Italian Drug Agency Research Articles

The use of new antibacterial drugs against infections caused by multidrug-resistant Gram-negative bacteria: an Italian real-world evidence study in a Lombardy hospital.

Infections caused by multidrug-resistant (MDR) bacteria are typically associated with high morbidity and mortality, especially in vulnerable individuals such as patients with prolonged hospitalizations, immunocompromised individuals, and the elderly. This study aimed to provide post-marketing surveillance results concerning the prevalence of antibiotic resistance against Gram-negative bacteria through the collaboration of a multidisciplinary team. Patients involved have been treated with new antibacterial drugs, in particular ceftazidime/avibactam (C/A), meropenem/vaborbactam (M/V), cefiderocol, and ceftolozane/tazobactam (C/T). The most resistant bacterial species were Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter baumannii. Italian Drug Agency (AIFA) monitoring records for inpatients have been collected and analyzed, assessing the characteristics of the patients involved. Adverse drug reactions (ADRs) and drugs involved have been reported using a descriptive analytical approach. All data have been collected retrospectively from patient's medical records and entered into an electronic case report form (CRF). Among the 104 treated patients, Klebsiella spp. accounted for 50.1% of infections, Pseudomonas aeruginosa for 32.7%, Acinetobacter baumannii for 3%, and other bacterial species for 1.92% configuring polymicrobial infections. Regarding treatment outcomes, healing was achieved in 61 (58.6%) patients, 23 (22.1%) patients died, 8 (7.7%) patients discontinued empirical therapy, and 3 (2.9%) patients were lost to follow-up. Despite the introduction of new antibacterial drugs active against Gram-negative bacteria is improving the clinical scenario, it is crucial that the use of new antibacterial drugs be implemented by appropriate antimicrobial stewardship, surveillance programs, and monitoring efforts to prevent further spread of resistance. This study showed that the new antibiotics have good efficacy against MDR bacteria and cause negligible side effects.

The Risks of Phosphate Enemas in Toddlers: A Life-Threatening Unawareness.

While oral laxatives represent the first-line treatment of fecal impaction, enemas are frequently used in clinical practice in pediatric emergency departments (PEDs) and by family pediatricians (FPs). Phosphate-containing enemas (PcEs) are commonly employed, even causing the risk of rare but lethal toxicity. We investigated pediatricians' awareness of PcE risks. We conducted an online survey by sending a multiple-choice questionnaire to the referents of 51 PEDs and 101 FPs. We collected and compared the answers with recommendations reported by the Italian Drug Agency (AIFA) and the available literature about PcE administration. Of the institutions and pediatricians receiving the questionnaire, 23 PEDs (45%) and 63 FP (62.3%) participated in the survey. Of PEDs, 95% and 33.0% of FPs treated fecal impaction with PcE. Moreover, 54% of PEDs and 86.0% of FPs did not provide treatment according to the AIFA recommendations for the daily dose. This study shows limited pediatricians' awareness of the potential risks related to PcE.

Mesenchymal stromal cells loaded with Paclitaxel (PacliMES) a potential new therapeutic approach on mesothelioma

Malignant pleural mesothelioma is an asbestos-related tumor originating in mesothelial cells of the pleura that poorly responds to chemotherapeutic approaches. Adult mesenchymal stromal cells derived either from bone marrow or from adipose tissue may be considered a good model for cell-based therapy, a treatment which has experienced significant interest in recent years. The present study confirms that Paclitaxel is effective on mesothelioma cell proliferation in 2D and 3D in vitro cultures, and that 80,000 mesenchymal stromal cells loaded with Paclitaxel inhibit tumor growth at a higher extent than Paclitaxel alone. An in vivo approach to treat in situ mesothelioma xenografts using a minimal amount of 106 mesenchymal stromal cells loaded with Paclitaxel showed the same efficacy of a systemic administration of 10 mg/kg of Paclitaxel. These data strongly support drug delivery system by mesenchymal stromal cells as a useful approach against many solid tumors. We look with interest at the favourable opinion recently expressed by the Italian Drug Agency on the procedure for the preparation of mesenchymal stromal cells loaded with Paclitaxel in large-scale bioreactor systems and their storage until clinical use. This new Advanced Medicinal Therapy Product, already approved for a Phase I clinical trial on mesothelioma patients, could pave the way for mesenchymal stromal cells use as drug delivery system on other solid tumors for adjuvant therapy associated with surgery and radiotherapy.

RAS testing of circulating cell-free DNA (cfDNA) from tissue RAS/BRAF wild-type metastatic colorectal carcinoma (mCRC) patients: Preliminary data from the Liquid Biopsy Monoclonal Antibodies in mCRC (LIBImAb) study.

3046 Background: In mCRC patients RAS/BRAF testing is usually performed on tissue biopsy in order to select patients for treatment with anti-EGFR monoclonal antibodies. Several studies described discordant RAS status between tissue and cfDNA testing from the same patients. In addition, up to 30% of patients with secondary resistance to anti-EGFR therapies become RAS mutant at progression. The LIBImAb study is a phase III, randomized, open-label, comparative, multi-centre trial to assess the superiority in terms of efficacy of bevacizumab versus cetuximab in combination with FOLFIRI chemotherapy in patients with mCRC, RAS/BRAF wild-type on tumor tissue and RAS mutant (RASmut) at liquid biopsy. This study is supported by the Italian Drug Agency (AIFA). We report preliminary data of liquid biopsy testing. Methods: Plasma samples from enrolled patients are analyzed for variants in exons 2, 3 and 4 of KRAS and NRAS genes and for codon 600 BRAF mutations using the fully automated Idylla system (Biocartis). Patients RASmut on liquid biopsy at baseline are randomized to receive FOLFIRI plus Cetuximab or FOLFIRI plus Bevacizumab. Patients RAS wild-type on cfDNA at baseline, are treated with FOLFIRI plus Cetuximab up to 8 cycles and, if not progressed, they are retested for RAS mutations on cfDNA. RASmut patients at re-screening are randomized to continue Cetuximab or to switch to Bevacizumab. Results: Plasma samples from 169 tissue RAS/BRAF wild-type mCRC patients at baseline and 75 patients at 8 cycles of treatment have been tested as of January 31, 2023. Analysis of baseline plasma samples detected 16 RAS mutations in 16/169 patients (9.5%). In particular, 12 KRAS variants (7.1%, 8 in exon 2 and 4 in exon 3) and 4 NRAS variants (2.3%, all in exon 2) were found. The Idylla test also detected 3 BRAFV600 mutations (1.8%) in 3 additional patients. The overall concordance between tissue and cfDNA testing for RAS/BRAF variants was 88.8%. RAS mutations were also detected in 6/75 (8%) plasma samples obtained at 8 cycles of FOLFIRI/cetuximab treatment. The cfDNA test revealed the presence of 5 KRAS (6.7%, 3 in exon 2 and 1 in exon 3) and 1 NRAS mutation (1.3%, exon 2). A BRAFV600 variant was detected in 1 additional patient (1.3%). The rate of RAS/BRAF mutant cases at 8 cycles of treatment was 9.3%. Conclusions: These preliminary data suggest that liquid biopsy might better recapitulate the heterogeneity of mCRC and might be useful in clinical practice to complement tissue testing. The clinical relevance of RAS variants detected in cfDNA will be determined in the LIBImAb trial.

Analysis of Adherence to anti-PCSK9 Antibody Therapy among Patients from Italy.

Hypercholesterolemia is one of the main risk factors associated with atherosclerotic cardiovascular disease and coronary heart disease. Statins are the standard cholesterollowering treatment; however, they have shown, in clinical practice, a reduced adherence to therapy (<50%) and a modest achievement of the expected outcomes for treatment. This condition prompt scientific research to develop drugs with different mechanisms of action. In this regard, excellent results have been achieved with therapeutic use of monoclonal antibodies against PCSK9, enzyme involved in recycling of Low density lipoprotein receptors (LDLR) on the hepatocytes surface. Indeed, the reduction in receptor density caused by PCSK9 is associated with increased serum LDL levels. After the data extraction of all Local Health Authority (ASL) of Foggia patients (302) who received, in 2021, at least one administration of Alirocumab or Evolocumab, the therapeutic adherence was calculated, for each individual patient, by indirect method (calculation of the Medication Possession Ratio - MPR). According to scientific literature, patients were classified into: adherents (MPR>80%), average adherents (MPR between 40% and 80%) and non-adherents (MPR<40%). Patients were then stratified by gender and age groups (0-18, 19-49, 50-64, >65). The results show that, for both drugs (Alirocumab and Evolocumab), women are more adherent than men and the group of young adults (19-49 years old) is the one with the lowest adherence to therapy, 69% for Alirocumab and 56% for Evolocumab. According to Italian Drug Agency (AIFA), poor therapeutic adherence is the main cause of ineffectiveness of drug therapies, and it is associated with increased hospitalizations, morbidity and mortality. Data obtained from this study allow to detect the categories of patients who need specific programs about the correct use of drugs, in order to increase therapeutic adherence and facilitate the achievement of the expected outcomes for treatment.

Is SARS-CoV-2 Vaccination of Subjects with a Prior History of Allergies Dangerous? Experiences in the Veneto Region of Italy.

Adverse events after SARS-CoV-2 vaccinations have caused alarm to some individuals with previously diagnosed allergies. The aim of this study was to investigate whether the risk of adverse reactions was actually higher in this subgroup. To this end, we carried out an observational descriptive analysis of vaccines administered in a "protected setting" in the Veneto region of Italy between December 2020 and December 2022. Reactions were classified using systemic organic classification (SOC), and their severity was assessed using the criteria of the Italian Drug Agency (AIFA). A total of 421 subjects were vaccinated with 1050 doses, 95.0% of which were administered without adverse events. In all, 53 subjects reported 87 SOC reactions (1.6 reactions/person), and 18.3% of these reactions were severe. One person was hospitalized, but all subjects enjoyed complete remission. Reporting rates were 9.0%, 3.1%, and 1.2% for first, second, and third doses, respectively. The most frequent reactions involved the respiratory system (2.3%), the cutaneous and subcutaneous systems (2.1%), and the nervous system (1.7%). Multivariate analyses (adjOR (95% CI)) revealed that the probability of experiencing at least one reaction significantly declined with increases in age [0.95 (0.94-0.97)] and in the number of doses received, i.e., 75% [0.25 (0.13-0.49)] for second doses and 88% [0.12 (0.04-0.39)] for third doses. These results indicated that vaccinations could be safely administered; few reactions were reported, and there were no permanent adverse outcomes.

Lung Ultrasound Is Useful for Evaluating Lung Damage in COVID-19 Patients Treated with Bamlanivimab and Etesevimab: A Single-Center Pilot Study

Background and Objectives: COVID-19 induces massive systemic inflammation. Researchers have spent much time and effort finding an excellent and rapid image tool to evaluate COVID-19 patients. Since the pandemic's beginning, lung ultrasound (LUS) has been identified for this purpose. Monoclonal antibodies (mAb) were used to treat mild patients and prevent respiratory disease worsening. Materials and Methods: We evaluated 15 Caucasian patients with mild COVID-19 who did not require home oxygen, treated with Bamlanivimab and Etesevimab (Group 1). A molecular nose-throat swab test confirmed the diagnosis. All were office patients, and nobody was affected by respiratory failure. They were admitted to receive the single-day infusion of mAb treatment in agreement with the Italian Drug Agency (AIFA) rules for approval. LUS was performed before the drug administration (T0) and after three months (T1). We compared LUS at T1 in other outpatients who came for follow-up and were overlapping at the time of diagnosis for admittance criteria to receive mAb (Group 2). Results: Our COVID-19 outpatients reported no hospitalization in a follow-up visit after recovery. All patients became SARS-CoV-2 negative within one month since T0. LUS score at T0 was 8.23 ± 6.46. At T1 we found a significant decrease in Group 1 LUS score (5.18 ± 4.74; p < 0.05). We also found a significant decrease in the LUS score of Group 1 T1 compared to Group2 T1 (5.18 ± 4.74 vs 7.82 ± 5.21; p < 0.05). Conclusion: Early treatment of the SARS-CoV-2 virus effectively achieves a better recovery from disease and reduces lung involvement after three months as evaluated with LUS. Despite extrapolation to the general population may be done with caution, based on our data this ultrasound method is also effective for evaluating and following lung involvement in COVID-19 patients.

Cost-effectiveness analysis of gemtuzumab ozogamicin for the treatment of de novo CD33-positive Acute Myeloid Leukaemia (AML) in Italy

BackgroundBased on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service.MethodsFor this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results.ResultsIn the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; €162,424 and €162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT).ConclusionsIf results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML.Trial registrationNot applicable.

EE515 Cost Per Responder Analysis of Methotrexate Versus Other Therapies in the Treatment of Moderate to Severe Plaque Psoriasis in Italy

Conventional synthetic disease modifying antirheumatic drugs (csDMARDs) was recommended in 2019 as first line therapy from Italian Drug Agency (AIFA) for the treatment of moderate to severe psoriasis. Updated local guidelines recommended methotrexate (MTX) as the drug of first choice. Nevertheless, MTX is reported by AIFA to be underused. Since no study evaluated jointly the first-line efficacy and costs of the most widely used biologic/biosimilar drugs (adalimumab, etanercept, secukinumab and ustekinumab) and methotrexate in Italy, a cost per responder analysis was performed.

The Potential Impact of Inducing a Restriction in Reimbursement Criteria on Vitamin D Supplementation in Osteoporotic Patients with or without Fractures.

In October 2019, the Italian Drug Agency (AIFA) restricted reimbursement criteria for vitamin D (VD) use outside the osteoporosis setting (Note 96). However, whether this restriction could also have involved patients at risk for or with osteoporotic fractures has not yet been investigated. We retrospectively analyzed databases from five Italian Local Health Units. Patients aged ≥50 years with either at least one prescription for osteoporosis treatment or with fragility fractures and evidence of osteoporosis from 2011 to 2020 were included. The proportion of subjects with an interruption in VD treatment before and after the introduction of the new reimbursement criteria and predictors of this interruption were analyzed. A total of 94,505 patients (aged 69.4 years) were included. Following the introduction of Note 96, a 2-fold (OR 1.98, 95% CI: 1.92–2.04) increased risk of VD discontinuation was observed. These findings were independent of seasonal variation, osteoporosis treatment patterns, as well as other confounding variables. However, a higher rate of interruption was observed in patients without vertebral/femur fracture (37.8%) vs. those with fracture (32.9%). Rheumatoid arthritis, dyslipidemia and previous fracture were associated with a lower risk of VD interruption, while stroke increased the risk of VD interruption. Our results highlight that a possible misinterpretation of newly introduced criteria for reimbursement restrictions in VD outside of osteoporosis have resulted in an inadequate level of VD supplementation in patients with osteoporosis. This undertreatment could reduce the effect of osteoporosis therapies leading to increased risk of negative outcome.

Adverse Drug Reactions of Acetaminophen and Ibuprofen in the Paediatric Population: Analysis of the Italian Spontaneous Reporting Database.

Acetaminophen and ibuprofen are the only antipyretics drugs approved in children, and are considered safe and well tolerated. However, data regarding the adverse drug reaction (ADR) profile of these drugs in children are scattered. The aim of our study is to evaluate the ADRs of acetaminophen and ibuprofen through an observational study over a period of 15 years (January 2005-April 2020). Reports of suspected ADRs to the active substances 'acetaminophen' and 'ibuprofen' are listed and accessible through the Italian spontaneous reporting database (RAM system) by AIFA (Pharmacovigilance of the Italian Drug Agency). Acetaminophen ADRs in paediatric populations were 15% of cases, with more frequent involvement of skin and soft tissue (54.36%) and gastrointestinal apparatus (44.09%); liver dysfunction accounts for 5.67%. Ibuprofen paediatric ADRs were 26%: skin and soft tissues in 63.16% of cases, gastrointestinal tract in 47.75%, hematemesis and melena in 6.38%; kidney injury in 2.25% of cases. Children aged 2 to 11 are more frequently affected by ADRs than infants and adolescents. The risk of gastrointestinal and renal side effects is significantly higher with ibuprofen. Hepatobiliary side effects are more frequently linked to acetaminophen. Potentially fatal ADRs have been reported sporadically for both drugs.

Ofatumumab or Rituximab for Children with Steroid- and Calcineurin Inhibitor -Dependent Nephrotic Syndrome - &lt;i&gt;A Superiority Randomized Controlled Trial (OFA2)&lt;/i&gt;

Background: The chimeric anti-CD20 monoclonal antibody rituximab has been successfully used in steroid- and calcineurin inhibitor-dependent forms of nephrotic syndrome to maintain oral-drug-free remission, but almost half of patients relapse at one year. Ofatumumab, a fully human anti-CD20 monoclonal antibody, may be superior to rituximab in maintaining remission in these patients. Here, we compared head-to head ofatumumab and rituximab in a randomized controlled clinical trial. Methods: In this single center superiority clinical trial, 140 children and young adults (age 2-24 years) with nephrotic syndrome in remission with steroids and calcineurin-inhibitors were randomized to receive intravenous ofatumumab (1.500 mg/1.73 m2; intervention) or rituximab (375 mg/m2; control). Following infusions, oral drugs were tapered and withdrawn within 60 days. Participants were followed for 36 months. The primary analysis followed an intent-to-treat approach. The primary outcome was relapse at one year, defined by proteinuria (creatinine ratio ≥2000 mg/g). The secondary endpoint included the occurrence of a disease relapse within 24 months from infusion. Cellular and safety data were assessed. Findings: At 12 months, 37 participants relapsed in the ofatumumab arm (52.8%) vs. 36 in the rituximab arm (51.4%; Odds Ratio [OR] 1.06; 95% confidence interval [CI] 0.55 to 2.06). At 24 months, 53 participants relapsed in the ofatumumab arm (75.7%) vs. 46 in the rituximab arm (65.7%; [OR] 1.6 [Cl] 0.8 to 3.3). Analyses stratified by age ≤9 and >9 years supported the same conclusion. Anti-rituximab antibodies did not modify the effects of the intervention. No important side effects occurred during infusion nor during follow up. Higher pretreatment levels of memory and IgM-memory B cells predicted relapse. Interpretation: Ofatumumab is not superior to rituximab in maintaining oral-drug-free remission in children with steroid-and calcineurin inhibitor-dependent nephrotic syndrome. Anti-CD20 antibodies may alter the course of the disease by interfering with memory B cell populations. Clinical Trial Registration Details: Clinical Trials.gov (identifier: NCT02394119) and Eudract.ema.europe.eu (identifier: 2015-000624-28). Funding Information: PR, FL, FM and GMG were supported by the Italian Ministry of Health, Ricerca Finalizzata, grant: WFR:PE-2016-02361576. MC and MV are supported by the Associazione per la Cura del Bambino Nefropatico ONLUS. GMG, MB, and MC are supported by ‘’Fondazione Malattie Renali del Bambino” ONLUS. The Institute Giannina Gaslini (trial sponsor) provided logistic and financial through grant ‘Cinque per mille of IRPEF-Finanziamento della ricerca sanitaria’. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Declaration of Interest: Authors declare no competing interests. Ethical Approval: We obtained study approval from the local Independent Ethics Committee (ComitatoEticoRegione Liguria), the Italian Drug Agency (AgenziaItaliana del Farmaco, AIFA).

High Dose Ivermectin for the Early Treatment of COVID-19 (COVIER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

Background: High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with initial SARS-CoV-2 infection. Methods: Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial performed in outpatients in Italy. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; participants under dialysis; severe medical condition with prognosis Findings. From 31th July, 2020 to 26th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively). Interpretation: High- dose ivermectin demonstrated safe, but did not prove efficacy to reduce viral load.Trial Registration: The protocol was registered with ClinicalTrials.gov , NCT04438850. Funding: The trial was partly funded by the Italian Ministry of Health.Declaration of Interest: None to declare. Ethical Approval: This study was approved by the national Ethics Committee of INMI – Spallanzani in Rome that is competent for all COVID-19 trials in Italy (resolution 139/2020 of 28th May, 2020), and by the Italian drug agency AIFA (resolution 136BIS/2020 of 18th May, 2020).

Humoral and Cellular Immune Response Elicited by mRNA Vaccination Against SARS-CoV-2 in People Living with HIV (PLWH) Receiving Antiretroviral Therapy (ART) According with Current CD4 T-Lymphocyte Count

Background: Data on SARS-CoV-2 vaccine immunogenicity in PLWH are currently limited. Aim of the study was to investigate immunogenicity according to current CD4 T-cell count and predictive role on immune response to vaccination in PLWH.Methods: PLWH attending a single-center SARS-CoV-2 vaccination program in Italy, were included in a prospective evaluation for immunogenicity after receiving BNT162b2 or mRNA-1273. PLWH were stratified according to current CD4 T-cell count (severe immunodeficiency, SID: 500/mm 3 ). RBD-binding IgG, SARS-CoV-2 neutralizing antibodies (nAbs) and cell-mediated (IFN-γ/IL-2) immune response were measured. As control group, not-matched HIV-negative healthcare workers (HCWs) were used.Findings: Participants were 166 PLWH (SID=32; MID=56; NID=78) on ART. After 1 month from the booster dose, detectable RBD-binding IgG in 86.7% of SID, in 100% of MID, in 98.7% of NID (SID vs NID, p=0.021) and nAbs (titre ≥1:10) in 70.0%, 88.2% and 93.1%, respectively (SID vs NID, p=0.002), were elicited. Compared to NID, magnitude of anti-RBD, nAbs and IFN-γ production was significantly lower in SID and comparable in MID. After adjusting for confounders, current CD4 T-cell Interpretation: Neutralizing and cell-mediated immune response against SARS-CoV-2 were elicited in most of PLWH receiving ART, albeit significantly poorer in those with current CD4 T-cell 500/mm 3 and HIV-negative controls. A marginal decreased immunogenicity than HCWs was also observed in PLWH with CD4 T-cell 200-500/mm 3 , whereas immune response elicited in PLWH with a CD4 T-cell >500/mm 3 was comparable to HIV-negative population.Funding: Italian Ministry of Health; European Commission, European Virus Archive – GLOBAL.Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Scientific Committee of the Italian Drug Agency (AIFA) and by the Ethical Committee of the Lazzaro Spallanzani Institute, as National Review Board for COVID-19 pandemic in Italy (approval number 323/2021).

Checkpoint Inhibition before Axicabtagene Ciloleucel Cell Therapy in Primary Mediastinal B-Cell Lymphoma (PMBCL) Treated in Real Life Setting

Background: Eighty-five percent of PMBCL are cured by standard therapy, but the outcome of refractory/relapsed (R/R) PMBCL is very poor. Checkpoint inhibitors (CPIs) have shown promising activity in relapsed PMBCL. Axibactagene ciloleucel (axi-cel) CAR-T cell therapy, can induce durable responses and is currently approved for the treatment of adult patients with R/R PMBCL. Aims of this analysis were: to register all Italian PMBCL patients candidate to CAR-T in the 6 active centers;to evaluate the intention to treat overall response rate (ORR, complete [CR] and partial response [PR]) in patients treated with axi-cel and CPIs for salvage or bridging before CAR-T and for relapse after CAR-T;to evaluate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Methods: In August 2019 the Italian Drug Agency (AIFA) approved axi-cel; before the reimbursement by AIFA, an expanded access program supported by Kite/Gilead started. One patient slot per month per qualified center was available. Patients were included in a large national CAR-T prospective observational study approved by ethics committees. Results: Since April 2019 to March 2020, 20 R/R PMBCL were evaluated and 18 were apheresized in order to receive axi-cel; 2 were excluded because active CNS disease in one, and eligibility to transplant, while in CR, in the second one. Their clinical characteristics were: median age 38 years (range 22-50), male 8 (44%), stage II 6 (33%), advanced stage III/IV 12 (66%), bulky disease 6 (33%); LDH upper than normal 3 (2%). Median number of prior lines was 3 (2-6); 5 patients (28%) had a previous autologous stem cell transplant and 12 (66%) received a prior radiotherapy. The majority of patients, 16 (89%) were refractory to the last treatment when they were evaluated for CAR-T eligibility; 9 of 18 patients had CPI exposure before leukoapheresis: 6 pembrolizumab and 3 nivolumab in combination with brentuximab-vedotin. No manufacturing failures were reported. Bridging therapy was performed in 16 of 18 patients (88%). Seventeen patients (94%) received lymphodepleting Flu-Cy chemotherapy and only 16 pts received CAR-T for central nervous system (CNS) progression during bridging therapy (n=1) and respiratory failure due to pneumonia (n=1); the 2 patient not infused were exposed to CPIs. Median vein to vein time was 40 days (30-79). Median follow-up time for infused patients was 209 days (9-444). CRS was observed in 12 of 16 infused patients: 5 grade 2 and 7 grade 1. ICANS (2 grade 1, 2 grade 2, 1 grade 3) was recorded in 5 patients. No differences regarding CRS and ICANS occurrence were observed in patients exposed or not to CPIs. At 30-days after the infusion, all the 16 infused patients were evaluable for response: 7 (44%) CR, 5 (31%) PR, with ORR 75%, 3 (19%) stable disease (SD) and 1 (6%) progressive disease (PD). Two patients in PR at 30 days converted to CR at 90 days, with continuous CR at 180 days; all the 3 patients in SD and 1 out of 5 in PR at 30 days progressed at 90 days. Considering the 9 patients exposed to CPIs before CAR-T, 7 out of 9 were infused and all the 7 infused were evaluable for response: 2 (29%) CR, 4 (57%) PR, with ORR 86%, and 1 (14%) died because of a rapid CNS progression after infusion. Two patients in PR at 30-days converted to CR at 90-days, one with continuous CR at 180 days after CAR-T. Conclusions: In our series of 16 infused patients, axi-cel was effective with an ORR of 75% (CR 44%) at 30-days after CAR-T infusion and ORR of 54% (CR 46%) in the 13 patients evaluable at the median follow-up time (180-days after CAR-T infusion). It is important to note the 4 patients from the original real life cohort never received axi-cel. It is noteworthy that ORR was 86% in patients receiving CPIs before CAR-T and 75% in those not exposed to CPIs. With the limitation of small number, the exposure of immune-checkpoint inhibitors seems not to affect negatively response rate and adverse events. Disclosures Chiappella: Janssen: Honoraria; Iqone: Honoraria; Servier: Honoraria; Roche: Honoraria; Celgene: Honoraria; Gilead-Kite: Honoraria; Takeda: Honoraria. Zinzani:Bayer: Consultancy. Corradini:BMS: Other; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria.

Trials and tribulations of coronavirus disease-2019 research: with a few bright lights in the fog.

Trials and tribulations of coronavirus disease-2019 research: with a few bright lights in the fog.

Value-based healthcare: Il nuovo approccio di AIFA alla determinazione multidimensionale del valore

In this viewpoint, we discuss the approach promoted by the Italian Drug Agency (AIFA) to the assessment of the value of new pharmaceuticals in the Italian Healthcare Service. On top of traditionally acknowledged components, such as quality adjusted life years gained and net costs, the overall value framework might include other elements such as productivity and adherence, equity, severity of disease, reduction in uncertainty, spillover effects. There is a residual dimension in the value framework that may capture the option value or reduction in fear of contagion for infectious disease treatments. We debate measurement issues on these elements of value and discuss open issues from a methodological and policy standpoint.

Access of medicines to the market: three years' experience of Sicily's regional drug formulary

BACKGROUND: In Italy, pharmaceutical market access depends on European Medicines Agency (EMA), Italian national drug agency (AIFA) and regional regulatory procedures (Sicilian Drug Formulary Committee). The regulatory and economic outcomes of the Sicilian Regional Drug Formulary Committee have not yet been described. The objective of this study was to quantify: 1) the number of drugs approved regionally; 2) the drug review time by European, national and regional competent authorities; 3) regional healthcare expenditure associated with the approved drugs. METHODS: All drugs approved by the Sicilian Drug Formulary Committee between 1st January 2013 to 1st April 2016 were identified. For these drugs, the median (with interquartile range, IQR) approval time taken by the European, national and regional competent authorities were estimated for all drugs and innovative drugs separately. Finally, the economic impact of regional regulatory decisions was estimated one year after drug approval. RESULTS: In total 117 drugs were approved. Median (IQR) time between EMA and AIFA approval was 1.17 years (0.93-1.66), while between AIFA and the Sicilian regional approval this was 0.35 years (0.27-0.94). The time elapsed for innovative drugs was 0.91 years (IQR: 0.66-1.75) between EMA and AIFA and 0.13 years (IQR: 0.02-0.25) between AIFA and Sicilian regional approval. Regional drug approvals were associated with a yearly cost of 525,489,586. CONCLUSIONS: The approval of 117 drugs over 3 years was associated with a 525 million pharmaceutical expenditure yearly. The total median time for pharmaceutical market access in Sicily was 1.52 years, and 1.04 years for innovative drugs.

Treatment of Graves' hyperthyroidism with thionamides: a position paper on indications and safety in pregnancy.

Graves' disease affects 3% of women and 0.5% of men in the general population. The first line treatment of Graves' hyperthyroidism is based on the administration of antithyroid drugs (ATD), propylthiouracil (PTU), methimazole (MMI) and carbimazole. A recent warning from the Italian Drug Agency (Agenzia Italiana del Farmaco AIFA) reported the risk of MMI-induced acute pancreatitis. In addition, AIFA highlighted the possible association of MMI treatment during the first trimester of pregnancy with congenital malformations, thus recommending the use of effective contraceptive methods in women of childbearing age treated with MMI. Revision of literature reported less than ten cases of the alleged MMI pancreatitis, allowing the inclusion of MMI in class III drug regarding the relative risk for drug-induced pancreatitis. Data available on the effect of hyperthyroidism per se on the risk of fetal malformations, although scanty, are sufficient to recommend treatment with ATD of the hyperthyroid pregnant woman. Case reports and population studies either suggesting or not suggesting MMI-induced fetal malformations do not allow unquestionable conclusions on this matter. This consensus by experts from Italian Endocrine and Gynecologic Scientific Societies has edited recommendations derived form the available data and published guidelines of International Scientific Societies.

1657P - The new mutational model in oncology. What changes in welfare, clinical practice, research, and regulatory procedures?

BackgroundThe diffusion of next-generation sequencing (NGS)-based tests for comprehensive genomic profiling (CGP), the development of new drugs matching specific genetic alterations, and the recent “agnostic approval” processes of anti-cancer agents represent an important innovation that favors the development of Precision Oncology. This “mutational model” supports and integrates the traditional approach to cancer therapy based on histology. Nevertheless, an uncontrolled use of CGP tests and of mutation-driven drugs can compromise their appropriateness, and put the sustainability of the health system at risk. MethodsA group of experts in pathology, molecular biology, medical oncology, organization of health systems and health economics has developed an organizational model for precision oncology based on multidisciplinarity, on the careful selection of patients to be submitted to CGP tests and on access to off-label drugs in the context of a regulatory framework. ResultsA network of Molecular Tumor Board (MTB) accredited by the Italian Drug Agency (AIFA) according to transparent criteria with regard to composition, activities, traceability, and processing of data can represent the very new tool for managing the mutational model in clinical practice. The multidisciplinary MTBs meet regularly to select patients to be analyzed with CGP tests in order to ensure the appropriateness of the test. The MTBs also discuss therapeutic options on information deriving from NGS analyses. When no clinical trials matching the genetic alterations are available and an off-label drug is recommended, this therapy will be authorized by the Italian Drug Agency and data on the outcome of the patients will be stored in a national registry. ConclusionsThe increasing availability of CGP tests and of possibly active targeted-based agents represents an important opportunity of cancer patients to access to new drugs. The proposed model will allow access of Italian patients to possibly active treatments and at the same time will contribute to ensure the sustainability of this new approach and to increase the knowledge on the activity of target-based agents in specific subgroups of patients. Legal entity responsible for the studyThe authors. FundingFondazione Ricerca&Salute. DisclosureAll authors have declared no conflicts of interest.