Johnson & Johnson (Sweden)

Existing models for predicting clinical visual acuity (VA) following lens replacement surgery use controlled experimental conditions where pupil size is typically fixed. However, pupil size may influence visual performance depending on the design of the intraocular lens (IOL) implanted. This study compares optical bench testing metrics to clinical VA in pseudophakic patients with different pupil sizes and IOL models. The area under the modulation transfer function (MTFa) and the weighted optical transfer function (wOTF) were obtained at vergences ranging from -3 D to 0.5 D, and different pupil sizes: 2, 3, and 4.5 mm. The simulated VA values obtained for both metrics were well correlated with clinical data (R2 ≥ 0.85) and had low root mean square errors (RMSe) for the entire defocus range, suggesting their suitability for predicting VA defocus curves in pseudophakic eyes with varying pupil size.

Abstract Recent efforts to improve tuberculosis (TB) treatment options have focused on developing molecules with novel mechanisms of action and identifying optimal treatment regimens. Inhibition of Mycobacterium tuberculosis cytochrome bc1 oxidase has emerged as a promising therapeutic target that could potentially contribute to improved TB combination regimens. Using a relapsing mouse model, we demonstrate that cytochrome bc1 inhibitors could serve as effective partner drugs, enhancing regimen sterilisation. We propose several novel regimen strategies for both multidrug-resistant TB (MDR-TB) and drug-sensitive TB (DS-TB), where cytochrome bc1 inhibitors contribute to sterilisation and treatment shortening. Additionally, we show that clinical isolates exhibit heightened susceptibility to cytochrome bc1 inhibitors compared to laboratory-adapted strains, further supporting their translational potential. These findings suggest that cytochrome bc1 inhibitors have significant potential to improve TB treatment outcomes and highlight the need for further studies to evaluate their clinical contribution to novel treatment regimens.

Abstract Background: Robotic-assisted technologies have been developed to increase surgical precision and reduce surgical variability in total knee arthroplasty (TKA). Several different robotic systems have been introduced in the last decade for TKA. The DePuy Synthes VELYSTM Robotic-Assisted Solution (VRAS) is an imageless system designed to eliminate the need for preoperative CT scans and is one of the latest entrants in the rapidly evolving field of robotic technology in TKA. This study compared the clinical and economic outcomes associated with VRAS compared to other robotic-assisted technology for primary TKA. Methods: A retrospective cohort study using the Premier Healthcare Database included patients who received their primary TKA with VRAS compared with other robotic-assisted technologies from January 1, 2022, to April 30, 2023. The primary outcome for the study was hospital follow-up visits (revisits) within 90 days post-TKA. Secondary outcomes included readmission and revision rates within 90-day post-TKA, operating room time, length of stay, discharge status and hospital costs. Cohorts were balanced using propensity score fine stratification and generalized linear models were constructed to evaluate outcomes. Results: The study included 827 VRAS TKA cases and 16,428 TKA cases performed with other robotic-assisted technologies. The 90-day all-cause and knee-related revisit rates were statistically significantly lower for VRAS compared to other robotic-assisted technologies (all-cause 13.9% vs. 22.8% and knee-related 2.8% vs. 5.4%, respectively, p-value < 0.01). The all-cause and knee-related 90-day readmission rates were also lower for VRAS though the differences were not statistically significant. 90-day revision rates were similar for VRAS and other robotic-assisted technologies (0.48% vs. 0.45%), as was operating room time (138 vs. 137 minutes). The 90-day knee-related cost for the VRAS cohort was $15,048 compared to $16,867 for other robotic technologies. Conclusions: This database study demonstrates that early post-operative revisit rates and total cost of care is lower for VRAS compared to the class of all other robotic-assisted technologies for TKA, while operating room time and discharge status were similar. These are important findings in ever-evolving healthcare systems which are increasingly cost-conscious and cognizant of principles associated with value-based care.

IntroductionCases of severe disease reactivation have been reported after natalizumab and fingolimod discontinuation.AimThe objective of this post-hoc analysis was to evaluate disease activity after short-term ponesimod-in- terruption versus after teriflunomide-washout.MethodsIn OPTIMUM, relapsing MS(RMS) patients were randomised(1:1) to ponesimod20mg or terifluno- mide14mg once-daily for up to 108weeks.Patients who completed the 108-week double-blind treat- ment-period and underwent accelerated elimination procedure for teriflunomide were eligible to enter the OLE(open-label extension study) and receive ponesimod20mg once-daily.ResultsOf 1133 patients in OPTIMUM, 877(77.4%)patients (439PP and 438TP)were enrolled in OLE.Duration of treatment interruption ranged from 13 to 51days(median 16 days).In time to first confirmed relapse at 3months, PPgroup(ponesimod OPTIMUM/ponesimod OLE) had median-time of 49.5days while TPgroup(- teriflunomide OPTIMUM/ponesimod OLE) had 41.0days.At 6months, PPgroup had median-time of 70.0days while TPgroup-44.0days. By OLEMonth3, confirmed relapses in 27PP versus 46TP patients(Kaplan- Meier[K-M] estimates 6.5%and10.8%log-rank p=0.018).By OLE Month6, confirmed relapses in 44PP versus 55TP patients(K-M estimates 11.6%and13.5%log-rank p=0.207). In CUAL analysis of MRI at OLE Week48 compared to end of treatment OPTIMUM, mean-number of CUALs was1.638 in the PPgroup(n=210) and1.693 in the TPgroup(n=231)(p=NS).ConclusionThese findings suggest that disease activity after interruption of ponesimod does not exceed the disease activity observed after teriflunomide washout-a DMT not associated with ‘rebound’ after treatment interruption.

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Teclistamab (TEC) is the first approved BCMA-targeting T-cell redirecting bispecific antibody (BsAb) with pronounced activity in heavily pretreated multiple myeloma (MM; ≥PR in 63.0%). The downside is the high incidence of infections (with median follow-up of 14.1 months: 76.4%; ≥grade 3: 44.8%). This may be explained in part by the long-term exposure to immunosuppressive therapies prior to TEC treatment. However, as BCMA is also expressed on normal plasma cells and a subset of B cells, the effect of BCMA BsAbs on normal immune cells may also play a role. Aims: To assess the impact of TEC on humoral immunity to provide improved guidance on infectious prophylaxis. Methods: Patients (pts) were included in the MajesTEC-1 study and treated with TEC. Eligible MM pts were aged ≥18 y, and had received ≥3 prior lines of therapy including a PI, an IMiD, and an anti-CD38 mAb. For pts treated with the RP2D of 1500 μg/kg TEC (n=165), B-cells and T cells were enumerated in peripheral blood by flow cytometry, and polyclonal IgG, IgA, and IgM levels were assessed by nephelometry or immunoturbidimetric assays. Vaccination responses were evaluated in a subset of pts who were treated in Amsterdam UMC and achieved at least PR after day 1 of cycle 3 (n=21), and these were compared to responses in pts with newly diagnosed MM (n=23), daratumumab-naïve relapsed/refractory (RR) MM (n=11) or daratumumab-treated RRMM (n=20). Vaccination responses were assessed according to local guidelines. Data on polyclonal immunoglobulins and vaccination response were collected until pts received intravenous immunoglobulin therapy (IVIG) or another anti-MM therapy. Results:Ex vivo killing assays showed that TEC depletes BCMA-positive normal plasma cells in bone marrow from healthy donors. TEC treatment also resulted in a rapid decline in circulating B-cells (CD45+CD19+) in pts treated at the RP2D (baseline: median=10.6 x106/L; C2D1: median=0.2 x106/L, p<0.001), which persisted during treatment (C7D1: median=0, p<0.001 [panel A]). In contrast, both CD4 and CD8 T-cells initially decreased but subsequently recovered to baseline levels or higher over time. As expected in these heavily pretreated pts, polyclonal immunoglobulins were suppressed at baseline. After start of TEC therapy, there was a further decrease in polyclonal immunoglobulin levels in sequential peripheral blood serum samples. Notably, a significant reduction in polyclonal IgG was observed (baseline: median=1.4 g/L; C5D1: median=0.8 g/L, p<0.05 [panel B]), as well as decrease in IgA (p<0.001), and IgM (p<0.001). Longitudinal analysis throughout TEC treatment, showed no recovery of polyclonal immunoglobulin levels over time. Vaccination response rates following S. pneumoniae (conjugated PCV-13 [prevenar], followed by the polysaccharide PPV-23 vaccine [pneumovax] 8 weeks later) and H. influenzae vaccination (Act-Hib) was significantly lower in TEC-treated pts (8% and 6%, resp.) versus response in newly diagnosed MM (76% and 88%), daratumumab-naïve RRMM (50% and 78%), or daratumumab-treated RRMM pts (65% and 82%; C and D). Maximum antibody titers were also significantly lower for each individual pneumococcal subtype and for H. influenzae in TEC-treated pts versus the other subgroups. After 3 mRNA vaccinations against COVID-19, none of the pts achieved a protective antibody response. Pts who received IVIG had a lower risk of grade ≥3 infections (16% vs 45% of pts after 6 months, p=0.002). Summary/Conclusion: TEC reduces the levels of polyclonal immunoglobulins and impairs humoral immune response following vaccination, which is explained by rapid depletion of B-cells and normal plasma cells. We recommend the initiation of IVIG supplementation in pts with polyclonal IgG levels <4 g/L to prevent infections.Keywords: Vaccination, Bispecific, Myeloma

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: The treatment landscape of Multiple Myeloma (MM) has evolved in the last decade with the approval of many drugs with different mechanisms of action, improving patient survival1. However, in low-resource regions such as Latin America (LA), the approval and access to novel therapies might be delayed, negatively impacting the outcomes of those patients2. Aims: The MYLACRE study aimed to describe the MM population concerning demographics and clinical characteristics and to profile the treatment landscape of LA MM patients. Methods: This was a retrospective and prospective non-interventional, multicenter study of MM patients treated at reference centers of 5 LA countries. Patients aged ≥ 18 diagnosed with MM between January 1, 2016 and June 30, 2021 were included. Data were extracted from patient´s medical charts between August 2019 and June 2022 and a descriptive analysis was conducted. Results: A total of 1,029 patients from 22 reference centers were enrolled, with a median follow-up of 26.8 months. Two thirds (66.8%) had private health insurance coverage. The median age at diagnosis was 64 years and most of the patients were diagnosed as International Staging System (ISS) stage III (44%). End-organ damage signs and symptoms at diagnosis were reported in most of the patients, with half of them (45.2%) presenting anemia, 12.7% hypercalcemia, 22% renal disfunction and 80.2% bone lesions. Approximately 60% of the patients underwent a cytogenetic test and, of these, one-third (27%) had a cytogenetic abnormality (32% translocation 4;14, 14% translocation 11;14, 20% translocation 14;16, 14% 1q amplification, 37% 17p deletion, 41% other). From the enrolled patients, 1,003 started the first line of therapy (LOT), 405 LOT2, 168 LOT3, 74 LOT4 and 20 LOT5, resulting in an attrition rate of approximately 23-34% from one LOT to the subsequent LOT. The majority of patients (69.9%) were eligible for stem cell transplant (SCT) upfront, but, of those, 26.8% did not receive it and the main reason was insufficient response, disease progression or death before SCT. Considering patients who underwent SCT, the majority in both private and public settings received a proteasome inhibitor (PI)-based therapy and considering those who did not undergo SCT, the majority in the private setting received a PI-based therapy, while in the public setting the majority received an immunomodulatory drug (IMiD) based therapy. The distribution of different regimens by LOT and by health insurance status is described in Table 1. The median progression-free survival (PFS) of LOT1 was 40 months (70 months for patients who underwent SCT and 19.7 months for non-SCT patients). For LOT2, the median PFS was 15.9 months, for LOT3 was 8.9 months, and for later LOT was 4.6 months. The median overall survival (OS) for all patients was 48.9 months. Summary/Conclusion: The attrition rate between subsequent LOTs is high and the pattern of treatment differs between private and public settings. The adoption of novel therapies in LA is still low compared with other regions in the world, and the unmet need is higher in earlier LOTs and for patients with no health insurance. REFERENCES: 1.Bobin A, Leleu X. Recent advances in the treatment of multiple myeloma: a brief review. Fac Rev. 2022 Sep 29;11:28. 2.Tietsche de Moraes Hungria V, Chiattone C, Pavlovsky M, et al. Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study. J Glob Oncol. 2019 Nov;5:1-19.Keywords: Epidemiology, Diagnosis, Treatment, Multiple myeloma

Corticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [34]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone, a 41 amino-acid peptide, urocortin 1, 40 amino-acids, urocortin 2, 38 amino-acids and urocortin 3, 38 amino-acids. CRF1 and CRF2 receptors are activated non-selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0-CRF or [125I]Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF1 receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF2 receptors are selectively antagonized by antisauvagine and astressin 2B.

Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [116, 27]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [9, 54, 64] and FFA4 receptors [45, 52, 94], while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [10, 66, 90] and FFA3 [10, 66] receptors. The crystal structure for agonist bound FFA1 has been described [113].