Lack Of Efficacy Research Articles

Safety and Efficacy of Fedratinib in Patients with Primary (P), Post-Polycythemia Vera (Post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) Previously Treated with Ruxolitinib: Primary Analysis of the FREEDOM Trial

Introduction: Fedratinib is an oral selective Janus kinase (JAK) 2 inhibitor approved for treatment (tx) of patients (pts) with MF, including those previously treated with ruxolitinib (RUX). In the single-arm phase 2 JAKARTA2 trial (NCT01523171), fedratinib 400 mg once daily improved spleen volume and MF symptom burden in pts with MF resistant/intolerant to prior RUX (Harrison et al. Am J Hematol 2020). Long-term data are lacking due to early termination. The ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518) further evaluates the safety and efficacy of fedratinib in pts with MF previously treated with RUX and includes proactive strategies to mitigate gastrointestinal (GI) adverse events (AEs), thiamine level decreases, and potential encephalopathy (including Wernicke's encephalopathy [WE]). Methods: Eligible pts aged ≥ 18 years with PMF, post-PV MF, or post-ET MF with ≥ 3 months prior tx with RUX were enrolled in the study. Pts were required to have Dynamic International Prognostic Scoring System (DIPSS) intermediate- or high-risk MF, Eastern Cooperative Oncology Group performance status ≤ 2 and baseline platelet count ≥ 50 x 109/L. Pts were treated with fedratinib 400 mg once daily in continuous 28-day cycles until lack of efficacy, intolerance, or disease progression, and followed for 12 months after end of tx (EOT). AE mitigation strategies included prophylactic use of antiemetics and symptomatic use of antidiarrheals, thiamine supplementation, surveillance for encephalopathy, and adjusting preferred time of day for fedratinib administration. Results: Thirty-eight pts were enrolled and treated. Due to accrual challenges during the COVID-19 pandemic, the study was capped early, and data lost statistical power due to reduced sample size. At the database cutoff (November 29, 2021), median tx duration was 38 weeks, 13 pts had tx ongoing, and 25 pts had discontinued tx. At baseline, median age was 68.5 years, 23 (60.5%) pts had a diagnosis of PMF, 9 (23.7%) post-PV MF, and 6 (15.8%) post-ET MF, with DIPSS assessment of intermediate-1 risk in 13 (34.2%) pts, intermediate-2 risk in 18 (47.4%) pts, and high risk in 7 (18.4%) pts. Baseline median spleen volume was 1831.6 mL. A total of 9/35 (25.7%) evaluable pts met the primary endpoint of ≥ 35% spleen volume reduction (SVR) by magnetic resonance imaging/computed tomography at end of cycle (EOC) 6; 13 (37.1%) pts had ≥ 35% SVR when missing EOC6 assessments were imputed with last observation carried forward (LOCF) method (Table). In addition, 9 (25.7%) pts achieved a ≥ 35% SVR before or after EOC6, for a best overall response of ≥ 35% SVR in 22 (62.9%) pts up to end of tx. With a ≥ 25% SVR threshold, 24 (68.6%) pts had a response with LOCF at EOC6. Of ≥ 35% SVR responders, 19/22 (86.4%) maintained durable response at data cutoff (Figure). In secondary endpoints, 21/36 (58.3%) and 16/36 (44.4%) evaluable pts showed ≥ 50% reduction in total symptom score (TSS) at EOC3 and EOC6, respectively. A total of 34/38 (89.5%) pts had 1 tx-emergent AE related to study medication; 3 (7.9%) were serious AEs. Anemia and thrombocytopenia were reported in 23 (60.5%) and 13 (34.2%) pts, respectively. GI AEs were reported in 34 (89.5%) pts, with nausea, vomiting, and diarrhea reported in 15 (39.5%), 7 (18.4%), and 15 (39.5%) pts, respectively. Most GI AEs were grade 1/2 and occurred during cycle 1, and decreased in the subsequent cycles. Grade 1/2 decreases in thiamine levels were reported in 6 pts after initial tx; all instances were treated and resolved at next assessment. No pts required tx discontinuation due to low thiamine levels. There were no cases of WE reported. There were 2 deaths during tx and 7 during follow-up; none were related to study medication. Conclusions: Clinically relevant and durable spleen and symptom responses were observed in FREEDOM study participants, with a majority of responders showing durable SVR at data cutoff. This supports the use of fedratinib in pts with MF previously treated with RUX. One limitation of the study was small pt sample size. In this first fedratinib study proactively assessing a GI mitigation strategy and thiamine monitoring, results showed GI AEs were easily mitigated and no WE was reported. Study support: This study was supported by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Bosutinib Vs Imatinib By Charlson Comorbidity Index in Newly Diagnosed Patients with Chronic Myeloid Leukemia

Introduction: The efficacy and safety of bosutinib (BOS) vs imatinib (IMA) in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) was assessed in the phase 3 BFORE trial (NCT02130557) after 5 years of follow-up (Brümmendorfet al., J Clin Oncol, 2022). Here we analyze the impact of comorbidities on efficacy and safety, reporting the results by Charlson Comorbidity Index (CCI) score. Methods: Patients with newly diagnosed CP CML were randomized 1:1 to receive BOS or IMA (starting dose: 400 mg QD). Outcomes were assessed after 5 years (240 weeks) of follow-up (database lock: June 12, 2020) according to the CCI score without the age component (mCCI). Patients were grouped by mCCI scores of 2 (BOS, n=195; IMA, n=196 [2 untreated]) and >2 (BOS, n=73; IMA, n=72 [1 untreated]). Efficacy was assessed in all randomized patients (intent-to-treat population) and safety in patients who received >1 dose of study medication (safety population). Results: In patients with mCCI 2 and >2, the median treatment duration was 55.1 and 53.4 months with BOS vs 55.0 and 55.1 months with IMA; respective median (range) dose intensity was 396.4 (39−583) and 367.2 (74−573) mg/day with BOS vs 400.0 (240−765) and 400.0 (189−754) mg/day with IMA. Permanent treatment discontinuations in patients with mCCI 2 and >2, respectively, were reported in 36.4% and 50.7% of patients with BOS vs 45.4% and 32.4% of patients with IMA. The most common primary reasons for permanent discontinuation were adverse events (AEs) in the BOS arm (BOS: mCCI 2, 21.0%; mCCI >2, 35.6%; IMA: mCCI 2, 13.9%; mCCI >2, 8.5%) and lack of efficacy (suboptimal response, treatment failure, or disease progression) in the IMA arm (BOS: mCCI 2, 6.7%; mCCI >2, 2.7%; IMA: mCCI 2, 20.6%; mCCI >2, 9.9%). In both treatment arms, the majority of permanent discontinuations due to AEs occurred in year 1 (BOS: mCCI 2, 11.3%; mCCI >2, 20.5%; IMA: mCCI 2, 7.7%; mCCI >2, 5.6%). Among patients with mCCI 2 and >2, respectively, the proportion who achieved an early molecular response (BCR::ABL1 ≤10% at 3 months) was 79.4% and 83.8% with BOS vs 56.5% and 71.0% with IMA (Table 1). Cumulative response rates according to mCCI score and treatment arm are shown in the Table 1. There were 14 deaths during the study period in both the BOS- (mCCI 2, n=7; mCCI >2, n=7) and IMA (mCCI 2, n=9; mCCI >2, n=5) arms; 3 and 4 deaths, respectively, were assessed by investigators as CML-related (all in patients with mCCI 2). Treatment-emergent AEs (TEAEs) occurred in ≥98.5% of patients in each treatment arm and across CCI subgroups. In patient with CCI 2 and >2, respectively, the most common (≥30% in either subgroup) TEAEs with BOS were diarrhea (79.5% and 63.0%), thrombocytopenia (37.4% and 31.5%), nausea (35.9% and 41.1%), increased alanine aminotransferase ([ALT] 34.4% and 31.5%), and fatigue (17.9% and 30.1%). Most common TEAEs with IMA were diarrhea (37.1% and 49.3%), nausea (41.2% and 45.1%), muscle spasms (33.0% and 23.9%), and anemia (17.5% and 36.6%). Among patients with CCI 2 and >2, respectively, grade 3/4 TEAEs were observed in 69.2% and 84.9% with BOS vs 55.2% and 62.0% with IMA. The most frequently reported grade 3/4 TEAEs are shown in Table 2. TEAEs resulting in death in the BOS arm (n=3) were acute cardiac failure, myocardial ischemia, and renal failure (all in patients with CCI >2). TEAEs leading to death in the IMA arm (n=4) were sepsis and CML in patients with CCI 2, and pneumonia and cerebrovascular accident in patients with CCI >2. Conclusions: After 5 years of follow-up in the BFORE study, a substantial proportion of patients across mCCI scores achieved molecular responses with BOS or IMA. In the BOS arm, there was a trend toward a higher rate (>10% difference) of MR4 in patients with CCI 2 vs CCI >2, with a similar proportion of patients achieving MMR and MR4.5 in both subgroups. Molecular response rates by 60 months were higher with BOS vs IMA in patients with CCI 2 and similar in patients with CCI >2. Safety data were consistent with the known safety profiles of BOS and IMA. Discontinuations due to AEs were higher (>10% difference) in patients with CCI >2 in the bosutinib arm and similar across CCI groups in the imatinib arm. However, in both treatment arms, there were no relevant differences in the frequency of TEAEs across the most commonly occurring AEs between patients with CCI 2 and CCI >2. These results support the use of 400 mg once daily BOS in patients with newly diagnosed CP CML irrespective of baseline comorbidities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

T Cells Expressing a Fully-Human Anti-BCMA Chimeric Antigen Receptor with a Heavy-Chain-Only Antigen-Recognition Domain Exhibit Rapid and Durable Activity Against Multiple Myeloma

Chimeric antigen receptor (CAR)-expressing T cells targeting B-cell maturation antigen (BCMA) are effective multiple myeloma therapy, but improvement in durability of responses is needed. We incorporated a fully-human heavy-chain-only anti-BCMA binding domain (FHVH33) into a CAR. Since it is only a heavy chain domain with no linker or artificial junctions, FHVH33 should be less immunogenic than a scFv. The CAR containing FHVH33 is called FHVH33-CD8BBZ. FHVH33-CD8BBZ contains CD8α hinge and transmembrane domains, a 4-1BB domain, and a CD3ζ domain; it was encoded by a γ-retroviral vector (Lam et al. Nature Communications 2020). T cells expressing FHVH33-CD8BBZ (FHVH-T) were produced from unsorted blood mononuclear cells in 7 days. Twenty-five patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine on days -5 to -3 followed by infusion of FHVH-T on day 0. Five dose levels were assessed, and 6x106 CAR+ T cells/kg was selected for an expansion cohort based on efficacy and manufacturing factors (Table). Patients had received a median of 6 lines of therapy (range 3 to 10) prior to enrollment. Twenty-three of 25 patients (92%) obtained partial response (PR) or better. Eighteen patients (72%) attained best responses of stringent complete response (sCR) or very good partial response (VGPR). Median progression-free survival (PFS) of all treated patients is 65 weeks to date; eleven patients have ongoing responses. One striking feature of the anti-myeloma activity of FHVH-T was the rapidity of myeloma elimination. Some myeloma markers including serum free light chains, urine monoclonal light chains, and bone marrow plasma cells decrease rapidly after any type of effective therapy while intact immunoglobulin monoclonal proteins decrease slowly due to long serum half-lives, which are 20-25 days for most types of IgG. Following rapidly changing myeloma markers such as free light chains shows the actual tempo of myeloma elimination without the confounding factor of long serum half-lives of intact immunoglobulins. Among the 12 patients with rapidly changing main myeloma markers, most anti-myeloma activity occurred within the first month after FHVH-T infusion since myeloma markers underwent a 99-100% reduction in all 12 patients by 1 month after FHVH-T infusion. In 10/12 patients with rapidly changing main myeloma markers, a 99-100% decrease had occurred by 14 days after FHVH-T infusion. We assessed FHVH-33 T early after infusion during the time of most anti-myeloma activity. Blood CAR+ cell levels were assessed by quantitative PCR (qPCR). The median peak blood CAR+ cell number was 121 (range 3 to 3414) cells/μL. Peak CAR+ cell levels occurred a median of 12 (range 7 to 15) days after FHVH-T infusion. One month after infusion, the median blood CAR+ cell number was 11 (range 0 to 305) cells/μL. Median blood CAR+ cell levels one month after infusion were 20 cells/μL in patients with a PFS of 12 months or more versus 4 cells/μL in patients with PFS less than 12 months (P=0.0273). The CD4/CD8 ratio of CAR+ T cells decreased from the time of infusion until the time of peak blood CAR+ cells (P=0.0004). From the time of infusion until the time of peak blood CAR+ cells, there was an increase the percentage of T cells with an effector memory phenotype (C-C-chemokine receptor-7 (CCR7)-negative and CD45RA-negative), (P<0.001). Expression of CCR7 on infusion CD4+ FHVH-T correlated with peak CAR+ cell level (P=0.0018). Frequency of infusion CD4+ FHVH-T with a central memory phenotype (CCR7+, CD45RA-negative) correlated with peak and 1-month post-infusion CAR+ cell levels. Peak interferon (IFN)γ and interleukin (IL)-6 levels were associated with Grade 3 or 4 CRS (P=0.0034). Peak serum levels of IFNγ, IL2, IL6, IL8, IL10, and IL15 were higher (P<0.003 for all) in patients with neurologic toxicity. Single-cell RNA sequencing revealed extensive changes in FHVH-T gene expression between infusion and the time of peak blood CAR+ cell levels. Surprisingly, humoral immune responses against the fully-human CAR expressed by FHVH-T were detected in 4/12 evaluated patients after one FHVH-T infusion. In one patient who received 2 FHVH-T treatments, a humoral anti-CAR response was associated with lack of efficacy and absence of blood FHVH-T. FHVH-T therapy led to durable responses with most anti-myeloma activity occurring within 14 days after FHVH-T infusion. Blood levels of FHVH-T correlated with CD4+CCR7+ infusion cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Psychotropic medicines are frequently dosed outside recommended ranges: a clinical audit in an Australian mental health hospital

AbstractBackgroundCompliance with psychotropic dosage guidelines has been shown to improve mental health status, reduce severity of symptoms, and decrease adverse effects. However, guideline recommendations are not always implemented. While deviation from dosage recommendations may be clinically appropriate in some patients, variation can cause a lack of efficacy or patient harm.AimTo evaluate the incidence of antidepressant and antipsychotic prescribing at doses outside the recommended range provided by local guidelines, Therapeutic Guidelines: Psychotropic.MethodThis study is a retrospective clinical audit of 793 patients admitted to hospital between August 2018 and July 2019. Data were collected through extensive file and chart reviews of patients treated with any of the antidepressant and antipsychotic medications listed in the Psychotropic Dosage Guidelines. Descriptive statistical analyses were performed to determine frequencies and proportions.ResultsThe audit identified that 38.0% of patients received doses of antidepressants or antipsychotics outside the recommended range. Most antidepressants were prescribed within recommended doses (83.0%), with 10.5% above the recommended dose, and 6.2% below. Fewer antipsychotics were prescribed within the recommended range (56.8%), 2.8% were prescribed at doses above the recommended range, and 40.3% were prescribed at doses below the recommendation range. Quetiapine was frequently prescribed at doses lower than recommended.ConclusionThe audit revealed a substantial amount of prescribing outside the recommended dosage ranges. It also highlighted the necessity of reviewing policies to limit the use of off‐label, low‐dose quetiapine. Audit and feedback could target psychiatrists who seem to have the highest propensity to prescribe outside the recommended dosage ranges.

Generation of NK cells with chimeric-switch receptors to overcome PD1-mediated inhibition in cancer immunotherapy

Multiple myeloma (MM) is an incurable hematological cancer, in which immune checkpoint inhibition (ICI) with monoclonal antibodies (mAbs) has failed due to uncontrollable immune responses in combination therapies and lack of efficacy in monotherapies. Although NK cell-specific checkpoint targets such as NKG2A and KIRs are currently being evaluated in clinical trials, the clinical impact of NK cells on the PD1 cascade is less well understood compared to T cells. Furthermore, while NK cells have effector activity within the TME, under continuous ligand exposure, NK cell dysfunctionality may occur due to interaction of PD1 and its ligand PD-L1. Due to above-mentioned factors, we designed novel NK cell specific PD1-based chimeric switch receptors (PD1-CSR) by employing signaling domains of DAP10, DAP12 and CD3ζ to revert NK cell inhibition and retarget ICI. PD1-CSR modified NK cells showed increased degranulation, cytokine secretion and cytotoxicity upon recognition of PD-L1+ target cells. Additionally, PD1-CSR+ NK cells infiltrated and killed tumor spheroids. While primary NK cells (pNK), expressing native PD1, showed decreased degranulation and cytokine production against PD-L1+ target cells by twofold, PD1-CSR+ pNK cells demonstrated increased activity upon PD-L1+ target cell recognition and enhanced antibody-dependent cellular cytotoxicity. PD1-CSR+ pNK cells from patients with MM increased degranulation and cytokine expression against autologous CD138+PD-L1+ malignant plasma cells. Taken together, the present results demonstrate that PD1-CSR+ NK cells enhance and sustain potent anti-tumor activity in a PD-L1+ microenvironment and thus represent a promising strategy to advance adoptive NK cell-based immunotherapies toward PD-L1+ cancers.

BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion.

Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1, encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]-expressing CD8+ CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]-expressing CD8+ T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)-driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3+CD8+ and toward TCF1+CD8+ to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.

Preclinical testing of dabigatran in trypsin-dependent pancreatitis.

Pancreatitis, the inflammatory disorder of the pancreas, has no specific therapy. Genetic, biochemical, and animal model studies revealed that trypsin plays a central role in the onset and progression of pancreatitis. Here, we performed biochemical and preclinical mouse experiments to offer proof of concept that orally administered dabigatran etexilate can inhibit pancreatic trypsins and shows therapeutic efficacy in trypsin-dependent pancreatitis. We found that dabigatran competitively inhibited all human and mouse trypsin isoforms (Ki range 10-79 nM) and dabigatran plasma concentrations in mice given oral dabigatran etexilate well exceeded the Ki of trypsin inhibition. In the T7K24R trypsinogen mutant mouse model, a single oral gavage of dabigatran etexilate was effective against cerulein-induced progressive pancreatitis, with a high degree of histological normalization. In contrast, spontaneous pancreatitis in T7D23A mice, which carry a more aggressive trypsinogen mutation, was not ameliorated by dabigatran etexilate, given either as daily gavages or by mixing it with solid chow. Taken together, our observations showed that benzamidine derivatives such as dabigatran are potent trypsin inhibitors and show therapeutic activity against trypsin-dependent pancreatitis in T7K24R mice. Lack of efficacy in T7D23A mice is probably related to the more severe pathology and insufficient drug concentrations in the pancreas.

Cost-effectiveness of Empagliflozin in Patients With Heart Failure With Preserved Ejection Fraction

In the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved), empagliflozin significantly reduced hospitalizations for heart failure while improving patient-reported health status compared with placebo. The long-term cost-effectiveness of empagliflozin among patients who have heart failure with preserved ejection fraction (HFpEF) remains unclear. To estimate the cost-effectiveness of empagliflozin in patients with HFpEF. This cost-effectiveness analysis performed from October 2021 to April 2022 included a Markov model using estimates of treatment efficacy, event probabilities, and utilities from EMPEROR-Preserved and published literature. Costs were derived from national surveys and pricing data sets. Quality of life was imputed from a heart failure-specific quality-of-life measure. Two analyses were performed, with and without a treatment effect on cardiovascular mortality. Subgroup analyses were based on diabetes status, ejection fraction, and health status impairment due to heart failure. The model reproduced the event rates and risk reduction with empagliflozin observed in EMPEROR-Preserved over 26 months of follow-up; future projections extended across the lifetime of patients. Empagliflozin or standard of care. Hospitalizations for heart failure, life-years, quality-adjusted life-years (QALYs), lifetime costs, and lifetime incremental cost-effectiveness ratio. A total of 5988 patients were included in the analysis, with a mean age of 72 years, New York Heart Association class II to IV heart failure, and left ventricular ejection fraction greater than 40%. At the Federal Supply Schedule price of $327 per month, empagliflozin yielded 0.06 additional QALYs and $26 257 incremental costs compared with standard of care, producing a cost per QALY gained of $437 442. Incremental costs consisted of total drug costs of $29 586 and savings of $3329 from reduced hospitalizations for heart failure. Cost-effectiveness was similar across subgroups. The results were most sensitive to the monthly cost, quality-of-life benefit, and mortality effect of empagliflozin. A price reduction to $153 per month, incremental utility of 0.02, or 8% reduction in cardiovascular mortality would bring empagliflozin to $180 000 per QALY gained, the threshold for intermediate value. Using Medicare Part D monthly pricing of $375 after rebates and $511 before rebates, empagliflozin would remain low value at $509 636 and $710 825 per QALY gained, respectively. Cost-effectiveness estimates were robust to variation in the frequency and disutility of heart failure hospitalizations. In this economic evaluation, based on current cost-effectiveness benchmarks, empagliflozin provides low economic value compared with standard of care for HFpEF, largely due to its lack of efficacy on mortality and small benefit on quality of life.

Discontinuation Rates of Tadalafil Alone and in Combination with a-Blockers in the Treatment of Male Lower Urinary Tract Symptoms with or without Coexisting Erectile Dysfunction: A Systematic Review and Meta-Analysis.

We examined the discontinuation rates of tadalafil alone and in combination with a-blockers (ABs) for the treatment of male lower urinary tract symptoms (LUTS), with or without erectile dysfunction (ED). We searched the EMBASE, PubMed, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases for studies published until May 15, 2022. The discontinuation rates associated with LUTS medications were subsequently analyzed by meta-analysis. Forty-four studies, including 1724 discontinued patients, were included. The combined discontinuation rate was 12.78% (95% confidence interval (CI) 9.89-15.98%), and the discontinuation rates because of adverse events and lack of efficacy were 4.56% (95% CI 3.39-5.90%) and 3.30% (95% CI 1.53-5.72%), respectively. The discontinuation rate of tadalafil alone or in combination with ABs for LUTS with or without ED was relatively low and varied according to the study type. Patients receiving monotherapy or combination therapy were similarly likely to abandon treatment. Treatment with a fixed-dose combination was associated with better persistence than with a free-dose combination. These data may help guide clinicians in selecting drug regimens when making decisions. Factors associated with treatment withdrawal need to be determined through high-quality clinical studies to reduce the drug discontinuation rate, which will ultimately reduce healthcare costs and improve patient outcomes.

PMON64 Economic Burden of Growth Hormone Deficiency in a US Adult Population

Abstract Background Growth hormone deficiency (GHD) is a rare disorder currently treated in adults with daily injections of somatropin. Adults with GHD have a diminished quality of life, central adiposity, which may put them at risk for metabolic syndrome and cardiovascular disease, and decreased bone mineral density. Treatment of adults with GHD is associated with improvement in metabolic impairment and quality of life. Poor adherence to or lack of treatment with somatropin is associated with reduced or lack of efficacy and increased costs. This study analyzed healthcare costs and daily somatropin use among adults with GHD who had Medicaid or commercial health insurance in the US. Methods Adult patients with a GHD diagnosis between January 1, 2008, and December 31, 2017 were identified in the IBM Marketscan Medicaid and Commercial Databases (index date = first diagnosis). Patients with GHD were directly matched (1: 3) to controls without GHD (or other short stature-related disorder) on age, gender, plan type, region, and race (Medicaid only). Baseline comorbidities and medications were measured during the 12 months pre-index. All-cause and GHD-related healthcare costs and somatropin use were measured during the variable follow-up period. Results The 2,579 Medicaid and 24,373 commercial patients with GHD who met the study inclusion criteria were matched to 7,728 Medicaid and 73,119 commercial controls. Little variation was observed between the demographic makeup of adult patients with and without GHD, demonstrating effective matching. Participants were evenly split between male and female. Median age at index was 37 years for Medicaid patients and 48 years for commercial patients. Mean follow-up time was 41 and 31 months for Medicaid patients and controls, and 35 and 37 months for commercial patients and controls, respectively. Compared to controls, GHD patients were disproportionately affected by comorbidities, including endocrine conditions (&amp;gt;68% in GHD cases vs. ≤10% in controls), metabolic conditions (&amp;gt;93% in GHD cases vs. ≤39% in controls), hepatic and renal function conditions (18-23% in GHD cases vs. &amp;lt;10% in controls), and cardiovascular disease (41-53% in GHD cases vs. &amp;lt;29% in controls), and were disproportionately treated with concomitant medications. Mean annual all-cause healthcare costs were 4.6 times greater ($42,309 vs. $9,146) for Medicaid GHD patients than controls and 4.1 times greater ($30,111 vs. $7,376) for commercial GHD patients than controls. For Medicaid GHD patients, inpatient costs were a primary driver ($22,385 vs. $3,494 for controls), while outpatient costs made up the largest proportion for commercial patients ($13,083 vs. $4,057 for controls). Few patients were treated with somatropin therapy in both Medicaid (5.8%) and commercial (9.5%) GHD cohorts. Conclusion Adult patients with GHD experience a substantial comorbidity and economic burden compared to non-GHD controls. Adult GHD remains primarily untreated and presents a significant healthcare burden. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy

AimTo evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP). MethodsThis was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. ResultsOne hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together. ConclusionsCannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.

Nanotherapeutics Plus Immunotherapy in Oncology: Who Brings What to the Table?

While the number of oncology-related nanotherapeutics and immunotherapies is constantly increasing, cancer patients still suffer from a lack of efficacy and treatment resistance. Among the investigated strategies, patient selection and combinations appear to be of great hope. This review will focus on combining nanotherapeutics and immunotherapies together, how they can dually optimize each other to face such limits, bringing us into a new field called nano-immunotherapy. While looking at current clinical trials, we will expose how passive immunotherapies, such as antibodies and ADCs, can boost nanoparticle tumor uptake and tumor cell internalization. Conversely, we will study how immunotherapies can benefit from nanotherapeutics which can optimize their lipophilicity, permeability, and distribution (e.g., greater tumor uptake, BBB crossing, etc.), tumor, tumor microenvironment, and immune system targeting properties.

Biosensor integrated tissue chips and their applications on Earth and in space

The development of space exploration technologies has positively impacted everyday life on Earth in terms of communication, environmental, social, and economic perspectives. The human body constantly fluctuates during spaceflight, even for a short-term mission. Unfortunately, technology is evolving faster than humans’ ability to adapt, and many therapeutics entering clinical trials fail even after being subjected to vigorous in vivo testing due to toxicity and lack of efficacy. Therefore, tissue chips (also mentioned as organ-on-a-chip) with biosensors are being developed to compensate for the lack of relevant models to help improve the drug development process. There has been a push to monitor cell and tissue functions, based on their biological signals and utilize the integration of biosensors into tissue chips in space to monitor and assess cell microenvironment in real-time. With the collaboration between the Center for the Advancement of Science in Space (CASIS), the National Aeronautics and Space Administration (NASA) and other partners, they are providing the opportunities to study the effects of microgravity environment has on the human body. Institutions such as the National Institute of Health (NIH) and National Science Foundation (NSF) are partnering with CASIS and NASA to utilize tissue chips onboard the International Space Station (ISS). This article reviews the endless benefits of space technology, the development of integrated biosensors in tissue chips and their applications to better understand human biology, physiology, and diseases in space and on Earth, followed by future perspectives of tissue chip applications on Earth and in space.

Antipsychotic Monotherapy for Major Depressive Disorder: A Systematic Review and Meta-Analysis.

Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.

Manufacturing processes of peanut (Arachis hypogaea) allergen powder-dnfp.

BackgroundImportant components of drug safety, efficacy, and acceptability involve manufacturing and testing of the drug substance and drug product. Peanut flour sourcing/processing and manufacturing processes may affect final drug product allergen potency and contamination level, possibly impacting drug safety, quality, and efficacy. We describe key steps in the manufacturing processes of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Palforzia®), a drug used in oral immunotherapy (OIT) for the treatment of peanut allergy.MethodsEstablished criteria for source material must be met for manufacturing PTAH drug product. Degree of roasting was determined with a Hunter colorimeter. Protein/allergen content, identity, potency, safety, and quality of each batch of PTAH drug substance were assessed with a combustion analyzer, allergen-specific Western blot (immunoblotting), ELISA, and HPLC. Contaminants (ie, aflatoxin) were measured by UPLC.ResultsRoasting degree beyond “light roast” was associated with variable degrees of protein allergen degradation, or potentially aggregation. Relative potency and amounts of protein allergens showed variability due in part to seasonal/manufacturing variability. Proportion of lots not meeting aflatoxin limits has increased in recent years. Up to 60% of peanut flour source material failed to meet screening selection acceptance criteria for proceeding to drug substance testing, mostly because of failure to meet potency acceptance criteria. Other lots were rejected due to safety (ie, aflatoxin) and quality. Influence of potency variation, within specification parameters, on safety/tolerability observed in trials was considered low, in part due to stringent controls placed at each step of manufacturing.ConclusionsExtensive variability in allergen potency is a critical issue during immunotherapy, particularly during OIT initial dose escalation and up-dosing, as it may result in lack of efficacy or avoidable adverse allergic reactions. Based on EU and US regulatory requirements, the production of PTAH includes manufacturing controls to ensure drug product safety, potency, and quality. For example, although PTAH contains all peanut allergens, each lot has met strict criteria ensuring consistent allergenic potency of Ara h 1, Ara h 2, and Ara h 6. The rigor of PTAH's manufacturing process ensures reliable dose consistency and stability throughout its shelf life.

Apremilast and biologics: Characteristics of patients treated with apremilast before, during, or after a biological treatment.

Apremilast is an oral small molecule approved for the treatment of psoriasis, psoriatic arthritis and oral ulcers associated with Behçet's disease. This research was conducted to describe the characteristics of patients who received treatment with apremilast for a skin disorder, either before, during, or after a biological treatment, with the aim of analyze the reasons that lead to start this drug in real clinical practice or suspend it for another. A total of 41 patients were enrolled: nine (22.0%) had received biological treatment prior to apremilast, seven (17.0%) both before and after apremilast and 25 (61.0%) after apremilast. One patient received concomitant treatment with adalimumab and apremilast. Most patients (85.4%) received apremilast as treatment for psoriasis. Reasons for starting apremilast were lack of efficacy with previous treatments (85.4%) and adverse effects or contraindication to previous treatments (14.6%), without statistically significant differences between patients who had received a previous biologic and those who had not. Drug survival was not influenced by previous biological treatment, but we found an increased risk of drug discontinuation in patients with chronic kidney disease (log-rank p=0.028). The main reason of apremilast withdrawal was lack of adequate disease control (60.0%), most of whom required treatment with biologics. Therefore, despite the extensive development of new therapies for psoriasis and other dermatological conditions, apremilast is a widely used drug even in patients who are candidates for biologic treatment. Its initiation is more frequent due to poor disease control than because of other therapies contraindications.

Cannabinoids and Their Role in Chronic Pain Treatment: Current Concepts and a Comprehensive Review.

For decades, chronic pain was managed with an almost conventional approach of using a wide range of analgesic spectrum, surgical approaches and complex interventional pain techniques to modulate or even interrupt pain pathways. These different approaches carry many pharmacological hazards together with the lack of efficacy and safety of many interventional and surgical management techniques for chronic pain have mandated searching for other effective therapies including alternative treatments. Cannabinoids are naturally occurring substances that are derived from Cannabis sativa L. The usage of cannabinoids and their related synthetic chemical compounds has emerged as a choice in the management of different chronic pain conditions is being evaluated, however, the efficacy is still not consistently established. In the present investigation, therefore, we discuss the different aspects related to cannabinoids and their implications in the management of chronic pain conditions. This review will also discuss the safety profile of the cannabinoids together with the legal considerations that hinder their use in different countries.

P059: Multi-effector cell targeting with half-life extended bispecific scFv in Hodgkin lymphoma

Immunotherapy has revolutionized the treatment of many hematological cancers. One form of cancer immunotherapy is exploiting immune effector cells, for example, T-cells or NK-cells, by retargeting them to cancer-associated antigens which have been identified and validated for most hematological cancers. However, most strategies to do so employed to date suffer from disadvantages such as unfavorable pharmacokinetics and unspecific immune system activation with current bispecific antibodies, high complexity and cost with CAR T-cells or lack of efficacy with many simple monoclonal antibodies targeting tumor-associated antigens. Thus, it is highly desirable to develop new technologies that can overcome these limitations. Here, we introduce our strategy to retarget various immune effector cells simultaneously with half-life extended bispecific scFv constructs to Hodgkin lymphoma-associated antigens e.g., CD30. In doing so, we target CD3, CD16 and CD28 on immune effector cells. Half-life extension is achieved by fusing the scFv constructs to a repetitive amino acid sequence without secondary structure and immunogenicity developed by us. After optimizing the production of our constructs in mammalian protein production systems we performed functional in vitro validation. Our data shows that the designed bispecific scFv constructs can bind their targets specifically and simultaneously and facilitate the formation of an artificial immunological synapse with immune cells secreting toxic proteins such as perforin and granzymes leading to the apoptosis of the lymphoma cells. We show direct cytotoxicity towards tumor cells in vitro and a target-cell specific release of cytokines such as TNFα and IFNγ by effector cells. We are now moving some constructs into cell line xenograft mouse models for further in vivo validation.

“Get-Rich-Quick Rituals, Remote Sex, and Herbs in Vaginal Canals”: Portrayal of Indigenous Fruits and Medicinal Herbs in Zimbabwe's The Mirror Newspaper

This article examines how The Mirror, a regional newspaper in Zimbabwe, represents issues related to indigenous knowledge, such as the use of medicinal herbs and fruits. The Mirror largely circulates in the Midlands and the Masvingo region, although it also has a presence in parts of Mashonaland East, Manicaland, and Matabeleland South. The article utilises a qualitative methodology, in which archival data were collected from The Mirror to examine its portrayal of indigenous fruits and medicinal herbs. As such, representation theory is the theoretical lens of the study, and the data are analysed using thematic analysis. The study found that stories related to indigenous fruits and medicinal herbs are narrated through an urban gaze, which is sometimes at odds with the common uses of such resources by rural communities. It is argued in this article that The Mirror, as a post-colonial media entity, does not deviate from the colonial practices of suppressing and attacking African culture. Indigenous herbs are framed in terms such as witchcraft, bizarre incidents, and lack of efficacy. Furthermore, news stories published by The Mirror do not provide complete information on the uses of indigenous fruits and medicinal herbs, but instead focus only on what journalists perceive as “newsworthy” and appropriate for their readers.

Retrospective Analysis of Treatment Pathways in Patients With BRAFV600E-mutant Metastatic Colorectal Carcinoma - MORSECRC.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease with distinct molecular subtypes. The BRAFV600E-mutation found in approximately 8-12% of mCRC patients is associated with poor prognosis. Guideline recommendations for this population are mostly based on small cohorts due to lack of clinical data. This retrospective analysis was designed to evaluate (approved) therapeutic approaches and algorithms in BRAFV600E-mutant mCRC prior to approval of the targeted combination encorafenib plus cetuximab in Germany, Austria, and Switzerland. Anonymized data from BRAFV600E-mutant mCRC patients were analyzed retrospectively regarding 1st-, 2nd- and 3rd-line treatment using descriptive statistics. Forty-two patients were eligible for analysis (mean age 62.1 years, 47.6% female). At initial diagnosis, 20 patients (47.6%) were documented with right-sided tumors. Most patients (81.0%) were tested for BRAF before 1st-line. Four patients (9.5%) showed high microsatellite instability (MSI-H). Based on 94 treatment lines, chemotherapy combined with targeted therapy (TT) was used mostly (61.7%), followed by chemotherapy alone (19.1%). Backbone therapies were most frequently FOLFOXIRI (27.7%), FOLFOX/CAPOX (22.3%), or FOLFIRI (20.2%). Anti-VEGF/VEGFR and anti-EGFR-treatments were used in 45.7% and 23.4% of patients, respectively. Across all treatment lines and types, the predominantly documented reason for discontinuation was lack of efficacy. Combined chemotherapy+TT (anti-VEGF/VEGFR and anti-EGFR) played a predominant role in BRAFV600E-mutated mCRC treatment prior to approval of the targeted combination encorafenib plus cetuximab. Since lack of efficacy was the major reason for treatment discontinuation, newly approved therapies including encorafenib plus cetuximab and - for MSI-H tumors - pembrolizumab represent urgently needed options for future mCRC patients.