Severe Injection Site Reactions Research Articles

Effectiveness of Switching to Subcutaneous Infliximab in Ulcerative Colitis Patients Experiencing Intravenous Infliximab Failure.

Studies on elective switching to the subcutaneous (SC) formulation of infliximab revealed comparable efficacy and safety and higher infliximab level than those exhibited by intravenous (IV) infliximab. However, no studies have reported on the effectiveness of SC switching in ulcerative colitis (UC) patients who experienced IV infliximab failure during maintenance treatment. This retrospective study included UC patients who had been switched to SC infliximab because of IV infliximab failure, between January 2021 and January 2023. Group A was defined as having clinically and biochemically active UC (secondary loss of response), and group B consisted of patients with stable symptoms but biochemically active UC. Twenty-three patients met the inclusion criteria: 15 in group A and eight in group B. The serum infliximab levels significantly increased after SC switching in both groups. The electively switched group also exhibited increased infliximab levels after SC switching. Patients in group A showed improved partial Mayo score with a significant decrease in fecal calprotectin and C-reactive protein after switching. In group B, the fecal calprotectin level significantly decreased without clinical relapse after switching. A high proportion of patients (≥80%) in both groups achieved clinical and/or biochemical responses at the last follow-up. During the follow-up period, only two patients in group A discontinued SC infliximab, and only one complained of severe injection site reaction. In UC patients who experience IV infliximab failure during maintenance treatment, switching to SC infliximab may be a promising option because of better efficacy and safety.

P585 Effectiveness of Switching to Subcutaneous Infliximab in Ulcerative Colitis Patients Experiencing Intravenous Infliximab Failure

Abstract Background Studies on elective switching to the subcutaneous (SC) formulation of infliximab revealed comparable efficacy and safety and higher infliximab level than those exhibited by intravenous (IV) infliximab. However, no studies have reported on the effectiveness of SC switching in ulcerative colitis (UC) patients who experienced IV infliximab failure during maintenance treatment. Methods This retrospective study included UC patients who had been switched to SC infliximab because of IV infliximab failure, between January 2021 and January 2023. Group A was defined as having clinically and biochemically active UC (secondary loss of response), and group B consisted of patients with stable symptoms but biochemically active UC. Results Twenty-three patients met the inclusion criteria: 15 in group A and 8 in group B. The serum infliximab levels significantly increased after SC switching in both groups. Electively switched group also exhibited increased infliximab levels after SC switching. Group A showed improved partial Mayo score with a significant decrease in faecal calprotectin (FC) and C-reactive protein after switching. In group B, the FC level significantly decreased without clinical relapse after switching. A high proportion of patients (≥ 80%) in both groups achieved clinical and/or biochemical response at last follow-up. During the follow-up period, only two patients in group A discontinued SC infliximab, and only one complained of severe injection site reaction. Conclusion In UC patients who experience IV infliximab failure during maintenance treatment, switching to SC infliximab may be a promising option because of its efficacy and safety.

Non-Invasive Transdermal Delivery of Antisense Oligonucleotides with Biocompatible Ionic Liquids.

Nucleic acid drugs, including antisense oligonucleotides (ASOs), have received considerable attention as novel therapeutics for the treatment of intractable diseases. Despite their potential benefits, ASOs are currently administered via injection, which can negatively impact patient quality of life because of the prevalence of severe injection site reactions. Non-invasive transdermal administration of ASOs is desirable but highly challenging owing to the strong barrier imposed by the stratum corneum, which only permits the penetration of small molecules under 500 Da. For ASOs to exert their antisense effect, they must traverse the negatively charged cell membrane and reach the cytoplasm. In this study, we used the solid-in-oil (S/O) dispersion technology to facilitate the skin permeation of ASOs by coating the drug with a hydrophobic surfactant molecule, specifically lipid-based ionic liquid (IL) surfactants with high biocompatibility and transdermal penetration-enhancing properties. To induce the antisense effect, it was important to achieve simultaneous transdermal delivery and intracellular entrapment of ASOs. In vitro investigations indicated that the newly prepared IL-S/O enhanced the transdermal penetration and intracellular delivery of ASOs, thus inhibiting mRNA translation of the target TGF-β. In addition, in vivo investigations of tumor-bearing mice suggested that the anti-tumor effect of the IL-S/O was similar to that of injection. This study demonstrates the potential of non-invasive transdermal delivery carriers based on biocompatible ILs, which can be applied to a variety of nucleic acid drugs.

P703 Real world experience of the transition from the intravenous to subcutaneous formulation of vedolizumab in inflammatory bowel disease: A review of current data

Abstract Background Vedolizumab (VDZ), a gut selective antilymphocyte trafficking anti-α 4β 7 integrin monoclonal antibody indicated for the treatment of IBD. After a 3 doses induction, maintenance can be achieved with a standard 8-weekly (Q8W) regimen, or–at any time during the maintenance– patients can be transitioned to 108 mg subcutaneous (SC) formulation at a standard 2 weekly (Q2W) regimen. Methods This was a literature review to identify real-world studies on the transition from the IV to SC VDZ. The Pubmed and Embase databases were searched up to October 2022 to identify publications on real-world data on the transition from IV to SC VDZ. Results In total, 9 studies were identified with a total of 1,323 IBD patients in the UK (5 studies), Norway, Sweden, Belgium and The Netherlands1-9. Two prospective studies reported no loss of effectiveness based on disease activity scores of VDZ after the IV-SC transition 1,2, along with maintenance of baseline status (status at the time of transition) reported in 84% of patients1. Biomarkers stability, including fecal calprotectin and C-reactive protein, were reported in three studies3-5. Persistence with VDZ treatment following IV-SC transition was 96% at 6 months and 89% at 12 months in one study3, while another study reported persistence of 86% at 6 months6. A preference for the SC formulation by patients was reported 59% and 56% in two studies7,8, with time savings and fewer hospital visits recorded as the main reasons for preference of the SC formulation7. Multivariate analysis of patient characteristics in two studies7,8 revealed no factor associated with preference for VDZ SC other than younger age in one study8. The most frequently reported adverse events with VDZ SC were injections site reactions: 15% and 18% in two studies1,5, with transient severe injection site reactions reported in 1% of patients in one study3. Conclusion Real-world data on IBD patients who transitioned from IV to SC VDZ showed no change in effectiveness, with a majority preferring the SC formulation due to time savings and the transition leading to fewer hospital visits. Safety of VDZ SC was generally comparable with that of IV VDZ.

Effect of different adjuvant formulations on the antibody response of horses to porcine zona pellucida proteins

Immunization with porcine zona pellucida (PZP) proteins is being used successfully to induce infertility in wildlife including horses. However, widespread adoption of this method to control the growth of horse populations requires further refinement in order to induce long-term infertility, reduce the frequency and severity of injection site reactions, and make the vaccines easier to administer. The next generation of PZP-based vaccines will likely be a controlled-release formulation with different adjuvants from the Freund’s adjuvants used in existing vaccines. We evaluated the response of equine peripheral blood mononuclear cells to a cationic nanoparticle adjuvant, Nano-11, alone and with the TLR agonists poly(I:C) and CpG ODN as a screen to develop an adjuvant system suitable for immunization of horses. The secretion of IL-1β, TNF and CXCL10 were used as readouts. The combination of poly(I:C) with Nano-11 significantly increased the secretion of IL-1β and TNF in comparison with Nano-11 only, with little effect of further addition of CpG ODN. The efficacy of the Nano-11/poly(I:C) adjuvant to enhance the immune response to native PZP proteins was determined in horses. Horses were immunized twice with the licensed Zonastat-H vaccine or PZP with Nano-11/poly(I:C) emulsified in silicone oil. A third group received PZP with the saponin adjuvant QA-21 emulsified in silicone oil. The horse sera collected monthly after the injections had increased anti-PZP IgG antibodies with the strongest response observed with Zonastat-H. We conclude that Nano-11/poly(I:C) is a potential candidate for the development of a controlled release formulation of a next generation PZP-based immunocontraception.

Safety and immunogenicity of VPM1002 versus BCG in South African newborn babies: a randomised, phase 2 non-inferiority double-blind controlled trial

Tuberculosis is a major public health problem worldwide. Immunisation with Mycobacterium bovis BCG vaccine is partially effective in infants, reducing the incidence of miliary and tuberculosis meningitis, but is less effective against pulmonary tuberculosis. We aimed to compare safety and immunogenicity of VPM1002-a recombinant BCG vaccine developed to address this gap-with BCG in HIV exposed and HIV unexposed newborn babies. This double-blind, randomised, active controlled phase 2 study was conducted at four health centres in South Africa. Eligible neonates were aged 12 days or younger with a birthweight of 2·5-4·2 kg, and could be HIV exposed (seropositive mothers) or unexposed (seronegative mothers). Newborn babies were excluded if they had acute or chronic illness, fever, hypothermia, sepsis, cancer, or congenital malformation, or if they received blood products or immunosuppressive therapy. Participants were excluded if their mothers (aged ≥18 years) had active tuberculosis disease, diabetes, a history of immunodeficiency except for HIV, hepatitis B or syphilis seropositivity, received blood products in the preceding 6 months, any acute infectious disease, or any suspected substance abuse. Participants were randomly assigned to VPM1002 or BCG vaccination in a 3:1 ratio, stratified by HIV status using the random number generator function in SAS, using a block size of eight paticipants. The primary outcome was non-inferiority (margin 15%) of VPM1002 to BCG vaccine in terms of incidence of grade 3-4 adverse drug reactions or ipsilateral or generalised lymphadenopathy of 10 mm or greater in diameter by 12 months. The primary outcome was assessed in all vaccinated participants (safety population) at regular follow-up visits until 12 months after vaccination. Secondary immunogenicity outcomes were interferon-γ levels and percentages of multifunctional CD4⁺ and CD8⁺ T cells among all lymphocytes across the 12 month study period. The study was registered with ClinicalTrials.gov, NCT02391415. Between June 4, 2015 and Oct 16, 2017, 416 eligible newborn babies were randomly assigned and received study vaccine. Seven (2%) of 312 participants in the VPM1002 group had a grade 3-4 vaccine-related adverse reaction or lymphadenopathy of 10 mm or greater in diameter compared with 34 (33%) of 104 participants in the BCG group (risk difference -30·45% [95% CI -39·61% to -21·28%]; p_{non-inferiority}<0·0001); VPM1002 was thus non-inferior to BCG for the primary outcome. Incidence of severe injection site reactions was lower with VPM1002 than BCG: scarring occurred in 65 (21%) participants in the VPM1002 group versus 77 (74%) participants in the BCG group (p<0·0001); ulceration occurred in one (<1%) versus 15 (14%; p<0·0001); and abscess formation occurred in five (2%) versus 23 (22%; p<0·0001). Restimulated IFNγ concentrations were lower in the VPM1002 group than the BCG group at week 6, week 12, month 6, and month 12. The percentage of multifunctional CD4⁺ T cells was higher in the VPM1002 group than the BCG group at day 14 but lower at week 6, week 12, month 6, and month 12. The percentage of multifunctional CD8⁺ T cells was lower in the VPM1002 group than the BCG group at week 6, week 12, and month 6, but did not differ at other timepoints. VPM1002 was less reactogenic than BCG and was not associated with any serious safety concern. Both vaccines were immunogenic, although responses were higher with the BCG vaccine. VPM1002 is currently being studied for efficacy and safety in a multicentric phase 3 clinical trial in babies in sub-Saharan Africa. Serum Institute of India.

Severe injection site reaction ensuing the first dose of mRNA COVID-19 vaccine.

Severe injection site reaction ensuing the first dose of mRNA COVID-19 vaccine.

Colonoscopy-guided therapy for the prevention of post-operative recurrence of Crohn's disease.

About half of patients with Crohn's disease (CD) require surgery within 10 years of diagnosis. Resection of the affected segment is highly effective, however the majority of patients experience clinical recurrence after surgery. Most of these patients have asymptomatic endoscopic recurrence weeks or months before starting with symptoms. This inflammation can be detected by colonoscopy and is a good predictor of poor prognosis.Therapy guided by colonoscopy could tailor the management and improve the prognosis of postoperative CD. To assess the effects of prophylactic therapy guided by colonoscopy in reducing the postoperative recurrence of CD in adults. The following electronic databases were searched up to 17 December 2019: MEDLINE, Embase, CENTRAL, Clinical Trials.gov, WHO Trial Registry and Cochrane IBD specialized register. Reference lists of included articles, as well as conference proceedings were handsearched. Randomised controlled trials (RCTs), quasi-RCTs and cohort studies comparing colonoscopy-guided management versus management non-guided by colonoscopy. Two review authors independently considered studies for eligibility, extracted the data and assessed study quality. Methodological quality was assessed using both the Cochrane 'Risk of bias' tool for RCTs and Newcastle-Ottawa scale (NOS) for cohort studies. The primary outcome was clinical recurrence. Secondary outcomes included: endoscopic, surgical recurrence and adverse events. We calculated the risk ratio (RR) for each dichotomous outcome and extracted the hazard ratio (HR) for time-to-event outcomes. All estimates were reported with their corresponding 95% confidence interval (CI). Data were analysed on an intention-to-treat (ITT) basis. The overall quality of the evidence was evaluated using GRADE criteria. Two RCTs (237 participants) and five cohort studies (794 participants) met the inclusion criteria. Meta-analysis was not conducted as the studies were highly heterogeneous. We included two comparisons. Intensification of prophylactic-therapy guided by colonoscopy versus intensification guided by clinical recurrence One unblinded RCT and four retrospective cohort studies addressed this comparison. All participants received the same prophylactic therapy immediately after surgery. In the colonoscopy-based management group the therapy was intensified in case of endoscopic recurrence; in the control group the therapy was intensified only in case of symptoms. In the RCT, clinical recurrence (defined as Crohn's Disease Activity Index (CDAI) > 150 points) in the colonoscopy-based management group was 37.7% (46/122) compared to 46.1% (21/52) in the control group at 18 months' follow up (RR 0.82, 95% CI: 0.56 to 1.18, 174 participants, low-certainty evidence). There may be a reduction in endoscopic recurrence at 18 months with colonoscopy-based management (RR 0.73, 95% CI 0.56 to 0.95, 1 RCT, 174 participants, low-certainty evidence). The certainty of the evidence for surgical recurrence was very low, due to only four cohort studies with inconsistent results reporting this outcome. Adverse events at 18 months were similar in both groups, with 82% in the intervention group (100/122) and 86.5% in the control group (45/52) (RR 0.95, 95% CI:0.83 to 1.08, 1 RCT, 174 participants, low-certainty of evidence).The most common adverse events reported were alopecia, wound infection, sensory symptoms, systemic lupus, vasculitis and severe injection site reaction. Perforations or haemorrhages secondary to colonoscopy were not reported. Initiation of prophylactic-therapy guided by colonoscopy versus initiation immediately after surgery An unblinded RCT and two retrospective cohort studies addressed this comparison. The control group received prophylactic therapy immediately after surgery, and in the colonoscopy-based management group the therapy was delayed up to detection of endoscopic recurrence. The effects on clinical and endoscopic recurrence are uncertain (clinical recurrence until week 102: RR 1.16, 95% CI 0.73 to 1.84; endoscopic recurrence at week 102: RR 1.16, 95% CI 0.73 to 1.84; 1 RCT, 63 participants, very low-certainty evidence). Results from one cohort study were similarly uncertain (median follow-up 32 months, 199 participants). The effects on surgical recurrence at a median follow-up of 50 to 55 months were also uncertain in one cohort study (RR 0.79, 95% CI 0.38 to 1.62, 133 participants, very low-certainty evidence). There were fewer adverse events with colonoscopy-based management (54.8% (17/31)) compared with the control group (93.8% (30/32)) but the evidence is very uncertain (RR 0.58, 95% CI 0.42 to 0.82; 1 RCT, 63 participants). Common adverse events were infections, gastrointestinal intolerance, leukopenia, pancreatitis and skin lesions. Perforations or haemorrhages secondary to colonoscopy were not reported. Intensification of prophylactic-therapy guided by colonoscopy may reduce clinical and endoscopic postoperative recurrence of CD compared to intensification guided by symptoms, and there may be little or no difference in adverse effects. We are uncertain whether initiation of therapy guided by colonoscopy impacts postoperative recurrence and adverse events when compared to initiation immediately after surgery, as the certainty of the evidence is very low. Further studies are necessary to improve the certainty of the evidence of this review.

237-OR: Insulin Icodec: An Insulin Analog Suited for Once-Weekly Dosing in Type 2 Diabetes

Insulin icodec* is a novel basal insulin analog designed for single once-weekly (OW) subcutaneous injection. This randomized, double–blind, double–dummy trial investigated the pharmacokinetics (PK), pharmacodynamics (PD) and safety of insulin icodec. Fifty individuals with type 2 diabetes (insulin treated±metformin; 43 men; mean±SD age 57±5 years, BMI 30.1±2.7 kg/m2, A1C 7.4±0.6%) received OW insulin icodec (12, 20 or 24 nmol/kg) plus once–daily (OD) placebo (N=13, 13, 12) or OD insulin degludec (0.4 U/kg) plus OW placebo (N=12) for 5 weeks in 3 dose level cohorts. PD properties were investigated at close to steady state in 24-h glucose clamps on days 2 and 7 after the last insulin icodec dose. Median tmax,insulin icodec was 16 h and geometric mean t½,insulin icodec was 196 h with no systematic differences between dose levels. The glucose–lowering effect over a weekly dosing interval was derived from the observed PK/PD data using a PK/PD model and showed close to even distribution over the 7 days across all dose levels (Figure). The adverse event (AE) incidence did not increase with increasing insulin icodec dose (100%, 69%, 75%, respectively). There were no serious or severe AEs, severe hypoglycemic episodes or injection site reactions. In conclusion, insulin icodec was safe and well-tolerated and showed PK/PD properties supporting once-weekly administration at clinically relevant dose levels. * Proposed INN. Disclosure U. Hövelmann: None. L. Brøndsted: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. N.R. Kristensen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. R. Ribel-Madsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J. DeVries: Advisory Panel; Self; Novo Nordisk A/S, Zealand Pharma A/S. Consultant; Self; Metronom Health. Employee; Self; Profil Institute for Clinical Research. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. H. Haahr: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Novo Nordisk

Observed discordance between outcomes reported by acromegaly patients and their treating endocrinology medical provider

BackgroundAcromegaly patients, even those with IGF-1 values within the normal range receiving somatostatin receptor ligands (SRLs), often suffer from significant symptoms. It is not known to what extent patients’ medical providers are aware of the frequency and severity of acromegaly symptoms or level of treatment satisfaction with SRLs. This study sought to examine the concordance between outcomes reported by acromegaly patients treated with long-acting SRLs and those perceived by their medical provider.MethodsUS acromegaly patients on a stable dose of SRL and seen by their medical provider in the past year completed an online survey which included the Acro-TSQ. Their medical providers were interviewed about the perception of their patient’s symptoms, level of control, and general health, and completed relevant portions of the Acro-TSQ. Concordance between patient and medical provider reported data was examined.ResultsMedical providers reported that their patients experienced acromegaly symptoms on a regular basis, however, there was poor agreement between patients and medical providers on the frequency, severity, and pattern of symptoms, as well as on the severity of injection site reactions and multiple domains of the Acro-TSQ, with patients generally reporting symptoms and injection site reactions more often and with higher severity than medical providers.ConclusionsMedical providers were aware that their patients who were receiving a stable dose of SRL regularly experienced acromegaly symptoms. Addressing discordance in patient- and medical provider-reported frequency and severity of acromegaly symptoms and injection site reactions by facilitating better communication may improve care of acromegaly patients.

Immunogenicity of Emicizumab in People with Hemophilia A (PwHA): Results from the HAVEN 1-4 Studies

IntroductionEmicizumab is a bispecific humanized monoclonal antibody given subcutaneously, which bridges FIXa and FX to restore the function of missing FVIIIa in PwHA. It is approved for routine prophylaxis in PwHA with inhibitors of all ages, and its efficacy and safety in PwHA without inhibitors was recently described (Mahlangu et al. N Engl J Med 2018, in press; Pipe et al. WFH 2018). Anti-drug antibody (ADA) formation is commonly observed with biologics (e.g. monoclonal antibodies). Presence of ADAs may alter the pharmacokinetics (PK) and pharmacodynamics (PD), and can affect efficacy and safety. Therefore, characterization of the rate and clinical significance of anti-emicizumab antibodies is of importance. Four patients (4/18) tested positive for ADAs in the phase I/II study of emicizumab (Shima et al. Blood Adv 2017). We optimized the immunoassay sensitivity and report here the updated analysis of the immunogenicity of emicizumab in four phase III studies: HAVEN 1, 2, 3 and 4.MethodsAll PwHA enrolled in HAVEN 1 (NCT02622321), HAVEN 2 (NCT02795767), HAVEN 3 (NCT02847637) or HAVEN 4 (NCT03020160) who had at least one ADA measurement after exposure to emicizumab were included in the analysis. Blood samples for detection of anti-emicizumab antibodies were collected at baseline and at regular intervals (initially monthly and later every 12 weeks) during emicizumab treatment or 24 weeks after the last dose for discontinuations. Samples were screened for the presence of ADAs with a sandwich enzyme-linked immunosorbent assay (ELISA) method. Positive samples underwent confirmatory analysis in the presence of unlabeled emicizumab to ensure binding specificity. The assay cut-point for ADA positivity was generated from all study patients' samples before emicizumab exposure (n=398). The confirmatory cut-point was generated from randomly selected baseline samples from these patients (n=100). ADA positivity was assessed according to the recommendations of the American Association of Pharmaceutical Scientists Therapeutic Protein Immunogenicity Focus Group (Shankar at al. AAPS J 2014). In absence of a sensitive neutralizing antibody assay, ADAs associated with consistent decline of emicizumab exposure were considered as having a neutralizing potential; associated loss of PD effect (e.g. decreased FVIII activity, decreased generation of thrombin and prolonged activated partial thromboplastin time) was reviewed as supportive information. The association between ADAs and clinical response or adverse events was also examined.ResultsOf 398 HAVEN patients included in this analysis, 14 (3.5%) tested positive for ADA (2/111, 4/88, 6/151 and 2/48 in HAVEN 1, 2, 3 and 4, respectively). For 7 patients, ADAs were transient, i.e. detected on a single occasion. Three patients (n=1 HAVEN 1; n=2 HAVEN 2), who tested positive for ADA and displayed decline of PK and reduced PD effect, were classified as having ADAs with neutralizing potential, i.e. 0.75% of the overall population. Of those, 1 patient discontinued emicizumab due to a loss of efficacy and resumed pre-study treatment without complication. The presence of ADAs without neutralizing potential was not associated with decreased efficacy. No cases of anaphylaxis or hypersensitivity were reported in ADA-positive patients. Patients who tested positive for ADA did not have a safety profile that differed from that of the overall population. Specifically, there was no trend towards increased frequency or severity of injection site reactions after patients tested positive for ADAs.ConclusionsEmicizumab treatment is associated with a low rate of patients who tested positive for ADA (3.5%), similar to other humanized monoclonal antibodies. ADAs with a neutralizing potential were observed in <1% of patients. Importantly, the presence of ADAs was not associated with impact on safety. Based on this analysis, the rate of ADA with risk of clinical consequences in patients treated with emicizumab is very low, suggesting that routine monitoring is not warranted. DisclosuresPaz-Priel:Genentech Inc: Employment. Chang:Genentech: Employment, Equity Ownership. Asikanius:Roche: Employment, Equity Ownership. Chebon:F. Hoffmann-La Roche: Employment. Emrich:Roche: Employment, Patents & Royalties. Fernandez:Roche: Employment. Kuebler:Genentech: Employment; Roche: Equity Ownership. Schmitt:F. Hoffmann-La Roche: Employment, Equity Ownership.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.

Severe persistent injection site reactions after subcutaneous 2′-O-methyl phosphorothioate oligonucleotide therapy for Duchenne muscular dystrophy

• Subcutaneous administration of 2'-O-methyl phosphorothioate antisense oligonucleotides can cause skin reactions

Severe injection site reactions after subcutaneous administration of Sayana©.

Sayana® was introduced as the first depot medroxyprogesterone acetate-containing contraceptive that is administered via subcutaneous injection. Within 10 months, the Regional Pharmacovigilance Centre (RPVC) Zurich received several anonymous reports of serious local reactions after Sayana® administration. In this retrospective study, individual case safety reports (ICSRs) on local adverse drug reactions (ADRs) related to Sayana® were analysed from the WHO pharmacovigilance database. International, national and regional ICSRs during Sayana® administration up to 1 January 2016 were examined. Data on ADRs were retrieved from the WHO Global Database VigiBase™. Demographic data, drug administration information, duration of Sayana® treatment, latency time of the ADR, and its course, severity and outcomes were analysed. Worldwide, 398 ICSRs after Sayana® use were registered in the database. We identified 20 reported terms that were potentially used to describe a persistent lipodystrophy. When only cases containing one or more of these 20 reported terms were selected, 323 (81.2%) international ICSRs remained for analysis. Of those, 91.6% (n = 296) were categorised as serious. The majority of the reactions (n = 193, 54.4%) did not recover. In the 67 Swiss ICSRs, 77 ADRs were reported using 10 different terms including severe or persistent local reactions like lipodystrophy, atrophy or fat necrosis. Thirty-two patients (47.7%) did not recover. All 11 regional cases reported to the RPVC Zurich were categorised as serious ADRs. For the majority of the patients (n = 7, 63.6%) the interval between the application of Sayana® and development of the lipodystrophy was between 2 and 4 months. Most of the reactions were irreversible (n = 9, 81.8%). One patient underwent plastic surgery for artificial infill of the dent. Persistent local injection site reactions such as lipodystrophy, fat tissue necrosis or atrophy occur frequently after subcutaneous Sayana® use. These adverse drug reactions were recently integrated in the Swiss product information. Physicians and patients should be informed and advised about these potentially irreversible effects.

Effect of mipomersen on LDL-cholesterol in patients with severe LDL-hypercholesterolaemia and atherosclerosis treated by lipoprotein apheresis (The MICA-Study)

Background and aimsIn this study, we evaluated the effect of mipomersen in patients with severe LDL-hypercholesterolaemia and atherosclerosis, treated by lipid lowering drugs and regular lipoprotein apheresis. MethodsThis prospective, randomized, controlled phase II single center trial enrolled 15 patients (9 males, 6 females; 59 ± 9 y, BMI 27 ± 4 kg/m2) with established atherosclerosis, LDL-cholesterol ≥130 mg/dL (3.4 mmol/L) despite maximal possible drug therapy, and fulfilling German criteria for regular lipoprotein apheresis. All patients were on stable lipid lowering drug therapy and regular apheresis for >3 months. Patients randomized to treatment (n = 11) self-injected mipomersen 200 mg sc weekly, at day 4 after apheresis, for 26 weeks. Patients randomized to control (n = 4) continued apheresis without injection. The primary endpoint was the change in pre-apheresis LDL-cholesterol. ResultsOf the patients randomized to mipomersen, 3 discontinued the drug early (<12 weeks therapy) for side effects. For these, another 3 were recruited and randomized. Further, 4 patients discontinued mipomersen between 12 and 26 weeks for side effects (moderate to severe injection site reactions n = 3 and elevated liver enzymes n = 1). In those treated for >12 weeks, mipomersen reduced pre-apheresis LDL-cholesterol significantly by 22.6 ± 17.0%, from a baseline of 4.8 ± 1.2 mmol/L to 3.7 ± 0.9 mmol/L, while there was no significant change in the control group (+1.6 ± 9.3%), with the difference between the groups being significant (p=0.02). Mipomersen also decreased pre-apheresis lipoprotein(a) (Lp(a)) concentration from a median baseline of 40.2 mg/dL (32.5,71) by 16% (−19.4,13.6), though without significance (p=0.21). ConclusionsMipomersen reduces LDL-cholesterol (significantly) and Lp(a) (non-significantly) in patients on maximal lipid-lowering drug therapy and regular apheresis, but is often associated with side effects.

Investigating adverse events following immunisation with pneumococcal polysaccharide vaccine using electronic General Practice data

BackgroundIn early 2011, following an increased number of reports of severe vaccine-related injection site reactions, Australian authorities recommended against administering repeat doses of the 23-valent pneumococcal polysaccharide vaccine (23vPPV) in otherwise healthy adults. The aim of this study was to assess a source of electronic medical record data from primary care providers (General Practitioners, GPs), for validity and ability to retrospectively detect this adverse event signal. MethodsThe General Practice Research Network (GPRN) holds data routinely collected from a representative sample of Australian GPs. Data were extracted on persons 18years or older who had received at least one dose of 23vPPV or influenza vaccine (as comparator) between January 2002 and June 2012. Increases above background levels were assessed using 95% confidence intervals of reaction rates, calculated from the Poisson distribution of counts. ResultsThere was an average of 253 practices and 532 GPs contributing data per year. Over the study period there were 95,760 recorded 23vPPV administrations and 823 reactions, of which 233 were local. For influenza vaccine the numbers were 683,829 doses, 3001 and 387 respectively. Patterns of vaccinations and reactions were consistent with known safety profiles. There were 3 local reactions following 23vPPV in early 2011 (235/100,000 doses, 95% CI 49–717), which was not significantly different to the historical average (260, 225–298). We estimate that this system could have detected a 3-fold increase over background levels. ConclusionsUsing GP consultation data, we were unable to confirm an increase in local reactions detected by passive surveillance, suggesting that this apparent signal was artefactual. GP consultation data captures large numbers of vaccine recipients and medically attended adverse reactions at low cost. If available in a timely manner and expanded, this system has significant potential for use in validation of apparent signals from passive surveillance.

Severe injection site reactions after subcutaneous administration of Sayana®: a retrospective, post-marketing analysis of WHO and Swiss spontaneous pharmacovigilance reports

Severe injection site reactions after subcutaneous administration of Sayana®: a retrospective, post-marketing analysis of WHO and Swiss spontaneous pharmacovigilance reports

Peripheral neuropathy outcomes and efficacy of subcutaneous bortezomib when combined with thalidomide and dexamethasone in the treatment of multiple myeloma.

Due to the safety, convenience and efficacy of subcutaneous administration of bortezomib (scBor), it is becoming increasingly common to treat multiple myeloma (MM) using this treatment method. The current retrospective study suggested a lower incidence of peripheral neuropathy (PN) outcomes and superior efficacy following treatment with scBor combined with thalidomide and dexamethasone (VTD) in MM when compared with intravenous Bor (ivBor) treatment. The data of 81 patients from the Affiliated Hospital of Nantong University between September 2011 and February 2014 were analyzed, including 37 scBor and 44 ivBor patients administered a median (range) of 5.5 (3-8) and 6 (3-10) chemotherapy cycles, respectively. Adverse events (AEs) were assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs, and response and progression were assessed by the International Myeloma Working Group criteria. Evidence of histopathology using transmission electron microscopy (TEM) was obtained from an in vivo model of adult Sprague Dawley (SD) rats. Following bortezomib-based VTD chemotherapy, patients had achieved very good partial remission or demonstrated no significant difference between the scBor and ivBor treatment groups (75.6 vs. 84.1%, respectively; P=0.350). The 1-year progression-free survival (83.8 vs. 84.1%, scBor vs. ivBor; P=0.921) and 1-year overall survival (OS) (91.9 vs. 90.9%, respectively; P=0.926) were also similar. PN rates of all the NCI grades were 51.3 and 61.3% (P=0.371); grade ≥2, 35.1 and 56.8% (P=0.052); and grade ≥3, 32.7 and 20.5% (P=0.015) in the subcutaneous and intravenous treatment groups, respectively, which suggests that severe PN may be less common following scBor treatment. There were no severe injection site reactions in the scBor-treated group. The incidence of adverse events were comparable between the two groups, including thrombocytopenia, anemia, fatigue and gastrointestinal symptoms such as nausea and vomiting. Furthermore, TEM images of the SD rat sciatic nerves revealed that all rats suffered PN to varying degrees, except the control group, and that the PN of ivBor-treated rats (in the presence and the absence of thalidomide) was more severe than that of scBor-treated rats. It was concluded that a subcutaneous dose of bortezomib of 1.3 mg/m2 may result in a lower incidence and severity of PN, with equivalent efficacy, as a component of combination VTD chemotherapy.

In Vitro L6 Irritation Assay Predicts Clinical Injection Site Reactions for Small Molecules.

Injection site reactions (ISRs) are commonly encountered in the development of parenteral drugs, and severe ISRs can lead to preclinical and clinical dose limiting toxicities. Tools to assess the risk of clinical ISRs during drug development are not well established. We developed an in vitro ISR screen using L6 rat myotubes to assess compounds for irritation risk. Reference compounds that were either known to induce ISRs or were non-irritating in the clinical setting were used to validate this method. We evaluated three compounds, two with known clinical ISRs (mitoxantrone and doxorubicin) and one without clinical ISR (metoprolol), using a preclinical in vivo rat model and the L6 in vitro model at clinically relevant concentrations, and showed that the L6 assay is a better prognostic indicator for clinical ISR risk. We then utilized this assay during early preclinical development to guide optimization of structure activity relationship (SAR), selection of dose concentrations for pre-clinical in vivo experiments, and prioritization of alternative formulations to minimize ISR risk. Our studies indicate that the L6 assay is a better measure of clinical ISR risk than current in vivo preclinical models, and that it can help guide not only compound selection, but also selection of dose concentration and formulation.

Chemotherapy with BCNU in recurrent glioma: Analysis of clinical outcome and side effects in chemotherapy-naïve patients.

BackgroundTo date, standardized strategies for the treatment of recurrent glioma are lacking. Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, particularly the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma.MethodsSurvival data of 34 mostly chemotherapy-naïve glioblastoma patients treated with BCNU at 1st relapse were compared to 29 untreated control patients, employing a multiple Cox regression model which considered known prognostic factors including MGMT promoter hypermethylation. Additionally, medical records of 163 patients treated with BCNU for recurrent glioma WHO grade II to IV were retrospectively evaluated for BCNU-related side effects classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0.ResultsIn recurrent glioblastoma, multiple regression survival analysis revealed a significant benefit of BCNU-based chemotherapy on survival after relapse (p = 0.02; HR = 0.48; 95 % CI = 0.26–0.89) independent of known clinical and molecular prognostic factors. Exploratory analyses suggested that survival benefit was most pronounced in MGMT-hypermethylated, BCNU-treated patients. Moreover, BCNU was well tolerated by 46 % of the 163 patients analyzed for side effects; otherwise, predominantly mild side effects occurred (CTCAE I/II; 45 %). Severe side effects CTCAE III/IV were observed in 9 % of patients including severe hematotoxicity, thromboembolism, intracranial hemorrhage and injection site reaction requiring surgical intervention. One patient presented with a clinically apparent pulmonary fibrosis CTCAE IV requiring temporary mechanical ventilation.ConclusionIn this study, BCNU was rarely associated with severe side effects, particularly pulmonary toxicity, and, in case of recurrent glioblastoma, even conferred a favorable outcome. Therefore BCNU appears to be an appropriate alternative to other nitrosoureas although the efficacy against newer drugs needs further evaluation.