Unmet Treatment Need Research Articles

Targeted Therapy Development in Acute Myeloid Leukemia

Therapeutic developments targeting acute myeloid leukemia (AML) have been in the pipeline for five decades and have recently resulted in the approval of multiple targeted therapies. However, there remains an unmet need for molecular treatments that can deliver long-term remissions and cure for this heterogeneous disease. Previously, a wide range of small molecule drugs were developed to target sub-types of AML, mainly in the relapsed and refractory setting; however, drug resistance has derailed the long-term efficacy of these as monotherapies. Recently, the small molecule venetoclax was introduced in combination with azacitidine, which has improved the response rates and the overall survival in older adults with AML compared to those of chemotherapy. However, this regimen is still limited by cytotoxicity and is not curative. Therefore, there is high demand for therapies that target specific abnormalities in AML while sparing normal cells and eliminating leukemia-initiating cells. Despite this, the urgent need to develop these therapies has been hampered by the complexities of this heterogeneous disease, spurring the development of innovative therapies that target different mechanisms of leukemogenesis. This review comprehensively addresses the development of novel targeted therapies and the translational perspective for acute myeloid leukemia, including the development of selective and non-selective drugs.

Clinical and economic burden associated with graft-versus-host disease following allogeneic hematopoietic cell transplantation in France

The real-world clinical and economic burden of graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation has not been comprehensively studied in France. Clinical outcomes, healthcare resource utilization and costs associated with acute GVHD (aGVHD), chronic GVHD (cGVHD), acute plus chronic GVHD (a+cGVHD) versus no GVHD were compared using French administrative claims data. After propensity score matching, 1934, 408, and 1268 matched pairs were retained for the aGVHD, cGVHD, and a+cGVHD cohorts, respectively. Compared with patients with no GVHD, odds of developing severe infection were greater in patients with aGVHD (odds ratio: 1.7 [95% confidence interval: 1.4, 2.1]). Compared with patients with no GVHD, mortality rates were higher in patients with aGVHD (rate ratio (RR): 1.6 [1.4, 1.7]) and with a+cGVHD (RR: 1.1 [1.0, 1.2]) but similar in patients with cGVHD (RR: 0.9 [0.7, 1.1]). Mean overnight hospital admission rates per patient-year were significantly higher in patients with aGVHD and a+cGVHD compared with no GVHD. Total direct costs (range €174,482–332,557) were 1.2, 1.5, and 1.9 times higher for patients with aGVHD, cGVHD, and a+cGVHD, respectively, versus patients with no GVHD. These results highlight the significant unmet need for effective treatments of patients who experience GVHD.

Cost Effectiveness of Difelikefalin Compared to Standard Care for Treating Chronic Kidney Disease Associated Pruritus (CKD-aP) in People with Kidney Failure Receiving Haemodialysis.

Chronic kidney disease-associated pruritus (CKD-aP) is associated with an increased risk of depression, poor sleep and reduced health-related quality of life. Two phase III studies (KALM-1 and KALM-2) of difelikefalin showed reduced CKD-aP severity and improved itch-related health-related quality of life in patients with moderate and severe CKD-aP receiving haemodialysis for kidney failure. We aimed to estimate the cost effectiveness of difelikefalin for patients with CKD-aP receiving haemodialysis for kidney failure compared to standard care from a UK National Health Service perspective. A cohort model was developed with four health states representing levels of pruritus intensity over time, based on the KALM trials augmented with longer term CKD-aP severity data from another haemodialysis trial (SHAREHD) for standard care. Utilities were estimated from a mapping study of 5-D Itch to EQ-5D-5L in 487 patients receiving haemodialysis, costs were estimated based on resource use alongside the SHAREHD and 2018 unit costs, and inflated to 2021 costs. Costs and quality-adjusted life-years were discounted at 3.5% per annum. A de novo economic model was developed in Microsoft Excel with scenario analyses performed using a range of assumptions. In the base-case analysis over a time horizon of 64 weeks,using a placeholder cost of £75 per 28-days for difelikefalin, the incremental cost-effectiveness ratio of difelikefalin compared with standard care was £19,558/quality-adjusted life-year (QALY). Scenario analyses resulted in incremental cost-effectiveness ratios that ranged from £10,154/QALY (severe only) to £16,957/QALY (5-year horizon) for difelikefalin compared to standard care. Probabilistic sensitivity analyses suggested difelikefalin has a 48.6% probability of being cost effective at a threshold of £20,000/QALY and a 57.2% probability of being cost effective at a threshold of £30,000/QALY. The cost effectiveness of difelikefalin in a range of scenarios could make it an important pharmacotherapy to address the high burden of disease and unmet need for treatments associated with CKD-aP in the UK.

Tumor treating fields (TTFields) concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer: The phase 3 PANOVA-3 study.

TPS770 Background: Tumor Treating Fields (TTFields) therapy is a loco-regional antimitotic treatment approved for glioblastoma and malignant mesothelioma. TTFields (150 kHz), with/without chemotherapy, induced antiproliferative and anticlonogenic activity in pancreatic cancer cell lines in vitro. The phase (ph) 2 PANOVA study (NCT01971281) demonstrated that TTFields therapy with gemcitabine and nab-paclitaxel (GnP; TTFields/GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Despite advances in the treatment of LAPC, prognosis is poor and available therapies negatively impact quality of life (QoL); there is an unmet need for effective and tolerable treatments. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, ph 3 trial investigating the efficacy and safety of TTFields/GnP in patients (pts) with LAPC, with a planned enrollment of 556 pts. Pts with unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment are eligible. Pts will be stratified by performance status and geographical region, and assigned 1:1 to TTFields/GnP or GnP alone. Standard doses of GnP will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) generated by the NovoTTF-200T System, will be delivered ≥ 18 h/day until local disease progression per RECIST v1.1. Pt usage is tracked by the device. Follow-up will be performed Q4W; CT scans of the chest and abdomen will be taken Q8W. After local disease progression, pts will be followed every month until death. The primary endpoint is overall survival. QoL, pain-free survival, and puncture-free survival will be compared between TTFields/GnP and GnP alone. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Device Support Specialists (DSS) will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. The device manufacturer will also provide guidance on preventing and managing skin adverse events in line with published guidance, by means of DSS, field personnel, and various information resources. Usage information from the NovoTTF-200T System is provided to pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches help pts to confidently operate the NovoTTF-200T System with the knowledge that a multi-faceted support structure is available, ensuring TTFields therapy is seamlessly integrated into everyday life, increasing likelihood of high usage and ultimately optimizing pt outcomes. The trial is currently recruiting at 148 sites, globally. The DMC last reviewed the trial in September 2022, and suggested that the trial continue as planned. Clinical trial information: NCT01971281 .

Antibacterial bone adhesive cement for preventing sternal infections after cardiac surgery

Deep Sternal wound infection (Mediastinitis) after cardiac surgery can be potentially caused by both Gram-positive and Gram-negative bacteria. The incidence of sternal infection appears to be on the rise in current practice and is associated with increased hospital stay, cost of care, and mortality. Due to the unmet need for mediastinitis treatment or prevention, we developed and characterized an antibacterial, biocompatible bone adhesive cement composed of tetracalcium phosphate, phosphoserine, and the antibacterial drugs, amikacin and vancomycin (TPAV). Vancomycin and amikacin show a continuous release pattern from TPAV for up to 60 and 90 days, respectively. In vitro and ex vivo analysis of TPAV's antibacterial properties shows inhibitory activity against the growth of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae) and Staphylococcus aureus (S. aureus), and their biofilm formation. TPAV is also capable of inhibiting the growth of E. coli, K. pneumoniae and S. aureus when grown together as co-culture. Furthermore, the in vivo studies are done in a rat sternotomy model infected with S. aureus and E. coli, and TPAV demonstrated significant inhibitory activity when compared to the infected control group. This study highlights the potential of the developed antibacterial bone adhesive cement for preventing mediastinitis in clinics.

P584 Efficacy, safety, and tolerability of AMT-101, a gut selective oral IL-10 fusion, in the Phase 2 FILLMORE trial of patients with chronic pouchitis

Abstract Background Chronic pouchitis can occur in up to half of patients within 10 years of ileal pouch-anal anastomosis (IPAA) after proctocolectomy for ulcerative colitis (UC). There is a large unmet need for medical treatments. Methods This was a phase 2, randomized double-blind, parallel-group, 2 active-arm trial of the combined phase 2/3 trial in adults (18-75 years) with a prior history of UC with proctocolectomy and subsequent IPAA, who presented with chronic or recurrent pouchitis. The trial was conducted in US, Canada, and Western Europe. Approximately 20 patients were planned to be randomized 1:1 to either 3 mg or 10 mg AMT-101 doses administered once daily, orally, for 12 weeks. The key efficacy endpoints were: 1) the proportion of patients with symptomatic improvement, as measured by stool frequency response, and 2) the proportion of patients with histologic healing, as measured by Geboes scores. Histology and endoscopy were centrally read. Results 22 patients were randomized to receive AMT-101 3 mg (n=10) or 10 mg (n=12). The mean (SD) baseline absolute stool frequency was 13.4 (4.5). Overall, 36.4% (8/22) of patients achieved stool frequency response, defined as either a reduction of ≥ 3 stools and a ≥ 30% reduction in number of stools from baseline, or a return to post-IPAA number of stools or lower, at Week 12. 40% (4/10) and 33% (4/12) of patients dosed with 3 mg or 10 mg, respectively, achieved stool frequency response at Week 12. Rapidity of stool frequency response was demonstrated as early as Week 2 in both arms and was substantially maintained through Week 12. Patients had a median (IQR) baseline Geboes score of 5.1 (3.2 to 5.2), representing severe pouchitis with ulceration and tissue destruction. Across both arms, 22.7% (5/22) [20.0% (3 mg) and 25.0% (10 mg)] of patients met the histologic healing response of Geboes score ≤ 3.1, an objective assessment of disease improvement. Endoscopic assessments (SES-CD, ≥50% reduction) were also performed, with modest improvements [10% (3 mg) and 8.3% (10 mg)] at Week 12. There was no systemic AMT-101 PK (by design) nor anti-drug antibodies detected. Translational analysis revealed IL-10 biological responses in both arms. In tissue, IHC results showed increases in anti-inflammatory FOXP3+ (Tregs) and CD163+ (M2-macrophages) cells in the lamina propria. Treatment emergent adverse events were mostly mild to moderate, with only one treatment-unrelated serious adverse event. Conclusion AMT-101 3 mg and 10 mg both appeared to be safe and generally well tolerated. PK and translational data confirmed AMT-101’s gut-restricted profile over the 12-week treatment with tissue-level PD effects and no systemic exposure. The AMT-101 3 mg dose is advancing into a Phase 3 trial for chronic pouchitis.

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations. To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD. In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software. Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations. The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence. Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population. This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States. The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

Hepatitis C virus prevalence, determinants, and cascade of care among people who inject drugs in Iran

BackgroundPeople who inject drugs (PWID) continue to experience the highest burden of hepatitis C virus (HCV). We aimed to characterize HCV antibody prevalence, determinants of infection, and the cascade of engagement in HCV care among PWID in Iran. MethodsParticipants were recruited in 11 cities of Iran using respondent-driven sampling. PWID underwent a structured interview capturing measures on socio-demographics, behaviors, and the HCV cascade of care. HCV and HIV were tested using antibody rapid tests. Multivariable logistic regression models identified characteristics associated with HCV seropositivity. ResultsHCV antibody prevalence was 26.0% among 2684 PWID enrolled. Of 699 participants who were HCV antibody positive, 88 (12.6%) were aware of past infections. HCV antibody prevalence was associated with older age (adjusted odds ratio [aOR] 2.09; 95% CI 1.18, 3.71), lower education (aOR 1.31; 95% CI 1.02, 1.69), >10 years of injecting (aOR 6.03; 95% CI 4.10, 8.85), methamphetamine injection (aOR 1.46; 95% CI 1.07, 1.99), daily injection drug use (aOR 1.26; 95% CI 1.01, 1.58), needle/syringe sharing (aOR 2.04; 95% CI 1.24, 3.34), recent incarceration (aOR 1.74; 95% CI 1.30, 2.32), and HIV seropositivity (aOR 7.93; 95% CI 4.12, 15.24). Additionally, 12.0% had ever tested for HCV, 4.0% had previously tested reactive for HCV antibody, and 3.7% had received an HCV diagnosis. Of diagnosed cases, 44.4% were linked to care, 15.2% initiated treatment, and 3.0% achieved sustained virologic response. ConclusionOur data show a high prevalence of HCV antibody and low engagement in HCV care, underscoring an unmet need for HCV prevention, screening, and treatment among PWID in Iran. HCV prevention and treatment programs tailored for PWID are needed to enhance harm reduction efforts and access to HCV care in Iran.

A Retrospective Claims Database Study to Clarify Disease Burden of Severe Asthma Patients with Type 2 High or Low Inflammation

The disease burden of severe asthma patients stratified by type 2 (T2) biomarkers is not well studied in large patient samples, especially for T2-low severe asthma patients. Using a Japanese medical record database, we investigated disease and economic burdens in T2-high and T2-low severe asthma patients. Data of severe asthma patients (receiving high-dose inhaled corticosteroids and additional asthma-related controller medications or oral corticosteroids [OCS] prescription [≥183 days] during the 1-year baseline period) were analyzed in the Real World Data database, comprising electronic medical records from Japanese medical institutions. Severe asthma patients were stratified into a T2-high population with higher eosinophils (≥150 cells/μL) and/or higher total immunoglobulin E (IgE, ≥75 IU/mL) or a T2-low population with lower eosinophils (<150 cells/μL) and lower total IgE (<75 IU/mL). The incidence of asthma exacerbation events and drug costs were analyzed for each population. Different T2 thresholds were explored, including eosinophil count 300 cells/μL and/or IgE 150 IU/mL. Of the 732 severe asthma patients, 599 (81.8%) patients had T2-high type, and 133 (18.2%) had T2-low type. Proportions of the T2-high patients (30.6%) with asthma exacerbations, defined as a composite outcome, including OCS burst, injectable steroid use, and hospitalization, were similar to those of T2-low type (34.6%). The annual drug cost was similar between T2-high (175,487 JPY) and T2-low (165,322 JPY) populations. In this large-scale study, both T2-high and T2-low severe asthma patients in Japan were shown to have a high disease burden and high economic burden, suggesting an unmet treatment need.

LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy.

The first-in-class, small molecule HIF-2αinhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 (ClinicalTrials.gov).

Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders.

A loss of prosecretory Cl- channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus, distal intestinal obstruction syndrome (DIOS) and constipation. Since CFTR modulators have minimal effects on gastrointestinal symptoms, there is an unmet need for novel treatments for CF-associated gastrointestinal disorders. Meconium ileus and DIOS mainly affect the ileum (distal small intestine). SLC26A6 (putative anion transporter 1, PAT1) is a Cl-/HCO3- exchanger at the luminal membrane of small intestinal epithelial cells which facilitates Cl- and fluid absorption. We recently identified first-in-class PAT1 inhibitors by high-throughput screening. Isoxazolopyrimidine PAT1inh-A01 was a hit compound, which had low potency (IC50 5.2 μM) for SLC26A6 inhibition precluding further preclinical development. Here we performed structure-activity relationship studies to optimize isoxazolopyrimidine SLC26A6 inhibitors and tested a potent inhibitor in mouse models of intestinal fluid absorption. Structure-activity studies of 377 isoxazolopyrimidine analogs identified PAT1inh-A0030 (ethyl 4-(benzyl(methyl)amino)-3-methylisoxazolo[5,4-d]pyrimidine-6-carboxylate) as the most potent SLC26A6 inhibitor with a 1.0 μM IC50. Selectivity studies showed that PAT1inh-A030 has no activity on relevant ion transporters/channels (SLC26A3, SLC26A4, SLC26A9, CFTR, TMEM16A). In a closed-loop model of intestinal fluid absorption, intraluminal PAT1inh-A0030 treatment inhibited fluid absorption in the ileum of wild-type and CF mice (CftrdelF508/delF508) with >90% prevention of a decrease in loop fluid volume and loop weight/length ratio at 30 minutes. These results suggest that SLC26A6 is the key transporter mediating Cl- and fluid absorption in the ileum and SLC26A6 inhibitors are novel drug candidates for treatment of CF-associated small intestinal disorders.

Use of focused computerized cognitive training (Neuroflex) to improve symptoms in women with persistent chemotherapy-related cognitive impairment.

Chemotherapy-related cognitive impairment (CRCI) is a distressing and increasingly recognized long-term sequela reported by breast cancer patients following cancer treatment. There is an urgent but unmet clinical need for treatments that improve CRCI. In this context, we proposed the use of a novel cognitive enhancement strategy called Neuroflex to target CRCI experienced by breast cancer survivors. The primary aim of this pilot study was to evaluate the feasibility and acceptability of Neuroflex, a novel digital cognitive enhancement strategy, in breast and gynecologic cancer survivors with CRCI. Secondary analyses focused on whether improvements in performance on Neuroflex were associated with improvement in subjective cognitive complaints and objective cognitive performance measures. Participants (N = 21) completed an average of 7.42 hours of Neuroflex training per week, an average of 44.5 (±1.01) hours total, and had a 100% completion rate. Participants exhibited significant improvement in self-reported cognitive function as well as significant improvement on tasks of verbal learning and memory and auditory working memory. Participants also exhibited improvement in mood, as well as improvement on a disability assessment. Results demonstrate feasibility and that breast cancer survivors are capable of completing a lengthy and challenging cognitive training program. Secondly, Neuroflex may confer specific cognitive benefits to both self-reported and objective performance. Results strongly support further investigation of Neuroflex in a larger controlled trial to establish efficacy for CRCI symptoms. Further studies may also result in optimization of this digital intervention for women with CRCI.

Patient profiles, treatment patterns, and outcomes among persistent, recurrent, or metastatic cervical cancer patients under routine care in the United States

ObjectivePatients with persistent, recurrent, or metastatic cervical cancer have poor prognosis. While recent advances have expanded treatment options, real-world data on treatment patterns and outcomes in this population are lacking. MethodsThis retrospective study identified adult females with persistent, recurrent, or metastatic cervical cancer from the ConcertAI Oncology Dataset who received systemic therapy on or after August 15, 2014. Patients were followed from persistent, recurrent, or metastatic diagnosis through third-line (3 L) therapy, death, end of record, or study end (June 2021). Data collection included patient characteristics, treatment patterns, and clinical outcomes. Kaplan-Meier methods were used for the three most common first-line (1 L) regimens to analyze real-world time on treatment (rwToT), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS). Analyses were stratified by bevacizumab receipt by treatment line. Results307 patients were included (mean [standard deviation] age 51.5 [13.2] years, 70.7% White). 91.2% of patients had metastatic disease, 8.5% had persistent disease, and <1% had recurrent disease. The most common 1 L regimen was carboplatin+paclitaxel+bevacizumab (40.7%) with median (95% confidence interval [CI]) rwToT of 3.5 (2.9–4.4) months. 57.0% of patients proceeded to second line (2 L), and 25.7% went to 3 L. Median (95% CI) rwPFS was 7.2 (6.4–8.1) months, and median (95% CI) rwOS was 16.5 (14.2–19.9) months, from initiation of 1 L. Conclusions1 L regimens received in patients with persistent, recurrent, or metastatic cervical cancer generally followed clinical guidelines, and the rwOS agrees with clinical trials. This study highlights the burden of disease and unmet need for specific treatments in these patients.

Antiparkinsonian Agents in Investigational Polymeric Micro- and Nano-Systems

Parkinson's disease (PD) is a devastating neurodegenerative disease characterized by progressive destruction of dopaminergic tissue in the central nervous system (CNS). To date, there is no cure for the disease, with current pharmacological treatments aimed at controlling the symptoms. Therefore, there is an unmet need for new treatments for PD. In addition to new therapeutic options, there exists the need for improved efficiency of the existing ones, as many agents have difficulties in crossing the blood-brain barrier (BBB) to achieve therapeutic levels in the CNS or exhibit inappropriate pharmacokinetic profiles, thereby limiting their clinical benefits. To overcome these limitations, an interesting approach is the use of drug delivery systems, such as polymeric microparticles (MPs) and nanoparticles (NPs) that allow for the controlled release of the active ingredients targeting to the desired site of action, increasing the bioavailability and efficacy of treatments, as well as reducing the number of administrations and adverse effects. Here we review the polymeric micro- and nano-systems under investigation as potential new therapies for PD.

Metacognitive training for negative symptoms: Support for the cognitive model.

Developing effective treatment options for negative symptoms of psychotic disorders remains a major unmet treatment need and area for further research. In a recent uncontrolled study by the main author, Metacognition Training (MCT) for negative symptoms was found to lead to fewer negative symptoms, less stigma and increased self-rated reflective ability. As the analysis examined negative symptoms as a whole, we here performed an additional analysis on individual negative symptom items as recent research has suggested that negative symptoms are best conceptualized through a five-factor model. It was found that the intervention led to changes specifically on sociality and blunted affect (with large effect sizes), which might reflect changes in both intrapersonal and interpersonal (meta)cognitive processes.

Non-engagement in substance use treatment among women with an unmet need for treatment: A latent class analysis on multidimensional barriers

BackgroundWomen with substance use disorders experience multifaceted barriers in accessing substance use treatment. Little is known about how these barriers may aggregate. Using a person-centered approach, this study evaluates patterns of treatment barriers and the factors associated with experiencing distinct sets of barriers among women. MethodsData were from the NSDUH (2015–2019). 461 adult women with an unmet need for substance use treatment in the last year reported on 14 treatment barriers. Latent class analysis examined classes of barriers; multinomial logistic regression assessed predictors of class membership. ResultsThree classes were identified: just not ready to abstain (71.2%), logistical barriers and stigmatization (18.2%), and barriers across all dimensions (10.6%). Higher education (aOR:1.94, p = 0.03) and psychological distress (aOR:2.19, p = 0.02) predicted higher odds—and identifying as African American predicted lower odds (aOR:0.17, p = 0.02)—of belonging to the “Logistics and Stigma Barriers” class relative to the “Just Not Ready” class. Similarly, higher education (aOR: 2.57, p = 0.02) and having children (aOR:2.28, p = 0.03) predicted higher odds—and marriage predicted lower odds (aOR:0.22, p = 0.02)—of belonging to the “High and Diverse Barriers” class relative to the “Just Not Ready” class. Having children predicted higher odds (aOR: 2.93, p = .02), and marriage predicted lower odds (aOR:0.19, p = 0.02) of belonging to the “High and Diverse Barriers” class relative to the “Logistics and Stigma” class. ConclusionA lack of readiness to abstain, socioeconomic circumstances, and family obligations are main barriers to SUD treatment among women. Interventions incorporating motivational interviewing, family systems, and social networks are needed.

Mobilizing stakeholders to drive the cervical cancer elimination agenda in Kenya: The national cervical cancer stakeholders' forum 2022.

Kenya is among the nineteen countries in Sub-Saharan Africa with the highest burden of cervical cancer globally. The high burden of cervical cancer in developing countries reflects the absence of effective cervical cancer prevention programs with limited resources invested to provide comprehensive services. We aimed to engage stakeholders in a structured consultative forum, to gain insights and forge effective partnerships to drive the cervical cancer elimination agenda in Kenya. The National Cervical Cancer Stakeholders Consultative Forum was organized as a part of activities to commemorate the National Cervical Cancer Awareness Month on 19th January 2022 in Nairobi, Kenya. The overall goal of the meeting was to provide a forum to sensitize stakeholders on the National Cervical Cancer Prevention and Control Program (NCCP) with a view to strengthen partnerships, increase coordination for improved service delivery and to provide a forum for resource mobilisation and alignment of key stakeholders towards elimination of cervical cancer in Kenya. Nominal group technique was adopted for structured discussions, and the findings analysed to derive key themes. Key challenges to primary and secondary prevention of cervical cancer were identified as low awareness, stigma and misinformation, high unmet need for treatment of early lesions, few health care providers with capacity to screen and treat, inadequate supplies, inefficient health information systems and poor referral pathways. Championing integration of cervical cancer screening and treatment services into routine health programs, strengthening policy implementation and robust monitoring and evaluation were identified as critical interventions. The National Cervical Cancer Stakeholders Forum 2022 provided insights for enabling Kenya to progress on the 2030 elimination targets. Such forums can be useful in bringing all actors together to evaluate achievements and identify opportunities for more effective national cervical cancer prevention and control programs.

EE16 Cost-Effectiveness of Cannabidiol Add-on Therapy Versus Placebo for the Treatment of Seizures in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a rare disorder with substantial unmet need for treatment providing early, effective seizure control with an acceptable safety profile. This analysis evaluated the cost-effectiveness of add-on cannabidiol (Epidyolex®; 100 mg/mL oral solution), versus placebo, in patients aged ≥2 years with treatment-refractory TSC-associated seizures managed with usual care.

Real world clinical perspective on PDE5i utility in dementia.

AbstractBackgroundThere is clearly a large unmet need for more drug treatments in dementia due to Alzheimer pathology (AD) and in VCID. Mechanistic studies in rodents and in vitro support a benefit of PDE5 inhibitors in AD.MethodA Big data approach recently confirmed this potential benefit with an independent study incorporating multiple levels of biology with in silico network drug discovery for amyloid and tau endophenotypes, data mining from insurance records, as well as in vitro modeling using derived induced pluripotent stem cell (iPSC) neuronal models of AD.ResultsCollectively, this body of work is cause of optimism. However, a real‐world randomized clinical trial (RCT) of the PDE5i tadalafil in older people, incorporating biomarkers, detected no significant effect with respect to cerebral blood flow.ConclusionThese results raise multiple questions for the dementia clinician‐scientist. Do in vitro and in vivo preclinical paradigms provide non‐translatable findings because these systems are not capturing a key component of AD, such as human aging? Is it still worth pursuing PDE5i as a therapeutic route? What could be some factors that contributed to the negative RCT results and what should be emphasized in the design of a definitive RCT for this class of therapeutics? Finally, what role do biomarkers play in filling critical gaps in knowledge to bridge the path between bench and bedside.

Moroctocog Alfa (AF-CC) for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Patients with Hemophilia A in India.

Hemophilia A is an X-linked congenital disorder, characterized by factor VIII (FVIII) deficiency. Globally, India has the highest population of patients with hemophilia, and there is a clear unmet need for appropriate and effective treatment for this patient population. This multicenter, open-label, post-approval study evaluated the safety and efficacy of moroctocog alfa in patients with moderate or severe congenital hemophilia A in India. Intravenous moroctocog alfa was administered 30 ± 5 IU/kg 3 times weekly for bleeding prophylaxis, according to the local product document. Participants were treated for up to 8 weeks, with an up to 4-week screening period and a subsequent post-treatment, 28-day safety observation period. Patients continued in the study until at least 24 exposure days or a period of up to 8 weeks on moroctocog alfa. A total of 50 participants were enrolled, and 48 (85.7%) completed the study. No participants developed FVIII inhibitors during the study. The mean (SD) annualized bleeding rate during moroctocog alfa prophylaxis was 0.79 (2.0) with a median (range) of 0.00 (0.0, 6.8). The mean (SD) annualized total factor consumption (TFC) per participant was 287,432 (93,866) IU; the mean (SD) annualized TFC by weight per participant was 4176 (858) IU/kg. Moroctocog alfa was well tolerated with no reported treatment-emergent adverse event-related dose reductions, discontinuations, or serious adverse events. Moroctocog alfa was safe, effective, and well tolerated in Indian participants with congenital moderate to severe hemophilia A. No participant developed FVIII inhibitors during the study.