and Osteoarthritis Outcomes Score) KOOS functional assessment. Preliminary 36-week data were presented at the Osteoarthritis Research Society International (OARSI) 2023 World Congress, the premier annual international forum in osteoarthritis research and treatment. The 52-week data have been accepted for presentation at OARSI 2024 taking place in Vienna, Austria in April 2024 and the company expects to present 104-week efficacy and safety data later this year. Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the development and review processes for promising therapies, including genetic therapies, that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and for which preliminary clinical evidence indicates that the drug or therapy has the potential to address an unmet medical need. RMAT designation provides the benefits of intensive FDA guidance on efficient drug development, including the ability for early interactions with FDA to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, potential priority review of the Biologics License Application (BLA), and other opportunities to expedite development and review. PCRX-201 was also granted Advanced Therapy Medicinal Products (ATMP) designation by the European Medicines Agency in May 2023. About PCRX-201 PCRX-201 was acquired from GQ Bio Therapeutics GmbH, a privately held biopharmaceutical company headquartered in Hamburg, Germany. GQ Bio’s product candidates are next-generation gene transfer vehicles. These gene therapy vectors are highly efficient in entering joint cells to confer multi-year clinical benefit. In PCRX-201, the high-capacity adenoviral gene therapy vector codes for the expression of IL-1Ra, a cytokine inhibitor that plays a central role in blocking inflammation and catabolic processes that are associated with pain and disease progression in osteoarthritis. Its unique design includes an inducible promoter so that, only in the presence of inflammation signaling, the vector turns joint cells into factories to produce sustained therapeutic levels of IL-1Ra to manage pain and mitigate osteoarthritis-related joint damage while remaining localized to the joint space. About Pacira Pacira BioSciences, Inc. (Nasdaq: PCRX) is committed to providing a non-opioid option to as many patients as possible to redefine the role of opioids as rescue therapy only. Pacira has three commercial-stage non-opioid treatments: EXPAREL® (bupivacaine liposome injectable suspension), a long-acting local analgesic currently approved for infiltration, fascial plane block, and as an interscalene brachial plexus nerve block for postsurgical pain management; ZILRETTA® (triamcinolone acetonide extended-release injectable suspension), an extended-release, intra-articular injection indicated for the management of osteoarthritis knee pain; and ioveraº®, a novel, handheld device for delivering immediate, long-acting, drug-free pain control using precise, controlled doses of cold temperature to a targeted nerve. To learn more about Pacira, including the corporate mission to reduce overreliance on opioids, visit www.pacira.com. Forward-Looking Statements Any statements in this press release about Pacira’s future expectations, plans, trends, outlook, projections and prospects, and other statements containing the words “believes,” “anticipates,” “plans,” “estimates,” “expects,” “intends,” “may,” “will,” “would,” “could,” “can” and similar expressions, constitute forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), and the Private Securities Litigation Reform Act of 1995, including, without limitation, statements related to our growth and future operating results and trends, our strategy, plans, objectives, expectations (financial or otherwise) and intentions, future financial results and growth potential, including our plans with respect to the repayment of our indebtedness, anticipated product portfolio, development programs, patent terms, development of products, strategic alliances and intellectual property and other statements that are not historical facts. For this purpose, any statement that is not a statement of historical fact should be considered a forward-looking statement. We cannot assure you that our estimates, assumptions and expectations will prove to have been correct. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including risks relating to, among others: the integration of our new chief executive officer; risks associated with acquisitions, such as the risk that the acquired businesses will not be integrated successfully, that such integration may be more difficult, time-consuming or costly than expected or that the expected benefits of the transaction will not occur; our manufacturing and supply chain, global and U.S. economic conditions (including inflation and rising interest rates), and our business, including our revenues, financial condition, cash flow and results of operations; the success of our sales and manufacturing efforts in support of the commercialization of EXPAREL, ZILRETTA and iovera°; the rate and degree of market acceptance of EXPAREL, ZILRETTA and iovera°; the size and growth of the potential markets for EXPAREL, ZILRETTA and iovera° and our ability to serve those markets; our plans to expand the use of EXPAREL, ZILRETTA and iovera° to additional indications and opportunities, and the timing and success of any related clinical trials for EXPAREL, ZILRETTA and iovera°; the commercial success of EXPAREL, ZILRETTA and iovera°; the related timing and success of U.S. Food and Drug Administration supplemental New Drug Applications and premarket notification 510(k)s; the related timing and success of European Medicines Agency Marketing Authorization Applications; our plans to evaluate, develop and pursue additional product candidates utilizing our proprietary multivesicular liposome (“pMVL”) drug delivery technology; the approval of the commercialization of our products in other jurisdictions; clinical trials in support of an existing or potential pMVL-based product; our commercialization and marketing capabilities; our ability to successfully complete capital projects; the outcome of any litigation; the ability to successfully integrate any future acquisitions into our existing business; the recoverability of our deferred tax assets; assumptions associated with contingent consideration payments; and factors discussed in the “Risk Factors” of our most recent Annual Report on Form 10-K and in other filings that we periodically make with the Securities and Exchange Commission (the “SEC”). In addition, the forward-looking statements included in this press release represent our views as of the date of this press release. Important factors could cause actual results to differ materially from those indicated or implied by forward-looking statements, and as such we anticipate that subsequent events and developments will cause our views to change. Except as required by applicable law, we undertake no intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, and readers should not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this press release. These forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from those expressed or implied by these statements. These factors include the matters discussed and referenced in the “Risk Factors” of our most recent Annual Report on Form 10-K and in other filings that we periodically make with the SEC.

ROSEMONT, Ill. , Feb. 2, 2024 /PRNewswire/ -- The 2024 Orthopaedic Research and Education Foundation (OREF) Clinical Research Award was presented to Christopher H. Evans, PhD (Mayo Clinic), Steven C. Ghivizzani, PhD (University of Florida), and Paul D. Robbins, PhD (University of Minnesota), for their research on local gene therapy for osteoarthritis (OA). Together, the team spearheaded the research from a laboratory concept to human clinical trials over the course of 30 years. The OREF Award recognizes outstanding clinical research related to musculoskeletal disease or injury. Continue Reading The 2024 Orthopaedic Research and Education Foundation (OREF) Clinical Research Award was presented to Christopher H. Evans, PhD (Mayo Clinic), Steven C. Ghivizzani, PhD (University of Florida), and Paul D. Robbins, PhD (University of Minnesota), for their research on local gene therapy for osteoarthritis (OA). To read more about the award, please click here. According to the Centers for Disease Control and Prevention, OA is the most common form of arthritis, affecting 32.5 million Americans and inflicting a significant economic burden on patients and the economy.i OA, which is caused by the breakdown of joint cartilage between bones, can cause pain, stiffness and swelling, potentially leading to reduced function or even disability.i There is no cure for OA and treatment options are limited. Many patients eventually receive a total joint replacement. When the researchers began to study the use of gene therapy—which modifies a person's genes to treat or cure diseaseii—for arthritis and other non-lethal diseases, gene therapy clinical trials were in the early stages and had only involved cancer and rare genetic diseases. "Gene therapy was focused on curing genetic diseases when we entered the field," said Dr. Evans, John and Posy Krehbiel Professor of Orthopedics, Mayo Clinic, and Professor of Molecular Medicine, Mayo Clinic Alix School of Medicine in Rochester, Minn. "At the time, studying gene therapy for arthritis was radically different because, instead of treating a genetic disease, we were looking at treating a non-genetic one, albeit one of the most common diseases on the planet. This was not a genetic fix, but we wanted to explore a sophisticated way of delivering anti-arthritic gene products to those who need therapy as there were not many treatment advances for OA." Evolution from Concept to Clinical Trials Dr. Evans and his colleagues targeted rheumatoid arthritis (RA) when they began their research 30 years ago at the University of Pittsburgh as, unlike with OA, there was significant information about the biology of the rheumatoid joint. The team accomplished a major milestone, the first-in-human transfer of a gene to a joint, made possible by several articular (joint) gene transfer technologies developed by Drs. Evans, Ghivizzani and Robbins. However, when numerous successful non-genetic RA treatments were introduced, it reduced the need for gene therapy for RA. The technologies and key learnings from the RA research were redirected to a new disease indication: OA. To transfer genes, vectors are used, which are essentially vehicles that deliver therapeutic genetic materials directly into a cell.iii The research team explored using self-complementary adeno-associated virus (scAAV), a small virus that can be engineered to deliver DNA to target cells,iv as it caused no known human disease and allowed for delivery directly to the joints. Dr. Evans and his colleagues developed the scAAV.IL-1Ra vector as a therapeutic agent for OA. Following animal studies that showed the efficacy of scAAV.IL-1Ra in joints with OA, a successful Investigational New Drug application was filed with the U.S. Food and Drug Administration (FDA) in 2015. In a Phase I clinical trial, nine patients (three cohorts of three patients) were injected with scAAV.IL-1Ra in escalating doses of 1011 (low dose), 1012 (medium dose), or 1013 (high dose) by an intra-articular injection into one knee joint with OA. Eligible patients had mid-stage disease, symptomatic OA and failed at least two conservative treatments prior to the study. Patients reported pain (visual analog scale, VAS) and function (Western Ontario MacMaster University Osteoarthritis Index, WOMAC) and were followed for one year. Outcomes included: No serious adverse events were reported. Patients reported improved symptoms based on VAS and WOMAC. Patients who received the lowest dose reported mild and temporary improvement. Patients who received the medium and high doses saw sustained symptomatic improvement during the entire 12-month follow-up timeframe. Expression of IL-1Ra, a natural anti-inflammatory protein, was higher in the high-dose and medium-dose groups. This elevated expression in these groups was sustained through the 12 months of follow up, suggesting that the 1012 dose could be the most cost-effective dose, but further investigation is needed. "This was the first study that used localized gene therapy, meaning we could deliver the therapeutic target directly to the joint, which has enormous implications for safety and significantly reduces the cost associated with this procedure/therapy," said Dr. Evans. "By focusing on the joint, you don't have to treat the whole body as many of the previous vectors delivered systemically go straight to the liver, causing liver damage. The amount of vector we delivered to the knee is significantly less than what is used in systemic diseases, which cuts down on the cost dramatically." Future Studies The team is currently enrolling for a Phase Ib trial with 50 patients who have mid-stage OA. The study will include a placebo group and examine how the level and persistence of IL-1Ra expression in the joint is affected by immune suppression. It will also determine the appropriate vector dose – 1012 or 1013. If the 1012 dose is found to be the most effective, it could mean a ten-fold lower cost and less risk of adverse events for patients. Due to the expense of gene therapy trials, Drs. Evans, Ghivizzani and Robbins co-founded an arthritis gene therapy startup company, Genascence Corporation, which will help fund future clinical trials. About the OREF Clinical Research Award The OREF Clinical Research Award was established in 1995 to recognize outstanding clinical research related directly to musculoskeletal disease or injury. All submitted manuscripts are reviewed, graded and selected by the AAOS Research Development Committee. The award provides $20,000 to recipients. For more information about the manuscript submission process, please visit aaos.org/kappadelta. About the OREF The Orthopaedic Research and Education Foundation (OREF) is an independent, 501(c)3 non-profit organization that raises funds to support research on diseases and injuries of bones, nerves and muscles and to enhance clinical care leading to improved health, increased activity and a better quality of life for patients. To further its mission, OREF is committed to exploring ways to partner with others to move the field of musculoskeletal research forward. For more information, visit . About the AAOS With more than 39,000 members, the American Academy of Orthopaedic Surgeons is the world's largest medical association of musculoskeletal specialists. The AAOS is the trusted leader in advancing musculoskeletal health. It provides the highest quality, most comprehensive education to help orthopaedic surgeons and allied health professionals at every career level to best treat patients in their daily practices. The AAOS is the source for information on bone and joint conditions, treatments and related musculoskeletal healthcare issues; and it leads the healthcare discussion on advancing quality. Follow the AAOS on Facebook, X, LinkedIn and Instagram. Disclosure Funding and Conflicts of Interest Drs. Evans, Ghivizzani and Robbins are co-founders of Genascence Corp., an arthritis gene therapy company Funding Sources: NIH Grants R01 AR43623 R21 AR049606 R01 AR048566 R01 AR057422 R01AR051085 AR048566-S X01NS066865 DoD Grants W81XWH-16-1-0540 W81XWH-14-1-0498 W81XWH-19-1-0515 i Centers for Disease Control and Prevention. Osteoarthritis (OA). . Reviewed 7/27/2020. Accessed 12/20/2023. ii U.S. Food and Drug Administration. What is Gene Therapy? . Published 7/25/2018. Accessed. 12/20/2023. iii American Society of Gene +Cell Therapy. Vectors 101. . Updated 11/05/2021. Accessed 12/21/2023. iv Naso MF, Tomkowicz B, Perry WL 3rd, Strohl WR. Adeno-Associated Virus (AAV) as a Vector for Gene Therapy. BioDrugs. 2017 Aug;31(4):317-334. SOURCE American Academy of Orthopaedic Surgeons