Research-Based Product Innovation to Address Critical Unmet Needs of Patients with Inflammatory Bowel Diseases

Despite progress in recent decades, patients with inflammatory bowel diseases face many critical unmet needs, demonstrating the limitations of available treatment options. Addressing these unmet needs will require interventions targeting multiple aspects of inflammatory bowel disease pathology, including disease drivers that are not targeted by available therapies. The vast majority of late-stage investigational therapies also focus primarily on a narrow range of fundamental mechanisms. Thus, there is a pressing need to advance to clinical stage differentiated investigational therapies directly targeting a broader range of key mechanistic drivers of inflammatory bowel diseases. In addition, innovations are critically needed to enable treatments to be tailored to the specific underlying abnormal biological pathways of patients; interventions with improved safety profiles; biomarkers to develop prognostic, predictive, and monitoring tests; novel devices for nonpharmacological approaches such as minimally invasive monitoring; and digital health technologies. To address these needs, the Crohn’s & Colitis Foundation launched IBD Ventures, a venture philanthropy–funding mechanism, and IBD Innovate®, an innovative, product-focused scientific conference. This special IBD Innovate® supplement is a collection of articles reflecting the diverse and exciting research and development that is currently ongoing in the inflammatory bowel disease field to deliver innovative and differentiated products addressing critical unmet needs of patients. Here, we highlight the pipeline of new product opportunities currently advancing at the preclinical and early clinical development stages. We categorize and describe novel and differentiated potential product opportunities based on their potential to address the following critical unmet patient needs: (1) biomarkers for prognosis of disease course and prediction/monitoring of treatment response; (2) restoration of eubiosis; (3) restoration of barrier function and mucosal healing; (4) more effective and safer anti-inflammatories; (5) neuromodulatory and behavioral therapies; (6) management of disease complications; and (7) targeted drug delivery.

Rapid and Successful Implementation of a COVID-19 Convalescent Plasma Programme—The South African Experience

Background: COVID-19 convalescent plasma (CCP) has been considered internationally as a treatment option for COVID-19. CCP refers to plasma collected from donors who have recovered from and made antibodies to SARS-CoV-2. To date, convalescent plasma has not been collected in South Africa. As other investigational therapies and vaccination were not widely accessible, there was an urgent need to implement a CCP manufacture programme to service South Africans. Methods: The South African National Blood Service and the Western Cape Blood Service implemented a CCP programme that included CCP collection, processing, testing and storage. CCP units were tested for SARS-CoV-2 Spike ELISA and neutralising antibodies and routine blood transfusion parameters. CCP units from previously pregnant females were tested for anti-HLA and anti-HNA antibodies. Results: A total of 987 CCP units were collected from 243 donors, with a median of three donations per donor. Half of the CCP units had neutralising antibody titres of >1:160. One CCP unit was positive on the TPHA serology. All CCP units tested for anti-HLA antibodies were positive. Conclusion: Within three months of the first COVID-19 diagnosis in South Africa, a fully operational CCP programme was set up across South Africa. The infrastructure and skills implemented will likely benefit South Africans in this and future pandemics.

HBV and HDV: New Treatments on the Horizon

Despite the accumulating knowledge, chronic hepatitis B (CHB) and HDV infection represent a global health problem, and there are still several critical issues, which frequently remain uncovered. In this paper, we provided an overview of the current therapeutic options and summarized the investigational therapies in the pipeline. Furthermore, we discussed some critical issues such as a “functional cure” approach, the futility of long-term NA therapy and the relevance of understanding drug actions and safety of antivirals, especially in special populations.

Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies

Follicular Lymphoma (FL) is the most common subtype of indolent B cell non-Hodgkin lymphoma. The clinical course can be very heterogeneous with some patients being safely observed over many years without ever requiring treatment to other patients having more rapidly progressive disease requiring multiple lines of treatment for disease control. Front-line treatment of advanced FL has historically consisted of chemoimmunotherapy but has extended to immunomodulatory agents such as lenalidomide. In the relapsed setting, several exciting therapies that target the underlying biology and immune microenvironment have emerged, most notable among them include targeted therapies such as phosphoinositide-3 kinase and Enhancer of Zeste 2 Polycomb Repressive Complex 2 inhibitors and cellular therapies including chimeric antigen receptor T cells and bispecific T cell engagers. There are several combination therapies currently in clinical trials that appear promising. These therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these agents will impact the therapeutic landscape in FL.

Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification

Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified neuroblastomas. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. Here, we investigate whether transcriptional subtyping of MYCN non-amplified neuroblastomas can identify molecular subtypes with discrete prognosis and therapeutic vulnerabilities. Using tumour expression data and ConsensusClusterPlus, we demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup 2 has the worst prognosis and this group shows a "MYCN" signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup 3 is characterised by an "inflamed" gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates unique prognosis and vulnerability to investigational therapies. We propose that matching baseline tumour subtype to therapy may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Plasma circulating tumor DNA (ctDNA) fraction and real-world overall survival (rwOS) in metastatic castration resistant prostate cancer (mCRPC).

e17035 Background: Assessment of disease burden and severity influences numerous decisions in cancer care yet is not always straightforward. In mCRPC, most patients (pts) have bone-only metastases, for which disease burden quantification by imaging is challenging. Using commercially available assays for comprehensive genomic profiling (CGP), we hypothesized higher levels of ctDNA would associate with worse rwOS in mCRPC. Methods: Pts with mCRPC who received care within Flatiron Health (FH) network between 1/1/2011-6/30/2020 were assessed. Pts had to have FoundationOne Liquid performed ≤60 days prior to initiation of at least one line of therapy (LOT). Clinical characteristics and treatment history were obtained from deidentified, EHR data and linked to genomic data in the FH-Foundation Medicine Clinico-Genomic Database. Univariable and multivariable Cox proportional hazard models were utilized for rwOS comparisons indexed to LOT start, adjusted for LOT, age, and PSA, hemoglobin, alkaline phosphatase, albumin, and recent ECOG status when available. For one pt with two samples, the earlier one was used. Plasma ctDNA levels were quantified using a composite tumor fraction (cTF) measure based on aneuploidy and variant allele fraction (VAF), dichotomized at a previously reported threshold of 10% (Stover et al, JCO, 2018). Association of cTF with rwOS across common solid tumors was then explored in the FH-FMI CGDB for advanced breast cancer (BC), metastatic colorectal cancer (mCRC) and advanced non-small cell lung cancer (aNSCLC). Results: 78 mCRPC pts met criteria with 36 deaths to date. 15 (19%), 19 (24%), 17 (22%) and 27 (35%) samples were respectively obtained prior to first, second, third, or fourth mCRPC LOT, and median PSA was 85.1 ng/mL (IQR: 23.2 – 177). 69/78 (88%) were from community sites. cTF was ≥ 10% in 46/78 samples (60%) and was significantly associated with median PSA (115 vs. 27 ng/mL, p = 0.006) and elevated alk phos (52.2% vs. 12.5%, p < 0.001). Pts with ≥ 10% cTF had significantly worse rwOS (median 6.2 mo vs. not reached, HR: 9.9, 95% CI: 3.0 – 32.4, p < 0.001), which persisted in the multivariable Cox regression (HR: 9.4, 95% CI: 2.4 – 36.4, p = 0.001, n = 65, 13 missing clinical data). Preliminary results in other cancers, adjusted for LOT number only, were consistent with mCRPC; cTF ≥ 10% was associated with a worse rwOS in mBC (n=245, HR: 1.8 CI: 1.1 – 3.0), mCRC (n=107, HR: 2.1 CI: 1.1 – 4.3) and aNSCLC (n=432, HR: 1.8 CI: 1.3 – 2.5). Conclusions: Pretreatment ctDNA level is a prognostic factor in mCRPC in a real-world setting. With prospective validation, cTF may permit identification of high risk pts requiring more aggressive or investigational therapies. This phenomenon may not be unique to mCRPC and could offer similar insights in other cancer types.

Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Quantitative PCR (qPCR) was used to profile miRNAs in serum and/or plasma samples collected for the discovery, validation and performance phases, and next generation sequencing (NGS) analysis was applied to serum samples assigned to the candidate screening phase. Forty-one differentially expressed candidate miRNAs were identified in the sera of patients (p < 0.05, log2 fold change > 1). The validation cohort revealed that of those, 27 miRNAs were upregulated in plasma and three miRNAs were upregulated in sera (p < 0.05). Through binary logistic regression analyses, five plasma miRNAs (miR-192-5p, miR-193a-5p, miR-194-5p, miR-215-5p and miR-34a-5p) and three serum miRNAs (miR-192-5p, miR-194-5p and miR-34a-5p) were shown to robustly distinguish MNGIE from healthy controls. Reduced longitudinal miRNA expression of miR-34a-5p was observed in all four patients treated with EE-TP and coincided with biochemical and clinical improvements. We recommend the inclusion of the plasma exploratory miRNA biomarker panel in future clinical trials of investigational therapies for MNGIE; it may have prognostic value for assessing clinical status.