Update on Amifampridine as a Drug of Choice in Lambert-Eaton Myasthenic Syndrome

US Neurology ◽  
2014 ◽  
Vol 10 (02) ◽  
pp. i ◽  
Author(s):  
Shin J Oh ◽  
Jörn Peter Sieb ◽  
◽  
Keyword(s):  
Drug Application ◽  
Clinical Trial Data ◽  
Autoimmune Disorder ◽  
Phase Iii ◽  
Drug Status ◽  
Double Blind ◽  
Drug Of Choice ◽  
Qt Intervals ◽  
The Us ◽  
Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a disabling autoimmune disorder involving impairment of neuromuscular transmission and producing serious muscle weakness, for which few effective medications are currently available. 3,4-diaminopyridine (3,4-DAP, INN/USAN: amifampridine) is the leading treatment for LEMS and has been available for over 25 years as an unapproved drug under treatment and expanded access protocols filed with the US Food and Drug Administration (FDA) or from compounding pharmacies in the US. Administering the correct dose of 3,4-DAP is critical—overdosing can increase the risk for seizures and other adverse events, while underdosing can result in a substantial loss of efficacy or even treatment failure. Two recent studies have shown a wide variation in the 3,4-DAP content of compounded preparations. A tablet formulation of 3,4-DAP phosphate salt (FIRDAPSETM) has been licenced in Europe with orphan medicinal product status since 2009 and appears to be as efficacious as the base in relieving the symptoms of LEMS. The product has also received orphan drug status in the US and is currently being evaluated in a multicenter, double-blind, placebo-controlled phase III trial to support New Drug Application (NDA) approval in the US. A recent safety trial in healthy volunteers using doses at and above normal levels has shown no effect on QT intervals, heart rate, or cardiac depolarization. Based on available clinical trial data, amifampridine phosphate was recently given Breakthrough Therapy designation by the FDA, which may enable fast-track NDA approval, thus increasing the potential for more patients with LEMS to receive an effective therapy.

scholarly journals Bevacizumab use in the frontline, maintenance and recurrent settings for ovarian cancer

2020 ◽  
Vol 16 (7) ◽  
pp. 225-246 ◽  
Author(s):  
Carolyn E Haunschild ◽  
Krishnansu S Tewari
Keyword(s):  
Ovarian Cancer ◽  
Gynecologic Oncology ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Gynecologic Oncology Group ◽  
Double Blind ◽  
Free Survival ◽  
Platinum Sensitive ◽  
The Us ◽  
Us Fda

On 13 June 2018, Genentech, Inc. issued a press release announcing that the US FDA had approved the antiangiogenesis drug, bevacizumab, in combination with chemotherapy for frontline and maintenance therapy for women with newly diagnosed ovarian cancer. Regulatory approval was based on the National Cancer Institute-sponsored Gynecologic Oncology Group (GOG) protocol 0218, the Phase III, randomized, placebo-controlled, double-blind, multi-center and multi-national clinical trial that met its primary end point, progression-free survival. Bevacizumab is now approved in the frontline, platinum-sensitive recurrent and platinum-resistant recurrent settings for epithelial ovarian cancer. This review will address the broad range of clinical trials addressing the efficacy of bevacizumab use in ovarian cancer.

ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5600-TPS5600 ◽  
Author(s):  
Anne-Claire Hardy-Bessard ◽  
Kathleen N. Moore ◽  
Mansoor Raza Mirza ◽  
Bernard Asselain ◽  
Andres Redondo ◽  
...  
Keyword(s):  
Residual Disease ◽  
Survival Rates ◽  
Standard Of Care ◽  
Figo Stage ◽  
Primary Objective ◽  
Phase Iii ◽  
Clinical Activity ◽  
Double Blind ◽  
The Us ◽  
Phase Iii Study

TPS5600 Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the US and Europe for maintenance treatment in pts with recurrent OC regardless of BRCAmut status. Preclinical data suggest synergy with PARPi + anti-PD-1 blockade. Niraparib + pembrolizumab has shown clinical efficacy in pts with platinum-resistant or secondary refractory OC regardless of biomarker status. Dostarlimab is an anti–PD-1 humanized monoclonal with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS (per RECIST v1.1) in pts treated with SOC + dostarlimab + niraparib to SOC. Methods: Eligible pts (up to 912) are FIGO stage 3 (with residual disease, CC0 high risk, or planned neoadjuvant therapy) or stage 4, non-mucinous epithelial OC and ECOG score < 2. After 1 cycle of SOC, pts are stratified by concurrent bev use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms (Table). An innovative feature of ENGOT-OV44/FIRST (NCT03602859; EUDRACT 2018-000413-20) is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC, allowing pts in the control arm to receive up to date SOC. These adaptations will occur when practice-changing data are released. Following publication of SOLO1 results, BRCAmut pts will only be randomized to arm 2 or 3 to ensure they receive niraparib. Further adaptations may be incorporated as new data become available, leading to stop randomization in arm 1 or 2 of pts based on their biomarker status. Clinical trial information: NCT03602859. [Table: see text]

3,4-diaminopyridine Phosphate in the Treatment of Lambert-Eaton Myasthenic Syndrome

2012 ◽  
Vol 7 (1) ◽  
pp. 56
Author(s):  
Jörn Peter Sieb ◽  
Keyword(s):  
Neuromuscular Transmission ◽  
Autoimmune Disorder ◽  
Special Treatment ◽  
Orphan Medicinal Product ◽  
Local Hospital ◽  
Correct Dose ◽  
The Us ◽  
Myasthenic Syndrome ◽  
Drug Doses ◽  
Variable Quality

3,4-diaminopyridine (3,4-DAP, amifampridine) is the leading treatment for Lambert–Eaton myasthenic syndrome (LEMS), an autoimmune disorder with impaired neuromuscular transmission, for which few effective medications are currently available. 3,4-DAP has been available as a therapy for LEMS in special treatment programmes for approximately 25 years. As an unlicensed drug, doses for oral administration are required to be compounded by local, hospital or other compounding pharmacies from the base chemical. Administering the correct dose of 3,4-DAP is critical; overdosing can increase the risk of seizures and other adverse events, while underdosing can result in a substantial loss of efficacy or even treatment failure. Two recent studies, have shown a wide variation in the 3,4-DAP content of compounded preparations (22.2–125.2 %, n=9) and (53.5–128.5 %, n=21), thereby reflecting the possibility of patients receiving dosages that might be above safety limits or even markedly below efficacy limits. This inconsistency results from the variable quality and instability of the base chemical and compounding errors. A formulation of 3,4-DAP phosphate salt has now been licensed in Europe and the US with orphan medicinal product status and appears to be as efficacious as the base in relieving the symptoms of LEMS.

Cost-Effectiveness Results from the US Carvedilol Heart Failure Trials Program

2001 ◽  
Vol 35 (7-8) ◽  
pp. 846-851 ◽  
Author(s):  
Montserrat Vera-Llonch ◽  
Joseph Menzin ◽  
Randel E Richner ◽  
Gerry Oster
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Cost Effectiveness ◽  
Inpatient Care ◽  
Phase Iii ◽  
Double Blind ◽  
Secondary Sources ◽  
The Us ◽  
Using Data ◽  
The Cost

OBJECTIVE: To evaluate the cost-effectiveness of carvedilol, a β-blocker that is approved for use in the US for the treatment of heart failure, based on data from Phase III clinical trials. METHODS: We conducted an economic evaluation alongside the US Carvedilol Heart Failure Trials Program, which consisted of four concurrent, randomized, double-blind, placebo-controlled clinical trials; the mean duration of follow-up across these four trials was 6.5 months (the program was terminated prematurely based on a finding of a 65% mortality benefit). Using data from these trials, we examined the cost-effectiveness of carvedilol in terms of the estimated cost per death averted among patients randomized to such therapy versus those receiving placebo. Attention was focused on the cost of carvedilol therapy plus the cost of cardiovascular-related inpatient care. Costs of care were estimated by combining information on healthcare utilization from the clinical trials with secondary sources of cost data. RESULTS: Patients randomized to receive carvedilol had lower mean ± SD estimated costs of cardiovascular-related inpatient care over 6.5 months compared with those receiving placebo ($1912 ± $7595 vs. $4463 ± $20 565, respectively). As mortality also was lower among carvedilol patients, the estimated cost per death averted was negative. The probability that carvedilol would both increase survival and decrease costs of cardiovascular-related care over a 6.5-month period was estimated to be 0.98. CONCLUSIONS: Data from the US Carvedilol Heart Failure Trials Program indicate that carvedilol reduces mortality in patients with heart failure; our study suggests that it also may be cost-saving over a period of approximately six months.

scholarly journals OnabotulinumtoxinA in the treatment of patients with chronic migraine: clinical evidence and experience

2017 ◽  
Vol 10 (12) ◽  
pp. 397-406 ◽  
Author(s):  
Chia-Chun Chiang ◽  
Amaal J. Starling
Keyword(s):  
Chronic Migraine ◽  
Clinical Evidence ◽  
Migraine Prophylaxis ◽  
Phase Iii ◽  
Short Term ◽  
Double Blind ◽  
The Us ◽  
Injection Protocol ◽  
Prophylaxis Therapy

Chronic migraine is a debilitating neurobiological disorder that affects approximately 1.4–2.2% of the population worldwide. Patients with chronic migraine have 15 or more headache days per month, with at least 8 days per month that meet the criteria for migraine. Injection of onabotulinumtoxinA, using a standardized injection protocol, was approved by the US Food and Drug Administration in 2010 for the treatment of chronic migraine. The approval was made based on results from two large, randomized, double-blind placebo-controlled trials: the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. Since then, numerous studies have been performed investigating the short-term and long-term benefits, risks and complications of the use of onabotulinumtoxinA injections for the treatment of chronic migraine. The purpose of this narrative review is to describe the currently available clinical evidence for the use of onabotulinumtoxinA injections for treating patients with chronic migraine.

Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim for the prevention of severe neutropenia, in patients with breast cancer receiving myelosuppressive chemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10116-10116 ◽  
Author(s):  
Andriy Krendyukov ◽  
Nadia Harbeck ◽  
Pedro Gascon ◽  
Sreekanth Gattu ◽  
Yuhan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Reference Group ◽  
Phase Iii ◽  
Severe Neutropenia ◽  
Double Blind ◽  
Myelosuppressive Chemotherapy ◽  
The Us ◽  
Baseline Characteristics ◽  
Biosimilar Filgrastim ◽  
Clinical Trial Information

10116 Background: In 2015, filgrastim EP2006 (Zarxio) became the first biosimilar approved by the FDA for commercial use in the US. This phase III randomized, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC) compares US-licensed filgrastim, Neupogen (reference), with two groups who received alternating treatment with reference and biosimilar every other treatment cycle. Methods: A total of 218 patients receiving 5µg/kg/day filgrastim over 6 chemotherapy cycles were randomized 1:1:1:1 into 4 arms. Two arms received only 1 product, biosimilar or reference (unswitched), and 2 arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over cycles 1─6). Since the switch occurred from Cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during Cycles 2─6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for Cycles 2─6 was shown if 95% confidence intervals (CIs) were within a pre-defined margin of -15%. Results: A total of107 patients switched treatment, and 51 patients received reference in all cycles. Baseline characteristics were similar between groups. Incidence of FN was 3.4% (switched) vs. 0% (reference) (95% CI: -9.65; 4.96), which is within the predefined non-inferiority margins. Infections occurred in 9.3% (switched) vs. 9.9% (reference). Hospitalization due to FN was low with 1 patient in Cycle 6 (switched). TEAEs related to filgrastim were reported in 42.1% (switched) vs. 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) vs. 39.2% (reference) (all cycles), including bone pain (30.8% vs. 33.3%). No anti-drug antibodies were identified. Conclusions: There was no evidence of clinically meaningful differences when patients with breast cancer were switched from reference to biosimilar filgrastim, or from biosimilar to reference filgrastim. Clinical trial information: NCT01519700.

Custodiol-N versus custodiol: A prospective randomized double blind multicenter phase III trial

2014 ◽  
Vol 62 (S 01) ◽  
Author(s):  
G. Szabó ◽  
A. Weymann ◽  
B. Schmack ◽  
D. Badowsky-Zyla ◽  
G. Veres ◽  
...  
Keyword(s):  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Multicenter Phase
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