On August 7, 2023 Duality Biologics (Suzhou) Co. Ltd. ("DualityBio"), a clinical-stage biotech company focusing on the discovery and development of next generation antibody-drug conjugate ("ADC") therapeutics to treat patients with cancer and autoimmune diseases, reported that the company has expanded its collaboration with BioNTech SE to develop, manufacture and commercialize a third ADC candidate DB-1305 globally, excluding Mainland China, Hong Kong Special Administrative Region and Macau Special Administrative Region (Press release, DualityBio, AUG 7, 2023, View Source [SID1234633892]). DB-1305 is currently in a Phase 1/2 clinical trial (NCT05438329) for solid tumors. The agreement further builds upon the strategic collaboration the companies announced in April 2023.

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Under the terms of the agreements, DualityBio will receive upfront payments, additional development, regulatory and commercial milestone payments, and single-digit to low-double digit tiered royalties on net sales of DB-1305. BioNTech will hold commercial rights globally (excluding Mainland China, Hong Kong Special Administrative Region and Macau Special Administrative Region), while DualityBio will retain commercial rights for Mainland China, Hong Kong Special Administrative Region and Macau Special Administrative Region.

About DB-1305

DB-1305, a third generation Trop2 ADC molecule built from DualityBio’s proprietary Duality Immune Toxin Antibody Conjugates (DITAC) platform, exhibited potent antitumor activity in preclinical tumor models and robust clinical efficacy in NSCLC and other solid tumors.

On August 7, 2023 Jacobio Pharma (1167.HK), a clinical-stage oncology company focusing on undruggable targets, reported that Jacobio’s in-house KRAS G12C inhibitor glecirasib was granted breakthrough therapy designation (BTD) by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) for the pancreatic cancer patients with a KRAS G12C mutation who have progressed after frontline standard care treatment (Press release, Jacobio Pharmaceuticals, AUG 7, 2023, View Source [SID1234633891]). This BTD was granted based on the clinical efficacy and safety data from ongoing gleciracib clinical trials. The BTD will expedite the clinical development of glecirasib and accelerate its early access to the patients.

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Glecirasib’s pivotal study for pancreatic cancer was approved by CDE in July 2023, which became the first global pancreatic cancer KRAS G12C registrational clinical study. The pivotal clinical trial will evaluate the efficacy and safety of single agent glecirasib in KRAS G12C-mutated locally advanced or metastatic pancreatic cancer patients who have progressed on frontline standard care treatment. This is a multi-center, single-arm, open-label study. Pancreatic cancer is a highly aggressive malignancy and with a limited effective treatment currently. The five-year overall survival rate is only 5%.

Pancreatic cancer is glecirasib’s second BTD indication in China. In December 2022, gleciracib was granted BTD for the second line setting and beyond of advanced or metastatic non-small cell lung cancer (NSCLC) patients with KRAS G12C mutation.

About CDE’s Breakthrough Therapy Designation

CDE’s Breakthrough Therapy Designation (BTD) is designed to expedite the clinical development of innovative drugs presenting significant clinical advantages. A breakthrough therapy must provide effective treatment for a seriously debilitating or life-threatening condition that has no effective therapy or demonstrate substantial improvement over available therapies. According to the CDE, the breakthrough therapy designation provides opportunities for more intensive CDE guidance and discussion with respect to clinical trials and development strategy, and for priority review later.

About Glecirasib

Glecirasib is a KRAS G12C inhibitor developed by Jacobio. A number of Phase I/II clinical trials of glecirasib are currently ongoing in China, the United States and Europe for patients with advanced solid tumors harboring KRAS G12C mutation. This includes a pivotal clinical trial in NSCLC in China; a monotherapy study for STK11 co-mutated NSCLC in the front-line setting, and combination therapy trials with SHP2 inhibitor JAB-3312 in NSCLC and with Cetuximab in colorectal cancer.

On August 7, 2023 Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) reported that first patient has been dosed in a Phase I study of the Company’s investigational therapy TLX101 (4-L-[131I] iodo-phenylalanine, or 131I-IPA) in combination with post-surgical standard of care treatment in patients with newly diagnosed glioblastoma, the most common and aggressive form of primary brain cancer (Press release, Telix Pharmaceuticals, AUG 7, 2023, View Source [SID1234633890]).

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IPAX-2 (ClinicalTrials.gov Identifier: NCT05450744) is a Phase I dose escalation study to confirm safety profile of TLX101 in combination with external beam radiation therapy (EBRT) and temozolomide in front-line glioblastoma. Twelve patients are expected to be recruited to evaluate whether the observed safety and drug interaction profile remains suitable in this setting before progressing to a proof-of-concept Phase II study.

IPAX-2 is being conducted at six sites across Australia, New Zealand and Europe. The study will build on data generated in IPAX-1 (ClinicalTrials.gov Identifier NCT03849105), which reported final results in September 2022.[1] The IPAX-1 study met its primary objective demonstrating safety and tolerability profile of intravenous 131I-IPA administered concurrently with second line EBRT. The study also delivered encouraging preliminary therapeutic effect, demonstrating a median overall survival of 13 months from the initiation of treatment in the recurring setting, or 23 months from initial diagnosis.

Professor Josef Pichler, Kepler University Hospital, Austria and Principal Investigator in the IPAX-2 study said, "Promising efficacy data observed in IPAX-1 clearly warrants further investigation in an earlier setting. We are therefore pleased to be exploring Telix’s glioblastoma therapy candidate in newly diagnosed patients, to accelerate development in this underserved disease area with few effective treatment options."

Dr. Colin Hayward, Telix Chief Medical Officer added, "Commencing this study supports Telix’s goal to expedite new radiopharmaceutical therapies in areas of unmet need. With IPAX-2, we are taking the development of TLX101 into front-line glioblastoma for the first time, and excited to see the potential impact of targeted radiation in patients after initial surgery."

Telix’s investigational positron emission tomography (PET) agent TLX101-CDx (18F-FET) will be used for imaging in the study to identify participants with over-expressed LAT-1 as suitable candidates for 131I-IPA therapy, and to provide baseline and follow up information on tumour response and progression.

In parallel to IPAX-2, TLX101 is being further investigated in the recurrent setting in the investigator-initiated Phase II IPAX-Linz study, which dosed a first patient in November 2022[2] and has now exceeded 70% of the patient enrolment target.

About TLX101

TLX101 (4-L-[131I] iodo-phenylalanine, or 131I-IPA) is one of Telix’s lead therapeutic clinical programs and has been granted orphan drug designation in the United States and Europe for glioblastoma therapy. TLX101 targets a membrane transport protein called L-type amino acid transporter 1 (LAT-1) that is typically highly expressed in glioblastoma. TLX101 is a novel approach that is readily able to pass through the blood-brain barrier, the normal protective barrier that prevents many potential drug candidates entering the brain.

About TLX101-CDx (18F-FET)

18F-FET has been widely used in clinical research settings while recently, new practice guidelines have been developed for the imaging of gliomas using PET with radiolabelled amino acids, of which 18F-FET is a key enabling radiopharmaceutical.[3] 18F-FET targets the amino acid transport system L (LAT) and is therefore highly suitable for use as a complementary diagnostic agent to TLX101. Telix is preparing to file a new drug application for TLX101-CDx with the United States Food and Drug Administration (FDA) during 2023, in preparation for U.S. commercial launch in 2024, pending regulatory approval.

On August 7, 2023 Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune, ophthalmology and other major diseases, reported that the preclinical results of IBI363 were published in Nature Cancer (IF=22.7). The publication entitled, "IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells" (Press release, Innovent Biologics, AUG 7, 2023, View Source [SID1234633889]).

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Interleukin 2 (Interleukin-2, IL-2) is the first cytokine to be discovered and identified as playing a pivotal role in T-cell growth and expansion. Aldesleukin (IL-2) was approved by U.S. Food and Drug Administration for metastatic renal cell carcinoma and metastatic melanoma in the early 1990s, but it has not been widely used in clinic due to poor selectivity, narrow therapeutic window, and side effects. As a bi-functional cytokine, IL-2 can not only activate CD4+ regulatory T cells (Treg) via interaction with IL-2 receptor αβγ to suppress the immune system, but also stimulate CD8+ T cells and natural killer cells via its interaction with IL-2 receptor βγ to exert its anti-tumor effects. Most developers use the approach of eliminating IL-2 and IL-2 receptor α (IL-2Rα) as a strategy to reduce Treg activation while maximizing the anti-tumor effect of IL-2. However, these "not-α" IL-2 muteins performed poorly in clinical studies. The published manuscript describes the mechanism underlying this discrepancy. The major observations include:

In comparison with "not-α" IL-2, α-biased IL-2 which retains intact IL-2Rα (CD25) binding showed superior anti-tumor efficacy and lower toxicity in multiple murine tumor models.
In tumor, α-biased IL-2 can more effectively activate tumor-specific T cells (TSTs) because TSTs highly express CD25, which increases their interactions with α-biased IL-2. In contrast, "not-α" IL-2 is prone to expand CD25 negative bystander T cells, and this limits its anti-tumor efficacy. In the periphery, "not-α" IL-2 can significantly expand peripheral T cells, while α-biased IL2 preferentially expand peripheral Treg to restrain systemic toxicity.
Intratumoral CD25+PD-1+CD8+ T cells exert more potent polyfunctionalities, including secreting effector molecules such as IL-2, IFN-γ, TNF-α and GZMB, than CD25-PD-1+CD8+ and CD25-PD-1+CD8- T cells. CD25-blocking or IL-2-neutralizing antibodies can limit the activation of TSTs and negatively affect the anti-tumor effects of PD-1 blockade.
The corresponding author, Dr. Kaijie He of Innovent Biologics stated, "We are very pleased that the results of this study are published and highlighted in the current issue of Nature Cancer. IL-2 is one of the most important cytokines in immune-oncology, but the mechanism of action underlying its potent antitumor activity is still elusive. In this study, we propose a previously underappreciated function of CD25 in regulating IL-2 autocrine signaling in TST cells to exert their antitumor functions, and challenge the "IL-2 dogma" that has dominated the whole field in the past decades, suggesting a new approach to designing safer and more effective IL-2 drugs. At the same time, this study also proposes to use "IL-2 signature" as a novel biomarker to predict the clinical benefits of anti-PD-1 antibody in cancer patients, and provides scientific rationales of combining IL-2 and PD-1 antibody in individuals who do not respond to PD-1 blockade. Based on the findings of this study, we designed IBI363, a PD-1/IL-2 bispecific antibody fusion protein, to expand and re-invigorate the TST cells in the cold tumors and overcome resistance to PD-1 antibodies in certain populations. At present, IBI363 is in clinical Phase 1 studies to evaluate the safety and preliminary antitumor efficacy in cancer patients who have failed or are not suitable for anti-PD-1 treatment. "

IBI363 is a potential First-in-Class candidate drug independently developed by Innovent. Its active ingredient is PD-1/IL-2 bispecific antibody fusion protein. The IL-2 arm of IBI363 has been engineered to maximize efficacy and reduce toxicity, whereas the PD-1 binding arm achieves PD-1 blockade and selective IL-2 delivery. Therefore, IBI363 has both functions of simultaneously blocking PD-1/PD-L1 pathway and activating IL-2 pathway, allowing more precise and efficient targeting and activation of tumor specific T cells. IBI363 not only showed promising anti-tumor activity in a variety of tumor-bearing pharmacological models, but also exhibited prominent antitumor efficacy in PD-1 resistant and metastatic models; meanwhile, IBI363 demonstrated a good safety profile in preclinical models. Currently, Phase 1 studies of IBI363 are conducted in China and Australia to assess the safety, tolerability, and preliminary efficacy in subjects with advanced solid tumors or lymphoma.

On August 7, 2023 Merus N.V. (Nasdaq: MRUS) (Merus, the Company, we, or our), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported financial results for the second quarter and provided a business update (Press release, Merus, AUG 7, 2023, View Source [SID1234633888]).

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"Receiving Fast Track Designation is an important milestone for petosemtamab, which we believe further validates its potential to address the unmet need of patients with previously treated recurrent or metastatic head and neck cancer," said Bill Lundberg, M.D., President, Chief Executive Officer of Merus. "We also believe the robust clinical data observed in previously treated HNSCC support a phase 3 trial of petosemtamab monotherapy in this setting, which could potentially start in mid-2024. Additionally, we are encouraged by our progress to date with the combination of petosemtamab and Keytruda as potential front-line therapy in advanced HNSCC, and are evaluating a phase 3 trial in this setting as well."

Petosemtamab (MCLA-158: EGFR x LGR5 Biclonics): Solid Tumors
Granted Fast Track Designation (FTD) for the treatment of patients with recurrent or metastatic head & neck squamous cell carcinoma (HNSCC), enrollment continues in dose expansion in the phase 1/2 trial with petosemtamab monotherapy in previously treated HNSCC, as well as in combination with Keytruda (pembrolizumab) as front-line therapy.

Petosemtamab is in clinical development in the expansion part of a phase 1/2 open-label, multicenter trial evaluating petosemtamab monotherapy in patients with advanced solid tumors, including previously treated (recurrent or metastatic) HNSCC. Enrollment is also ongoing in a cohort investigating petosemtamab in combination with Keytruda in patients with untreated HNSCC to evaluate the safety and clinical activity in this population. Merus plans to report initial interim clinical data from this cohort in the first half of 2024.

Initiation of potential registration-enabling trial

Merus is enrolling up to a total of approximately 40 patients in previously treated (2L/3L) HNSCC with petosemtamab monotherapy at the 1100 or 1500 mg dose levels to confirm a suitable dose for future randomized trials. Based on these data and additional information and analyses, Merus anticipates potentially initiating a randomized phase 3 trial of petosemtamab monotherapy, or investigators’ choice of single agent chemotherapy or cetuximab in 2L/3L HNSCC. Merus anticipates such a trial could potentially start in mid-2024. Merus believes a randomized registration trial in HNSCC with an overall response rate (ORR) endpoint could potentially support accelerated approval and the overall survival (OS) results from the same study could potentially verify its clinical benefit to support regular approval.

Merus is also evaluating a phase 3 trial investigating petosemtamab with Keytruda as a potential front-line therapy for advanced HNSCC expressing PD-L1 (CPS > 1), pending analysis of additional data on the tolerability and safety of the drug combination.

Fast Track Designation

The U.S. Food & Drug Administration (FDA) has granted FTD for petosemtamab for the treatment of patients with recurrent or metastatic HNSCC whose disease has progressed following treatment with platinum-based chemotherapy and an anti-programmed cell death protein 1 (anti-PD-1) antibody.

FTD is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill unmet medical needs.

Interim data from AACR (Free AACR Whitepaper)

In April, Merus provided an interim clinical update at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023. As of a February 1, 2023 data cutoff date, 49 previously treated HNSCC patients were treated with petosemtamab at the initial recommended phase 2 dose of 1500 mg intravenously every two weeks. The ORR, in 43 evaluable patients, was 37.2% by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. per investigator assessment. Median duration of response was 6.0 months and median progression free survival was 5.3 months. 63% of responders had an ongoing response at the data cutoff date. Median OS was 11.5 months. Petosemtamab continued to demonstrate a manageable safety profile.

Zenocutuzumab (Zeno or MCLA-128: HER2 x HER3 Biclonics): NRG1 fusion (NRG1+) cancer and other solid tumors
Granted Breakthrough Therapy Designation (BTD) for both NRG1+ non-small cell lung cancer (NSCLC) and NRG1+ pancreatic cancer; enrollment continues in the eNRGy trial of Zeno monotherapy in NRG1+ cancer and a phase 2 trial of Zeno in combination with androgen deprivation therapy (ADT) in castration resistant prostate cancer (CRPC); as well as in combination with afatinib in NRG1+ non-small cell lung cancer (NSCLC)

The FDA has granted BTD to Zeno for the treatment of patients with advanced unresectable or metastatic NRG1+ pancreatic cancer following progression with prior systemic therapy or who have no satisfactory alternative treatment options. Additionally, the FDA has granted BTD to Zeno for the treatment of patients with advanced unresectable or metastatic NRG1+ NSCLC, following progression with prior systemic therapy. Zeno is being investigated in the phase 1/2 eNRGy trial and Early Access Program (EAP) which are assessing the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer (Phase 1/2: NCT02912949, EAP: NCT04100694).

As of June 2023, more than 175 patients with NRG1+ cancer have been treated with Zeno monotherapy. The company continues to work with the FDA and is focused on accumulating data to support a potential Biologics License Application.

Merus believes that obtaining a commercialization partnership agreement will be an essential step in bringing Zeno to patients with NRG1+ cancer, if approved.

Merus plans to present a clinical update on Zeno in NRG1+ cancer at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 taking place in Madrid, Spain October 20-24, 2023. The presentations will consist of a mini-oral lecture titled: Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC) and a poster presentation titled: Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC).

Further, Merus is evaluating Zeno in combination with an ADT (enzalutamide or abiraterone) in men with CRPC, irrespective of NRG1+ status. Merus plans to provide initial clinical data on Zeno in CRPC in the second half of 2023.

Merus is also evaluating Zeno in combination with afatinib in patients with NRG1+ NSCLC.

MCLA-129 (EGFR x c-MET Biclonics): Solid Tumors
Enrollment continues in the expansion cohorts in the phase 1/2 trial; clinical update planned for 2H23

MCLA-129 is in clinical development in a phase 1/2, open-label clinical trial evaluating MCLA-129 monotherapy in patients with EGFR ex20 NSCLC, MET ex14 NSCLC, and in HNSCC, as well as MCLA-129 in combination with Tagrisso, a third generation EGFR TKI, in patients with treatment-naïve EGFR mutant (m) NSCLC and in patients with EGFRm NSCLC that have progressed on Tagrisso.

In April, Merus provided a pre-clinical presentation of MCLA-129 in comparison with amivantamab at the AACR (Free AACR Whitepaper) Annual Meeting 2023. The Company plans to provide an initial clinical data update from the expansion cohorts, and a further clinical development strategy update in the second half of 2023.

MCLA-129 is subject to a collaboration and license agreement with Betta Pharmaceuticals Co. Ltd. (Betta), which permits Betta to develop MCLA-129 and potentially commercialize exclusively in China, while Merus retains global rights outside of China.

In July, the National Medical Products Administration in China approved the investigational new drug application permitting Betta to investigate the combination of MCLA-129 and befotertinib, a third generation EGFR tyrosine kinase inhibitor, in adult patients in China that have locally advanced or metastatic NSCLC, with an EGFR Exon 19 deletion mutation or Exon 21 (L858R) substitution mutation.

MCLA-145 (CD137 x PD-L1 Biclonics): Solid Tumors
Enrollment continues in the phase 1 trial, including in combination with Keytruda (pembrolizumab), a PD-1 inhibitor

MCLA-145 is in clinical development in a global, phase 1, open-label, clinical trial evaluating MCLA-145 in patients with solid tumors. The trial is in the dose expansion phase evaluating the combination of MCLA-145 with Keytruda, with enrollment ongoing.

Collaborations

Incyte Corporation
Since 2017, Merus has been working with Incyte Corporation (Incyte) under a global collaboration and license agreement focused on the research, discovery and development of bispecific antibodies utilizing Merus’ proprietary Biclonics technology platform. The agreement grants Incyte certain exclusive rights for up to ten bispecific and monospecific antibody programs. The collaboration is progressing, with multiple programs in various stages of preclinical and clinical development. For each program under the collaboration, Merus receives reimbursement for research activities and is eligible to receive potential development, regulatory and commercial milestones and sales royalties for any products, if approved. Further, Incyte announced, in 2023, that INCA33890, a novel TGFBr2xPD1 bispecific antibody developed through the collaboration is currently being evaluated in clinical studies. In July 2023, Merus achieved a milestone and expects a payment of $2.5 million related to the advancement of this program in the third quarter of 2023.

Loxo Oncology at Lilly
In January 2021, Merus and Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (Lilly), announced a research collaboration and exclusive license agreement to develop up to three CD3-engaging T-cell re-directing bispecific antibody therapies utilizing Merus’ Biclonics platform and proprietary CD3 panel along with the scientific and rational drug design expertise of Loxo Oncology at Lilly. The collaboration is progressing with multiple active research programs underway.

Cash Runway, existing cash, cash equivalents and marketable securities expected to fund Merus’ operations into 2026
As of June 30, 2023, Merus had $311.5 million cash, cash equivalents and marketable securities. Based on the Company’s current operating plan, the existing cash, cash equivalents and marketable securities are expected to fund Merus’ operations into 2026.

Second Quarter 2023 Financial Results

We ended the second quarter with cash, cash equivalents and marketable securities of $311.5 million compared to $326.7 million at December 31, 2022.

Collaboration revenue for the three months ended June 30, 2023 decreased by $2.2 million as compared to the three months ended June 30, 2022, primarily as a result of decreases in reimbursement revenue of $0.5 million, milestone revenue of $1.0 million and amortization of deferred revenue of $0.7 million.

Research and development expense for the three months ended June 30, 2023 decreased by $2.8 million as compared to the three months ended June 30, 2022, primarily as a result of decreases in external clinical services and drug manufacturing costs, including costs to fulfill our obligations under our collaboration agreements, related to our programs of $3.8 million and a decrease in facilities costs of $0.5 million, partially offset by an increase in personnel related expenses including stock-based compensation of $1.5 million due to an increase in employee headcount.

General and administrative expense for the three months ended June 30, 2023 increased by $3.4 million as compared to the three months ended June 30, 2022, primarily as a result of increases in facilities costs including depreciation of $1.6 million, consulting costs of $1.2 million, IP and license costs of $0.4 million, and travel expenses of $0.4 million, partially offset by a decrease in finance and human resources costs of $0.2 million.

Collaboration revenue for the six months ended June 30, 2023 decreased by $0.3 million as compared to the six months ended June 30, 2022, primarily as a result of a decrease in reimbursement revenue of $0.9 million, decrease of amortization of deferred revenue of $0.9 million partially offset by an increase in milestone revenue of $1.5 million.

Research and development expense for the six months ended June 30, 2023 increased by $5.1 million as compared to the six months ended June 30, 2022, primarily as a result of increases in personnel related expenses including stock-based compensation of $3.7 million, external clinical services and drug manufacturing costs, including costs to fulfill our obligations under our collaboration agreements, related to our programs of $1.6 million, consulting expenses of $0.6 million, and consumables expenses of $0.3 million and travel costs of $0.2 million, partially offset by decreases in facilities costs of $0.8 million and partner expenses of $0.5 million. General and administrative expense for the six months ended June 30, 2023 increased by $7.0 million as compared to the six months ended June 30, 2022, primarily as a result of increases in consulting costs of $3.6 million, facilities costs including depreciation of $2.8 million, travel costs of $0.6 million, personnel related expenses including stock-based compensation of $0.5 million due to an increase in employee headcount, and IP and license costs of $0.3 million, partially offset by decreases in finance and human resources costs of $0.8 million.

Other income (loss), net consists of interest earned and fees paid on our cash and cash equivalents held on account, accretion of investment earnings and net foreign exchange (losses) gains on our foreign denominated cash, cash equivalents and marketable securities. Other gains or losses relate to the issuance and settlement of financial instruments.