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#Post#: 280--------------------------------------------------
(AAN) Tysabri every 8 weeks might cut PML risk?
DIR By: agate
Date: May 3, 2014, 7:46 pm
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The authors are working on the idea that Tysabri infusions every
8 weeks might be an equally effective dosing regimen and might
reduce the PML risk.
Presented at the annual AAN conference in Philadelphia, April
29, 2014:
--- Quote ---
> [P2.251] Multicenter Retrospective Study Of Extended Dosing Of
Natalizumab In Multiple Sclerosis: A Strategy For Mitigating
Risk Of Progressive Multifocal Leukoencephalopathy While
Maintaining Efficacy?
>
>
> Joseph Herbert,1Lana Zhovtis Ryerson,2Carlo- Use #013651
Tornatore,3John Foley,4Bianca Weinstock-Guttman,5Ilya
Kister,2Krupa Pandey,6Gina Remington,7Teresa Frohman,7Eugene
Major,8Sara Qureshi,7Shin Beh,7Darin Okuda,7Puspa Utomo,2Channa
Kolb,9David Hojnacki,5Elliot Frohman7
>
> 1Fair Lawn, NJ, USA, 2New York, NY, USA, 3Washington, DC, USA,
4Salt Lake City, UT, USA, 5Buffalo, NY, USA, 6Livingston, NJ,
USA, 7Dallas, TX, USA, 8Bethesda, MD, USA, 9Williamsville, NY,
USA
>
> OBJECTIVE:
>
> Investigate whether Natalizumab extended dosing schedule
mitigates progressive multifocal leukoencephalopathy risk while
maintaining clinical and radiological efficacy in multiple
sclerosis.
>
> BACKGROUND:
>
> Progressive multifocal leukoencephalopathy (PML) caused by JC
virus (JCV) is the most serious complication associated with use
of Natalizumab (NTZ) in patients with Multiple Sclerosis (MS).
PML risk after previous JCV exposure may be as high as 8.5/1,000
in long term NTZ recipients with high JCV antibody index. PML
susceptibility may reflect, at least in part, excessive
reduction in discrete tissue compartment trafficking of immune
cells required for JCV surveillance. While current MS treatment
guidelines utilize a standard 300 mg NTZ dose administered every
4 weeks, percentage saturation of α4β1 integrin
receptor on circulating lymphocytes is contingent upon NTZ serum
concentrations, which in turn may be influenced by individual
metabolism, body mass, dosage, and dose frequency. Pivotal trial
and postmarketing data suggest MRI and clinical activity
generally recur 12-16 weeks following cessation of NTZ therapy.
We hypothesized that transition to an 8-week dosing regimen
would, in a sense, establish the phenomenon of oscillating and
therapeutic anti-microbial immune reconstitution against a
ubiquitous viral pathogen, JCV.
>
> DESIGN/METHODS:
>
> Retrospective analysis of data provided by six MS Centers for
patients who received NTZ extended dosing (ED) schedules (every
6,7 or 8 weeks) will be presented.
>
> RESULTS:
>
> 586 patients have received ED NTZ for at least 3 consecutive
doses. Average age: 44 years; Male:female 32:68%; mean duration
NTZ treatment (total): 37 doses; mean duration NTZ (ED): 12
doses; JCV immunopositivity: 63%.Relapse rate and MRI
progression remained extremely low despite trend toincrease with
increasing ED interval. Not a single case of PML was reported.
>
> Subgroup analysis, tolerability data, annualized relapse rates
and MRI analysis will be presented.
>
> CONCLUSIONS:
>
> Our collective observations support the hypothesis that
extended dosing NTZ regimen may represent an effective strategy
to mitigate PML risk, while maintaining clinical and
radiological efficacy in MS. Prospective study is planned.
>
> Category - MS and CNS Inflammatory Disease: Clinical Science
>
>
>
--- End Quote ---
#Post#: 729--------------------------------------------------
Extending Tysabri dosage to 8 wks. shown safe, effective
DIR By: agate
Date: April 20, 2015, 6:53 pm
---------------------------------------------------------
More on this from the current AAN conference (April 2015) via
Medical Xpress, April 20, 2015:
--- Quote ---
> Extending natalizumab up to 8 weeks shown safe and effective
in patients with MS
>
> In a study of 1,964 patients with multiple sclerosis (MS) led
by researchers at the NYU Langone Multiple Sclerosis
Comprehensive Care Center, extending the dose of natalizumab
from 4 weeks up to 8 weeks was shown to be well-tolerated and
effective in patients, and resulted in no cases of the
potentially fatal side effect progressive multifocal
leukoencephalopathy (PML).
>
>
> The drug showed similar efficacy in treating disease activity
among patients, according to the study led by Lana
Zhovtis-Ryerson, MD, an assistant professor of neurology at the
NYU Langone Multiple Sclerosis Comprehensive Care Center.
>
> The findings were presented at the American Academy of
Neurology Annual Meeting held April 18-25, in Washington, D.C.
>
> Natalizumab is an infusion drug known as a monoclonal antibody
that is used to prevent MS symptoms and flare-ups and slow
worsening disability.
>
> However, taking the medication longer than two years may
increase risk for a rare but potentially fatal side effect
called PML, an untreatable brain infection caused by the JC
virus that occurs in up to 1.3 percent of patients taking
natalizumab.
>
> The medication is typically prescribed in 300-milligram
infusions every four weeks.
>
> "There remains much unknown about whether the drug will lose
effectiveness if dosing is extended," explains Dr.
Zhovtis-Ryerson. "Our study showed treatment with natalizumab
was safe for patients with similar efficacy reported as the
standard dosing, potentially enabling patients to stay on
effective MS medication at a reduced frequency of infusions and
with lower risk of PML. "
>
> Zhotvis-Ryerson and colleagues at 10 U.S. M.S. Centers sought
to compare the safety and efficacy of an extended dose of
natalizumab to the standard dose. They retrospectively compared
1,078 patients taking a standard 4-week dose to 886 taking an
extended dose between 4 weeks, 3 days and 8 weeks, 5 days.
>
> The researchers found extending the dosing schedule of
natalizumab to between 5 and 8 weeks does not affect the drug's
efficacy profile with 65 percent of participants in each group
not showing clinical MS activity, and comparable rates of new
lesions reported on imaging.
>
> Zero cases of PML were reported in the extended dosing group,
while two cases were reported in the standard dose group, though
the researchers said statistical significance has not been
reached yet. No other major adverse events were reported.
>
> "While the findings are encouraging, more research is needed
to determine whether extending natalizumab dosing may reduce
disability progression," says Dr. Zhovtis-Ryerson.
>
> More information: [P3.267] Safety and Efficacy of Extended
Dose Natalizumab in Multiple Sclerosis: An Ongoing Multicenter
Study.
> Session: P3: Poster Session III: MS and CNS Inflammatory
Diseases: Treatment Efficacy, Safety and Tolerability (2:00
PM-6:30 PM)?Date/Time: Tuesday, April 21, 2015 - 2:00 pm
>
> Provided by New York University School of Medicine
--- End Quote ---
#Post#: 778--------------------------------------------------
Re: (AAN) Tysabri every 8 weeks might cut PML risk?
DIR By: agate
Date: May 7, 2015, 7:39 pm
---------------------------------------------------------
From Multiple Sclerosis News Today, April 27, 2015:
--- Quote ---
> Study Tests Safety & Efficacy of New Treatment Intervals For
MS Therapy Natalizumab
>
> Diogo Bruno, MD
>
>
> A new study presented last week during the American Academy of
Neurology’s 67th Annual Meeting in Washington, DC provides new
treatment strategies for multiple sclerosis (MS) using a
monoclonal antibody already used in some MS patients.
>
> ... Natalizumab is a drug used for treating
relapsing-remitting MS, usually administered by intravenous
infusion once per month that reduces the ability of inflammatory
immune cells to enter the brain and affect nerve cells. The drug
was approved in 2004 by the U.S. Food and Drug Administration
and has been proven effective in treating MS relapse, vision
loss, and cognitive symptoms. Nevertheless, extended (longer
than two years) use of this medication is associated with an
increased risk for progressive multifocal leukoencephalopathy
(PML), a rare but severe complication caused by JC virus
infection that takes advantage of this immunodepression in the
brain.
>
>
> A team of researchers led by Dr. Lana Zhovtis-Ryerson,
assistant professor of neurology at NYU Langone’s Multiple
Sclerosis Comprehensive Care Center reported on an ongoing
multiple center study of close to 2,000 patients in which they
extended the dosing schedule of natalizumab to between 5 and 8
weeks. More specifically, Dr. Zhovtis-Ryerson and colleagues are
retrospectively comparing patients in from ten U.S. MS treatment
centers, collecting data every 4 weeks in a combination of
schedules.
>
> The treatment efficacy at this point appears similar to
standard schedule (every 4 weeks) with comparable rates of
symptomatic MS activity and new lesions in imaging studies.
Extended schedule groups had no cases of PML, while the standard
schedule group had 2 cases reported. There were no other major
adverse effects seen in any group.
>
> Nevertheless, while these differences in safety between
schedules are encouraging, statistical significance was not
reached. Consequently, further research is needed to ascertain
the maintenance of natalizumab efficacy with a more favorable
safety profile.
--- End Quote ---
HTML http://multiplesclerosisnewstoday.com/2015/04/27/study-tests-safety-efficacy-new-treatment-intervals-ms-therapy-natalizumab/
HTML http://multiplesclerosisnewstoday.com/2015/04/27/study-tests-safety-efficacy-new-treatment-intervals-ms-therapy-natalizumab/
#Post#: 785--------------------------------------------------
Re: (AAN) Tysabri every 8 weeks might cut PML risk?
DIR By: agate
Date: May 12, 2015, 7:01 pm
---------------------------------------------------------
More on this in MedPage Today, May 12, 2015:
--- Quote ---
> Increasing Tysabri Dosing Interval Appears Effective
>
>
> by John Gever
> Managing Editor, MedPage Today
>
>
> Freedom from relapse was maintained in multiple sclerosis
patients on natalizumab (Tysabri) who received the infusion drug
less frequently than the recommended 4-week interval, with lower
risk of progressive multifocal leukoencephalopathy (PML),
preliminary results from an ongoing analysis indicated.
>
> Among 886 patients treated with "extended" dosing at 10
multiple sclerosis centers nationwide, the mean annualized
relapse rate was the same at 0.1 per year as in 1,078 patients
receiving natalizumab at the standard 4-week interval, according
to Lana Zhovtis-Ryerson, MD, of NYU Langone Medical Center in
New York City. MRI lesions counts were also similar.
>
> Although patients testing positive for the JC virus -- the
pathogen whose reactivation triggers PML, a sometimes fatal
brain inflammation -- comprised 59% of the extended dosing
group, none have so far developed PML.
>
> With a total of 1,023 patient-years of exposure to natalizumab
in this JC-positive subgroup, published risk algorithms show an
expected incidence of 2.5 cases, Zhovtis-Ryerson and colleagues
calculated.
>
> At this point the finding of zero cases with extended dosing
is not statistically significant, the researchers cautioned --
but if the exposure reaches 1,248 patient-years with still no
cases, it will be significant at P<0.05, Zhovtis-Ryerson
indicated.
>
> Meanwhile, two PML cases have developed in the standard-dosing
group, among whom 41% are JC-positive and who have received a
mean of 30 natalizumab doses (SD 22).
>
> Brian Weinshenker, MD, of the Mayo Clinic, who was not
involved with the study, told MedPage Today that the approach
deserves more study but urged caution in adopting it clinically.
>
> He noted that if just one patient in the extended dosing group
developed PML, "it would have completely negated any trend to
reduced risk."
>
> PML has been the primary concern with natalizumab almost since
it was introduced in 2004. When several cases turned up shortly
after its approval, the drug was withdrawn for some months, then
relaunched with a restricted distribution program that included
clinician and patient education on the risk.
>
> The question of how to reduce PML risk with natalizumab --
which exceeds 1% in patients positive for JC virus and who have
two other risk factors (treatment duration >2 years and history
of immunosuppressant therapy) -- has occupied MS neurologists
since the relaunch. Most studies have shown that patients who
discontinue the drug or take long "holidays" experience a spike
in relapse risk.
>
> Switching to another drug has not prevented such spikes
because a months-long washout period after natalizumab
discontinuation is needed before starting a different agent.
> Some clinicians have been experimenting instead with longer
dosing intervals, in the belief that the 4-week schedule keeps
the drug's target -- alpha4beta1 integrin, an adhesion molecule
involved in immune cell trafficking -- so saturated that JC
virus immune surveillance is eliminated. Extending the interval
may relax the immune suppression just enough to keep latent JC
virus under control while still maintaining the anti-relapse
effect.
> In the current study, reported at the American Academy of
Neurology's annual meeting, Zhovtis-Ryerson and colleagues
sought to capture this empirical experience by canvassing
centers that have adopted the strategy with some patients.
>
> They defined extended dosing as any interval from 31 days up
to 61 days. They further subdivided the extended dosing patients
into those with early extended dosing (31 to 48 days; n=284) and
late extended dosing (49 to 61 days; n=293). Another 309
patients had dosing that varied and could not be classified into
either of those groups.
>
> Patients in the extended dosing groups were at somewhat higher
risk for PML than those treated at the recommended interval,
with a higher proportion testing positive for JC virus, more
patients with a history of immunosuppressant therapy (18% versus
11%), and more total natalizumab doses (mean 39 versus 30).
Patient age, disease duration, and gender balance did not differ
markedly between standard and extended dosing groups, however.
>
> Among extended dosing patients, the mean duration of that
schedule was 23 months overall (SD 14, range 3-116). These
varied only modestly between the early, late, and variable
dosing regimens.
>
> Treatment efficacy (natalizumab's forte) was excellent
irrespective of dosing interval. Some 65% of standard and 65% of
extended dosing groups showed no evidence of disease activity
(NEDA) -- that is, no active MRI lesions and no clinical
activity. The variable extended dosing group suffered a little
bit in this respect, with 55% meeting the NEDA standard compared
with about 70% for both early and late dosing (P<0.001 versus
early extended dosing, P=0.126 versus late dosing).
>
> Weinshenker commented that selection of patients for extended
dosing, which was not random, might have involved "biases
against committing more aggressive MS patients on the extended
interval program, which might reduce the ability of the
investigators to detect reduction in efficacy."
>
> Nevertheless, he said, extended dosing "is a promising and
sensible approach that might turn out to be effective."
> Zhovtis-Ryerson and colleagues have established a registry
called EXTEND to which other clinicians may contribute, at
HTML http://www.msbase.org
HTML http://www.msbase.org
. They are also planning a prospective
study to examine effects of the different regimens on disability
progression over time.
>
> __________________
> The study had no external funding and authors declared they
had no financial interests relevant to the work.
>
> Reviewed by Robert Jasmer, MD Associate Clinical Professor of
Medicine, University of California, San Francisco
--- End Quote ---
The article can be seen here
HTML http://www.medpagetoday.com/Neurology/MultipleSclerosis/51485.
#Post#: 960--------------------------------------------------
New data show longer Tysabri dosing interval in MS is feasible
DIR By: agate
Date: October 7, 2015, 6:20 pm
---------------------------------------------------------
Excerpted from MedPage Today, October 7, 2015:
--- Quote ---
> New Data Show Longer Tysabri Dosing Interval in MS Is Feasible
>
> But available data remain underpowered to confirm PML risk
reduction
>
>
> by John Gever
> Managing Editor, MedPage Today
>
>
> BARCELONA -- Updated data from an ongoing study indicate that
relapse rates and MRI lesion activity may actually be improved
among multiple sclerosis patients receiving natalizumab
(Tysabri) every 8 weeks as compared with the standard 4-week
interval, with a possibly reduced risk of progressive multifocal
leukoencephalopathy (PML).
>
> With almost 2,000 patients enrolled in the study -- a
prospectively scheduled chart review of patients at 11 U.S.
centers who are receiving natalizumab on either the standard
schedule or some type of extended-dosing interval -- the
percentage of patients with relapses or clinical worsening,
annualized relapse rate, and the percentage of patients with new
T2 lesions were all significantly lower among those on extended
dosing, said Lana Zhovtis-Ryerson, MD, of NYU Langone Medical
Center in New York City, who presented the findings at a
platform session during the European Committee for Treatment and
Research in Multiple Sclerosis annual meeting here.
>
> Moreover, there have been four PML cases among those on
standard dosing versus none in the extended-dosing group, she
reported. But the difference is not statistically significant,
because the numbers of patients and duration of treatment have
not yet met the threshold needed to demonstrate a significant
difference, Zhovtis-Ryerson said.
>
> But at this point, it may not be premature to state that the
extended-dosing strategy does not sacrifice efficacy. Specific
findings were as follows:
>
> ~Percentage of patients with relapse or clinical worsening:
23% with standard dosing, 18% with extended dosing (P=0.03)
>
> ~Annualized relapse rate: 0.14 standard, 0.09 extended
(P=0.02)
>
> ~Percentage with new T2 lesions: 17% standard, 14% extended
(P=0.02)
>
> ~Percentage with gadolinium-enhancing lesions: 7% standard, 9%
extended (P=0.08)
>
> ~Percentage with no evidence of disease activity (clinical and
radiographic): 62% standard, 61% extended (P=0.83)
>
> Earlier this year, when Zhovtis-Ryerson and colleagues
reported initial results from the study, there were two cases of
PML in the standard-dose group versus none receiving extended
dosing, and relapse rates and MRI activity levels were similar.
At that time, and again here, she said that 1,248 patient-years
of exposure would be needed to pronounce a significant advantage
for one dosing strategy over the other at the P<0.05 level.
>
> Currently, she said the standard-dose group had 1,052
patient-years among JC virus-positive participants and 1,090
patient-years in the extended-dosing group.
>
> However, accrual of patient-years of exposure is proceeding
slowly, she told MedPage Today here, and the research team
expects it will be another 18 months before both groups reach
the 1,248 mark.
>
> Label instructions for natalizumab dosing call for the drug to
be given every 4 weeks. But researchers have wanted to determine
whether the same degree of clinical efficacy, in reducing risk
of relapses and MRI lesion activity, can be maintained with
longer intervals -- the point being to reduce the overall drug
exposure and with it, presumably, the risk of developing PML.
>
> Rates of PML have been found to increase with years of
natalizumab exposure, but it remains unknown whether reducing
the exposure in terms of milligrams per year will also cut the
PML risk.
>
> PML has been the biggest barrier to use of natalizumab, which
otherwise is a highly effective and relatively safe agent for
relapsing-remitting MS. Among patients positive for JC virus
(the actual causative agent) who remain on natalizumab for more
than 2 years at standard dosing, about 0.5%-1% will develop PML,
depending on prior exposure to immunosuppressants. Roughly 20%
of PML cases are fatal and many survivors have permanent
disabilities.
>
> The current study's design involves regular chart reviews,
conducted on a prospective basis but without randomized
treatment assignments, of patients receiving natalizumab on a
variety of dosing schedules chosen by their treating physicians.
Zhovtis-Ryerson and colleagues have stratified patients into the
following groups:
>
> Standard dosing (every 4 weeks)
> Extended dosing (every 31 to 61 days)
>
> That no patients in the latter group developed PML, versus
four with standard dosing, is all the more impressive because
the recognized risk factors for PML were more common in those
receiving the extended dosing -- as might be expected since
clinicians may be inclined to recommend less frequent
natalizumab dosing for patients deemed to have high PML risk.
>
> Of the 905 patients in this group, 59% were positive for JC
virus and 18% had received prior immunosuppressants, compared
with 48% and 12% of the standard-dosed patients, respectively
(both P≤0.01). Moreover, Zhovtis-Ryerson said, the
percentage receiving natalizumab for longer than 2 years was
higher in the extended-dosing group, although she didn't present
specific numbers.
>
> Zhovtis-Ryerson said that recent data from other studies
support the concept that a longer dosing interval could preserve
natalizumab efficacy. These data point to the drug's saturation
of its target, the alpha-4/beta-1 integrin molecule, as a key
factor.
>
> Specifically, it appears that target saturation need not be
100% to stop relapses and lesion activity. Partial saturation
may be all that's necessary, and by allowing a degree of the
target's normal function, it may allow immune surveillance and
function in the nervous system to remain strong enough to
maintain JC virus suppression. PML is believed to result from a
diminution of immune surveillance and function that allows
latent JC virus infection to become active within the brain.
>
> Zhovtis-Ryerson emphasized that data from the current study
may never be fully adequate to justify extended dosing as a
routine strategy. She urged that a prospective, randomized
non-inferiority trial be conducted.
> The current study had no commercial funding.
>
> ____________________
>
> Zhovtis-Ryerson and several co-authors reported research
support and/or consulting relationships with Biogen Idec,
manufacturer of natalizumab. Authors reported relationships as
well with other commercial entities including Teva, EMD Serono,
Novartis, Genzyme, Genentech, Acorda, Shire, and Questcor
--- End Quote ---
But what about this?
--- Quote ---
> ~Percentage with gadolinium-enhancing lesions: 7% standard, 9%
extended (P=0.08)
--- End Quote ---
It looks to my untrained eye as if those on the extended dose
were at greater risk of having gadolinium-enhancing lesions.
Also,
--- Quote ---
> Standard dosing (every 4 weeks)
> Extended dosing (every 31 to 61 days)
>
--- End Quote ---
At least some of those on the experimental extended dosing were
receiving Tysabri more often than once every 8 weeks. In fact,
those who were receiving it every 31 days, for instance, were
getting Tysabri only slightly less often than those on the
standard dose. Or don't I understand this right?
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