proliferative nephritis unspecified

Topline data delivered to Ono Pharmaceutical, representing the first of two data sets that will trigger Ono’s option exercise decision for itolizumab Itolizumab continues to show clinically meaningful response in highly proteinuric subjects More than 80% of subjects achieved >50% reduction in urine protein creatinine ratio (UPCR) Itolizumab demonstrated a favorable safety and tolerability pro > LA JOLLA, Calif.--(BUSINESS WIRE)-- Equillium, Inc. (Nasdaq: EQ), a clinical-stage biotechnology company focused on developing novel therapeutics to treat severe autoimmune and inflammatory disorders, today announced positive topline data from the Type B portion of the Phase 1b EQUALISE study evaluating itolizumab in lupus nephritis patients. The data suggests high complete and partial response rates with rapid and deep reduction in urine protein creatinine ratio (UPCR) when itolizumab was added to mycophenolate mofetil/mycophenolic acid (MMF/MPA) and corticosteroids. The topline data delivered to our partner, Ono Pharmaceutical, represents the first of two data set triggers leading to their decision as to whether to exercise their option to acquire itolizumab, which is expected in the second half of 2024. “Physicians want to rapidly and safely reduce the levels of proteinuria in patients with lupus nephritis, as this has been associated with improved long-term outcomes, so it is important that we saw both early and large reductions in proteinuria in this study,” said Dr. Maple Fung, chief medical officer at Equillium. “The high complete and partial response rates compare favorably to those observed in the registrational studies of voclosporin, which demonstrated an overall response rate of seventy percent at six and twelve months in the active treatment groups. These itolizumab results occurred in the setting of patients tapering their systemic corticosteroids, maintaining stable kidney function, or eGFR, and increasing serum albumin while on study.” A total of 17 subjects were enrolled in the study, with 16 subjects analyzed as completing through Week 36 (12 weeks following the final dose, or their end of study (EOS) visit). Based on published guidelines for the management of lupus nephritis from the European League Against Rheumatism (EULAR) and European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), clinical activity assessments in this study are focused on the change in UPCR from baseline; proportion of apLN subjects with a complete response (CR), defined as 50% or greater reduction in UPCR and less than 0.5-0.7 g/g; and proportion of subjects achieving a partial response (PR), defined as 50% or greater reduction in UPCR. Key topline data from the Type B portion of the EQUALISE study in lupus nephritis: Subjects were highly proteinuric: baseline mean UPCR of 4.9 g/g. Percent reduction from baseline in median spot UPCR is ~73%. Best clinical response observed by week 36 or their EOS visit: 6 of 16 (37.5%) subjects achieved CR (UPCR < 0.7 g/g) Additional 7 of 16 (43.8%) subjects achieved PR (UPCR > 50% reduction) There was a greater overall response rate (ORR) achieved in patients receiving itolizumab by 12 and 28 weeks than expected compared to the ORR in patients receiving standard of care alone using data generated from the Accelerating Medicines Partnership® (AMP) Lupus Network. Results are comparable to those observed in the Phase 3 AURORA1 study of voclosporin (ORR 70% at 6 and 12 months in active treatment). Consistent with the decline in UPCR overtime, subjects were able to taper their systemic corticosteroids over the course of the study with >80% reduction by Week 24. Itolizumab induced consistent pharmacodynamic responses in patients reducing the levels of cell surface CD6 on T cells, which is known to reduce T cell activity. Itolizumab treatment (over 6 months) was also associated with reductions in absolute lymphocyte counts (ALC), another known pharmacodynamic effect. As noted in other studies of drugs whose mechanism leads to reductions in ALC, such as the S1P modulators, the reduction in ALC observed here was not associated with increased rates of infection or other adverse clinical signals. The majority of TEAEs were assessed as mild (Grade 1) or moderate (Grade 2) in severity, with the two most common TEAEs being lymphopenia and peripheral edema. Two subjects had at least one serious adverse event, none of which were related to study treatment. About Systemic Lupus Erythematosus (SLE) & Lupus Nephritis (LN) SLE is an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs. It can affect the joints, skin, brain, lungs, kidneys, and blood vessels. LN is a serious complication of SLE, occurring in approximately 30% – 60% of individuals with SLE. LN involves the body’s own immune system attacking the kidneys, causing inflammation and significantly reducing kidney function over time. LN is associated with an increase in mortality compared with the general population and may lead to end-stage renal disease. About the EQUALISE Study The EQUALISE study was a two-part Phase 1b open-label proof-of-concept study of itolizumab in patients with SLE and LN. The Type A portion of the study was a multiple ascending-dose clinical study evaluating the safety and tolerability of subcutaneous delivery of itolizumab over a two-week treatment period in 35 patients with SLE. The Type B portion of the study evaluated the safety, tolerability and clinical activity of subcutaneous delivery of itolizumab dosed at 1.6 mg/kg every two weeks over a 24-week treatment period, with follow up out to 36 weeks, in patients with active proliferative LN. Patients in the Type B portion of the study must have presented with greater than 1 gram of proteinuria and had a recent kidney biopsy showing ISN/RPS class III or IV apLN to be eligible for the study. Consistent with standard of care, patients on study also received 2-3 g/day of mycophenolate mofetil/mycophenolic acid (MMF/MPA), and patients may have received pulse systemic corticosteroids that were rapidly tapered. About Itolizumab Itolizumab is a clinical-stage, first-in-class anti-CD6 monoclonal antibody that selectively targets the CD6-ALCAM signaling pathway to selectively downregulate pathogenic T effector cells while preserving T regulatory cells critical for maintaining a balanced immune response. This pathway plays a central role in modulating the activity and trafficking of T cells that drive a number of immuno-inflammatory diseases. About Equillium Equillium is a clinical-stage biotechnology company leveraging a deep understanding of immunobiology to develop novel therapeutics to treat severe autoimmune and inflammatory disorders with high unmet medical need. The company’s pipeline consists of the following novel first-in-class immunomodulatory assets and product platform targeting immuno-inflammatory pathways. EQ101: a selective tri-specific cytokine inhibitor targeting IL-2, IL-9, and IL-15; currently under evaluation in a Phase 2 proof-of-concept clinical study of patients with alopecia areata being conducted in Australia and New Zealand by Equillium’s Australian subsidiary as the trial sponsor. EQ302: an orally delivered, selective bi-specific cytokine inhibitor targeting IL-15 and IL-21; currently in pre-clinical development. The multi-cytokine platform: generates rationally designed composite peptides that selectively block key cytokines at the shared receptor level targeting pathogenic cytokine redundancies and synergies while preserving non-pathogenic signaling. Itolizumab: a monoclonal antibody that targets the CD6-ALCAM signaling pathway which plays a central role in the modulation of effector T cells; currently under evaluation in a Phase 3 clinical study of patients with acute graft-versus-host disease (aGVHD) and recently completed a Phase 1b clinical study of patients with lupus/lupus nephritis. Equillium acquired rights to itolizumab through an exclusive partnership with Biocon Limited and has entered a strategic partnership with Ono Pharmaceutical Co., Ltd., for the development and commercialization of itolizumab under an option and asset purchase agreement. For more information, visit . Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words such as “anticipate”, “believe”, “could”, “continue”, “expect”, “estimate”, “may”, “plan”, “outlook”, “future” and “project” and other similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These statements include, but are not limited to, statements regarding Equillium’s plans to deliver the results of the interim review of the EQUATOR study to Ono Pharmaceutical and the expected timeline for Ono Pharmaceutical to make its decision regarding exercising its option; plans for developing EQ101, EQ302 and itolizumab; and the potential benefits of Equillium’s product candidates. Because such statements are subject to risks and uncertainties, many of which are outside of Equillium’s control, actual results may differ materially from those expressed or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: Equillium’s ability to execute its plans and strategies; risks related to performing clinical and pre-clinical studies; whether the results from clinical and pre-clinical studies will validate and support the safety and efficacy of Equillium’s product candidates; Equillium’s plans and product development, including the initiation and completion of clinical studies and the reporting of data therefrom; changes in the competitive landscape; risks related to Ono’s financial condition and decision to exercise its option, if ever, to purchase itolizumab or terminate the asset purchase agreement; and uncertainties related to Equillium’s capital requirements. These and other risks and uncertainties are described more fully under the caption "Risk Factors" and elsewhere in Equillium's filings and reports, which may be accessed for free by visiting the Securities and Exchange Commission’s website and on Equillium’s website under the heading “Investors.” Investors should take such risks into account and should not rely on forward-looking statements when making investment decisions. All forward-looking statements contained in this press release speak only as of the date on which they were made. Equillium undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

IMPT-514 is the first-and-only CD19/CD20 CAR T-cell therapy in development for lupus Designed to reset the immune system, IMPT-514 is a one-time treatment option with potential to replace the need for chronic immune suppression Initial efficacy and safety data from Phase 1b/2 dose escalation trial expected 2H 2024 LOS ANGELES, Feb. 28, 2024 /PRNewswire/ -- ImmPACT Bio USA, Inc. ("ImmPACT Bio"), a clinical-stage company developing transformative logic-gate-based chimeric antigen receptor (CAR) T-cell therapies for treating cancer and autoimmune diseases, today announced that the Company has been awarded an $8 million grant from the California Institute for Regenerative Medicine (CIRM) to ImmPACT Bio's ongoing Phase 1b/2 study evaluating IMPT-514 for the treatment of refractory lupus nephritis (LN) and systemic lupus erythematosus (SLE). IMPT-514 is a potentially first-in-class CD19/CD20 bispecific CAR T-cell therapy designed for deep and extensive depletion of autoreactive immune cells. "CAR T-cell therapies have transformed the treatment of blood cancers, but their therapeutic potential in autoimmune diseases is a promising opportunity," said Abla Creasey, Ph.D., vice president of therapeutics development at CIRM. "We are pleased to award ImmPACT Bio this funding to help advance their dual-targeting CAR T-cell therapy approach outside the realm of oncology. Importantly, we believe the ImmPACT Bio approach with IMPT-514 as a one-time treatment holds significant potential to change the treatment paradigm and clinical care of severe, refractory lupus." Jonathan Benjamin, M.D., Ph.D., chief medical officer of ImmPACT Bio stated, "We are extremely grateful that CIRM has recognized the scientific merit and technical feasibility of our clinical trial evaluating IMPT-514 for the treatment of both LN and SLE. Lupus is a debilitating, multi-organ disease that primarily affects women, often in young adulthood. There is a critical unmet medical need for well-tolerated therapies that offer improved efficacy and durable disease remission. Based on the promising responses and a favorable safety profile observed in the UCLA trial in non-Hodgkin lymphoma, we are encouraged that IMPT-514 has potential to alleviate symptoms and spare patients the need for chronic immune suppression. We expect initial efficacy and safety data from our Phase 1b/2 dose escalation trial in the second half of 2024." "It is important to understand that due to the heterogeneity of lupus, no two patients are alike. No 'one size fits all' treatment exists for complex individuals like me," said Kathleen A. Arntsen, president and CEO of Lupus and Allied Diseases Association, Inc. "What works in one person may not work in another. Therefore, our physicians need an arsenal of therapies to treat lupus and lupus nephritis." IMPT-514 is being evaluated in an open label Phase 1b/2 dose escalation clinical trial in participants with active, refractory SLE that have been treated with at least two prior standard-of-care therapies and have a SLE Disease Activity Index score (SLEDAI-2K) > 8. The Phase 1 dose escalation cohort is limited to patients with active, biopsy-proven, proliferative LN. Additional patients with and without active proliferative LN will be enrolled during the Phase 2 portion of the clinical trial. IMPT-514 has received Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of both active and refractory LN and SLE. About Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE), commonly known as lupus, is a chronic, often severe, systemic autoimmune disease. Systemic lupus erythematosus results from an immune attack on healthy tissues and the development of widespread inflammation that results in tissue damage throughout the body. B cells are known to play an early and central role in disease pathogenesis. Lupus afflicts more than 200,000 patients in the U.S. alone, with approximately 50 percent having lupus nephritis, the most severe manifestation of SLE which can result in end-stage renal disease and increased mortality. Despite various therapies used for the treatment of SLE, including approved biologics, there remains a significant unmet need for safe and highly effective therapies for this disease. About IMPT-514 IMPT-514 is a CD19/CD20-targeting chimeric antigen receptor (CAR) T-cell therapy that utilizes a potent bispecific CAR and a 4-1BB costimulatory domain. It is the same CAR construct as ImmPACT's IMPT-314, which is under development for certain types of non-Hodgkin's lymphoma. IMPT-314 and IMPT-514 are based on work by Yvonne Chen, Ph.D., associate professor, and Sarah Larson, M.D., associate professor of medicine, both of the University of California, Los Angeles. In preclinical studies, IMPT-514 was successfully and efficiently manufactured from heavily immunosuppressed patients with lupus nephritis and systemic lupus erythematosus and showed potent elimination of autologous B cells and a moderate cytokine profile. About the California Institute for Regenerative Medicine (CIRM) At CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission. To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of today's most promising stem cell technologies. With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is one of the world's largest institutions dedicated to helping people by bringing the future of cellular medicine closer to reality. For more information go to . About Lupus and Allied Diseases Association, Inc. The Lupus and Allied Diseases Association, Inc. (LADA) was founded in 1978 and is a national patient advocacy organization led by people with lupus dedicated to ensuring that the patient stakeholder is included as an equal participant in the healthcare, regulatory, and public policy arenas and across the research continuum. LADA's goal is to improve access to care and quality of life by fostering collaboration among stakeholders, promoting unity in the community, and wielding the patient and care partner voice as a catalyst to advance innovative advocacy, education, awareness and biomedical research initiatives. For more information, please visit . About ImmPACT Bio ImmPACT Bio USA, Inc., is a clinical-stage company dedicated to the discovery of transformative chimeric antigen receptor (CAR) T-cell therapies that address key biological challenges in treating cancer and autoimmune diseases. The company's logic-gate-based CAR T-cell platforms, licensed from University of California, Los Angeles (UCLA) Technology Development Group, are specifically designed to deplete B cells, prevent antigen escape, and overcome the immunosuppressive tumor microenvironment. The company's technology is based on the work of pioneering scientists Yvonne Chen, Ph.D., and Antoni Ribas, M.D., Ph.D., both from UCLA. For more information, visit . SOURCE ImmPACT Bio USA Inc.

Itolizumab continues to show clinically meaningful response in highly proteinuric subjects At Week 28, 73% of subjects achieved >50% reduction in urine protein creatinine ratio (UPCR) Itolizumab demonstrated a favorable safety and tolerability pro > LA JOLLA, Calif.--(BUSINESS WIRE)-- Equillium, Inc. (Nasdaq: EQ), a clinical-stage biotechnology company focused on developing novel therapeutics to treat severe autoimmune and inflammatory disorders, today announced that data from the Type B portion of the EQUALISE study evaluating itolizumab in lupus nephritis patients was presented at ACR Convergence, the annual meeting of the American College of Rheumatology (ACR). The data presented by Dr. Kenneth Kalunian, Professor, Medicine, UCSD School of Medicine, highlights that subjects had high complete and partial response rates with rapid and deep reduction in urine protein creatinine ratio (UPCR) when itolizumab was added to mycophenolate mofetil (MMF) and corticosteroids. “This data presentation represents all but the last patient in the follow up period, and a preview of what will be delivered to Ono Pharmaceutical under the terms of our strategic partnership in early 2024,” said Bruce Steel, chief executive officer at Equillium. “It’s important that we saw both early and large reductions in proteinuria,” said Dr. Maple Fung, chief medical officer at Equillium. “Physicians are looking for a treatment that can safely and rapidly reduce the levels of proteinuria in patients, as this is historically associated with improved long-term outcomes. These results demonstrating high complete and partial response rates compare favorably to those observed in the phase three study of voclosporin, which had an overall response rate of seventy percent at six and twelve months of active treatment. Importantly, these results occurred in the setting of patients tapering their systemic corticosteroids, maintaining stable kidney function, or eGFR, and increasing serum albumin while on study.” The Type B portion of the EQUALISE study in patients with active proliferative LN (apLN) is evaluating the safety, tolerability and clinical activity of subcutaneous delivery of itolizumab. Patients must present with greater than 1 gram of proteinuria and have a recent kidney biopsy showing ISN/RPS class III or IV apLN to be eligible for the study. During the 24-week treatment period, patients receive a subcutaneous dose of 1.6 mg/kg every two weeks, with follow up out to 36 weeks. Consistent with standard of care, patients on study also receive 2-3 g/day of mycophenolate mofetil/mycophenolic acid (MMF/MPA), and patients may receive pulse systemic corticosteroids that are rapidly tapered. A total of 17 subjects have been enrolled in the study, with 15 subjects reaching Week 28 (4 weeks following the final dose, or the end of study (EOS)). Based on published guidelines for the management of lupus nephritis from the European League Against Rheumatism (EULAR) and European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), clinical activity assessments in this study are focused on the change in UPCR from baseline; proportion of apLN subjects with a complete response (CR), defined as 50% or greater reduction in UPCR and less than 0.5-0.7 g/g; and proportion of subjects achieving a partial response (PR), defined as 50% or greater reduction in UPCR. Poster Presentation at the American College of Rheumatology Title: Clinical Safety and Efficacy Results from EQUALISE Type B: A Phase 1b Open-label Clinical Study of itolizumab, a Novel anti-CD6 Therapy, in Subjects with Active Proliferative Lupus Nephritis Author: Dr. Kenneth Kalunian, Professor, Medicine, UCSD School of Medicine Poster: 1496 Key findings from analysis of the Type B portion of the EQUALISE study in lupus nephritis: Subjects were highly proteinuric: baseline mean UPCR of 4.9 g/g Percent reduction from baseline in median spot UPCR is ~73% Clinically meaningful responses were observed: By week 28 (EOS): 6 of 15 (40%) subjects achieved CR (UPCR < 0.7 g/g) Additional 5 of 15 (33%) subjects achieved PR (UPCR > 50% reduction) There was a greater overall response rate (ORR) achieved in patients receiving itolizumab by 12 and 28 weeks than expected compared to the ORR in patients receiving standard of care alone using data generated from the Accelerating Medicines Partnership® (AMP) Lupus Network. Results are comparable to those observed in the Phase 3 AURORA1 study of voclosporin (ORR 70% at 6 and 12 months in active treatment). Consistent with the decline in UPCR overtime, subjects were able to taper their systemic corticosteroids over the course of the study. Itolizumab induced consistent pharmacodynamic responses in patients reducing the levels of cell surface CD6 on T cells, which is known to reduce T cell activity. Itolizumab treatment (over 6 months) was also associated with reductions in absolute lymphocyte counts (ALC), another known pharmacodynamic effect. As noted in other studies of drugs whose mechanism leads to reductions in ALC, such as the S1P modulators, the reduction in ALC observed here was not associated with increased rates of infection or other adverse clinical signals. 77% of TEAEs were assessed as mild (Grade 1) or moderate (Grade 2) by the investigators. Two subjects had at least one serious adverse event. The poster presentation is available on the Presentations page of Equillium’s website under the Lupus tab. About Systemic Lupus Erythematosus (SLE) & Lupus Nephritis (LN) SLE is an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs. It can affect the joints, skin, brain, lungs, kidneys, and blood vessels. LN is a serious complication of SLE, occurring in approximately 30% – 60% of individuals with SLE. LN involves the body’s own immune system attacking the kidneys, causing inflammation and significantly reducing kidney function over time. LN is associated with an increase in mortality compared with the general population and may lead to end-stage renal disease. About the EQUALISE Study The EQUALISE study is a two-part Phase 1b open-label proof-of-concept study of itolizumab in patients with SLE and LN. The Type A portion of the study was a multiple ascending-dose clinical study evaluating the safety and tolerability of subcutaneous delivery of itolizumab over a two-week treatment period in 35 patients with SLE. The Type B portion of the study, is evaluating the safety, tolerability and clinical activity of subcutaneous delivery of itolizumab dosed at 1.6 mg/kg every two weeks over a 24-week treatment period in patients with active proliferative LN. About Itolizumab Itolizumab is a clinical-stage, first-in-class anti-CD6 monoclonal antibody that selectively targets the CD6-ALCAM signaling pathway to selectively downregulate pathogenic T effector cells while preserving T regulatory cells critical for maintaining a balanced immune response. This pathway plays a central role in modulating the activity and trafficking of T cells that drive a number of immuno-inflammatory diseases. About Equillium Equillium is a clinical-stage biotechnology company leveraging a deep understanding of immunobiology to develop novel therapeutics to treat severe autoimmune and inflammatory disorders with high unmet medical need. The company’s pipeline consists of the following novel first-in-class immunomodulatory assets targeting immuno-inflammatory pathways. EQ101: a tri-specific cytokine inhibitor that selectively targets IL-2, IL-9, and IL-15; currently under evaluation in a Phase 2 proof-of-concept clinical study of patients with alopecia areata. EQ102: a bi-specific cytokine inhibitor that selectively targets IL-15 and IL-21; currently under evaluation in a Phase 1 first-in-human clinical study to include healthy volunteers and celiac disease patients. EQ302: an orally-delivered, bi-specific inhibitor of IL-15 and IL-21; currently in preclinical development. Itolizumab: a monoclonal antibody that targets the CD6-ALCAM signaling pathway which plays a central role in the modulation of effector T cells; currently under evaluation in a Phase 3 clinical study of patients with acute graft-versus-host disease (aGVHD) and a Phase 1b clinical study of patients with lupus/lupus nephritis. Equillium acquired rights to itolizumab through an exclusive partnership with Biocon Limited and has entered a strategic partnership with Ono Pharmaceutical Co., Ltd. for the development and commercialization of itolizumab under an option and asset purchase agreement. For more information, visit . Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words such as “anticipate”, “believe”, “could”, “continue”, “expect”, “estimate”, “may”, “plan”, “outlook”, “future” and “project” and other similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These statements include, but are not limited to, statements regarding Equillium’s plan to deliver full data package from its EQUALISE study to Ono Pharmaceuticals in early 2024, the potential benefits of itolizumab as a treatment for SLE and LN; and other statements regarding management’s intentions, plans, beliefs or expectations for the future. Because such statements are subject to risks and uncertainties, many of which are outside of Equillium’s control, actual results may differ materially from those expressed or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: Equillium’s ability to execute its plans and strategies; risks related to performing clinical and pre-clinical studies; whether the results from clinical and pre-clinical studies will validate and support the safety and efficacy of Equillium’s product candidates; the risk that interim results of a clinical study do not necessarily predict final results and that one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data, and as more patient data become available; potential delays in the commencement, enrollment and completion of clinical studies and the reporting of data therefrom; the risk that studies will not be completed as planned; Equillium’s plans and product development, including the initiation and completion of clinical studies and the reporting of data therefrom; changes in the competitive landscape; and uncertainties related to Equillium’s capital requirements. These and other risks and uncertainties are described more fully under the caption "Risk Factors" and elsewhere in Equillium's filings and reports, which may be accessed for free by visiting the Securities and Exchange Commission’s website at and on Equillium’s website under the heading “Investors.” Investors should take such risks into account and should not rely on forward-looking statements when making investment decisions. All forward-looking statements contained in this press release speak only as of the date on which they were made. Equillium undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.