Interim Clinical Data Research Articles

407P RGX-202, an investigational gene therapy for the treatment of Duchenne muscular dystrophy: interim clinical data

407P RGX-202, an investigational gene therapy for the treatment of Duchenne muscular dystrophy: interim clinical data

RGX-202, an Investigational Gene Therapy for the Treatment of Duchenne Muscular Dystrophy: Interim Clinical Data (S21.005)

RGX-202, an Investigational Gene Therapy for the Treatment of Duchenne Muscular Dystrophy: Interim Clinical Data (S21.005)

A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis).

528 Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]

Interim Phase I Clinical Data of FT576 As Monotherapy and in Combination with Daratumumab in Subjects with Relapsed/Refractory Multiple Myeloma

Introduction: Despite the recent FDA approval of autologous chimeric antigen receptor (CAR) T-cell therapies targeting B-cell maturation antigen (BCMA), multiple myeloma (MM) remains incurable and relapsed/refractory (R/R) disease remains an area of high unmet medical need. Additionally, patient access to autologous CAR T-cell therapies is currently limited due to manufacturing constraints, the need for bridging therapy, and potentially life-threatening toxicities including cytokine release syndrome and neurologic toxicities (Munshi et al. 2021). Off-the-shelf natural killer (NK) cell therapies may offer an improved therapeutic profile and broader patient access than autologous CAR T-cell therapies. FT576 is a first-of-kind, multiplexed-engineered BCMA CAR NK cell therapy generated from a clonal master engineered induced pluripotent stem cell line, which can be used as a renewable source for the mass production of off-the-shelf NK cells of uniform composition. FT576 is engineered with 4 modalities to combine multifaceted innate immunity with multi-antigen-targeting capability: (1) high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor for augmented antibody-dependent cellular cytotoxicity; (2) IL-15/IL-15 receptor fusion that promotes NK cell persistence; (3) CD38 knockout to mitigate NK cell fratricide by CD38-directed monoclonal antibodies (mAbs) and that provides improved metabolic fitness and resistance to oxidative stress within the tumor microenvironment; and (4) a BCMA-directed CAR to target plasma cells. These modalities are designed to enhance the potency and persistence of FT576 and to enable multi-antigen targeting when combined with tumor-targeting mAbs. In preclinical studies, FT576 combined with the anti-CD38 mAb daratumumab demonstrated highly effective tumor control compared to either treatment alone or to primary CAR T cells in a disseminated MM xenograft model (Goodridge et al. 2021), suggestive that limitations in MM treatment confounded by clonal heterogeneity and antigen loss can be overcome with a dual antigen-targeting approach. Methods: This is a Phase I trial of FT576 in patients with R/R MM. The primary objectives are to assess safety and tolerability and to determine the recommended Phase II dose of FT576, given as single or multiple doses, as monotherapy and in combination with daratumumab in R/R MM. Key secondary objectives include anti-tumor activity and pharmacokinetics. The dose-escalation stage of the trial has the following 4 arms: single-dose FT576 monotherapy on Day 1 (Regimen A); multi-dose FT576 monotherapy on Days 1 and 15 (Regimen A1); single-dose FT576 + daratumumab on Day 1 (Regimen B); and multi-dose FT576 + daratumumab on Days 1 and 15 (Regimen B1). Dose levels of FT576 starting from 100 million cells/dose are being evaluated using a modified toxicity probability interval dose-escalation design. Daratumumab is administered per approved dose and schedule. Outpatient conditioning chemotherapy consists of 3 consecutive days of fludarabine and cyclophosphamide administered prior to the first dose of FT576. Results: As of a data cutoff date of 18 Jul 2022, 9 patients with R/R MM were treated and evaluable for safety and efficacy, in the first 2 dose levels of Regimen A (n = 6) and in the first dose level of Regimen B (n = 3). No dose-limiting toxicities, and no events of any grade of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease (GvHD), were observed. Conclusions: Administration of a single dose of FT576 at 100 or 300 million cells/dose alone or in combination with daratumumab is safe and well tolerated thus far without CRS, neurotoxicity, or GvHD. Interim clinical data, including safety and tolerability and initial anti-tumor activity, from the ongoing Phase I dose-escalation study of FT576 will be presented at the conference.

From the Editor in Chief

Genetic Engineering & Biotechnology NewsVol. 40, No. 6 Free AccessFrom the Editor in ChiefPublished Online:11 Jun 2020https://doi.org/10.1089/gen.40.06.01AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail John Sterling“[If] we don't run into … unanticipated setbacks … we could have a vaccine that we could [begin] to deploy at the end of this calendar year, December 2020, or into January 2021.”—Anthony S. Fauci, MDNPR, May 22, 2020The above statement is extraordinary. If Fauci is right, a vaccine will be created from start to finish in less than a year, an unusually short time span. According to The History of Vaccines, a website created by the College of Physicians of Philadelphia, successful vaccine development often lasts 10–15 years.It is possible that the global medical research community has never marshalled so many resources so quickly to confront a new health threat. For an up-to-date rundown of the R&D efforts aimed at the coronavirus pandemic, see our COVID-19 Drug & Vaccine Candidate Tracker (www.genengnews.com/covid-19-candidates). It currently lists over 200 candidates.The week beginning May 18 was bursting with vaccine news. Moderna, for example, reported positive interim clinical data from a Phase I study of its mRNA-1273 vaccine candidate. Fauci called the data “quite promising” and “better than we expected,” noting that all-important neutralizing antibodies were found in eight of the trial participants.The United States, which indicated that it plans to start a multicandidate testing effort in July involving over 100,000 volunteers, also announced that it will provide up to $1.2 billion to accelerate the late-stage development and manufacture of at least 300 million doses of AZD1222, an experimental vaccine that Oxford University has licensed to AstraZeneca.Inovio Pharmaceuticals announced that preclinical results in mice and guinea pigs of its potential vaccine showed “robust neutralizing antibody and T cell immune responses against coronavirus SARS-CoV-2.”Such early results may look promising, but they shouldn't excite us too much, say experts such as William A. Haseltine, PhD, a former Harvard Medical School professor. He wrote in the Washington Post that announcements such as those issued by Moderna amount to “publication by press release.” The practice, he warned, is “damaging trust in the fundamental methods of science and medicine at a time when we need it most.”Nevertheless, Paul Stoffels, MD, CSO at Johnson & Johnson, which is testing its own vaccine in animals, told Fox News that positive trial results from one company are good news for everyone involved in vaccine development. He predicted that there will be “significant numbers of COVID-19 vaccines early next year.”Let's hope so.FiguresReferencesRelatedDetails Volume 40Issue 6Jun 2020 Information© 2020 by GEN PublishingTo cite this article:Genetic Engineering & Biotechnology News.Jun 2020.6-6.http://doi.org/10.1089/gen.40.06.01Published in Volume: 40 Issue 6: June 11, 2020PDF download

Use of Accelerometer Activity Monitors to Detect Changes in Pruritic Behaviors: Interim Clinical Data on 6 Dogs.

Veterinarians and pet owners have limited ability to assess pruritic behaviors in dogs. This pilot study assessed the capacity of the Vetrax® triaxial accelerometer to measure these behaviors in six dogs with pruritus likely due to environmental allergens. Dogs wore the activity monitor for two weeks while consuming their usual pet food (baseline), then for eight weeks while consuming a veterinary-exclusive pet food for dogs with suspected non-food-related skin conditions (Hill’s Prescription Diet® Derm DefenseTM Canine dry food). Veterinarians and owners completed questionnaires during baseline, phase 1 (days 1–28) and phase 2 (days 29–56) without knowledge of the activity data. Continuous 3-axis accelerometer data was processed using proprietary behavior recognition algorithms and analyzed using general linear mixed models with false discovery rate-adjusted p values. Veterinarian-assessed overall clinical signs of pruritus were significantly predicted by scratching (β 0.176, p = 0.008), head shaking (β 0.197, p < 0.001) and sleep quality (β −0.154, p < 0.001), while owner-assessed quality of life was significantly predicted by scratching (β −0.103, p = 0.013) and head shaking (β −0.146, p < 0.001). Among dogs exhibiting pruritus signs eating the veterinary-exclusive food, the Vetrax® sensor provided an objective assessment of clinically relevant pruritic behaviors that agreed with owner and veterinarian reports.

Developing a community HCV service: project ITTREAT (integrated community-based test - stage - TREAT) service for people who inject drugs.

We justify the need for a community HCV service and review the different community based models. Our experiences in engaging with stakeholders, obtaining funding, service set up, challenges faced and key recommendations are discussed. Finally, a summary of interim clinical outcomes is presented. A successful community based "one-stop" nurse led HCV service was set up in Dec 2013 at a large SMS. It provides all aspects of care (blood borne virus screening, non-invasive assessment of hepatic fibrosis, Hepatology input, HCV treatment, peer mentor, social and psychiatrist support, and opiod substitution) at one site. Interim clinical data indicate high service uptake with HCV treatment outcomes comparable to secondary care. The advent of direct acting antivirals provides a unique opportunity for HCV elimination in England by 2030. Our "one-stop" integrated and multidisciplinary community HCV model suggests that HCV care can be successfully delivered outside of a hospital setting and warrants national adoption.

1072P - Recruit-Tandab AFM13 - Overcoming Limitations of Monoclonal Antibodies in Hodgkin Lymphoma

ABSTRACT AFM13 is a RECRUIT-TandAb (CD30xCD16A) for treating Hodgkin Lymphoma by recruiting NK-cells and macrophages to the specific CD30 surface antigen on Reed-Sternberg cells. This redirected immune response leads to potent tumor cell killing. RECRUIT TandAbs are tetravalent and bispecific, and address key deficiencies of monoclonal antibodies such as (i) differential binding to V/F allotypes of CD16A receptor and (ii) non-selective binding to activating CD16A and non-signalling CD16B receptors. Furthermore, RECRUIT-TandAbs have significant advantages over other antibody fragment technologies such as (i) bivalent binding to the targets and, (ii) longer half-life. AFM13 binds with high affinity to both CD30 and CD16A and is able to rapidly induce lysis of CD30+ cells at picomolar concentrations in the presence of PBMCs. Intensive in vitro characterization demonstrated that AFM13 is specific for the CD16A receptor, which becomes activated only in the presence of tumor cells: there is no systemic activation of NK-cells in the absence of target cells. A robust GMP production process in mammalian cells and a lyophilized formulation with excellent stability have been established. Toxicology testing in Cynomolgus monkeys did not reveal any toxicity. Currently, AFM13 is being investigated in a single arm phase I dose escalation trial for patients with relapsed and/or refractory Hodgkin Lymphoma (HL). Patients receive a single cycle of 4 weekly doses, which are escalated in cohorts of 3 patients at the dose levels of 0.01, 0.04, 0.15, 0.5, 1.5, 4.5 and 7.0 mg/kg. Study objectives are the assessment of safety and tolerability, PK, immunogenicity, antitumor activity, as well as the determination of the maximum tolerated dose (MTD) or the optimal biological dose (OBD). The safety of the MTD or OBD will be confirmed in further patients receiving 2 cycles of AFM13. AM13 was shown to be safe and well tolerated by highly pre-treated Hodgkin Lymphoma patients in weekly doses of up to 7.0 mg/kg. Adverse events were generally mild, with the most frequent drug-related event being fever. An objective response was achieved on the dose level 1.5mg/kg. Nine cases of stable disease/minor response were also observed. In ex vivo assays AFM13 restored impaired cytotoxic activity of NK cells from HL patients. Preclinical and interim clinical data will be presented, showing that AFM13 may become a safe and effective targeted therapy for CD30 positive malignancies. Disclosures E. Zhukovsky: The author is the employee of Affimed Therapeutics and the member of the Management Board, M. Ravic: A consultant to Affimed Therapeutics and a Chief Medical Officer, M. Topp: Consultant to Affimed, S. Knackmuss: The coauthor is an employee of the company. U. Reusch: The coauthor is an employee of the company. E. Rajkovic: The coauthor is an employee of the company. C. Hucke: The co-author is a former employee of Affimed Therapeutics and currently is a clinical development consultant M. Little: The co-author is a consultant to Affimed Therapeutics and owns the warrants of the company.

Abstract 3521: RECRUIT-TandAb AFM13: Overcoming limitations of monoclonal antibodies in Hodgkin lymphoma

Abstract Introduction: AFM13 is a RECRUIT-TandAb (CD30xCD16A) for treating Hodgkin Lymphoma by recruiting NK-cells and macrophages to the specific CD30 surface antigen on Reed-Sternberg cells. This redirected immune response leads to potent tumor cell killing. RECRUIT TandAbs are tetravalent and bispecific, and address key deficiencies of monoclonal antibodies such as (i) V/F polymorphism and (ii) non-selective binding to immune effector cells vs. granulocytes via CD16B receptor. Furthermore, RECRUIT-TandAbs have significant advantages over other antibody fragment technologies such as (i) bivalent binding to the targets and, (ii) longer half-life. Methods: AFM13 binds with high affinity to both CD30 and CD16A and is able to rapidly induce the lysis of CD30+ cells at picomolar concentrations in the presence of PBMCs. Intensive in vitro characterization demonstrated that AFM13 is specific for the CD16A receptor, which becomes activated only in the presence of tumor cells: there is no systemic activation of NK-cells in the absence of target cells. A robust GMP production process in mammalian cells and a lyophilized formulation with excellent stability have been established. Toxicology testing in Cynomolgus monkeys did not reveal any toxicity. Currently, AFM13 is being investigated in a single arm phase I dose escalation trial for patients with relapsed and/or refractory Hodgkin Lymphoma (HL). Patients receive a single cycle of 4 weekly doses, which are escalated in cohorts of 3 patients at the dose levels of 0.01, 0.04, 0.15, 0.5, 1.5, 4.5 and 7.0 mg/kg. Study objectives are the assessment of safety and tolerability, PK, immunogenicity, antitumor activity, as well as the determination of the maximum tolerated dose (MTD) or the optimal biological dose (OBD). The safety of the MTD or OBD will be confirmed in further patients receiving 2 cycles of AFM13. Results and Conclusion: So far, AM13 was shown to be safe and well tolerated by highly pre-treated Hodgkin Lymphoma patients in weekly doses of up to 1.5mg/kg. Adverse events were generally mild, with the most frequent drug-related event being fever. A first objective response was achieved on the dose level 1.5mg/kg. Five cases of stable disease / minor response were observed on lower dose levels. Further patients are being treated in the ongoing dose escalation study. Preclinical and interim clinical data will be presented, showing that AFM13 may become a safe and effective targeted therapy for CD30 positive malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3521. doi:1538-7445.AM2012-3521

CM-dextran-polyalcohol-camptothecin conjugate: DE-310 with a novel carrier system and its preclinical data.

The pharmacokinetics of DX-8951f were greatly improved by DE-310 with the extremely longer retention in bloodstream, resulting in the preferential tumor-targeting, and with the slow release appropriate to camptothecin analog DX-8951f in tumor tissue. On the basis of the pharmacokinetic improvement, DE-310 exhibited enhanced antitumor effects with reduced toxicities by a single and low dose, compared with DX-8951f. These preclinical results suggest that DE-310 is a promising agent for cancer treatment. The phase I trials are still ongoing and recently, the interim clinical data have been reported15, 16.