BACKGROUND:Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. METHODS:Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. RESULTS:The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). CONCLUSION:Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis.

Objectives Gadolinium deposition is widely believed to occur, but questions regarding accumulation pattern and permanence remain. We conducted a retrospective study of intracranial signal changes on monthly triple-dose contrast-enhanced magnetic resonance imaging (MRI) examinations from the previously published Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial (N = 67) to characterize the dynamics of gadolinium deposition in several deep brain nuclei and track persistence versus washout of gadolinium deposition on long-term follow-up (LTFU) examinations (N = 28) obtained approximately 10 years after enrollment in the Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial. Materials and Methods Using T2 and proton density images and using image analysis software (ITK-SNAP), manual regions of interest were created ascribing boundaries of the caudate nucleus, dentate nucleus, globus pallidus, pulvinar, putamen, white matter, and air. Intensity analysis was conducted on T1-weighted fat-saturated (fat-sat) images using the FSL package. A linear rigid-body transform was calculated from the fat-sat image at each target time point to the region of interest segmentation reference time point fat-sat image. Serial MRI signal was analyzed using linear mixed regression modeling with random intercept. Annual MRI signal changes including LTFU scans were assessed withttest. Results During monthly scanning, all gray matter structures demonstrated a significant (P< 0.0001) increase in contrast-to-noise ratio. Yearly changes in deposition showed distinctive patterns for the specific nucleus: globus pallidus showed complete retention, pulvinar showed partial washout, while dentate, caudate, and putamen returned to baseline (ie, complete washout). Conclusions Monthly increased contrast-to-noise ratio in gray matter nuclei is consistent with gadolinium deposition over time. The study also suggests that some deep gray matter nuclei permanently retain gadolinium, whereas others demonstrate washout of soluble gadolinium.

AbstractBackground and purposeCanine distemper virus (CDV) is a candidate agent in the etiology of multiple sclerosis (MS). Elevated anti‐CDV levels were previously found in the sera from MS patients compared with controls. We now investigated whether there was an age‐related association with the presence of antibodies specific to CDV‐hemagglutinin (H) protein in MS.MethodsSera from patients with MS, other neurological diseases, and inflammatory and/or autoimmune diseases, and healthy individuals were screened for anti‐CDV in an ELISA using linear peptides of the CDV‐H protein as antigen. Antibody levels to measles and varicella‐zoster virus were measured and served as controls.ResultsAnalysis of the new cohort of MS patients and controls confirmed our initial finding of elevated anti‐CDV‐H levels in MS patients. An increase in measles but not varicella‐zoster virus antibody levels was found in MS patients compared with healthy controls. Data from the new cohort of patients and controls were combined with data from the original study and analyzed with respect to age distribution of anti‐CDV IgG. Mean CDV antibody levels were significantly elevated in each decade from 20 to 50 years of age in MS compared with healthy and disease controls. Antibody levels to measles virus were not consistently elevated during this age span. A striking relationship (p < .0001, odds ratio = 5.0) was observed between elevated anti‐CDV‐H levels and diagnosis of MS.ConclusionsThe finding that anti‐CDV levels are elevated in MS patients of all ages provides substantial evidence of a strong association between elevated anti‐CDV and MS.

In CLARITY, cladribine tablets 10 mg, (cumulative dose 3.5 mg/kg [CT3.5] over 2 years [yrs]) were efficacious versus placebo in patients with relapsing multiple sclerosis (RMS). This was maintained without further treatment in CLARITY Extension. The effect of CT3.5 was evaluated in patients with RMS aged >45 and ≤ 45 yrs.

Monday, April 27April 14, 2020Free AccessReduction of Risk of Secondary Progressive Multiple Sclerosis Within Two Years of Treatment with Cladribine Tablets (1961)Patrick Vermersch, Gavin Giovannoni, Per Soelberg-S⊘rensen, Kottil Rammohan, Stuart Cook, Birgit Keller, and Sanjeev RoyAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1961 Letters to the Editor

Background and Aims Many studies of corneal transplantation focus on graft failure or rejection as endpoints, or report visual outcomes at one postoperative time point. We aimed to study the stability of visual outcomes between 2 and 5 years following corneal transplantation. Methods All patients with keratoconus (868) or Fuchs endothelial dystrophy (FED) (569) receiving their first corneal transplant for visual purposes in the UK between January 2003 and December 2009 were included. The probability of visual improvement or deterioration (gain or loss of ≥2 Snellen lines, respectively) between 2 and 5 years after keratoplasty was modelled by multivariable logistic regression. Results The majority of keratoconus patients with a penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty maintained their visual acuity (651/868; 75%) while 15% (133/868) improved and 10% (84/868) deteriorated. Similarly, most patients with FED who received a PK maintained their vision (395/569; 70%) while 18% (105/569) improved and 12% (68/569) deteriorated.

Background: An independent meta-analysis determined that malignancy risk was not increased with cladribine tablets (CT) compared with other DMDs in patients with RMS. An unusually low rate was observed in the placebo (PBO) group.1 lymphocyte reductions occur following annual courses of CT, but are transient relative to the sustained clinical efficacy characteristic of selective immune reconstitution therapy. Data from additional trials/registry with CT3.5 mg/kg (CT3.5) (up to 8 years of follow up) are now available. The objective was assessment of malignancy risk with CT3.5 monotherapy and PBO 3 phase III trials and the premiere registry, and comparison with a global malignancy database.

Background: In clarity, patients with high disease activity (HDA) relapsing multiple sclerosis generally had better/comparable clinical and imaging responses to cladribine tablets (CT) 3.5 mg/kg compared with the overall clarity population. These post hoc analyses assessed the lymphopenia rate in patients with HDA in clarity/clarity ext who received CT 3.5 mg/kg only in years 1&2 (CT3.5) and patients re-exposed in years 3&4 (CT7.0).

Background: In clarity, cladribine tablets 3.5 mg/kg (CT3.5) showed strong efficacy vs placebo over 2 years in patients with relapsing multiple sclerosis (RMS). Age-related variability in response to disease modifying treatments has been observed in patients with MS. This post-hoc analysis assessed the effect of CT3.5 in patients with RMS ≤45 and >45 years of age.

IntroductionAn independent meta-analysis; Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158) in Phase III trials (with a 2 year duration) of disease modifying drugs (DMDs) in patients with relapsing multiple sclerosis found no increased rate of malignancy with cladribine tablets (CT) versus other DMD treatments. Data from additional trials involving CT 3.5 mg/kg (CT3.5) and a safety registry (up to 8 years’ follow-up) allow further insights into malignancy risk. Objective is to assess malignancy risk with CT3.5 monotherapy and placebo (PBO) in data from 3 Phase III trials and a registry, and compare the incidence rate with a global database.MethodsThe CT 3.5 population comprised 923 patients (3433 patient-years’ [PY] total exposure time) and the PBO group comprised 641 patients (2026 PY). Individual case reports of malignancies were reviewed by independent, blinded adjudication committee. Standardised incidence ratios (SIR) were calculated using the GLOBOCAN reference population (excluding non-melanoma skin cancers [NMSCs]) and a Danish reference population for NMSC rates.ResultsThe incidence per 100 PY of confirmed malignancy was CT3.5 0.293 (95%CI 0.158–0.544) and PBO 0.148 (95%CI 0.048–0.460); the risk difference 95% CI included 0 (−0.166–0.414). The CT 3.5 malignancy SIR was almost identical (0.97, 95% CI 0.44–1.85) to the GLOBOCAN matched reference population. The PBO group SIR was numerically lower (0.48, 95% CI 0.14–1.53). There were no cases of haematological, lymphoproliferative or virus-induced cancers. There was no clustering of specific tumour types, and the incidence of skin cancer was not increased after treatment with CT3.5 versus PBO. The incidence of malignancies with CT3.5 was constant and did not increase over time.ConclusionAnalysis of malignancy rates in a cohort that includes patients with up to 8 years’ follow-up confirms the Conclusion of the earlier meta-analysis; the incidence of malignancies with CT3.5 is similar to a matched reference population.