Long-term Tolerability Research Articles

Allergen-specific sublingual immunotherapy altered gut microbiota in patients with allergic rhinitis

IntroductionAllergen-specific immunotherapy (AIT) induces long-term immune tolerance to allergens and is effective for treating allergic rhinitis (AR). However, the impact of sublingual immunotherapy (SLIT) on gut microbiota from AR patients and its correlation with treatment efficacy remains unclear.MethodsIn the present study, we enrolled 24 AR patients sensitized to Dermatophagoides farinae (Der-f) and 6 healthy donors (HD). All AR patients received SLIT treatment using standardized Der-f drops. Stool samples were collected from AR patients before treatment, and 1- and 3-months post-treatment, as well as from HD, for metagenomic sequencing analysis.ResultsAR patients had significantly lower richness and diversity in gut microbiota compared to HD, with notable alterations in composition and function. Besides, three months post-SLIT treatment, significant changes in gut microbiota composition at the genus and species levels were observed in AR patients. Streptococcus parasanguinis_B and Streptococcus parasanguinis, which were significantly lower in AR patients compared to HD, increased notably after three months of treatment. LEfSe analysis identified these species as markers distinguishing HD from AR patients and AR patients pre- from post-SLIT treatment. Furthermore, changes in the relative abundance of S. parasanguinis_B were negatively correlated with changes in VAS scores but positively correlated with changes in RCAT scores, suggesting a positive correlation with effective SLIT treatment. DiscussionSLIT treatment significantly alters the gut microbiota of AR patients, with S. parasanguinis_B potentially linked to its effectiveness. This study offers insights into SLIT mechanisms and suggests that specific strains may serve as biomarkers for predicting SLIT efficacy and as modulators for improving SLIT efficacy.

Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation.

Mitochondrial disease is a group of rare conditions, with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This Phase 2b program, aiming at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety, and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100- or 50-mg sonlicromanol, or placebo twice daily (bid) for 28 days with ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study wherein they received 100-mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). 15 patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier Phase 2a study. The RCT primary endpoint (change from placebo in the attentional domain of cognition score [IDN: visual identification, Cogstate]) did not reach statistical significance. Using a categorisation of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (p=0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, p=0.0143), Cognitive Failure Questionnaire (CFQ, p=0.0113), and the Depression subscale of the Hospital Anxiety and Depression Scale (p=0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study (Test of attentional performance [TAP] with alarm, p=0.0102; TAP without alarm, p=0.0047; BDI somatic, p=0.0261; BDI Total, p=0.0563; SF12 physical component score, p=0.0008). Seven of nine domains of RAND-Short form-36 like SF-36 pain improved (p=0.0105). Other promising results were observed in Neuro QoL-Fatigue-SF (p=0.0036), MiniBESTest (p=0.0009), McGill Pain Questionnaire (p=0.0105), EQ-5D-5L-VAS (p=0.0213) and EQ-5D-5L-index (p=0.0173). Most patients showed improvement in the 5× sit-to-stand test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to one year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline.

Use of Stiripentol in Patients with Dravet Syndrome: Common Practice Among Experts in Spain.

Despite considerable evidence for the efficacy and safety of stiripentol in Dravet syndrome (DS), some aspects of stiripentol use remain challenging in clinical practice, such as dose titration and the adjustment of concomitant antiseizure medications (ASMs) to prevent potential adverse effects. To (1) provide practical recommendations on the initiation of stiripentol treatment in patients with DS, (2) evaluate its effectiveness in the patient, and (3) guide the management of drug interactions and other aspects of treatment monitoring. Six Spanish neurologists (the authors) with expertise in the management of pediatric and adult patients with DS held a meeting in early 2024 to develop expert recommendations regarding the use of stiripentol in DS, based on a review of the literature and their common clinical experience. According to these recommendations, stiripentol can be administered to patients with DS of any age, although its initiation and titration vary according to age group. Individualized adjustment of concomitant ASMs, such as valproic acid and clobazam or drugs specifically for DS (i.e., fenfluramine), at initiation and during stiripentol treatment, can mitigate drug interactions, thereby increasing the long-term tolerability of stiripentol treatment. In specific cases, stiripentol doses of>50 mg/kg/day may be contemplated, and acute stiripentol administration may be considered to control refractory status epilepticus. Blood tests should be performed before starting stiripentol, at 3, 6, and 12 months after starting treatment, and then annually, except in the event of adverse effects, when additional testing may be necessary. Most adverse effects can be adequately managed by adjusting concomitant medications. These practical recommendations may be easily adapted for use in different countries, and should increase physicians' confidence in the initiation and monitoring of stiripentol treatment, thus facilitating effective management of patients with DS and improving clinical outcomes.

Long-term safety and efficacy of antibody ALXN2220 for depletion of cardiac amyloid transthyretin: results of treatment beyond 12 months in the open-label extension of study NI006-101

Abstract Introduction ALXN2220 (formerly NI006) is an investigational human monoclonal antibody in development for the treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). ALXN2220 is designed to deplete cardiac amyloid transthyretin (ATTR) deposits in patients with ATTR-CM on top of standard of care. Data from the first-in-human, ascending dose study NI006-101 show that ALXN2220 is safe and well tolerated. A reduction of surrogate markers of cardiac amyloid load and cardiac biomarkers was observed in participants receiving doses of ≥ 10mg/kg of ALXN2220 over a period of 12 months of treatment. Purpose Long-term safety, tolerability and efficacy of ALXN2220 treatment beyond 12 months was studied in a prolonged Open-Label Extension (OLE) of the NI006-101 study. Methods Participants completing 12 months in dose cohorts ≤ 30 mg/kg were allowed to receive additional 6 to 12 monthly open-label ALXN2220 infusions with up-titration of all participants to 30 mg/kg. Cardiac biomarkers were measured centrally, and serial cardiac imaging was performed with echocardiography and cardiac MRI or scintigraphy. Results Out of 27 participants completing 12 months, 23 (18 ATTRwt, all male, median age 70 years at screening (range 28-83)) continued treatment in the prolonged OLE. Median number of infusions of ALXN2220 received and median time followed across the full study were 20 infusions (range 11-24) and 125 weeks (range 83-153). Overall adherence to treatment was high in the prolonged OLE, 97% of planned infusions administered, 87% of participants received all planned doses. No severe or serious adverse events were considered related to ALXN2220 or resulted in the discontinuation during OLE, and no events of cytokine release syndrome or thrombocytopenia were observed. None of the participants had anti-drug antibodies throughout the trial. Cardiac biomarkers (NT-proBNP, troponin) and cardiac imaging indicated continued treatment effects beyond 12 months and supported the up-titration of participants who previously received lower doses of ALXN2220. Conclusions Up-titration and long-term treatment at a dose level of 30 mg/kg in the OLE was safe and well tolerated, with overall good adherence to treatment. Cardiac imaging and cardiac biomarker data indicated continued treatment effects beyond 12 months and supported the up-titration of patients to 30 mg/kg.

Long-term safety and efficacy of adjunctive lacosamide in the treatment of generalized onset tonic-clonic seizures: An open-label extension trial.

This study was undertaken to assess long-term safety, tolerability, and efficacy of lacosamide (LCM) as adjunctive therapy for generalized onset tonic-clonic seizures (GTCS) in patients aged ≥4 years with idiopathic generalized epilepsy (IGE). EP0012 (NCT02408549) was a phase 3, multicenter, open-label extension (OLE) trial. Patients were enrolled from SP0982 (NCT02408523). Trial duration was ≥2 years (adults) and ≤5 years (children). The trial consisted of a treatment period, ≤4-week taper period, and 30-day safety follow-up. Safety (primary) variables were incidence of treatment-emergent adverse events (TEAEs), discontinuations due to TEAEs, incidence of onset of absence or myoclonic seizures, and increase in days with absence or myoclonic seizures per 28 days. Efficacy (secondary) variable was percent change in GTCS frequency per 28 days. Kaplan-Meier estimated retention rates and analyses by number of lifetime antiseizure medications (ASMs) were performed post hoc. Overall, 239 patients (mean age = 27.9 years, 56.1% female, 18.4% children) were enrolled and received ≥1 dose of LCM in this OLE (median treatment duration = 3.2 years); 157 (65.7%) completed the trial, and 82 (34.3%) discontinued. The most common reason for discontinuation (≥10%) was withdrawn consent (30 [12.6%]). Kaplan-Meier estimated retention rate was 87%, 72%, and 60% at 1, 3, and 5 years, respectively. Overall, 222 (92.9%) patients reported TEAEs; 19 (7.9%) discontinued due to TEAEs. Few patients had an increase in number of days with absence or myoclonic seizures, or incidence of new absence or myoclonic seizures. Median percent change in GTCS frequency per 28 days from the combined baseline was -88.6% (range = -100.0 to 465.4, n = 238). Post hoc analyses demonstrated small numerical differences between patients with 1, 2, and ≥3 lifetime ASMs. The results support the use of long-term adjunctive LCM for GTCS in patients with IGE. Long-term adjunctive LCM was efficacious and well tolerated independent of the number of ASMs used before LCM initiation. ClinicalTrials.gov: NCT02408549.

Olokizumab plus methotrexate: safety and efficacy over 106 weeks of treatment

ObjectiveTo report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT)...

Long-Term Efficacy and Tolerability of an Emollient Containing Glycerol and Paraffin for Moderate-to-Severe Uremic Xerosis: A Randomized Phase3 Study.

There is an unmet need for effective topical therapies for patients with uremic xerosis and chronic kidney disease-associated pruritus (CKD-aP). The long-term efficacy and tolerability of an emollient containing glycerol 15% and paraffin 10% (V0034CR) was evaluated in a phase3 study. In this randomized, double-blind, two-parallel group, vehicle-controlled study, patients with moderate-to-severe uremic xerosis were randomized to once-daily application of V0034CR or vehicle control for 28days (periodI). This was followed by a treatment-free period of ≤ 21days (periodII), then all patients received open-label treatment with V0034CR for ≥ 84days (periodIII). Outcomes included treatment response at the end of periodI (El Gammal's xerosis severity score), instrumental measures of scaling (D-Squame technique), time to relapse during periodII, rate of recurrence during periodIII, pruritus severity over time, patient acceptability, and adverse events (AEs). The intent-to-treat population comprised 235 patients randomized to V0034CR (n = 118) or vehicle control (n = 117) during periodI. Treatment response at the end of periodI was achieved by 71 patients (60.2%) in the V0034CR group versus 48 (41.0%) with vehicle control (p = 0.0041). This coincided with greater reductions in the total surface area of squames (p = 0.001 vs vehicle control). Xerosis relapsed progressively without treatment in periodII; however, remission was durable under maintenance therapy in periodIII. Improvements in pruritus severity were comparable between V0034CR and vehicle control, suggesting that the antipruritic effect of V0034CR was mainly exerted by its oil-in-water emulsion base. V0034CR had high patient acceptability and was well tolerated; the most common treatment-related AEs were irritation or erythema (2.1%), exacerbated pruritus (1.3%), and vesicles at the application site (0.9%). These data support the use of V0034CR, with its hydrating and occlusive properties, for the long-term management of patients with moderate-to-severe uremic xerosis and CKD-aP. ClinicalTrials.gov identifier NCT01084148; EudraCT number 2006-002201-31.

Bone impairment in atypical hemolytic and uremic syndrome treated by long-term eculizumab.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy, related to complement dysregulation, including Factor H deficiency (FH) treated by lifelong eculizumab therapy. Its long-term tolerance is not yet fully described. We report two patients with genetic FH deficiency receiving long-term eculizumab and displaying a peculiar bone phenotype. First case is a 13-year-old girl, presenting with bone pains, arthritis, and deformities, for which X-rays and MRI described multifocal osteochondritis. Bone biopsy revealed an active remodeling bone (many areas of bone formation and resorption) and C3c accumulation on immunohistochemical staining. The second patient is an 11-year-oldgirl, displaying mechanical bone pains, for which bone scintigraphy found hypofixation of wrists and ankles. These findings could be consistent with a side effect of eculizumab, as C3c accumulation may result from the downstream C5-blockade. Alternatively, bone alterations could be due to the absence of FH, as described in murine models. Further investigations are required to characterize bone disease in aHUS.

Contribution of tryptophan and its metabolites to transplant outcome: a mini-review.

Long-term tolerance in the absence of immunosuppressive drugs is a major goal in the transplantation field, not yet attained. Recent research on the role of commensal microbiota in the control of immunity has opened new avenues for the search of novel clinical interventions. Indeed, products of intestinal metabolism generated by both host cells and the microbiota have been identified as modulators of the immune response. Among these, tryptophan (Trp) and its derivatives are being investigated to understand their impact on alloimmunity and their potential usefulness as therapeutic targets to improve allograft survival. Here, we reviewed the latest findings on the contribution of Trp metabolic pathways to transplant outcomes.

The Initial Experience of Eslicarbazepine in Children at Three Canadian Tertiary Pediatric Care Centers.

Eslicarbazepine (ESL) is a once-daily, third-generation antiseizure medication for focal-onset seizures. The primary mechanism of action is enhancing the slow inactivation of voltage-gated sodium channels. The study objective was to review real-world experience regarding retention rate, efficacy, and tolerability of eslicarbazepine, soon after it became available for children in Canada. A retrospective review was performed on all patients prescribed eslicarbazepine from September 2017 to June 2020, with at least 3 years of follow-up data, at 3 Canadian tertiary care pediatric centers. Fifty patients were identified, and the mean age of eslicarbazepine initiation was 12.4 years (range 3-19 years). Most patients had drug-resistant epilepsy, trying a mean of 5.04 (range 0-14) antiseizure medications before the initiation of eslicarbazepine. Twenty-four patients (48.0%) experienced adverse effects, including dizziness (n = 10), drowsiness (n = 6), dizziness and drowsiness (n = 1), nausea and abdominal pain (n = 4), transient unsteadiness and diplopia (n = 1), and negative mood changes (n = 2). None had serious adverse effects, including rash. The retention rate of eslicarbazepine at last follow-up was 70%. Fifteen (30%) had ≥50% seizure reduction, with 2 of these patients becoming seizure free. Ten (20%) had 25% to 50% reduction, 2 (4%) had worsening of seizures, and 17 (34%) had no change in seizure frequency. The study results support the long-term effectiveness and tolerability of eslicarbazepine in a cohort of children with predominantly drug-resistant epilepsy in a real-life setting from 3 Canadian centers with initial use after approval. Adverse effects were nonserious, infrequently leading to eslicarbazepine discontinuation.

Long-Term (12-Month) Safety and Tolerability of STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment of Migraine: Data from the Phase 3 Open-Label ASCEND Study.

STS101 is an investigational drug-device combination comprising 5.2 mg dihydroergotamine (DHE) powder (6.0 mg DHE mesylate) in a single-use nasal delivery device for the acute treatment of migraine. The primary objective of the ASCEND trial was to assess long-term safety and tolerability of STS101 in the acute treatment of migraine attacks across 12-18 months, with secondary objectives describing efficacy. ASCEND was an open-label study of STS101 in adults aged 18-65 years with a ≥ 1 year history of migraine with or without aura, with onset before the age of 50 years and 4-12 migraine attacks/month and < 15 headache days/month in each of the 3 months prior to screening. Exclusion criteria included diagnosis of non-migraine headache, history of cerebrovascular disease, and ≥ 2 cardiovascular risk factors. After establishing eligibility, participants could self-administer STS101 5.2 mg as needed for up to 2 doses within 24 h to treat a single migraine attack and up to 12 doses/month. Safety and tolerability evaluations included physical and nasal examinations, vital signs, laboratory tests, and treatment-emergent adverse event (TEAE) assessments. Participants used an electronic diary to record exploratory efficacy parameters, including intensity of headache pain and associated migraine symptoms (photophobia, phonophobia, and nausea). Participant impression questions were asked at months 3, 6, and 12. Of the 6610 migraine attacks treated with a total of 8234 STS101 doses in 344 participants, 945/6610 (14.3%) were associated with a TEAE. Events were predominantly mild or moderate in nature and rarely led to premature study discontinuation (15/344 [4.4%] participants). Treatment was associated with rapid onset of freedom from pain (36.6%, 67.1%, and 85.5% of treated attacks 2, 4, and 24 h post-dose, respectively), freedom from most bothersome symptoms (54.3%, 79.6%, and 91.3%), and headache relief (66.5%, 89.1%, and 94.3%). Most participants rated treatment results as good or very good and ease of use as easy or very easy at all time points (months 3, 6, and 12) and indicated they were likely or very likely to use STS101 again. The repeated long-term, as-needed use of STS101 was well tolerated, demonstrating a favorable safety profile in the acute treatment of migraine attacks in appropriately indicated adults. Exploratory efficacy evaluations indicated beneficial effects, which warrant further evaluation. ClinicalTrials.gov identification NCT04406649.

Relevance of charged and polar amino acids for functionality of membrane toxin TisB

Bacterial dormancy is marked by reduced cellular activity and the suspension of growth. It represents a valuable strategy to survive stressful conditions, as exemplified by the long-term tolerance towards antibiotics that is attributable to a fraction of dormant cells, so-called persisters. Here, we investigate the membrane toxin TisB (29 amino acids) from the chromosomal toxin-antitoxin system tisB/istR-1 in Escherichia coli. TisB depolarizes the inner membrane in response to DNA damage, which eventually promotes a stress-tolerant state of dormancy within a small fraction of the population. Using a plasmid-based system for moderate tisB expression and single amino acid substitutions, we dissect the importance of charged and polar amino acids. We observe that the central amino acids lysine 12 and glutamine 19 are of major importance for TisB functionality, which is further validated for lysine 12 in the native context upon treatment with the DNA-damaging antibiotic ciprofloxacin. Finally, we apply a library-based approach to test additional TisB variants in higher throughput, revealing that at least one positive charge at the C-terminus (either lysine 26 or 29) is mandatory for TisB-mediated dormancy. Our study provides insights into the molecular basis for TisB functionality and extends our understanding of bacterial membrane toxins.

TV-46000, A Long-Acting Subcutaneous Antipsychotic Agent, Demonstrated Improved Patient-Centered Outcomes in Patients with Schizophrenia.

TV46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone approved for the treatment of schizophrenia in adults. The RISE study (NCT03503318) compared TV-46000 once monthly (q1m) and once every 2months (q2m) with placebo (1:1:1) in patients with schizophrenia who underwent stabilization on oral risperidone. The SHINE study (NCT03893825) evaluated the long-term safety, tolerability, and effectiveness of TV-46000 in patients who completed RISE without relapse (rollover; placebo rollover randomized [1:1] to q1m or q2m; TV-46000 rollover continued assigned treatment) or who were newly recruited (de novo; randomized [1:1] to q1m or q2m after oral stabilization). Patient-centered outcomes included the Schizophrenia Quality of Life Scale (SQLS), the 5-Level EuroQoL 5-Dimensions Questionnaire (EQ-5D-5L), the Personal and Social Performance Scale (PSP), and the Drug Attitudes Inventory 10-item version (DAI-10). In RISE, SQLS least-squares mean changes (SE) improved to last assessment (LA) for TV-46000 q1m (-4.15 [1.03]) and q2m (-3.28 [1.06]) but worsened for placebo (1.75 [1.07]; P<0.001 for both). PSP, EQ5D-5L, and DAI-10 showed similar trends. In SHINE, SQLS decreased (improved) at LA for both TV-46000 q1m (-0.43 [0.98]) and q2m (-2.16 [0.98]); reductions were observed in the de novo (q2m only) and placebo rollover (q1m and q2m) cohorts, but not for the TV46000 rollover cohort. Results for PSP, EQ5D-5L, and DAI-10 were consistent with those reported in the RISE study. Improvements in patient-centered outcomes were observed across cohorts, with the largest improvements observed for patients who began TV-46000 during SHINE (ie, de novo and placebo rollover cohorts), while gains made during RISE were minimally improved or maintained in the TV-46000 rollover cohort, indicating the benefit of uninterrupted TV-46000 treatment. These data support the effectiveness of TV-46000 to improve patient-centered outcomes in patients with schizophrenia.

Case report: A novel high-dose intravenous immunoglobulin preparation for the treatment of severe pemphigus vulgaris failing standard therapy.

Pemphigus vulgaris (PV) is a severe autoimmune bullous dermatosis that is characterized by autoantibodies against epidermal adhesion proteins causing painful mucosal and skin blistering. Standard treatments for PV include corticosteroids, steroid-sparing immunosuppressants, or intravenous monoclonal anti-CD20-antibody therapy. The European guidelines suggest high-dose intravenous immunoglobulin (IVIg) therapy as a promising approach for severe or treatment-resistant cases. We report on a 65-year-old woman with severe and recurrent disease who achieved long-term disease stabilization with IVIg treatment. Because of recurrent fatigue and headache, the patient was switched to an alternative IVIg preparation with a novel manufacturing process, thus ensuring high purity and better tolerability. We observed excellent efficacy, yet side effects remained largely unchanged. Further studies are necessary to evaluate the long-term efficacy and tolerability of this new IVIg preparation.

Epicutaneous immunotherapy for the treatment of peanut allergy.

Peanut allergy treatment options remain limited, but novel approaches are being studied, including epicutaneous immunotherapy (EPIT). EPIT uses the cutaneous immune system to promote tolerance to food allergens. Viaskin™ Peanut, an approach to EPIT in late-stage clinical development uses an occlusive patch with a condensation chamber that enables natural epidermal water loss to solubilize dry antigen on the patch, which is then absorbed and captured by skin Langerhans cells. This form of EPIT does not require disruption of the skin barrier, thus avoiding a proinflammatory cytokine response by targeting the nonvascularized epidermis and limiting systemic allergen exposure. Extensive preclinical research suggests that Viaskin Peanut has a distinct mechanism of desensitization, including the potential for disease modification, driven by a unique population of regulatory T cells. Numerous clinical studies of Viaskin Peanut have demonstrated desensitization and reductions in reaction severity, particularly in children aged 1 through 11 years, as well as a favorable safety profile with mostly mild-to-moderate skin reactions that were observed to decrease over time. EPIT with Viaskin Peanut may be a potential therapeutic option for peanut allergy that is clinically practical with long-term efficacy and tolerability.

Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON)

BackgroundEfficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab’s tolerability and safety profile in individuals experiencing episodic and chronic migraines.MethodsThe study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption (‘drug holiday’) of up to 24 weeks.Results701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed.ConclusionsAPOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment.Trial registrationClinicalTrials.gov ID: NCT04084314 (https://clinicaltrials.gov/study/NCT04084314), First submitted: 2019-09-06.

Effects of dietary interventions for metabolic acidosis in chronic kidney disease: a systematic review and meta-analysis.

Metabolic acidosis is a common complication of kidney disease and can result in further disease progression. Alkali therapy has been used to treat metabolic acidosis for decades. However, some concerns have been raised regarding its safety and long-term tolerability. Existing data suggest that dietary interventions can be beneficial in the management of chronic kidney disease (CKD). This systematic review and meta-analysis aims to summarize findings from studies comparing dietary interventions with placebo/usual care/no treatment in the management of metabolic acidosis in outpatient adults with CKD. Medline, Embase, Cochrane Central, CINAHL, and Web of Science Core Collection were searched from inception to June 2022. Our primary outcome measure was change in serum bicarbonate. Any dietary intervention looking to manipulate dietary acid load was considered as an intervention. Data screening and extraction were performed by two independent reviewers. Random effects meta-analysis was performed to pool data. Dietary interventions resulted in clinically significant improvement in serum bicarbonate (mean difference (MD):2.98, 95% CI: [0.77, 5.19]; I2: 91%) and higher eGFR levels (MD: 3.16, 95%CI: [0.24, 6.08], I2: 67%) compared to controls. Serum potassium, albumin and body mass index remained unchanged. Dietary interventions were reported to be safe. Subgroup analyses indicated a superiority of plant-based over non-plant-based interventions in the improvement of acid-base balance and eGFR, however, these findings are from low quality and heterogenous studies. Our findings support the beneficial effects of dietary interventions aimed at reducing acid or adding base in the management of metabolic acidosis and kidney function in adults with CKD, with no adverse effects on serum potassium and nutritional status. Well-designed clinical trials looking at the treatment of metabolic acidosis with dietary interventions with a focus on adding base through fruit and vegetables are required.

Long-term Tolerance to Islet Transplantation via Targeted Reduction of beta cell-specific T cells.

Activated beta-cell reactive CD4 + and CD8 + T effector cells undergo a profound DNA-damage response which is targetable by small molecule inhibitors of the p53 and cell cycle pathways that lead to apoptosis. The use of a combination of MDM2 and WEE1 inhibitors, which termed "p53 potentiation with checkpoint abrogation" (PPCA), conferred significant therapeutic efficacy in treating mouse models of new onset T1D. Specific targeting of these T effector cells by PPCA results in a loss of inflammatory T cell subsets, notably proliferation CD4 + Th0 and Th1 subsets and CD8 + T effector memory cells, as determined by single cell RNA-seq studies with the preservation of T regulatory cells. When autologous islet grafts are given to established diabetic NOD mice, a single course of PPCA results in long-term islet graft acceptance, restoration of normoglycemia and loss of beta cell specific CD4 + and CD8 + T cells. PPCA shows promise as a potential means of estimating islet graft tolerance in T1D recipients of islet graft transplantation.

Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: A phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+)

ADAPT-SC (NCT04735432) was designed to evaluate noninferiority of subcutaneous (SC) efgartigimod PH20 to intravenous (IV) efgartigimod in participants with generalized myasthenia gravis (gMG). ADAPT-SC+ (NCT04818671) is an open-label extension study designed to assess long-term safety, tolerability, and efficacy of efgartigimod PH20 SC. Adult participants in ADAPT-SC were randomly assigned to receive a treatment cycle of 4 once-weekly administrations of efgartigimod PH20 SC 1000 ​mg or efgartigimod IV 10 ​mg/kg, followed by 7 weeks of follow-up. Primary endpoint was percentage change from baseline in total immunoglobulin G (IgG) level at week 4 (1 week after the fourth administration). Secondary efficacy endpoints assessed number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) responders and mean change from baseline in total score for each measure. The primary endpoint was met, demonstrating noninferiority in total IgG reduction between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg. Clinically meaningful improvements were seen as early as 1 week following the first administration in both treatment arms, with maximal improvements at week 4. Continued treatment cycles of efgartigimod PH20 SC in ADAPT-SC+ have demonstrated long-term safety and consistent improvements in MG-ADL total score. Findings from ADAPT-SC and ADAPT-SC+ demonstrate similar safety and efficacy as observed in the placebo-controlled ADAPT study. Collectively, these findings support noninferiority between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg, as well as long-term safety, tolerability, and efficacy of efgartigimod PH20 SC for treatment of a broad population of patients with gMG.

406.7: Inducing long-term heart allograft tolerance through selective Treg expansion by IL-2 complex treatment.

406.7: Inducing long-term heart allograft tolerance through selective Treg expansion by IL-2 complex treatment.