Author Topic: (AAN) Tysabri every 8 weeks might cut PML risk?  (Read 401 times)

0 Members and 0 Guests are viewing this topic.

Offline agate

  • Administrator
  • *****
  • Posts: 7471
  • Location: Pacific Northwest
(AAN) Tysabri every 8 weeks might cut PML risk?
« on: May 03, 2014, 03:46:33 pm »
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


 





SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

  • Administrator
  • *****
  • Posts: 7471
  • Location: Pacific Northwest
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





SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

  • Administrator
  • *****
  • Posts: 7471
  • Location: Pacific Northwest
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.

http://multiplesclerosisnewstoday.com/2015/04/27/study-tests-safety-efficacy-new-treatment-intervals-ms-therapy-natalizumab/
« Last Edit: May 07, 2015, 03:43:09 pm by agate »





SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

  • Administrator
  • *****
  • Posts: 7471
  • Location: Pacific Northwest
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 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

The article can be seen here.





SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

  • Administrator
  • *****
  • Posts: 7471
  • Location: Pacific Northwest
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

But what about this?

Quote
~Percentage with gadolinium-enhancing lesions: 7% standard, 9% extended (P=0.08)

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)

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?





SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.