Early Clinical Studies Research Articles

Transcatheter Left Atrial Appendage Exclusion: Preclinical and Early Clinical Results With the Laminar Device

BackgroundThe Laminar device rotates and closes the left atrial appendage (LAA) using an integrated ball and lock that excludes and eliminates the LAA pouch. There is a low device surface area, minimizing the risk of peridevice leak (PDL) and device-related thrombus (DRT) formation. ObjectivesThis study evaluates the safety and efficacy of the Laminar LAA exclusion device in healthy animals and human subjects with nonvalvular atrial fibrillation at risk of ischemic stroke and systemic thromboembolism. MethodsThe preclinical study implanted the Laminar device into canine subjects that underwent transesophageal echocardiography (TEE) and fluoroscopic evaluation, followed by necropsy and histological assessment at 45 and 150-days post-implant. The early clinical study implanted the device in human subjects, followed to 12 months postimplantation. Procedural success was defined as device implantation in the intended location without residual LAA leak >5 mm as seen by TEE. Safety endpoints included freedom from stroke, systemic embolism, pericardial effusion, or tamponade, life-threatening/major bleeding, or death. ResultsThe Laminar device was successfully implanted in 10 canines. In all animals at 45 days and 150 days, no PDL or DRT was found, and histological examination showed fully closed LAAs covered with neo-endocardium. The device was successfully implanted in 15 human subjects with no safety events out to 12 months postimplantation. All subjects had successful protocol-defined LAA closure without DRT at 45 days by TEE and computed tomography, which remained stable through 12 months’ follow-up. ConclusionsThe preclinical and early clinical results demonstrate a promising safety and efficacy profile for the Laminar LAA exclusion device.

Cardioneuroablation Using Epicardial Pulsed Field Ablation for the Treatment of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting millions of people worldwide. The cardiac autonomic nervous system (ANS) is widely recognized as playing a key role in both the initiation and propagation of AF. This paper reviews the background and development of a unique cardioneuroablation technique for the modulation of the cardiac ANS as a potential treatment for AF. The treatment uses pulsed electric field energy to selectively electroporate ANS structures on the epicardial surface of the heart. Insights from in vitro studies and electric field models are presented as well as data from both pre-clinical and early clinical studies.

P294 BIOPROSTHETIC AORTIC VALVE REPLACEMENT IN PATIENTS AT INCREASED RISK OF EARLY STRUCTURAL VALVE DEGENERATION

Abstract Background Biological prostheses are increasingly been used in young patients to avoid anticoagulation. The Edwards Inspiris aortic bioprosthesis is extremely promising in this population, since it has shown reduced calcification of the prosthetic leaflets in preclinical and early clinical studies. Little data are available, however, in patients younger than 65. This study investigates the hemodynamic performance and clinical outcome of the Inspiris bioprosthesis in patients aged 56 ± 10.7 years. Methods and Results Between may 2018 and December 2022, 342 patients aged 56 ± 10.7 years underwent AVR with the Edwards Inspiris bioprosthesis at our institution. 37 of them (10.8%) were younger than 40, and 98 (28.6%) had a BMI >30 kgm2. A minimally invasive approach was used in all isolated AVR patients. Associated procedures were performed in 157 (45.9%) patients. There were 56 redo patients (16.4%). 7 patients died (2%). Major complications included bleeding (32), respiratory failure (20) and BAV requiring PMK (4). The mean follow up was 23 ± 15.2 months (range 2–55). Late valve–related events included endocarditis (5) requiring reoperation. There were no thromboembolic events, valve thrombosis or SVD cases. At follow up, all except four patients reported a significant improvement of their symptomatic status (98.8% were in NYHA II) and quality of life. Conclusion Our study demonstrates excellent early haemodynamics and promising results at up to four years in a cohort of very young patients. Further studies with longer follow–up are needed.

P345 INTERMEDIATE–TERM RESULTS OF A NEW AORTIC BIOPROSTHESIS IN PATIENTS AT INCREASED RISK OF EARLY SVD

Abstract Background and aim Biological prosthesis are increasingly been used in young patients to avoid anticoagulation. The Edwards Inspiris aortic bioprosthesis is extremely promising in this population, since it has shown reduced calcification of the prosthetic leaflets in preclinical and early clinical studies. Little data are available, however, in patients younger than 65. This study investigates the haemodynamic performance and clinical outcome of the Inspiris bioprosthesis in patients aged < 50 years. Methods Between May 2018 and May 2022, 58 patients aged 41±7.8 years underwent AVR with the Edwards Inspiris bioprosthesis. Twenty–three (39.65%) were younger than 40, and 7 (12.06%) had a BMI >30 kgm2. A minimally invasive approach was used in all isolated AVR patients. Associated procedures were performed in 25 (43.10%) patients. There were 10 redo patients (17.2%). Results Major complications included bleeding (4), respiratory failure (1) and BAV requiring PMK (1). Two patients died (3.45%). The mean follow up was 29.6±12.3 months (range 10–51). Late valve–related events included endocarditis (2) requiring reoperation. There were no thromboembolic events, valve thrombosis or SVD cases. At follow up, all except one patient reported a significant improvement of their symptomatic status (96.29% were in NYHA II) and quality of life. The mean interval to return to the normal activity was of 5.37±3.3 months. Conclusion Our study demonstrates promising results at up to 4 years in a cohort of very young patients. Further studies with longer follow–up are needed.

Differential expression of RET and GDNF family receptor, GFR-α1, between striatum and substantia nigra following nigrostriatal lesion: A case for diminished GDNF-signaling

Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson's disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment began ∼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), which represents a time point of initiating GDNF treatment later than reported in some preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemiparkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) hemilesion. Whereas GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred, returning to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors thus appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Significance statementAlthough preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, there is uncertainty if it can alleviate motor impairment in Parkinson's disease patients. Using the established 6-OHDA hemiparkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery.

Treating Clostridioides difficile: Could Microbiota-based Live Biotherapeutic Products Provide the Answer?

Clostridioides difficile infection (CDI) is a pressing health care issue due to the limited effectiveness of current treatments and high recurrence rates. Current available antibiotic options for CDI disrupt the fecal microbiome which predisposes recurrent CDI. Fecal microbiota transplantation (FMT) has improved the outcomes of recurrent CDI, but concerns surrounding the safety and standardization of the product persist. Microbiota-based live biotherapeutic products (LBPs), are emerging as potential alternatives to FMT for CDI treatment. This review explores the potential of LBPs as safe and effective therapy for CDI. While preclinical and early clinical studies have shown promising results, further research is necessary to determine the optimal composition and dosage of LBPs and to ensure their safety and efficacy in clinical practice. Overall, LBPs hold great promise as a novel therapy for CDI and warrant further investigation in other conditions related to disruption of the colonic microbiota.

Review of Treatments for ADPKD on Tolvaptan and ketogenic Dietary Intervention as a Novel Therapy

Autosomal dominant polycystic kidney disease (ADPKD), the most prevalent genetic kidney disease, affected millions of individuals worldwide. And it is also one of the most prevalent causes of kidney failures and transplants. Previously, in many years, mitigating its symptoms had been the only treatment for this disease. After more than a decade after the early clinical studies of medicines for ADPKD began, the first medication that may successfully delay the course of the condition is now on the market. Due to the severe side effects and high cost of tolvaptan, it cannot be considered a full success, but rather the beginning of therapeutic research. More recently, enlightened by the discovery of the defective metabolism of PKD related cells, researchers have been designing dietary plans and new lifestyles for ADPKD patients to slow down or even halt the disease progression. Current outcomes have been promising. This article will address the best practices for treating ADPKD patients, with a focus on medications that have been proved to be beneficial in preserving kidneys function and structure.

Abstract LB199: A personalized neoantigen vaccine is well tolerated and induces specific T-cell immune response in patients with resected melanoma

Abstract Tumor mutations giving rise to neoantigens have recently emerged as promising targets for cancer immunotherapy. Vaccines delivering tumor-specific neoantigens have demonstrated favorable efficacy and safety results in numerous preclinical and early clinical studies. However, selecting therapeutically relevant neoantigens amongst the myriad of cancer mutations has proven challenging. To overcome this, we have developed a proprietary AI-based target discovery platform, PIONEER, with enhanced predictive performance and increased precision. The PIONEER top-ranked neoantigens were selected and included in the personalized DNA vaccine candidate EVX-02. To assess the ability of the PIONEER designed neoantigen vaccine candidate to induce neoantigen immunogenicity and anti-tumor effect in preclinical models, mice were immunized with a mouse surrogate EVX-02 molecule, mEVX-02. mEVX-02 vaccination completely prevented establishment of tumors and induced neoantigen-specific, polyfunctional CD4+ and CD8+ T cells in the blood and spleen of immunized mice. An enhanced antitumor effect was obtained when combining mEVX-02 with anti-PD-1 mAb treatment. Encouraged by the preclinical results, we conducted a first-in-human multicenter Phase I clinical study of EVX-02 in combination with nivolumab in patients with resected malignant melanoma. The objectives of the trial were to investigate safety and tolerability, operational and clinical feasibility, and immunogenicity of the applied personal neoantigens. Each patient received a fully personalized drug that was produced in a complex process, from biopsy, through genome sequencing, AI-profiling, vaccine design, manufacturing, quality testing, and drug product release. This was succeeded with every single step for each patient. In all patients, EVX-02 treatment was well tolerated, and only very mild adverse events (AEs) have been observed in relation to immunization with EVX-02. Interim data demonstrated neoantigen-specific T-cell immune responses upon EVX-02 treatment and that the responses were mediated by activated CD4+ and CD8+ T cells. The measured T-cell responses were robust and long lasting. Together, these findings validate the precision and predictive power of our proprietary AI platform, PIONEER, and provide proof of mechanism for the DNA-delivery technology in that the encoded neoantigens gave rise to significant immune reactions. Citation Format: Daniela Kleine-Kohlbrecher, Nadia Viborg Petersen, Michail Angelos Pavlidis, Thomas Trolle, Stine Friis, Jens Kringelum, Anders Bundgaard Soerensen, Thomas Strandet Jepsen, Camilla Højgaard, Anders Jespersen, Erik D. Heegaard, Britt Winding Lauenborg, Birgitte Rønø. A personalized neoantigen vaccine is well tolerated and induces specific T-cell immune response in patients with resected melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB199.

Device profile of the FlareHawk interbody fusion system, an endplate-conforming multi-planar expandable lumbar interbody fusion cage

ABSTRACT Introduction The FlareHawk Interbody Fusion System is a family of lumbar interbody fusion devices (IBFDs) that include FlareHawk7, FlareHawk9, FlareHawk11, TiHawk7, TiHawk9, and TiHawk11. These IBFDs offer a new line of multi-planar expandable interbody devices designed to provide mechanical stability, promote arthrodesis, and allow for restoration of disc height and lordosis through a minimal insertion profile during standard open and minimally invasive posterior lumbar fusion procedures. The two-piece interbody cage design consists of a PEEK outer shell that expands in width, height, and lordosis with the insertion of a titanium shim. Once expanded, the open architecture design allows for ample graft delivery into the disc space. Areas covered The design and unique features of the FlareHawk family of expandable fusion cages are described. The indications for their use are discussed. Early clinical and radiographic outcome studies using the FlareHawk Interbody Fusion System are reviewed, and properties of competitor products are outlined. Expert opinion The FlareHawk multi-planar expandable interbody fusion cage is unique amongst the many lumbar fusion cages currently on the market. The multi-planar expansion, open architecture, and adaptive geometry set it apart from its competitors.

Abstract 1547: The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies

Abstract Background: Soft tissue sarcoma (STS) is a complex family of rare malignancies with high unmet medical need. uPARAP is an endocytic receptor expressed at low levels on selected mesenchymal cell types, which internalizes fragments of collagen and transfers them to the lysosome for degradation. Besides its physiological role, uPARAP is considered a critical modulator of the tumor microenvironment. Here, for the first time, we explored the molecular epidemiology of uPARAP in sarcoma tissue to validate this receptor as target for the development of ADCs in this indication. Methods: uPARAP expression was assessed in STS-specific tissue microarrays by immunohistochemistry in tissue samples from more than three hundred individual donors. Stainings were assessed by histopathologic scoring and grouped into high, medium and low expressing subgroups. Results: uPARAP was found to be strongly over-expressed in a high percentage of cases of common STS, with variations in terms of incidence and level of expression between histological subtypes. High uPARAP expression was found in fibro- (86% of cases), synovial (84%), dedifferentiated lipo- (68%), pleomorphic lipo- (65%), myxofibro- (59%), leiomyo- (49%), and myxoid liposarcoma (24%). Work is ongoing in additional sarcoma subtypes. Conclusions: Based on protein expression uPARAP is an attractive emerging therapeutic target for the development of uPARAP-binding ADCs in a broad range of mesenchymal malignancies. In addition, expression of uPARAP in STS may serve as a potential marker for patient selection in early clinical studies with uPARAP-targeting ADCs. Citation Format: Pernille Barkholt, Agnieszka Wozniak, Chao-Chi Wang, Che-Jui Lee, Lore De Kock, Lars H. Engelholm, Carmel Lynch, Dominik Mumberg, Patrick Schöffski. The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1547.

Abstract 4128: AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor models

Abstract Agonist CD40 antibody (αCD40) has shown excellent anti-tumor efficacy in both pre and early clinical studies. However, in clinics, αCD40 has failed to prove its potential as αCD40 is associated with dose-limiting toxicity due to cytokine release syndrome (CRS), grade 3 to 4 hematological and liver toxicities. In addition, αCD40 induces immune checkpoint proteins (PD-L1, CTLA-4) which makes the tumor microenvironment (TME) immunosuppressive. In this context, this study investigates the therapeutic efficacy of a novel combination of αCD40 and AJ17, a small molecule inhibitor of receptor tyrosine kinase. Combination treatment showed a significant delay in the tumor growth and improved overall survival in mice bearing B16-F10 melanoma and 4T1 orthotopic tumor by increasing the population of CD8+ T cells and lowering the expression of PD-L1, Foxp3+, and arginase in both tumor and spleen. Most interestingly, AJ17 lowered the in vivo toxicity associated with αCD40 monotherapy by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and IL-6 in serum. In conclusion, this combination can be further explored in clinics to improve the in vivo anti-tumor efficacy of αCD40 while lowering the associated toxicity. Citation Format: Vidit Gaur, Anjali Barnwal, Bushra Ateeq, Jayanta Bhattacharyya. AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4128.

Abstract 6793: In vivo effects and molecular mechanisms of Minnelide mediated enhancement of measles virus oncolysis in human colorectal cancer

Abstract Background: The development of novel biotherapies for metastatic colorectal cancer (CRC), a fatal disease when advanced, is an urgent medical need. Oncolytic viruses (OVs) are novel cancer biotherapies, and the oncolytic measles virus (MV) has demonstrated safety and antitumor activity in early clinical studies. Triptolide (TRP), a diterpenoid epoxide extracted from the thunder god vine, and Minnelide (MN), its water-soluble compound, are novel agents associated with potent antitumor, anti-proliferative, pro-apoptotic, antiangiogenic, and ER stress inducing effects. The objectives of this study are to characterize the in vitro and in vivo effects and molecular mechanisms of measles virotherapy in combination with TRP and MN in CRC. Methods: The in vitro effects of TRP, MV-GFP (Edmonston strain of Measles virus expressing eGFP), MV-CD46-muPA (dual targeted MV against the murine uPA receptor and human CD46), or virus-triptolide combinations on tumor cell cytotoxicity were assessed on HT-29, HCT116 and SW620 CRC cells. Molecular and mechanistic characterization of TRP’s effects alone and combination with MV in HT29 cells was analyzed by the Reverse Phase Protein Array (RPPA) and validated by western blot analysis. In vivo effects (tumor progression and survival) of MN alone and in combination with MV vectors using different treatment schemes were assessed in HT-29 tumor bearing NSG mice, and tumor correlative studies were performed. Results: MV and TRP had single agent antitumor activity against human CRC cell lines. MV-TRP combinations were associated with increased in vitro cytotoxicity compared to single agent treatments. Functional proteomics analysis showed that TRP-MV combinations were associated with inhibition of survival and proliferation pathways, such as AKT, ERK, inhibition of HSP70 as well as induction of autophagy, at a higher level than each agent alone. In vivo, both a 7-days MN treatment and a 21-days MN treatment significantly improved long term tumor control and significantly improved survival, compared to each agent alone. Tumor studies showed that MN increased MV tumor deposition, as well as enhancement in apoptosis and inhibition of proliferation. Molecular characterization of oncogenic pathways modulated by MV-Minnelide combinations (Nanostring) are underway and will be presented at the meeting. Conclusions: Our results demonstrated that, in human CRC xenografts, Minnelide safely and significantly enhances measles virus oncolysis in vivo, leading to improved antitumor effects and prolonged survival. These effects were associated with enhanced antiproliferative and pro-apoptotic effects with the MV-Minnelide combination, suggesting in vivo synergy. Studies characterizing the molecular mechanisms of in vivo synergy and assessing this promising combination in immunocompetent CRC models are underway. Citation Format: Valery A. Chavez, Floritza Bustamante, Carolina Merchan-Mendes, Ashok Saluja, Jaime Merchan. In vivo effects and molecular mechanisms of Minnelide mediated enhancement of measles virus oncolysis in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6793.

5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice.

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early phase clinical studies. However, relatively little is known about the behavioral and neural mechanisms of 5-MeO-DMT, particularly the durability of its long-term effects. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.

Abstract 2934: BYON4228, an antagonistic SIRPα mAb with a unique and favorable preclinical profile compared to three comparator SIRPα mAbs

Abstract A growing body of data from early clinical studies supports that targeting the myeloid immune checkpoint CD47-SIRPα represents a successful strategy towards establishing effective new therapies for cancer patients. Initial studies focused on CD47 blockers and more recently also SIRPα antagonistic mAbs entered clinical studies. The latter approach is thought to be more advantageous since SIRPα expression is primarily myeloid restricted whereas CD47 is broadly expressed and -besides SIRPα- binds other ligands as well.We generated BYON4228, an antibody directed against the two existing allelic variants of human SIRPα that does not recognize the closely related T-cell expressed SIRPγ. Functional studies demonstrate that BYON4228 potentiates both macrophage- and neutrophil-mediated elimination of hematologic and solid cancer cells in vitro in the presence of a variety of tumor targeting antibodies, including rituximab, daratumumab, trastuzumab and cetuximab. In vivo, BYON4228 increases the anti-tumor activity of rituximab in a B-cell Raji xenograft model in mice and shows a favorable safety profile in cynomolgus monkeys.To position BYON4228 in the emerging field of myeloid checkpoint inhibitors, head-to-head comparison studies were performed. For these studies, previously described anti-SIRPα mAbs HEFLB, 1H9, and SIRPAB-11 were generated in house that in all probability are representative for three clinical stage SIRPα mAbs. These comparative studies focused on principal characteristics of this class of mAbs that are anticipated to affect their clinical profile, namely 1) recognition of both common allelic forms of SIRPα which determines the broadness of its clinical applicability; 2) binding to SIRPγ on T-lymphocytes which is reported to affect T-cell extravasation and activation and thereby the adaptive immune response; 3) functionality of the Fc-region of the mAb which can mediate depletion of SIRPα-positive host myeloid immune effector cells thereby compromising host defense and undermining the effect of immunotherapy. The comparative studies show that in contrast to HEFLB, BYON4228 recognizes both common allelic forms of SIRPα. Furthermore, lack of binding to T-cell expressed SIRPγ differentiates BYON4228 from 1H9 and SIRPAB-11. Finally, with its impaired Fc-region BYON4228 does not deplete SIRPα+ myeloid cells, in contrast to SIRPAB-11.Thus, BYON4228 differentiates from all three comparator SIRPα mAbs based on at least one fundamental characteristic, thereby underlining its potential to become a best-in-class drug. We therefore endorse its further development for which clinical studies are planned to start in 2023. Citation Format: Mary van Helden, Seline Zwarthoff, Roel Arends, Inge Reinieren-Beeren, Marc Parade, Lilian Driessen-Engels, Karin de Laat-Arts, Desiree Damming, Ellen Santegoeds-Lenssen, Daphne van Kuppeveld, Imke Lodewijks, Ellen Mattaar, Hugo Olsman, Hanke Matlung, Katka Franke, Marloes Stokman, Benny de Wit, Dirk Glaudemans, Danielle van Wijk, Lonnie Joosten Stoffels, Jan Schouten, Paul Boersema, Monique van der Vleuten, Jorien Sanderink, Wendy Kappers, Diels van den Dobbelsteen, Marco Timmers, Ruud Ubink, Gerard Rouwendal, Gijs Verheijden, Miranda M.C. van der Lee, Wim Dokter, Timo van den Berg. BYON4228, an antagonistic SIRPα mAb with a unique and favorable preclinical profile compared to three comparator SIRPα mAbs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2934.

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

Acute severe hepatitis as a presenting symptom in clinically stable patients admitted with SARS-CoV-2 Omicron infection.

Suggested mechanisms for SARS-CoV-2 direct liver infection have been proposed by others to involve both cholangiocytes and hepatocytes. Early clinical studies have highlighted abnormal liver biochemistry with COVID-19 infection as often not being severe, with elevated liver enzymes <5X the upper limit of normal. Liver enzymes were evaluated and compared in patients admitted with a diagnosis of COVID-19 in a deidentified Internal Medicine-Medical Teaching Unit/hospitalist admission laboratory database. Comparisons in the incidence of severe liver injury (alanine aminotransferase >10 times upper limit of normal) were made for patients with pre-Omicron SARS-CoV-2 (November 30, 2019, to December 15, 2021) and Omicron SARS-CoV-2 (December 15, 2021, to April 15, 2022). Comprehensive hospital health records were also reviewed for the 2 patient cases discussed. One patient had a liver biopsy that was evaluated with H&E and immunohistochemistry staining using an antibody against COVID-19 spike protein. The evaluation of a deidentified admissions laboratory database found the incidence of severe liver injury was 0.42% with Omicron versus 0.30% with pre-Omicron variants of COVID-19. In both patient cases discussed, abnormal liver biochemistry and a negative comprehensive workup strongly suggest COVID-19 as the cause of severe liver injury. In the one patient with liver biopsy, immunohistochemistry staining suggests SARS-CoV-2 presence in the portal and lobular spaces in association with immune cell infiltration. The Omicron variant of SARS-CoV-2 should be considered in the differential diagnosis of severe acute liver injury. Our observation suggests that this new variant, either through direct liver infection and/or mediating immune dysfunction, can result in severe liver injury.

Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity.

Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk.

Darren P. Baker, PhD A Pioneer in the Development of Pegylated Interferon-β for Clinical Use

Darren P. Baker, PhD A Pioneer in the Development of Pegylated Interferon-β for Clinical Use

Early feasibility studies in the United States: Focus on electrophysiology.

The care of patients with heart rhythm disorders is often dependent on technologies developed to address their unique clinical needs. Although much innovation occurs in the United States, recent decades have seen a significant proportion of early clinical studies performed outside the United States, driven largely by costly and time-inefficient processes seemingly inherent to the United States research ecosystem. As a result, the goals of early patient access to novel devices to address unmet needs and efficient technology development in the United States remain incompletely realized. This review will introduce key aspects of this discussion, organized by the Medical Device Innovation Consortium, in an effort to broaden awareness and encourage engagement by stakeholders in an effort to address central issues and therefore further a growing effort to shift Early Feasibility Studies to the United States for the benefit of all involved.

Intervention strategies in early childhood to prevent celiac disease-a mini-review.

A higher intake of gluten during childhood is associated with increased risk of celiac disease, and the incidence of celiac disease peaks shortly after the time point when associations with higher gluten intake during the second and third year of life occur. Additional environmental factors are most likely necessary for celiac disease to develop. It is hypothesized that gastrointestinal infections increase gut permeability and exposure to gluten. Alternatively, infections may lead to gut dysbiosis and chronic inflammation, with leakage of self-antigens that mimic gluten peptides that leads to an autoimmune-like response. Different gluten interventions to prevent celiac disease have been proposed. Early clinical studies suggested an optimal time point introducing gluten between 4 and 6 months of age while the infant is being breastfed. However, later clinical trials on reduced gluten intake given to infants have shown no protection from celiac disease if gluten introduction was delayed or if gluten was introduced in small amounts during the child's first year of life. Still, more randomized clinical trials (RCTs) are warranted to answer the question if a reduced amount of gluten, not only at the time of introduction during infancy but also in a longer time frame, will prevent children at genetic risk from having lifelong celiac disease. It needs to be clarified whether dietary interventions are effective strategies to be proposed as future prevention of celiac disease in the general population. The present mini-review provides an overview of ongoing or completed RCTs that have focused on interventions during early childhood with the aim of preventing celiac disease.