Compassionate Use Research Articles

Appreciating international scholarships’ potential impact in Palestine’s extreme context

The article presents original findings of career gains perceived by 32 Palestinian alumnae and alumni of 12 master’s scholarship programs. I draw on these original findings in responding to one key research question: How do scholarships work, or not, as a pathway of development in Palestine? I argue that scholarships evidently work well as such because of key mechanisms underlying their perceived career impact: Expanded access to career resources, experiential (global) learning, key skills cultivation, specialized knowledge advancement, and enhanced employers’ appreciation. However, I outline limits of this argument by reflecting on the difficulty of recreating the efficacy of these mechanisms and scaling up their perceived impact in Palestine’s currently extreme context. I finally extend a call for increased, serious reflection on ways to defy this difficulty.

Effect of Timely Availability of TTR-Stabilizing Therapy on Diagnosis, Therapy, and Clinical Outcomes in ATTR-CM.

Background: Tafamidis reduces cardiovascular morbidity and mortality in transthyretin amyloid cardiomyopathy (ATTR-CM), yet availability and access to therapy vary. Objective: To determine how availability and access to tafamidis impact time-to-diagnosis, time-to-therapy, and cardiovascular outcomes in ATTR-CM. Methods: Ninety-one consecutive ATTR-CM (~97% wt-TTR) patients diagnosed between June 2019 and June 2021 were evaluated for tafamidis. Access to therapy was regulated by compassionate use [n(CU) = 42] prior to, and insurance [n(IA) = 49] after regulatory approval. Results: Tafamidis was started in 37/42 (88.1%), and 39/49 (79.6%) patients, respectively. At diagnosis, ATTR-CM disease stage (≤stage 2: 88.2% vs. 90.9%, p = 0.92) was similar between groups. Timely access (after tafamidis approval) reduced the median time from first presentation to diagnosis from 6.2 (IQR: 1.3-28.9) to 2.4 (0.7-21.7) months, and from first presentation to therapy from 24.4 (10.7-46.8) to 11.8 (6.4-32.4) months. While RV function significantly worsened between diagnosis and therapy initiation in CU patients diagnosed before tafamidis approval (S'-velocity 10.0 ± 2.2 to 9.2 ± 2.2 cm/s; p = 0.018; TAPSE 17.3 ± 4.7 to 15.7 ± 3.9 mm, p = 0.008), it remained unchanged in IA patients (S'-velocity 9.6 ± 2.6 to 9.4 ± 2.3 cm/s; p = 0.83; TAPSE 15.6 ± 4.2 to 16.3 ± 3.1 mm, p = 0.45). After a median follow-up of 42.3 and 24.9 months in CU and IA patients, respectively, timely availability was associated with a reduction in annual heart failure hospitalizations (0.40 vs. 0.16 per patient, p < 0.001) and improved MACE-free survival (HR = 0.51; 95%CI: 0.26-1.00; p = 0.051). Timely diagnosis (<12-months) prolonged MACE-free survival (HR = 0.424; 95%CI: 0.22-0.81; p = 0.004), and reduced HFH (HR = 0.40; 95%CI: 0.19-0.81); p = 0.011) and all-cause mortality (HR = 0.29; 95%CI: 0.11-0.74); p = 0.009). Conclusions: Availability of tafamidis improves diagnostic efficacy in ATTR-CM patients. Timely diagnosis and initiation of therapy reduces adverse cardiovascular events.

Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial

Under compassionate use, chimeric antigen receptor (CAR) T-cells have elicited durable remissions in patients with refractory idiopathic inflammatory myopathies (IIM)1. Here, we report on the safety, efficacy, and correlative data of the first subject with the immune-mediated necrotizing myopathy (IMNM) subtype of IIM who received a fully human, 4-1BBz anti-CD19-CAR T-cell therapy (CABA-201) in the RESET-Myositis™ phase I/II trial (NCT06154252). CABA-201 was well-tolerated following infusion. Notably, no evidence of cytokine release syndrome (CRS) or immune effector-cell associated neurotoxicity syndrome (ICANS) was observed. CK levels decreased, and muscular strength improved post-infusion. Peripheral B-cells were depleted rapidly following infusion, and the subject achieved peripheral B-cell aplasia by day 15 post-infusion. Peripheral B-cells returned at 2 months post-infusion and were almost entirely transitional. Autoantibodies to SRP-9, SRP-72, SRP-54, and Ro-52, decreased relative to baseline whereas antibodies associated with pathogens and vaccinations remained stable. The infusion product consisted of predominantly CD4+ effector memory T-cells & exhibited in vitro cytolytic activity. Post-infusion, CABA-201 expansion peaked at day 15 and was preceded by a serum IFN-γ peak on day 8 with peaks in serum IL-12p40 and IP-10 on day 15. These data detail the safety, efficacy, and pharmacodynamics of CABA-201 in the first IMNM subject.

197: Expanding Access: Seven-year Outcomes and Experience of a New Low-Volume Pediatric ECMO Program

197: Expanding Access: Seven-year Outcomes and Experience of a New Low-Volume Pediatric ECMO Program

225P Nivolumab for cancer of unknown primary (CUP): Clinical efficacy and biomarker analysis from NivoCUP2 expanded access program (WJOG14620M)

225P Nivolumab for cancer of unknown primary (CUP): Clinical efficacy and biomarker analysis from NivoCUP2 expanded access program (WJOG14620M)

Toward Expanded Access to Cancer Care With Cost Awareness: An Optimization Modeling Analysis of Rwanda.

Cancers are a growing cause of mortality especially in low- and middle-income countries in Africa. Rwanda is no exception. Two cancer centers currently provide care to the public, but there are both political and human interest in expanding access to tertiary cancer care. Improved geographic access could lead to both better patient outcomes and a better understanding of the existing cancer burden across Rwanda. To identify cost-aware ways of expanding geographic access, we adopt an optimization approach and identify expansion plans that minimize the average travel time to a cancer center across the country while remaining under a given monetary budget. Three additional hospitals could reduce average travel times by 40%, with the largest decrease in travel times observed in populations with long travel times. However, such an expansion would require a 50% increase in the number of in-country oncologists. We find that oncologist scarcity, as opposed to monetary constraints, is likely to be a limiting factor for improved access to cancer care. We present an array of expansion plans and suggest that further modeling approaches that incorporate oncologist scarcity can help deliver better policy recommendations.

52509 Expanding access to scalp cooling therapy: a review of post-capping satisfaction in patients who received financial assistance from a non-profit organization

52509 Expanding access to scalp cooling therapy: a review of post-capping satisfaction in patients who received financial assistance from a non-profit organization

Elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and rare mutations.

The triple combination of elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically improved the outcome of people with Cystic Fibrosis (pwCF) with at least one F508del mutation. However, carriers of rare cystic fibrosis transmembrane conductance regulator (CFTR) variants are not candidates for this innovative treatment. In this observational study, we report the results of the compassionate use of ETI in 10 pwCF carriers of rare mutations after 2 months of treatment. Rectal organoids and short-term cultures of nasal epithelium obtained from rectal suction biopsies and nasal brushing were obtained from four subjects. After 2 months of ETI, all patients (4 males, mean age 30.1 ± 13.3 years) showed a significant increase of FEV1% predicted values [+8.0 (3.5-12.7) %, p < 0.010], body mass index [+0.85 (0-1.22) kg/m2, p < 0.020] and cystic fibrosis questionnaire-revised [+19.5 (6.3-29.2) points, p < 0.009]. A significant decrease of sweat chloride concentration [-11.2 (-1.7 to -34.0) mmol/L, p < 0.020] and exacerbations [-1.5 (-2 to -1), p < 0.008] was also recorded. Overall, 7 out of 10 participants were considered full responders. All patients reported cough disappearance (n = 3) or reduction (n = 7). Long-term oxygen was discontinued in two out of three patients and one also stopped noninvasive ventilation and was removed from the lung transplantation waiting list. Despite the limited number of cases, our results support the use of CFTR modulators in patients with rare CFTR variants that are not currently approved for ETI in Europe.

Effectiveness of risankizumab induction and maintenance therapy for refractory Crohn’s disease: a real-world experience from a preapproval access programme and early access to medicines scheme

ObjectiveSince approval in Crohn’s disease (CD) of risankizumab, there has been widespread use. Real-world data are, however, limited and our aim is to address that gap.Design/methodWe performed a retrospective, observational...

Psychedelic and dissociative agents in psychiatry: challenges in the treatment

With the discovery of the antidepressive effects of ketamine and the increasing withdrawal of the pharmaceutical industry from the development of new psychotropic drugs, the psychiatric research into the clinical application of hallucinogens in psychiatry has literally blossomed in the last two decades. Promising results for various treatment approaches with psychedelic agents, such lysergic acid diethylamide (LSD) and psilocybin, and dissociative agents, such as ketamine and esketamine, have raised great hopes among researchers, clinicians and patients in recent years, so that there was already talk of a new era in psychiatry. As one of the first of these substances, in December 2019 intranasal esketamine was approved in the USA and the EU for the treatment of treatment-resistant depression and Switzerland followed in 2020. Recently, psilocybin was approved in Australia, Canada and Switzerland for compassionate use in exceptional cases for the treatment of depression, while large approval studies with various psychedelic agents are currently ongoing worldwide. The medical application of psychedelic agents and ketamine/esketamine is considered to be safe; however, as with all new forms of treatment it is of crucial importance that, in addition to the hopes, the specific challenges of these new treatment approaches must also be carefully considered and assessed. Excessive expectations and an insufficient risk-benefit estimation are detrimental to the patients and the reputation of the treating physician. Although a possible paradigm shift in the care of mental health is already being discussed, this review article consciously concentrates on the possible risks of treatment and the methodological weaknesses of the studies carried out so far.

Bacteriophage therapy: an alternative to antibiotics in the age of multi-drug resistance

Phage therapy involves the use of specific viruses that can infect and lyse pathogenic bacteria. Since, antibiotic resistance is widely increasing among bacteria phages offer a promising field as natural, self-replicating and self-limiting antibiotics. Clinical trials are conducted to use phages against multi-drug resistant bacterial infections. The most powerful and cost-effective application of phage therapy is in the treatment of diseases such as cholera and dysentery. While phage therapy has been around for over 100 years, the treatment still is not a main part of medicine. Phage therapy has largely existed on the fringes of medicine, particularly in Western countries like the USA, where it is occasionally approved for compassionate use, on emergency basis when no other approved therapies are available. This review was undertaken to discuss, review and highlight the importance and future research of phage therapy.

Disease flares with baricitinib dose reductions and development of flare criteria in patients with CANDLE/PRAAS

ObjectivesPatients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) respond to the janus kinase inhibitor 1/2 inhibition with baricitinib at exposures higher than in rheumatoid...

Barriers to access of precision guided therapies for children with high-risk cancer.

Accessing compassionate access schemes to obtain novel therapeutic agents for children with hard-to-treat cancers can be fraught with challenges such as regulatory barriers and limited resources. This study aimed to explore clinician perspectives on the barriers, impacts and ethical considerations of accessing novel therapeutic agents within the context of a paediatric oncology precision medicine trial. We gathered data from 37 semi-structured interviews with paediatric oncologists participating in the PRecISion Medicine for Children with Cancer (PRISM) study, a precision medicine clinical trial in Australia. The interviews, conducted over 2years, focused on paediatric oncologist's experiences with the PRISM trial. Interviews were re-analysed to identify themes related to access pathways and any challenges in obtaining novel agents through thematic analysis. The resulting thematic framework was discussed and refined by a multidisciplinary team. Three main themes were identified: (i) barriers to access, including poor drug availability, lack of evidence and the time burden of the application process; (ii) impacts of inaccessibility, encompassing medical consequences and financial burden on families; and (iii) ethical considerations, centred around balancing realistic expectations and providing compassionate care to patients and families. Paediatric oncologists expressed frustration with the complex regulatory landscape and the lack of systematic reporting on applications and outcomes of obtaining novel agents. Lengthy wait times for decision notifications were also highlighted, raising concerns about missed therapeutic opportunities for patients. This study provides insight to the challenges faced when seeking access to novel therapies for paediatric oncology patients. There is a clear need for improved communication, streamlining processes and increased resources to facilitate access to novel agents. Further resource development is necessary to address these complexities in accessing novel therapy agents to ultimately ensure equitable and timely access.

If it walks like a duck…: Monitored Emergency Use of Unregistered and Experimental Interventions (MEURI) is research

Monitored Emergency Use of Unregistered and Experimental Interventions (MEURI) is an ethical framework developed by the WHO for using unproven interventions in public health emergencies outside the context of medical...

The Synergy Between Fintech and Islamic Banking: Expanding Access to Financial Inclusion

This study aims to examine how the synergy between Fintech and Islamic banking can expand inclusive financial access in Indonesia. Through a literature review, this research identifies the role of Fintech in digital finance based on Islamic principles and the integration of the economic ecosystem. The findings indicate that the synergy between these two sectors holds significant potential for enhancing financial inclusion. However, the study also identifies several challenges, including regulations that have not fully accommodated innovation and the need for improved digital financial literacy. The study concludes that the synergy between Fintech and Islamic banking is a strategic step towards achieving inclusive financial goals in Indonesia, but it requires support from various stakeholders to overcome the existing challenges.

A Decade of Implementing Preexposure Prophylaxis (PrEP) Clinical Guidelines: The Vital Role of Nurses to Expand Access to PrEP in the United States

A Decade of Implementing Preexposure Prophylaxis (PrEP) Clinical Guidelines: The Vital Role of Nurses to Expand Access to PrEP in the United States

Pexidartinib Upfront in a Case of Tenosynovial Giant Cell Tumor: Proof of Concept for a Treatment Paradigm Shift.

Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive tumor of the joints, bursa, and tendon sheath that can cause considerable pain and substantial morbidity. Although surgery is the primary treatment for patients with TGCT, surgical resection is associated with high rates of recurrence, particularly for patients with diffuse TGCT. Pexidartinib, a colony-stimulating factor1 receptor inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. A 32-year-old man presented with intra-articular diffuse TGCT with pain and received noncurative treatment for 5years (2014-2019). In 2019, the patient was found to have extensive disease accompanied by pain and limited range of motion. The patient's case was presented to a sarcoma multidisciplinary tumor board, who determined that surgery would cause significant morbidity and macroscopic residual tumor. As a result of the extent of disease, young age, and otherwise good health, treatment with pexidartinib was started through a compassionate use program at 800mg/day. After dose reductions to pexidartinib at 400mg/day and then 200mg/day as a result of creatine phosphokinase elevations, the patient achieved a complete response after 2years of treatment; pain was reduced and mobility was restored. The patient reported no side effects related to pexidartinib treatment. Treatment was stopped in 2022 for future family planning. After pexidartinib therapy was interrupted, the patient's wife had a successful pregnancy and delivery; however, the disease showed a slow but constant clinical deterioration, with a reduction in the range of movement of the affected knee and an apparent increase in widespread TGCT nodules. Our case is unique because it provides support for pexidartinib use as upfront therapy for TGCT, instead of surgery, in selected cases.

Compassionate use of evinacumab for the treatment of homozygous familial hypercholesterolaemia (HoFH) in children under 5 years of age: Clinical experience

Compassionate use of evinacumab for the treatment of homozygous familial hypercholesterolaemia (HoFH) in children under 5 years of age: Clinical experience

Peptide Receptor Radionuclide Therapy in Advanced Refractory Meningiomas: Efficacy and Toxicity in a Long Follow-up.

Recurrence of meningiomas after surgery and radiotherapy deserves specific attention because of the lack of active third-line therapies. Somatostatin receptors are usually overexpressed on the cell membrane of meningiomas, and this has led the way to a radionuclide theranostic approach. Diagnoses with 68Ga-DOTA-octreotide and peptide receptor radionuclide therapy (PRRT) with 90Y/177Lu-DOTA-octreotide are currently possible options within experimental protocols or as compassionate use in small patient groups. Methods: From October 2009 to October 2021, 42 meningioma patients with radiologic recurrence after standard therapies were treated with 90Y-DOTATOC (dosage of 1.1 or 5.5 GBq) or with 177Lu-DOTATATE (dosage of 3.7 or 5.5 GBq) in a mean of 4 cycles. All patients showed intense uptake at diagnostic 68Ga-DOTATOC PET/CT or in an 111In-octreotide scan. Results: Of 42 patients treated, 5 patients received 90Y-DOTATOC with a cumulative activity of 11.1 GBq and 37 patients received 177Lu-DOTATATE with a cumulative activity of 22 GBq. The disease control rate was 57%. With a median follow-up of 63 mo, median progression-free survival was 16 mo, and median overall survival was 36 mo. Retreatment 177Lu-PRRT was performed in 6 patients with an administered median activity of 13 GBq in a mean of 5 cycles. With a 75.8-mo follow-up, median progression-free survival and overall survival were 6.5 and 17 mo, respectively. Only 1 patient discontinued the treatment because of grade 3 platelet toxicity. A rapidly transient grade 2 neutropenia was recorded in 1 retreated patient. Conclusion: PRRT in patients with advanced meningiomas overexpressing somatostatin receptor 2 was active and well tolerated, showing a 57% disease control rate. Furthermore, PRRT could represent a potential retreatment option. Further studies, also in combination with other treatments, are warranted.

Adjunctive cenobamate in people with focal onset seizures: Insights from the Italian Expanded Access Program.

This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. A total of 236 subjects with a median age of 38 (Q1-Q3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1-Q3 = 2.50-4.47) at baseline to 2.50 (Q1-Q3 = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam.