Eight-year immunogenicity and safety of interferon beta-1a-Avonex®treatment in patients with multiple sclerosis

2005 ◽  
Vol 11 (4) ◽  
pp. 409-419 ◽  
Author(s):  
Robert M Herndon ◽  
Richard A Rudick ◽  
Frederick E Munschauer ◽  
Michele K Mass ◽  
Andres M Salazar ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Median Time ◽  
Interferon Beta ◽  
Phase Iii ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pivotal Phase ◽  
Phase Iii Trial ◽  
Laboratory Test Results ◽  
Phase Iii Study

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNβ-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNβ-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNβ-1a-Avonex 30 mg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNβ-1a-Avonex in the phase III trial. Serum levels of IFNβ antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNβ-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNβ-naïve. At baseline, 281 patients were negative for IFNβ antibodies (NAb-). NAbs (titre≥ 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNβ-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNβ-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres <100; 36 of these 39 seroconverted to NAb-while on IFNβ-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres ≥ 100; five remained NAb+ during six years on IFNβ-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNβ-1a-Avonex during the clinical trial were NAb+ with titres <100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNβ-1a-Avonex had NAb titres ≥100; five of these remained NAb+ at six years. No patient with a NAb titre >1000 seroconverted to NAb-, whether initially treated with IFNβ-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNβ-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNβ product.

Interferon beta treatment for multiple sclerosis: persisting questions

1996 ◽  
Vol 1 (6) ◽  
pp. 321-324 ◽  
Author(s):  
Donald E Goodkin
Keyword(s):  
Multiple Sclerosis ◽  
Interferon Beta ◽  
Neutralizing Antibody ◽  
Optimal Dose ◽  
Phase Iii ◽  
Exacerbation Rate ◽  
Phase Iii Trial ◽  
Imaging Results ◽  
Relapsing Remitting ◽  
Ambulatory Patients

Doctors Noteworthy and Summerfield have reviewed the results of placebo-controlled, double-masked, clinical trials of interferon beta-1b (IFNB-1b, Betaseron) and interferons beta-1a (IFNB-1a, Avonex,) in patients with relapsing multiple sclerosis (MS). IFNB-1b, administered subcutaneously every other day to ambulatory patients with relapsing-remitting MS, significantly reduces annual exacerbation rate and percentage change from baseline MRI T2-weighted total lesion area.1-4 There is also evidence that IFNB-1b reduces the number of new gadolinium-enhancing lesions in patients with relapsing-remitting MS.5 IFNB-1a (Avonex), administered intramuscularly every week to patients with relapsing MS, significantly reduces annual exacerbation rate, the number and volume of new focal gadolinium-enhanced T1-weighted lesions, and slows the accumulation of physical disability over time.6 However, questions remain regarding the efficacy of these treatments, the significance of neutralizing antibody formation, indications for therapy, adverse events, optimal dose, and route of administration. Design limitations of the Phase III trial of IFNB-1b have been reviewed elsewhere, 7 and a critical review of the results of the Phase III trial of IFNB-1a should be undertaken after the publication of the clinical and imaging results of that study.

EUFORIA study (Eribulin Use for the Treatment of Advanced Breast Cancer: Observational, Retrospective Analysis): Initial experience with eribulin in daily clinical practice in Spain.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e12015-e12015
Author(s):  
Manuel Ruiz-Borrego ◽  
José Ángel Garcia Saenz ◽  
Javier Hornedo ◽  
Luis Manso ◽  
Isabel Calvo ◽  
...  
Keyword(s):  
Adverse Events ◽  
Observational Study ◽  
Retrospective Analysis ◽  
Ethics Committees ◽  
Public Hospitals ◽  
Receptor Expression ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Pivotal Phase ◽  
Phase Iii Study

e12015 Background: Spanish MoH authorized eribulin in 04/2011 for use in patients as per license. Pending reimbursement, public hospitals used it through a national compassionate use program. After 1 year, we analyzed the pre-specified patient selection criteria and eribulin efficacy and safety results in a representative sample to confirm whether real world use matched the data from the pivotal phase III study. Methods: An observational, retrospective analysis was proposed to the top 20 hospitals by eribulin use, with at least 3 candidate patients who had/could have received ≥3 cycles of treatment by 03/2012. Patient and disease characteristics, as well as efficacy and safety parameters were obtained. Patient´s data were collected until September 2012. Living patients able to respond at the time of the study signed an informed consent. Study was approved by ethics committees. Results: Out of 112 screened ABC patients in 19 participating hospitals, 104 were enrolled. Median age was 56.6 years and 66% were post-menopausal. Visceral disease occurred in 2/3 of patients. ECOG status was ≤1 in 75,4% of patients. Estrogen receptor expression was found in 64.4% of tumors; 15.4% overexpressed HER2. 49% of patients received 1-5 treatment lines for ABC before eribulin. Mean eribulin treatment duration was 3 months (4,7 cycles). Disease control rate was 48.8% (1.1% CR, 22.1% PR, 25.6% SD). By 09/2012, 64,4% patients were still alive and median PFS was 97 days (95% IC: 81-129). 78.8% of patients reported ≥1 adverse events, being asthenia, neutropenia, anemia, alopecia, nauseas, and mucositis the most frequent ones (≥10%). Grade ≥3 adverse events occurred in ≤5% of patients. Conclusions: The favorable efficacy and safety profile of eribulin observed in this observational study is consistent with the pivotal phase III study (EMBRACE) and confirms its position for the treatment of ABC. Pre reimbursement usage has been restricted to later lines but use per the licensed indication in 3L is expected to yield additional clinical benefit. A confirmatory observational study (EUFORIA-2) is planned.

Peripheral Neuropathy In Multiple Myeloma Patients Treated with Lenalidomide

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5024-5024
Author(s):  
Carmen Castaneda ◽  
Lilia Weiss ◽  
Neil A. Minton ◽  
Alex Kim ◽  
John Freeman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Median Time ◽  
Study Drug ◽  
Phase Iii ◽  
Immunomodulatory Activity ◽  
Pivotal Phase ◽  
History Of ◽  
Time To Onset

Abstract Abstract 5024 Background: Lenalidomide is an oral IMiD® immunomodulatory compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity. As demonstrated by 2 randomized, double-blind, placebo-controlled pivotal phase III registration trials, lenalidomide plus dexamethasone (Len/Dex) was well tolerated and achieved significant clinical efficacy and survival outcomes vs placebo plus Dex (PBO/Dex) in patients (pts) with relapsed/refractory multiple myeloma (MM) (Weber 2007; Dimopoulos 2007). In MM, the rate of symptomatic peripheral neuropathy (PN) is 3–13%, although the rate of subclinical neuropathy detected by electrophysiological studies or histopathological evaluation is estimated to be much higher (40-60%; Kwan 2007). Published incidence of PN has been notable with thalidomide (Thal) ranging from 0 to 90%, depending on pt characteristics, concomitant treatments, dose/exposure duration, and techniques for identifying PN. We present the result of our analysis of PN adverse events (AEs) reported with Len. Methods: Reports of PN from the 2 registration studies (MM-009, MM-010; data cutoff June and August 2005, respectively), and postmarketing safety reports (Dec 2005 to Dec 2009) were retrieved from Celgene clinical and safety databases utilizing the Preferred Terms for PN AEs within the PN Standardized MedDRA (v13.0) Query (SMQ) to obtain all possible cases. Severity grades were according to the NCI CTCAE (V3). Results: Clinical Studies 703 pts (353 Len/Dex; 350 PBO/Dex) from the 2 registration studies were included in this analysis. The proportion of pts with ≥1 Grade (G) 1–4 PN AEs and ≥1 serious adverse event (SAE) was similar between the Len/Dex and PBO/Dex arm (45.6% vs 44.9% and 1.1% vs 1.1%, respectively). However, the proportion of pts with ≥1 G3/4 PN was slightly higher with Len/Dex vs PBO/Dex (9.3% vs 5.1%). Among the Len/Dex pts with PN AEs, prior Thal or vincristine was reported in 39.1% and 60.9% of pts, respectively and 24.8% of pts had history of PN. Among the PBO/Dex pts with PN AEs, prior Thal or vincristine was reported in 46.5% and 58.0% of pts, respectively and 29.3% of pts had a history of PN. Within this SMQ analysis, the PN AEs reported in ≥5% of the pts were peripheral neuropathy, hypoaesthesia, paraesthesia, and muscle weakness in both treatment arms. 98.3% of PN AEs were not SAEs and 83.2% were G1/2 in the Len/Dex arm. Among pts in the Len/Dex arm and with PN AEs, PN resolved in 61.5% and study drug was continued in 78.9% of pts. Study drug was reduced due to PN in 12.4% and interrupted in 5.0% of pts in the Len/Dex arm. The median time to onset of PN event was longer in the Len/Dex arm compared with the PBO/Dex arm (41 vs 31 days). Postmarketing A total of 2857 PN AEs were reported in 2329 of an estimated 73,592 MM pts. The reporting rate of PN AEs is 3.2% in the MM indication. Within this SMQ analysis, the PN AEs reported in ≥0.5% of the pts were peripheral neuropathy, hypoaesthesia, and paraesthesia. 93.8% of PN AEs were not SAEs. Most pts were males and elderly with a median age of 66 yrs (range: 29–95). Among MM pts with PN AEs and available information, 13% had prior Thal, 5% had prior bortezomib, and 11% had a history of PN. In the majority of reports, outcome was unknown and Len was continued. The median time to onset of PN event was 60 days (range: 1–1460). Conclusion: In 2 pivotal phase III registration trials, the incidence rate of peripheral neuropathy adverse events was similar between the Len/Dex and PBO/Dex arms. Most pts had prior anti-myeloma therapies associated with PN and a quarter of the pts had a history of PN. Limited information in postmarketing reports on prior therapies and medical history may have underestimated pre-existing PN and exposure to prior anti-myeloma therapies associated with PN. PN AEs occurred within a median of 60 days of starting Len. In conclusion, peripheral neuropathy adverse events in MM pts treated with Len are generally not SAEs and did not commonly require dose modification or interruption. References Dimopoulos et al. NEJM 2007;357(21):2123-2132. Kwan JY. Neurol Clin 2007;25(1):47-69. Weber et al. NEJM 2007;357(21):2133-2142. Disclosures: Castaneda: Celgene: Employment. Weiss:Celgene: Employment. Minton:Celgene: Employment. Kim:Celgene: Employment. Freeman:Celgene: Employment. Yu:Celgene: Employment. Knight:Celgene: Employment.

Results of an Ongoing, Open-Label, Safety-Extension Study of Interferon Beta-1a (Avonex) Treatment in Multiple Sclerosis

1999 ◽  
Vol 1 (2) ◽  
pp. 3-11 ◽  
Author(s):  
RM Herndon ◽  
LD Jacobs ◽  
ME Coats ◽  
DE Goodkin ◽  
MK Mass ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Injection Site ◽  
Interferon Beta ◽  
Phase Iii ◽  
Extension Study ◽  
Duration Of Treatment ◽  
Open Label ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Long Term Treatment

Abstract In a phase III, double-blind, placebo-controlled, 2-year clinical trial, interferon beta-1a (IFN-β-1a, Avonex) treatment significantly delayed disability progression, decreased exacerbations, and reduced brain lesions on magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS). In this open-label, safety-extension study, we evaluated the longer-term safety and antigenicity of IFN-β-1a. An open-label, safety-extension study of IFN-β-1a, administered at a dose of 30 μg intramuscular (IM) per week in patients with MS, was initiated in May 1995. Subjects enrolled in this study included interferon-naive patients and patients who had prior treatment with either IFN-β-1a in the phase III trial, IFN-β-1b (Betaseron), or both. Safety was evaluated by assessment of adverse events, tolerability by treatment discontinuations, and antigenicity by measurements of neutralizing antibody (NAB) titers. The number of intravenous (IV) steroid courses required per patient per year was determined as a surrogate measure of clinical relapses. There were 382 patients enrolled, with a median duration of treatment, including the phase III trial, of 2.5 years. Twenty-eight percent of participants have been on treatment for at least 3 years. The adverse event profile was similar to that observed in the phase III trial. Injection site reactions were rare and injection site necrosis was not observed. The incidence of NAB to IFN-β over 30 months of treatment was approximately 5%. IFN-β-1a was well tolerated in subjects who had switched from IFN-β-1b. Seventy-seven percent of the patients with NAB to IFN-β-1b at study entry had lost their NAB by month 24 on IFN-β-1a treatment. There was a 47% reduction in IV steroid use in the safety-extension study in those who had previously received placebo in the phase III trial. Long-term treatment of MS patients with IFN-β-1a continues to have a favorable safety profile, with low NAB titers and continuing clinical benefit.

P136 Efficacy and safety of olokizumab in a phase III trial in patients with moderately to severely active RA inadequately controlled by TNF-α inhibitor therapy

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Eugen Feist ◽  
Saeed Fatenejad ◽  
Sergey Grishin ◽  
Elena Korneva ◽  
Michael Luggen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Primary Endpoint ◽  
Inhibitor Therapy ◽  
Phase Iii ◽  
Major Adverse Cardiovascular Events ◽  
Research Support ◽  
Acr20 Response ◽  
Phase Iii Trial ◽  
Tnf Α ◽  
To Receive

Abstract Background/Aims  Olokizumab (OKZ) is a new humanised monoclonal antibody targeting IL-6. Here we present the results of the phase III study of OKZ in anti-TNF-IR patients. Methods  Patients with moderately to severely active RA who had previously failed TNF inhibitors (ClinicalTrials.gov Identifier NCT02760433/CREDO3) were randomized in a 2:2:1 ratio to receive subcutaneous (SC) injections of OKZ 64 mg every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or placebo (PBO), plus MTX. At week 16, all subjects in the PBO group were randomized in a 1:1 ratio to receive either of OKZ regimes. The primary endpoint was ACR20 response at week 12. Results  368 subjects were randomised according to the protocol and 320 patients (87%) completed the 24-week treatment period. Baseline characteristics were comparable across arms. Both regimens of OKZ were significantly better in primary endpoint: ACR20 were 60.9% (p = 0.0029 in comparison vs. PBO) in OKZ q2w, 59.6% in OKZ q2w (p = 0.0040 in comparison vs. PBO) and 40.6% in PBO. The key efficacy outcomes were maintained throughout the 24-week period of the study. Overall incidences of treatment-emergent adverse events (TEAE) were 65.5% in OKZ q2w, 65.0% in OKZ q4w and 50.7% in PBO. Subsequent randomization of PBO arm at week 16 did not change TEAEs incidence rate per treatment group significantly: 64.3% in any OKZ q2w and 59.7% in any OKZ q4w. The majority of TEAEs in all groups were not serious and were of mild or moderate severity. Incidence of treatment-emergent serious adverse events (TESAE) were: 12 (7.0%) subjects in any OKZ q2w; 6 subjects (3.2%) in any OKZ q4w group, all in the first 16 weeks. The most frequently reported TESAEs across all treatment groups were infections and infestations: 2 (1.2%) in OKZ q2w group, 2 (1.1%) in OKZ q4w group. No opportunistic infections including active tuberculosis, major adverse cardiovascular events, gastrointestinal perforations or deaths were reported. Conclusion  In this global Phase III trial in patients with moderately to severely active RA inadequately controlled by TNF-α inhibitor therapy, treatment with OKZ plus MTX in both regimes (OKZ 64 mg q2w and OKZ 64 mg q4w) was associated with significant improvements in the signs and symptoms of RA compared to PBO plus MTX over a 24-week period. Treatment with OKZ q2w and q4w in this difficult to treat population was well tolerated and consistent with the established safety profile of anti-IL-6 agents. Disclosure  E. Feist: Consultancies; R-Pharm, Abbvie, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi. Honoraria; R-Pharm, Abbvie, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Member of speakers’ bureau; R-Pharm, Abbvie, AB2Bio, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Grants/research support; Lilly, Novartis, Pfizer, Roche/Chugai. S. Fatenejad: Consultancies; RPharm International. Shareholder/stock ownership; Pfizer. S. Grishin: Corporate appointments; Employed by R-Pharm. E. Korneva: Corporate appointments; Employed by R-Pharm. M. Luggen: Consultancies; Amgen, Sun Pharmaceuticals, R-Pharm International. Grants/research support; I havAbbvie, R-Pharm, Sun Pharmaceuticals, Pfizer, Novartis, Lilly, and GSK. E. Nasonov: Honoraria; Lilly, Abbnie, Prizer, Biocad, R-Pharm. Member of speakers’ bureau; Lilly, Abbnie, Prizer, Biocad, R-Pharm. M. Samsonov: Corporate appointments; Employed by R-Pharm.

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