Role of Credit Access Program on the Performance of Women Owned MSES Incubated at KIRDI

Women owned Micro and Small Enterprises (MSEs) are a source of employment and wealth creation in most of the world economies and Kenya not an exemption. However, the survival rate of the women owned MSEs is minimal. The main objective of the study was to evaluate the role of credit access program on the performance of women owned MSEs which have been incubated at KIRDI. The study was a survey study design. The target population was 259 MSE women entrepreneurs who have graduated from KIRDI business incubation programs. The researcher did a census since it was appropriate for this study and used questionnaires to collect qualitative and quantitative data. The study analyzed data using descriptive and inferential statistics through Correlation and regression of variables. Results were reported through tables and figures. Statistical Package for Social Sciences (SPSS) was used to aid analysis of data. Data was analyzed and presented using descriptive and inferential statistics. The findings revealed a positive and significant relationship between credit access program and performance of women owned MSEs incubated by KIRDI (β=0.348, p=0.000). The study concluded that business incubation support programs simplified into incubator training and development, business development services, credit access program and technology absorption positively and significantly influenced the performance of women owned MSEs incubated at KIRDI in Nairobi. The study recommends that the government should consider looking towards setting a single window to manage business incubators all over the country and to coordinate the activities of all institutions and companies that are in the process of incubating new businesses. Keywords: Credit access, Women owned MSEs, Business performance, Business incubation, KIRDI

Experience of the nivolumab use in patients with metastatic renal cell carcinoma provided under the expanded access program in Russia. Subgroup analysis of the correlation between expression markers and the effectiveness of nivolumab therapy

Nivolumab was registered in Russia in December 2016 as a monotherapy for advanced renal cell carcinoma (RCC) and it remains a second‑line treatment choice for patients with disease progression after the use of tyrosine kinase inhibitors. Even though immunotherapy has already proven to be an effective approach for the treatment of RCC, predictive biomarkers for the rational selection of patients remain unidentified.Seventy‑five patients with metastatic renal cell carcinoma (mRCC) who received nivolumab in the 2nd and subsequent lines of therapy from 2015 to 2020 under the expanded access program were enrolled in this study. The objective response rate was 21,3 %. Median progression‑free survival (PFS) was 5,5 months. Median overall survival (OS) was not reached.To analyze molecular biomarkers correlated with the response to immunotherapeutic treatment, we performed whole‑transcriptome RNA sequencing of 16 samples (FFPE) in 15 patients with the assessment of the expression level for individual genes (PDCD1, CD274, CD8A, CD8B, CD4) and gene signatures (Angio, Teff, Myeloid Inflammation).Disease control rates were not different for the subgroups of patients with high and low expression of any of the signatures examined, and further principal component analysis did not reveal clustering of patients with and without objective response.Further studies on a larger sample of patients will help confirm or deny the predictive role of biomarkers selected for analysis in a heterogeneous population of RCC patients.

Artificial Neural Networks and Deep Learning for Genomic Prediction of Binary, Ordinal, and Mixed Outcomes

In this chapter, we provide the main elements for implementing deep neural networks in Keras for binary, categorical, and mixed outcomes under feedforward networks as well as the main practical issues involved in implementing deep learning models with binary response variables. The same practical issues are provided for implementing deep neural networks with categorical and count traits under a univariate framework. We follow with a detailed assessment of information for implementing multivariate deep learning models for continuous, binary, categorical, count, and mixed outcomes. In all the examples given, the data came from plant breeding experiments including genomic data. The training process for binary, ordinal, count, and multivariate outcomes is similar to fitting DNN models with univariate continuous outcomes, since once we have the data to be trained, we need to (a) define the DNN model in Keras, (b) configure and compile the model, (c) fit the model, and finally, (d) evaluate the prediction performance in the testing set. In the next section, we provide illustrative examples of training DNN for binary outcomes in Keras R (Chollet and Allaire, Deep learning with R. Manning Publications, Manning Early Access Program (MEA), 2017; Allaire and Chollet, Keras: R interface to Keras’, 2019).

Use of Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)—(Equine) (BAT®) in Clinical Study Subjects and Patients: A 15-Year Systematic Safety Review

Botulism is a rare, sometimes fatal paralytic illness caused by botulinum neurotoxins. BAT® (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)—(Equine)) is an equine-derived heptavalent botulinum antitoxin indicated for the treatment of symptomatic botulism in adult and pediatric patients. This review assesses the cumulative safety profile for BAT product from 2006 to 2020, using data received from clinical studies, an expanded-access program, a post-licensure registry, spontaneous and literature reports. The adverse event (AE) incidence rate for BAT product was calculated conservatively using only BAT product exposures for individuals with a record (512) and was alternatively estimated using all BAT product exposure data, including post-licensure deployment information (1128). The most frequently reported BAT product-related AEs occurring in greater than 1% of the 512–1128 BAT product-exposed individuals were hypersensitivity, pyrexia, tachycardia, bradycardia, anaphylaxis, and blood pressure increase reported in 2.3–5.1%, 1.8–3.9%, 1.0–2.2%, 0.89–2.0%, 0.62–1.4%, and 0.62–1.4%, respectively. For patients properly managed in an intensive care setting, the advantages of BAT product appear to outweigh potential risks in patients due to morbidity and mortality of botulism. AEs of special interest, including bradycardia, hemodynamic instability, hypersensitivity, serum sickness, and febrile reactions in the registry, were specifically solicited.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study

Background The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. Methods and findings Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician–principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had—or were at risk of progression to—severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. Conclusions These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. Trial registration ClinicalTrials.gov NCT#: NCT04338360.

Expanded Access Program: Evaluating Safety of Erythrocytes Encapsulating L-Asparaginase in Combination with Polychemotherapy in Patients Under 55 Years Old with Acute Lymphoblastic Leukaemia (ALL) at Risk to Receive Other Formulations of Asparaginase

Introduction Asparaginase is an important part of the treatment of acute lymphoblastic leukemia (ALL). Hypersensitivity is found in 16.8% of patients treated with pegylated asparaginase (PEG-asp). Hypersensitivity is the most common cause of truncated asparaginase therapy which has been associated with decreased event free survival. Asparaginase (ASNase) encapsulated in erythrocytes (eryaspase) is an alternative formulation of ASNase aiming to prolong the half-life of ASNase and to reduce toxicity e.g. hypersensitivity, since the erythrocyte membrane protects asparaginase against elimination and prevents activation of the immune system. In the NOR-GRASPALL 2016 trial eryaspase consistently demonstrated prolonged ASNase activity in patients who developed hypersensitivity reactions to PEG-asp. Treatment with eryaspase was well tolerated when combined with multiagent chemotherapy. The objective of this expanded access program was to explore the tolerability of eryaspase (150 U/Kg) combined with polychemotherapy in patients under 55 years of age with ALL, unable or at risk to receive any other available ASNase formulation. Patients in this study had developed hypersensitivities to prior E-Coli- and Erwinia-derived asparaginase therapies. Methods This was a non-randomized, multicentre, open label, Phase 1 study to assess the limiting toxicities, global safety and biological efficacy of eryaspase in combination with chemotherapy regimens. Patients were under 55 years of age with ALL de novo or in relapse or refractory; eligible for a chemotherapy treatment including ASNase; known contraindication and/or at risk of toxicity from other ASNase formulations. Eryaspase (150 U/Kg) was given as a replacement therapy for the remaining intended courses of asparaginase therapy. The number of courses was not defined and depended on therapeutic treatment chosen by the Investigator and the patient's response and tolerance. The primary endpoint was the exploration of the toxicity of eryaspase defined as the number and percent of patients presenting at least one limiting toxicity (LT) of eryaspase in combination with chemotherapy. Major secondary endpoints included: adverse events (AEs), pharmacokinetics (PK), pharmacodynamics (PD) and complete remission (CR) status at end of induction and survival status up to 12 months after inclusion. Results Eighteen patients enrolled of which seven (38.8%) patients experienced a total of 24 AE limiting toxicities, which were primarily bone marrow failure, and were indicative of the underlying ALL disease process and of the concomitant chemotherapy-related myelosuppression. All patients experienced at least one AE and Treatment Emergent (TEAE) and most (11 [61.1%] patients) experienced at least one SAE. A total of 17 (94.4%) patients experienced a TEAE of Grade 3 or above. No TEAEs led to withdrawal or dose reduction of eryaspase. Sparse whole blood ASNase concentrations following 150 U/Kg were within the range of concentrations expected for this dose level. At 14 days following the first infusion, the range of whole blood ASNase was 111 to 1160 U/Kg, which would be equivalent to the trough (nadir) for infusions every 2 weeks. Mean and median plasma asparagine (ASN) concentrations over time demonstrated a reduction by approximately 50% at 3 days post eryaspase infusion, followed by a slow return toward baseline before the next infusion of eryaspase. Seventeen (94.4%) patients achieved CR at least once overall. Fourteen (77.8%) patients were alive at the end of the study. Survival rate was 88.9% at 6 months and 77.8% at 12 and 18 months. Conclusion The AE profile of eryaspase was consistent with other studies and was as expected for this cohort of patients. Serious AEs were generally consistent with those that would be expected in this study population. A total of 17 patients in the study achieved a CR at least once overall and 14 were still alive at the end of the study. This study evaluated additional asparaginase therapy in double (and even triple) allergic patient population, who have received prior E-Coli- or Erwinia-derived asparaginase therapy. All patients achieved target asparaginase activity. Therefore, eryaspase provides an additional option for patients for whom further ASNase treatment is contraindicated due to toxicity and/or immunization. Disclosures Boissel: Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; CELGENE: Honoraria. Recher: Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Incyte: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. El-Hariry: Erytech: Current Employment, Current holder of stock options in a privately-held company.

The First Results of Asciminib Therapy in Highly Pretreated Chronic Myeloid Leukemia Patients Under the Managed Access Program (MAP) in Russian Federation

Background: The problem of resistance and intolerance to 2nd generation tyrosine kinase inhibitors (2G TKIs) in patients (pts) with chronic myeloid leukemia (CML) currently remains relevant. Ponatinib has demonstrated a high effectiveness and may be an option in CML pts with resistance or intolerance to available TKIs but the high incidence of vascular adverse events (AEs) limits its broad use. A STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor asciminib has demonstrated a superiority over bosutinib in CML pts previously treated with 2 or more TKIs (Phase III Study). Asciminib is available in Russia under the Managed Access Program (MAP) approved by Novartis. Aim: to present the first results of the use of asciminib in clinical practice under the MAP program in Russia. Methods: In total 46 CML pts from 3 Russian clinics were enrolled into the MAP program and received asciminib from September 2019 to June 2021 (1 pt started asciminib in a cinical trial and was transferred to MAP later). We analyzed therapy results of 32 pts who received asciminib for at least 3 months. Patient recruitment, dosing regimen, response monitoring, and toxicity control were performed according to the MAP treatment plan. Complete cytogenetic response (CCyR), major molecular response (MMR) and deep molecular response (MR4) rates were assessed by cumulative incident function (CIF). Differences between the subgroups were considered significant with p value ≤ 0.05 by the Gray's test. Results: Baseline characteristics: male: 41%; Меdian (Me) age 54 years (range 26-81); Me duration of CML before asciminib was 8 years (range 2-24); 23 pts were in chronic phase (CP) CML, 7 and 2 pts had a history of accelerated phase (AP) and blast crisis (BC), respectively, but were in a second CP at baseline. Nineteen (59%) pts had BCR-ABL mutations, 10 pts (31%) had BCR-ABLt315i clones, 7 (22%) pts had at least two mutations. Eight (25%) pts had additional chromosomal abnormalities (ACAs). Twenty one (66%) pts received ≥4 TKIs, 14 (44%) pts had a history of ponatinib treatment. Me duration of asciminib treatment at the time of analysis was 7 months (range 4-24), 4 (12.5%) pts discontinued asciminib due to lack of efficacy; all pts were alive. The initial asciminib dose was 40 BID in 22 (69%) pts and 200 mg BID in 10 (31%) pts. CCyR, MMR and MR4 at the time of analysis was achieved in 32% (8/25), 34% (10/29) and 17% (5/30) pts, respectively (considering pts without this kind of response at baseline). The 6 month CIF of CCyR, MMR and MR4 was 27%, 24% and 19%, respectively. Univariate analysis was performed in 29 pts without MMR at baseline evaluating the following factors of 6 month MMR achievement: initial dose of asciminib, CML phase, presence of BCR-ABL mutations and ACAs, best molecular response on previous TKIs, molecular response at the time of asciminib starting, history of ponatinib treatment, number of TKIs and duration of TKI therapy before asciminib. The duration and number of TKIs, the history of advanced phases, BCR-ABL kinase domain mutations and ACAs did not significantly effect on MMR rate (tab.1). BCR-ABL&lt;1% on previous TKIs (54% vs 0%, p=0.0008, hazard ratio 20.9 (2.6-170)) and BCR-ABL&lt;10% at the time of asciminib start (44% vs 15%, p=0.035, hazard ratio 3.8 (1.05-13.6)) were found as a predictive factors for MMR at 6 month. Fourteen (44%) of 32 pts had AEs of any grade and 7 (22%) had AEs of grade 3-4 (hematological AEs -6 (19%), non-hematological AE- 1 (3%)) (tab.2). Conclusion: Asciminib has shown promising efficacy and a good toxicity profile in a cohort of highly pre-treated CML pts and should be considered as a therapeutic option for CML pts resistant or intolerant to other TKIs. Figure 1 Figure 1. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Chelysheva: Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau.

Comparison of Salvage Autologous Hematopoietic Cell Transplantation with Outcomes Following Selinexor Combinations Among Double/Triple Refractory Myeloma Patients

Introduction: A vast majority of multiple myeloma (MM) patients requires subsequent lines of therapy following relapses. The choice of regimen following relapse is influenced by response, tolerance to prior therapies, as well as by disease and patient features. Treatment options are limited for those who develop triple-class refractory disease. In this setting, the role of a salvage autologous stem cell transplantation (sAHCT) is controversial. This unmet need has driven the development of new therapies with novel mechanisms of action. Selinexor, an oral selective inhibitor of nuclear export (SINE) compound, was recently approved by the FDA and EMA for use in heavily pretreated relapse refractory (RRMM) patients, including triple-class refractory RRMM and FDA has also approved the agent in patients with first relapse. In the absence of head-to-head studies, comparison of treatment options among triple-class treated patients is based on real world experience. Here we performed a retrospective comparison between outcomes following sAHCT versus Selinexor combinations administered among RRMMs. Patients & Methods: Between January 2015 and April 2021, 22 patients at our center underwent sAHCT for treatment of refractory relapse. A transplant was defined as salvage if the patient had already received one prior AHCT and underwent a further AHCT after evidence of disease progression not responding to second generation proteasome inhibitors (PI), İmmunomodulating agents (IMID) or antiCD38 monoclonal antibody. We compared the outcomes of these patients with 10 RRMM patients who had exhausted their treatment options and were progressing on their last line of therapy to receive Selinexor, dexamethasone in combination with either bortezomib (n=7) (XVd) or carfilzomib (n=3) (XCd) as a part of a Karyopharm Expanded Access Program (KEAP). Selinexor was administered 80-100 mg po weekly in combination. Response and disease progression were assessed according to the IMWG criteria. Results: Patients' characteristics and the outcome of treatments are shown in Table. The median age of patients was similar in both groups. Patients were heavily treated with a median of 6 prior lines of therapy (4-9) and 2 out of 10 carried high-risk cytogenetics in SVd group. Seven (31.8%) patients with high-risk cytogenetics underwent sAHCT. All patients were treated with or refractory to immunomodulators and proteasome inhibitors. Five patients responded to DCEP bridging therapy prior to sAHCT. Five patients received Selinexor after sAHCT. One patient underwent sAHCT due to progression under Selinexor treatment. In sAHCT group, 68.2% of patients relapsed within a median of 6.3 months (Figure-1). Figure-2 shows the impact of the prior lines of therapy and selinoxor on PFS.Adverse events on selinexor regimens included fatigue, nausea, thrombocytopenia which were managed with Selinexor dose adjustment and supportive care. Two patients eventually transitioned to new therapies, while 4 still remain on SVd due to continued response. Conclusion: Our results based on a small number of patients, compared with outcomes post sAHCT reflects comparable duration of response and disease control rates with Selinexor-PI regimens among selected patients. Hospitalization and prolonged infusions are not required with the selinexor regimens, and prolonged treatment is possible with advance in lines of therapy duration of response lessens with any treatment modality. Despite of a DCEP bridging therapy prior to sAHCT, Selinexor combos have achieved similar PFS even among triple class refractory MM patients. For countries where CAR-T therapies are not accessible, sAHCT and Selinexor combinations may be considered as a valid clinical option after failing CD38 monoclonal antibodies, PI and IMIDs. These data support the use of selinexor-based regimens in the treatment of relapsed MM, and given the potency of the combinations, in earlier lines of therapy including in patients who have received anti-CD38 mAbs. Figure 1 Figure 1. Disclosures Kashyap: Karyopharm: Current Employment. Niblock: Karyopharm: Current Employment. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. OffLabel Disclosure: Selinexor has not been approved for myeloma patients in Turkey. It could be used as a part of Karyopharm Expanded Access program (KEAP).