Selecting disease-modifying medications in 5q spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an inherited lower motor neuron disease. SMA occurs secondary to alterations in the survival motor neuron 1 gene (SMN1), which is the main driver of SMN protein production. The severity of the disease is determined by the number of copies of the SMN2 gene, which is a homolog to SMN1 but not as efficient in protein production. Three medications have recently been approved for the treatment of SMA. Nusinersen is an intrathecal antisense oligonucleotide that alters SMN2 pre-mRNA, onasemnogene abeparvovec-xioi is an intravenous SMN1 gene replacement therapy, and risdiplam is an oral small molecule splicing modifier of SMN2. No head-to-head studies have been conducted comparing these medications, so selection of one of these medications for an individual with SMA can be challenging. In this article we outline the efficacy, safety, and other pertinent factors to consider when selecting a therapy for an individual with SMA. The age of the individual and comorbidities, such as liver or kidney disease, help guide treatment choices. All three of these medications are efficacious, and early initiation is critical for obtaining the best outcomes.

Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A.

Compared to conventional antisera strategies, monoclonal antibodies (mAbs) represent an alternative and safer way to treat botulism, a fatal flaccid paralysis due to botulinum neurotoxins (BoNTs). In addition, mAbs offer the advantage to be produced in a reproducible manner. We previously identified a unique and potent mouse mAb (TA12) targeting BoNT/A1 with high affinity and neutralizing activity. In this study, we characterized the molecular basis of TA12 neutralization by combining Hydrogen/Deuterium eXchange Mass Spectrometry (HDX-MS) with site-directed mutagenesis and functional studies. We found that TA12 recognizes a conformational epitope located at the interface between the HCN and HCC subdomains of the BoNT/A1 receptor-binding domain (HC ). The TA12-binding interface shares common structural features with the ciA-C2 VHH epitope and lies on the face opposite recognized by ciA-C2- and the CR1/CR2-neutralizing mAbs. The single substitution of N1006 was sufficient to affect TA12 binding to HC confirming the position of the epitope. We further uncovered that the TA12 epitope overlaps with the BoNT/A1-binding site for both the neuronal cell surface receptor synaptic vesicle glycoprotein 2 isoform C (SV2C) and the GT1b ganglioside. Hence, TA12 potently blocks the entry of BoNT/A1 into neurons by interfering simultaneously with the binding of SV2C and to a lower extent GT1b. Our study reveals the unique neutralization mechanism of TA12 and emphasizes on the potential of using single mAbs for the treatment of botulism type A.

Effective long-term treatment with incobotulinumtoxin (Xeomin®) without neutralizing antibody induction: a monocentric, cross-sectional study.

BACKGROUND: Among the spectrum of licensed botulinum neurotoxin preparations incobotulinumtoxin (incoBoNT/A; Xeomin®) is the only one which does not contain complex proteins. Therefore, incoBoNT/A has been suggested to have a low antigenicity, but precise estimations on incidence and prevalence of neutralizing antibody formation during long-term treatment are outstanding so far. METHODS: For the present cross-sectional study, 59 patients having exclusively been treated with incoBoNT/A (mono group) and 32 patients having been treated with other BoNT/A preparations less than nine times and who were then switched to at least 14 sessions of incoBoNT/A treatment (switch group) were recruited from one botulinum toxin outpatient clinic. Side effects and doses were extracted from the charts, and the efficacy of treatment was assessed by the patients using a visual analogue scale (0-100). The prevalence of neutralizing antibodies was tested by means of the mouse hemi-diaphragm assay (MHDA). FINDINGS: None of the patients in the mono and only two in the switch group had a positive MHDA-test. Across all indications and patients, mean improvement exceeded 67%. Improvement did not depend on age at onset, sex, change of dose or duration of treatment, but on disease entity. In patients with cervical dystonia, improvement was about the same in the mono and switch subgroup, but the last dose was different. CONCLUSIONS: The present study confirms the low antigenicity of incoBoNT/A, which has immediate consequences for patient management, and the use of higher doses and shorter durations of reinjection intervals in botulinum toxin therapy.

Immunogenicity induced by botulinum toxin injections for limb spasticity: A systematic review.

BACKGROUND: The imputability of neutralizing antibodies (NABs) in secondary non-response (SnR) to botulinum toxin (BoNT) injections for limb spasticity is still debated. OBJECTIVE: This systematic literature review aimed to determine the prevalence of NABs after BoNT injections for limb spasticity and analyze their determinants and their causal role in SnR. METHODS: We searched MEDLINE via PubMed, Cochrane and Embase databases for articles published during 1990-2018. Two independent reviewers extracted the data and assessed the quality of studies with a specific scale (according to PRISMA and STROBE guidelines). Because the techniques used to detect NABs did not influence the results, we calculated the global (all studies) sensitivity and specificity of NAB positivity to reveal SnR. RESULTS: We included 14 articles published from 2002 to 2018 (including an epublication) describing 5 randomized controlled trials and 5 interventional and 4 observational studies. The quality was satisfactory (mean score 18/28 arbitrary units). NAB detection was the primary criterion in 5 studies and a secondary criterion in 9. In total, 1234 serum samples for 1234 participants (91% with stroke) were tested after injection. NAB prevalence was about 1%, with no significant difference among formulations. NAB positivity seemed favoured by long-duration therapy with high doses and a short interval between injections. The identification of non-response by NAB positivity had poor global sensitivity (56%) but very high specificity (99.6%). No consensual criteria were used to diagnose non-response to BoNT injection. CONCLUSIONS: NAB prevalence is much lower after BoNT treatment for limb spasticity than cervical dystonia. Consensual criteria must be defined to diagnose non-response to BoNT injection. Because immunogenicity is not the most common cause of non-response to BoNT injection, NABs should be sought in individuals with SnR with no other cause explaining the treatment inefficacy. A test with 100% specificity is recommended. In cases for which immunogenicity is the most likely cause of non-response to BoNT injections, some biological arguments suggest trying another BoNT, but no clinical evidence supports this strategy.

IncobotulinumtoxinA: A Highly Purified and Precisely Manufactured Botulinum Neurotoxin Type A

Aesthetic dermatologic applications of botulinum neurotoxin (BoNT), including treatment of glabellar lines, horizontal forehead lines, and crow's feet, were the most common non-surgical cosmetic procedures in the US in 2017, with high levels of subject satisfaction. Since the first BoNT type A (BoNT-A) formulation was approved in 1989, the number of formulations available on the world's commercial markets has increased and new approvals are expected. BoNT is produced by Clostridium botulinum in nature as part of a large protein complex. However, the unnecessary clostridial proteins, which dissociate from BoNT under physiological conditions with a half-life of <1 minute, have no role in clinical applications. Data demonstrate that BoNT administration can elicit an immunological response, leading to production of neutralizing antibodies that can be associated with reduced efficacy or treatment non-response. As repeat treatments are required to maintain efficacy, clinicians should be aware of the possibility of antibody development and choose a BoNT with the lowest risk of immunogenicity. IncobotulinumtoxinA is manufactured using advanced technology to precisely isolate the pure BoNT without unnecessary clostridial proteins, and with low immunogenicity and high specific activity. In incobotulinumtoxinA clinical studies, no previously BoNT-naïve subjects developed neutralizing antibodies, and there was no secondary non-response to incobotulinumtoxinA treatment. Here we review the role of unnecessary clostridial proteins in BoNT-A and discuss the unique incobotulinumtoxinA manufacturing and purification process with a focus on the implications for use in aesthetic medicine. J Drugs Dermatol. 2019;18(1):52-57.

Clinical resistance to three types of botulinum toxin type A in aesthetic medicine.

Botulinum toxin injections have become the most frequent noninvasive cosmetic procedure carried out worldwide. Botulinum toxin has also multiple other indications in different medical fields. However, with the repetition of injections, a new concern has emerged: clinical resistance and loss of effectiveness of the treatment. After reporting a case of primary nonresponsiveness to three types of botulinum toxin type A injections, we conducted a review about all factors leading to the primary or secondary nonresponsiveness, as well as the factors affecting the immunogenicity of this neurotoxin. Most of the reports and studies focused on secondary resistance to botulinum toxin (BT) and the neurotoxin immunogenicity; primary nonresponsiveness was rarely reported. Factors leading to primary or secondary resistance to BT injections were numerous. In the majority of the studies, development of neutralizing antibodies to botulinum toxin was considered responsible of the induced clinical resistance. Patients should be aware of this rising concern as well as clinicians who should learn how to minimize the risk of resistance development, sparing the patients more invasive treatment modalities. Further studies related to botulinum toxin resistance are needed.

Effectiveness of switching therapy from complexing protein-containing botulinum toxin type A to a formulation with low immunogenicity in spasticity after stroke: a case report.

OBJECTIVE: Some patients receiving botulinum toxin type A therapy develop immunological resistance due to the production of neutralizing antibodies against the neurotoxin, thus partially or completely reducing the therapeutic effect. CASE REPORT: We report here neurophysiological and clinical findings for a 58-year-old man treated with botulinum toxin type A for spasticity after ischaemic stroke, who became a secondary non-responder patient. Subsequent treatment with a different preparation of botulinum toxin type A had a great therapeutic effect on his spasticity. The muscles injected and the dosages were the same for each treatment, but evaluation with the Modified Ashworth Scale after treatment with the second preparation showed a reduction of approximately 2 points compared with the first examination. The clinical results were also supported by extensor digitorum brevis testing of the right muscle, which showed a reduction in compound muscle action potential, whereas it was unchanged in the non-injected muscle. No side-effects were reported, and after 1 year of treatment with this formulation clinical benefits were still evident. CONCLUSION: The neurophysiological and clinical results obtained in this patient suggest that switching therapy from a complexing protein-containing product to a product potentially free of complexing proteins, which has low immunogenicity, may be a viable therapeutic option in secondary non-responder patients.

Evaluation of specific immune responses to BoNT/A and tetanus toxoid in patients undergoing treatment for neurologic disorders.

Botulinum neurotoxins (BoNTs) are used in the treatment of many neurological disorders. The primary structure of BoNTs shows a high degree of homology with the tetanus neurotoxin, the toxoid of which is used as a vaccine. Because of the potential cross-reactivity between these toxins, we investigated the effects of Botulinum neurotoxin A (BoNT/A) and tetanus toxoid on peripheral blood mononuclear cells (PBMC) and the corresponding serum antibody levels, in twenty patients who had been treated with BoNT/A. We observed very low PBMC immunostimulation by BoNT/A at the tested dose (15 units/ml), as demonstrated by the low lymphocyte proliferation, and the absence of detectable antibodies cross-reacting with tetanus. However, exposure of PBMC from tetanus-sensitized patients to both neurotoxins showed that BoNT/A exerted a co stimulatory effect on tetanus-stimulated cells. Interestingly, in flow cytometry analysis, BoNT/A seemed to also alter the ratio of naïve (CD45RA) : memory/effector (CD45RO) T lymphocyte subsets, in favour of CD45RO. These preliminary data give a new insight on the potential immune crossreactivity between the two antigens. In view of the wide use of both neurotoxins, these immunotoxic effects merit a more detailed investigation.

Immunoresistance in cervical dystonia patients after treatment with abobotulinumtoxinA.

Formation of antibodies against botulinum toxin type A has been observed following treatment of Cervical Dystonia (CD). We present the immunological findings from two 12-week Phase III prospective, randomized, double-blind, single-dose, placebo-controlled studies (Study 1, n = 116; Study 2, n = 136). Patients in both studies were administered abobotulinumtoxinA 500U or placebo intramuscularly at baseline. Patients could receive up to three or four additional treatments (250-1000U) in an open-label follow-up period. Blood samples were collected at baseline and during treatment to test for antibodies to abobotulinumtoxinA using a radioimmunoprecipitation assay (Study 2 only) and a mouse protection assay. Loss of response was predefined using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score at 4 weeks following injection. No subjects in Study 1 and one individual in Study 2 developed neutralizing antibodies (nABs) during the double-blind treatment phase; the individual who developed immunoresistance had received botulinum toxin type A treatment prior to the study and did not respond to treatment. Two subjects demonstrated a change in nAB status during open-label treatment and overall responsiveness was maintained in these patients. In conclusion, the development of immunoresistance was rare and, in the presence of circulating nABs, patients may still gain benefit from intramuscular abobotulinumtoxinA treatment.

The effect of total cumulative dose, number of treatment cycles, interval between injections, and length of treatment on the frequency of occurrence of antibodies to botulinum toxin type A in the treatment of muscle spasticity.

A large cumulative dose of botulinum toxin type A (BoNT-A), frequent injections, a short interval between treatment cycles, and a long duration of treatment have all been suggested, but not confirmed, to be associated with a high incidence of neutralizing antibodies to the neurotoxin. The aim of this study was to investigate whether these variables predispose to BoNT-A neutralizing antibody formation. A mouse protection (neutralization) bioassay was used for the detection of BoNT-A antibodies in 17 patients who received large doses of BoNT-A, over at least 10 consecutive treatment cycles or for 5 years or more. BoNT-A antibodies were not detected in any of the study patients. The study findings did not confirm an association between the above-mentioned variables and BoNT-A antibody formation.

Five-year experience with incobotulinumtoxinA (Xeomin(®) ): the first botulinum toxin drug free of complexing proteins.

In 2005, incobotulinumtoxinA (Xeomin(®) ), a new botulinum toxin (BT) type A drug without complexing proteins (CPs), became available. This paper reviews the specific features of Xeomin(®) and the experience gathered with it during the last 5 years. Compared with conventional BT drugs, Xeomin(®) 's extended shelf live and its simplified temperature restrictions indicate that CPs are not necessary for BT drug stability. Its reduced molecular size does not translate into diffusion differences, and its potency labelling is identical to that of onabotulinumtoxinA (Botox(®) ). With a reduced content of inactivated botulinum neurotoxin, Xeomin(®) should have reduced antigenicity. Lack of CP's may further reduce antigenicity. Xeomin(®) 's therapeutic efficacy against cervical dystonia, blepharospasm and spasticity has been proven in large randomised, double-blind and placebo-controlled studies leading to registrations in many countries. Additional successful clinical use in axillary hyperhidrosis, hemifacial spasm, re-innervation synkinesias and hypersalivation as well as in dystonia and spasticity in extended doses and throughout extended observation periods has been documented meanwhile. Lack of reported cases of antibody-induced therapy failure (ABF), as to date, support the hypothesis of an improved antigenicity.

Antibody-induced secondary treatment failure in a patient treated with botulinum toxin type A for glabellar frown lines.

Botulinum toxin type A (BTX-A) preparations are widely used nonsurgical treatments for facial wrinkles. Higher doses of BTX-A are also used for therapeutic purposes in the treatment of conditions involving increased muscle tone, such as cervical dystonia. The phenomenon of antibody-induced treatment failure is well known in the therapeutic setting, but reports are also emerging following cosmetic use of BTX-A. We describe the case of a 41-year-old female nurse who developed secondary treatment failure during 6 years of BTX-A treatment for glabellar lines. After a good response to the first BTX-A injection, the intensity and duration of effect decreased after subsequent treatments. Antibody tests revealed a high titer of neutralizing anti-BTX-A antibodies. This case shows secondary treatment failure due to the production of neutralizing antibodies following administration of BTX-A formulations for cosmetic purposes and demonstrates that immunogenicity of BTX-A preparations is an important consideration, even in the cosmetic setting.

Antibodies after botulinum toxin A injection into musculus detrusor vesicae: incidence and clinical relevance.

OBJECTIVES: Botulinum toxin A (BTX-A) injection into the detrusor muscle has changed therapy options for patients with overactive bladder (OAB). However, in some patients, therapy fails or the effects of BTX-A decrease. The aim of this prospective study was to evaluate the incidence of BTX-A antibodies (BTX-A Abs) after injection of BTX-A and its clinical relevance. METHODS: 31 patients (27 women, 4 men) were treated with BTX-A for OAB between January 2009 and August 2010. Eleven patients were treated once, 16 patients were treated twice and 4 patients were treated three times. Blood was collected before and 3 months after the BTX-A injection and BTX-A Abs were determined. RESULTS: In 5 patients (16%) BTX-A Abs were detectable after the BTX-A injection. The BTX-A Ab titer was clearly positive in 1 patient (3.2%). This patient showed complete failure of BTX-A therapy. In 4 patients (13%) BTX-A Abs were slightly positive after the first BTX-A injection. The second BTX-A injection showed no positive effects in only 1 patient with borderline BTX-A Ab titers; the second BTX-A injection was successful in 2 patients. CONCLUSIONS: The incidence of BTX-A Abs should be verified in nonresponders. More data are necessary to check the clinical relevance and risk of BTX-A Ab formation, especially in long-term follow-up, to optimize patient selection for this minimally invasive treatment option in OAB.

Results of a BoNT/A antibody study in children and adolescents after onabotulinumtoxin A (Botox®) detrusor injection.

BACKGROUND: Onabotulinumtoxin A (OnaBoNT/A, Botox®) is effective in the treatment of neurogenic detrusor overactivity, however this therapy can fail. In a prospective study, we analyzed patient serum for BoNT/A antibodies (BoNT/A-AB) as a possible cause of therapy failure. METHODS: 17 patients (average age 14.5 years) who had neurogenic detrusor overactivity were admitted for repeated OnaBoNT/A injection into the detrusor muscle. We analyzed their serum for BoNT/A-AB. The clinical findings were correlated with the incidence of BoNT/A-AB. RESULTS: Positive BoNT/A-AB were clearly or marginally determined in 6 patients. Therapy had failed in all 6. In 4 of the 6, therapy might have failed because of a low-compliance bladder (3 patients) or tethered-cord syndrome (1), but BoNT/A-AB were found as the only possible cause in 2 patients. Thus, the incidence of BoNT/A-AB in the 17 patients was 35%, and the antibodies were clinically significant in 12%. All patients with BoNT/A-AB had a history of recurrent urinary tract infections. CONCLUSIONS: Patients who show a failure of therapy after OnaBoNT/A injections for which no other causes can be determined should have their serum checked for BoNT/A-AB. Recurrent urinary tract infection might be a predisposing factor for BoNT/A-AB.

Antibody-induced failure of botulinum toxin a therapy in cosmetic indications.

BACKGROUND: Botulinum toxin (BT) is a safe and effective treatment for cosmetic indications. Formation of BT antibodies can occur but has previously been reported in cosmetic indications in two cases only. OBJECTIVE: To report another four patients with this phenomenon. OBSERVATIONS: Two patients received abobotulinumtoxinA; one received the current formulation of onabotulinumtoxinA and one both abobotulinumtoxinA and onabotulinumtoxinA. Complete secondary therapy failure (CSTF) occurred after 3-, 5-, 10-, and 13-injection series; cumulative treatment times of 18, 16, 25, and 65 months; and cumulative doses of 240 MU onabotulinumtoxinA, 245 MU abobotulinumtoxinA, 1,180 MU abobotulinumtoxinA, and 120 MU onabotulinumtoxinA/270 MU abobotulinumtoxinA, respectively. Average interinjection intervals were 87, 273, 150, and 119 days, and average single doses were 80 MU onabotulinumtoxinA, 68 MU abobotulinumtoxinA, 82 MU abobotulinumtoxinA, and 30 MU abobotulinumtoxinA/30 MU onabotulinumtoxinA. Risk factors for CSTF included booster injections (2 patients) and increased immune system reagibility (1 patient). BT antibody titers were 2.7, 7.0, and more than 10.0 mU/mL on the mouse diaphragm assay. CONCLUSIONS: CSTF can occur after cosmetic BT injections in patients with high immune system reagibility and in patients receiving booster injections, but also in unremarkable patients with typical treatment parameters. Its incidence is unknown. Recommended treatment parameters may reduce the risk of CSTF, but may not eliminate it.

Current and future botulinum neurotoxin type A preparations in aesthetics: a literature review.

Botulinum neurotoxin type A (BTX-A) preparations are well established for cosmetic use. BTX-A inhibits the release of acetylcholine, resulting in temporary muscle paralysis, which has been utilized successfully to treat glabellar frown lines, periorbital wrinkles and other facial enhancement procedures. Two BTX-A products are approved for aesthetic procedures in the United States (U.S.) and Europe, and a next generation of preparations free from complexing proteins has recently been approved in Germany. Despite established efficacy profiles, concerns remain regarding the propensity for immunogenic reactions, which can lead to premature loss of effect and secondary therapy failure. NT 201 is a BTX-A preparation that is free from complexing proteins and is in the advanced stages of aesthetic development. Pivotal clinical studies in therapeutic indications demonstrate noneriority and comparable safety of NT 201 to another available BTX-A preparation. This article reviews the pharmacologic and clinical profiles of BTX-A preparations currently available and in development. Novel BTX-A preparations may offer advantages over existing products in terms of handling and immunogenicity.

Antibody formation following botulinum toxin type A (Dysport) injection in children with intractable bladder hyper-reflexia.

OBJECTIVES: To investigate the pattern of anti-Dysport antibody (ADA) formation after Dysport injection in patients with neuropathic bladder. Antibody formation may lead to failure or allergic reactions in patients undergoing Dysport injection. METHODS: Forty-four children with neuropathic bladder were enrolled and classified into 3 groups: group I, without history of previous injection (n = 8); group II, with history of one or more injections (n = 7); and group III, who had been injected 3-36 months before this study (n = 29). Groups I and II were subjected to Dysport injection. Fifty-five age-matched healthy children were selected as controls. Urinary incontinence score was assessed before and 6 months after injection. Under cystoscopic guidance, Dysport (10 IU/kg) was injected into the detrusor muscle, sparing the trigone and ureteral orifices. ADA level was measured by enzyme-linked immunosorbent assay technique before injection and then monthly for at least 4 months in groups I and II, and for just once in group III and control subjects. RESULTS: ADA level was increased 1-2 months after the last injection in 3 (38%) of group I and 5 (71%) of group II. However, ADA level in group III was not higher than controls. All patients had complete or partial improvement in urinary incontinence score except for 1 patient in group I. No resistance to treatment was detected. CONCLUSIONS: Increment of ADA titer in patients is not permanent. Repeated injections will not boost the immune system to produce higher levels of antibody. Increased levels of ADA may not be associated with treatment failure at follow-up visit.

National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study.

BACKGROUND: The aim of this study was to test, on a multinational level, the pholcodine (PHO) hypothesis, i.e. that the consumption of PHO-containing cough mixtures could cause higher prevalence of IgE antibodies to PHO, morphine (MOR) and suxamethonium (SUX). As a consequence the risk of anaphylaxis to neuromuscular blocking agents (NMBA) will be increased. METHODS: National PHO consumptions were derived from the United Nations International Narcotics Control Board (INCB) database. IgE and IgE antibodies to PHO, MOR, SUX and P-aminophenyl-phosphoryl choline (PAPPC) were measured in sera from atopic individuals, defined by a positive Phadiatop test (>0.35 kU(A)/l), collected in nine countries representing high and low PHO-consuming nations. RESULTS: There was a significant positive association between PHO consumption and prevalences of IgE-sensitization to PHO and MOR, but not to SUX and PAPPC, as calculated both by exposure group comparisons and linear regression analysis. The Netherlands and the USA, did not have PHO-containing drugs on the markets, although the former had a considerable PHO consumption. Both countries had high figures of IgE-sensitization. CONCLUSION: This international prevalence study lends additional support to the PHO hypothesis and, consequently, that continued use of drugs containing this substance should be seriously questioned. The results also indicate that other, yet unknown, substances may lead to IgE-sensitization towards NMBAs.