Tag: clinical-trials

• FDA Summary Review: Avonex (Interferon beta-1a) (PLA: 95-0979; ELA: 95-0975)

  FDA Summary Review: Avonex (Interferon beta-1a) (PLA: 95-0979; ELA: 95-0975)

  -”Interferon beta-1a (AVONEX) is indicated for the treatment of relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations”

  -”…the primary endpoint includes 123 placebo patients and 151 interferon patients for time to confirmed progression.  There were 60 confirmed progressions during the study; 36 in the placebo, 24 in the interferon group.  The analysis was performed with Kaplan-Meir survival curves and the Mantel-Cox statistic with a log-rank test…These curves show a decrease in the number of progressions in interferon group (p = 0.024)” 

  -time to first exacerbation: Exacerbation within the first three months on-study occurred nearly equally in both arms (26% placebo, 24% interferon)

  -Distribution of Exacerbations per Patient: Although there was a modest trend to fewer exacerbations in the interferon group in the first-year-on-study date, there was no statistically significant difference between the groups”

  -For the subset of patients with at least 2 years on study (85 interferon, 87 placebo) there were more with no exacerbations in the interferon group (38%) than the placebo group (26%), and fewer with more than one exacerbation (32%) than the placebo group (3%).  This was statistically significant (p = 0.027), Mann-Whitney rank sum test)

  1. The sponsor suggested a lag time between initiation of treatment and onset of clinical benefit.  Thus exacerbations are more appropriately assessed over a full 2 years.  However, this analysis discards considerable patient on-study experience.  The two-years-on-study analysis discards all patients who did not reach 2 full years on-study, ie, all patients enrolled in the later portion of the study.  An advantage of these analyses is an equality of patient weighting due to equal time contributed.  
  2. To address this, the data were reanalyzed in groups that still maintained the equality of patient followup time, but allowed an exploratory comparison of the effects of treatment.  The data were divided into three subset, each describing patient experience over a one-year period, with a full year of experience for each patient included (Table 2)

  -Distributions of Exacerbations per Patient

  1. 1 year patient subset: p value: 0.664
  2. 2 year patients during year 1: p value: 0.112
  3. 2-year patients during year 2: p-value: 0.096

  -There is no indication that benefit from interferon is delayed after treatment initiation 

  -Exacerbation Rate: Calculation of exacerbation rate on-study was not a prospectively defined endpoint, it was requested by CBER at the time of a pre-PLA meeting, ,due to the widespread use of this value for entry criteria or for an endpoint in MS clinical trials

  -annualized exacerbation rates: 2 years: p value: 0.002

  -steroid treatment course

  1. Year 1 patient subset: p value: 0.295
  2. Year 1 and 2 Patient subset: p value: 0.010

  -MRI Gadolinium Lesion Endpoints

  1. Number of Gadolinium-enhancing lesions per patient
     1. Year 1 patient subset: p value: 0.024
     2. 2 Year patient subset: p value: 0.051
  2. Volume of Gadolinium-enhancing lesions per patient, mm cubed

  1. Year 1 patient subset: p value: 0.020
  2. 2-Year patient subset: p value: 0.010

  -T2-weighted MRI Lesion Volume

  1. Baseline: p value: 0.143
  2. Year 1: p value: 0.023
  3. Year 2: p value: 0.355

  -These numerous analyses (of limb functional tests?) failed to show statistically significant differences between arms except for the time to sustained progression in the 25 Foot Walk time

  -the neuropsychologic batteries did not show differences in the treatment arms

  -the primary endpoint was progression of disability, as measured by a 1.0 change in the EDSS, sustained for at least 6 months to lessen effects of variability from disease fluctuation and intrarater variablity 

  -MRI T2 lesion volume showed statistically different effects at the end of year  but not year 2 scans (bold and underline mine)

  -Exacerbation rates per year per patient were similar.  They were statistically different for the 2-year patient subset but not for the 1-year patient subset.  When all patients on-study time was analyzed there was a treatment effect (bold and underline mine)

  -The distribution of number of exacerbations per patient improved with interferon treatment in the subset of patients on-study for at least two years but was not significant when analyzed using the larger number of patients on-study for at least 1 year (bold and underline mine)
  -MRI T2 lesion volume showed statistically different effects at the end of year 1 but not year 2 scans (bold and underline mine)

  January 21, 2025

  clinical-trials, health, healthcare, mental-health, wellness

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• FDA Summary Review (202992Orig1s000): Aubagio/Teriflunomide

  FDA Summary Review (202992Orig1s000): Aubagio/Teriflunomide

  -FDA agreed in principle to an NDA supported by one apparently robust primary

  study with additional supportive evidence.

  -the sponsor presents the results from one controlled Phase 3 efficacy study (EFC6049 or TEMSO).

  -The primary efficacy endpoint was the annualized relapse rate (ARR) over a 2 year treatment

  period. This is widely used in multiple sclerosis studies.

  -The “key” secondary efficacy endpoint was time to disability progression (defined as the time

  to an increase from baseline of at least 1 point on EDSS if the baseline EDSS score was < 5.5,

  or the time to an increase from baseline of at least 0.5 points on EDSS if the baseline EDSS

  score was > 5.5, with the respective increase in EDSS score sustained for at least 12 weeks).

  -The results for the secondary outcome concerning disability progression in the standard ITT

  population, presented by the sponsor and confirmed by the review team, are below:

  progression probability at year 2 p-value hazard ratio p-value

  -7mg: 1) progression probability at year 2 (21.7%); p-value: 0.0835; hazard ratio: 0.762; p-value: 0.0962

  -14 mg: 1) progression probability at year 2 (20.2%); p-value: 0.0279; hazard ratio: 0.702; p-value: 0.0337

  -placebo: progression probability at year 27.3%

  -An analysis of progression sustained for 24 weeks (rather than 12) revealed no significant treatment effect in either teriflunomide group.

  -Dr. Yan conducted an analysis of the change in EDSS score from baseline at 1 year and 2

  years and found little change between groups (Dr. Yan’s review, Table 8). She argues that this

  diminishes the significance of the 14 mg group’s improvement in the probability of

  progression.

  -Dr. Yan performed an additional subgroup analysis on the Americas population in TEMSO in

  order to further evaluate disability progression. She found that in this population of about 80

  patients per treatment group, both teriflunomide groups progressed notably more than the

  placebo group, with the placebo group experiencing virtually no progression. There was no

  baseline imbalance in the EDSS scores to potentially explain this subgroup finding.

  -An analysis of another clinical secondary endpoint, the FIS, was not significant for either dose

  of teriflunomide, though it did trend in favor of 14 mg.

  -Dr. Yan points out that the above two analyses may not be viewed as statistically valid due to

  the failure of the 7 mg dose to significantly differ from placebo in disability progression.

  -A descriptive analysis of progression on EDSS in Study 2001 is below:

    -7mg: 29% with progression

    -14mg: 7% with progression

    -placebo: 21%

    -*placebo outperformed 7mg Aubagio

  -Dr. Green also briefly discusses the efficacy results of two open-label extension trials (LTS 6048 and LTS 6050)…Although the results are not discouraging, the nature of these trials precludes the drawing of any meaningful conclusions regarding efficacy

  -…Dr. Yan…feels that the disability findings in TEMSO, while promising, require further confirmation…

  January 21, 2025

  clinical-trials, health, healthcare, mental-health, wellness

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• FDA Summary Review (NDA 204063/S-10: Tecfidera/dimethyl fumarate

  FDA Summary Review (NDA 204063/S-10: Tecfidera/dimethyl fumarate

  -There was no statistically significant effect on disability progression

  -Table 3: Clinical and MRI Results of Study 2:

    -Proportion with disability progression: 1) Tecfidera 240 mg BID: 13%; Placebo: 17%; p-value: 

    0.25 (not statistically significant)

    -relative risk reduction: 1)Tecfidera 240 mg BID: 21%; 2) Placebo: not listed; p-value: not listed

  -”Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis” by Ralf Gold MD et al (DEFINE study):

   -confirmed progression of disability at 2 yr: placebo 27%; twice-daily BG-12: 16% (*data were available for 409 patients in this group; thrice-daily BG-12: 18%; hazard ratio vs placebo: twice daily BG-12: 0.62 (p = 0.005) (statistically significant); thrice-daily BG-12: 0.66 (p = 0.01) 

  -As compared with placebo, BG-12 reduce the risk of confirmed progression of disability that was sustained for 12 weeks by 38% over the 2-year study period in the twice-daily BG-12 group (p = 0.005) and by 34% in the thrice-daily BG-12 group (p = 0.01)

  -”Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis” by Robert J Fox, MD et al (CONFIRM study)

  -Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo were not significant

  -In a preplanned sensitivity analysis, 24-week confirmed disability progression was not significantly reduced versus placebo in the twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate groups

  -time to disability progression when comparing twice-daily BG-12 and thrice-daily BG-12 with glatiramer acetate:.(twice daily BG-12 v glatiramer acetate: p = 0.44) (not statistically significant) and (thrice-daily BG-12 v glatiramer acetate: p = 0.37) (not statistically significant)

  -…neither BG-12 (at either dose) nor glatiramer acetate had a significant effect on disability progression in the CONFIRM study

  January 21, 2025

  clinical-trials, health, mental-health, placebo, wellness

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