Tysabri abstracts from ECTRIMS

[xo++]

Several Tysabri abstracts are still unavailable at the ECTRIMS site.

We had been having a discussion about relative risk reduction vs. absolute risk reduction over at the temporary Braintalk. And in the past I have complained that the drug companies too often overemphasize relative risk reduction while seeming to hide the absolute numbers in the medical papers.

But relative risk is sometimes more important. For example, if a clinical trial lasting two years finds that 40% of the placebo group suffers disability progression, but 0% of the treatment group, then that therapy would be 100% effective relative to placebo. But the absolute number would still be 40%. I would argue that in this case the 100% is more significant.

Here the results of cognitive function testing exactly mirrored the reduction in disability progression seen in the AFFIRM trial (~42 - 43% effective relative to placebo).

Other abstracts here demonstrate that the effects of Tysabri evaporate over time, after cessation of treatment. This is both good and bad. On the one hand, it would be good if we could take a drug which safely protected us for a long time. On the other, if the drug is having a bad effect on us, we would like for it to clear our system quickly.

The effects of natalizumab on brain atrophy and cognitive function: results from the AFFIRM study

E. Fisher, P.W. O'Connor, E. Havrdova, M. Hutchinson, L. Kappos, D.H. Miller, J.T. Phillips, C.H. Polman, F.D. Lublin, G. Giovannoni, A. Wajgt, R.A. Rudick, F. Lynn, M.A. Panzara, A.W. Sandrock for the AFFIRM and SENTINEL Investigators

Studies have shown that brain atrophy correlates with cognitive change in multiple sclerosis (MS) patients. The efficacy and safety of natalizumab (TYSABRI), an alpha4-integren antagonist, were evaluated in a randomized, double-blind, placebo-controlled phase 3 trial (the AFFIRM study).

Results from AFFIRM showed that natalizumab significantly reduced the cumulative probability of sustained disability progression and annualized relapse rate over 2 years compared with placebo. On MRI, there were 92% fewer gadolinium-enhancing lesions and 83% fewer new or enlarging T2-hyperintensities in the natalizumab group compared with placebo. Changes in brain parenchymal fraction (BPF) (a normalized measure of whole brain atrophy) and scores on the 3-second Paced Auditory Serial Addition Test (PASAT 3) (a measure of cognitive function) were additional pre-specified end points in AFFIRM.

There were 942 patients randomized to natalizumab (n=627) or placebo (n=315). During Year 1, the mean percent change in BPF was significantly greater with natalizumab compared with placebo (-0.558 vs -0.395, p=0.002). In contrast, during Year 2, mean percent change in BPF was significantly less in the natalizumab group compared with placebo (-0.242 vs -0.427, p=0.004).

Natalizumab significantly reduced the proportion of patients with worsening (0.5 standard deviation decrease) in PASAT 3 score sustained for 12 weeks by 43% compared with placebo (hazard ratio [95% confidence interval] = 0.57 [0.37, 0.89]; p=0.013).

A positive correlation was observed between change in BPF and time to sustained worsening of cognitive function over 2 years in placebo patients (SRCC=0.213, p=0.0004). In natalizumab patients, there was no correlation between BPF change and time to sustained worsening of cognitive function (SRCC=0.014, p=0.734). Natalizumab significantly reduced brain atrophy during the second year of treatment and significantly improved cognitive function.

Consistent with previous studies, brain atrophy was correlated with worsening cognitive function in the placebo group. The dissociation between atrophy and cognitive function in the natalizumab group indicates that the increased atrophy rate in the first year may be due to resolution of edema rather than actual tissue loss, which would be consistent with the dramatic reduction in active lesions. Correlations broken down by year and the kinetics of BPF change in Year 1 are currently under investigation.

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Results of clinical and magnetic resonance imaging analyses following cessation of natalizumab dosing in patients with multiple sclerosis

P.W. O'Connor, A. Goodman, L. Kappos, F.D. Lublin, D.H. Miller, C.H. Polman, R.A. Rudick, F. Lynn, M.A. Panzara, A.W. Sandrock for the AFFIRM and SENTINEL Investigators

Natalizumab is a selective alpha4-integrin antagonist that significantly reduced annualized relapse rate and magnetic resonance imaging (MRI)-detectable brain lesion development in patients with relapsing multiple sclerosis (MS) during phase 3 studies. Dosing of natalizumab was voluntarily suspended when 3 cases (2 in MS and 1 in Crohn’s disease) of progressive multifocal leukoencephalopathy (PML) were reported during natalizumab therapy.

This paper reports annualized relapse rate and the number of gadolinium-enhancing (Gd+) lesions over time following suspension of natalizumab dosing. Patients who completed AFFIRM, SENTINEL, or GLANCE studies were eligible to participate in an open-label extension study that evaluated the long-term safety and tolerability of natalizumab. SENTINEL and the open-label extension study were terminated early due the voluntary suspension of natalizumab.

All patients who received natalizumab were examined by physicians at a dose-suspension safety evaluation; at this evaluation, patients were also assessed for adverse events and had a cranial MRI scan. In addition, patients who participated in the safety-extension study continued with follow-up visits every 3 months for up to 12 months.

At these visits, and at unscheduled visits during this time, relapses were assessed. The annualized relapse rate was 0.175 (n=1866; 95% CI: 0.114, 0.259) during the 1st month post dosing, 0.262 (n=1853; 95% CI: 0.184, 0.361) during the 2nd month post dosing, and 0.270 (n=1839; 95% CI: 0.191, 0.371) during the 3rd month post dosing, peaking at 0.64 (n=1756; 95% CI: 0.51, 0.79) during the 7th month post dosing; at no time did it exceed the placebo/Avonex control relapse rate during the 2nd year of the AFFIRM and SENTINEL studies (0.67).

The mean number (± SD) of Gd+ lesions was 0.1 (± 0.4) at 2–3 months post dosing (n=147), 0.4 (±1.1) at >3–4 months post dosing (n=65), and 1.0 (± 3.2) at >4–6 months post dosing (n=70); the number of Gd+ lesions was lower than the baseline (pre-dose) number of Gd+ lesions (1.5 [± 4.2]; n=339) for 6 months post dosing.

These findings are consistent with pharmacodynamic data showing that both alpha4-integrin saturation levels and lymphocyte counts return to baseline within 12 to 16 weeks.

Consistent with the results of a phase 2 study of natalizumab in MS, which was designed to specifically test for rebound, clinical and MRI data indicate the absence of a rebound effect after cessation of natalizumab dosing.

[xo++]

Twelve months after suspension of natalizumab: experience at our multiple sclerosis centre

E. Moral, O. Carmona, V. Casado, L. Romero-Pinel, L. Gubieras, J. Niub*, C. Polo, S. Martínez-Yélamos, T. Arbizu (Hospitalet de Llobregat, E)

Background: In spite of promising results, clinical trials with natalizumab were suspended at the beginning of 2005 because 3 patients treated with natalizumab and other immunosuppressants/immunomodulators developed progressive multifocal leukoencephalopathy (PML).

Goals: To describe the 12-month clinical and analytical follow-up of 14 patients at our MS centre included in c-1802 double-blind and c-1808 open-label extension trials after drug suspension, with emphasis on relapse rate.

Methods: Eight patients were initially treated with natalizumab (32 doses) plus Avonex and 6 with Avonex plus placebo (at least 4 natalizumab doses in c-1808). Avonex was continued in all patients after suspension of natalizumab, except 1 treated initially with placebo, switched to Rebif44.

After suspension, we initiated a diagnostic protocol lasting 12 months with scheduled visits every 3 months and unscheduled visits whenever an adverse event or relapse occurred to detect possible signs of PML. Tests included physical and neurological exam, brain MRI and quantification of blood lymphocyte subpopulations. Qualitative PCR were used to test JC virus in urine and CSF of all patients who accepted lumbar puncture.

Results: No patient showed any change suggestive of PML in neurological exam or brain MRI. No abnormalities were detected in blood lymphocyte subpopulations. All 10 CSF samples were negative for JC virus whereas 3/14 urine samples were positive. No adverse effects were reported during follow-up.

During initial treatment with natalizumab, 3/7 patients had remained relapse free and the rest had a 50% reduction in their previous annualised relapse rate (ARR medians, from 1.0 to 0.5). After suspension, 6/7 presented new relapses and ARR was higher (1.71) than pre-natalizumab relapse rate. One natalizumab-treated patient was excluded from this analysis because of persistent high titres of anti-natalizumab antibodies and a poor clinical outcome. Half the patients initially on placebo remained relapse free after drug suspension.

Conclusions:

-No patients in our centre presented signs suggestive of PML despite treatment.

-An increase in the annualised relapse rate was observed during the follow up period, when they did not received natalizumab, compared with treatment period. This indicates that the biological affects of natalizumab wane after stopping therapy.

-The presence of anti-natalizumab antibodies neutralised the effect of natalizumab, in line with results for the full cohort.

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Natalizumab in relapsing multiple sclerosis: appropriate patient selection, management guidelines, and a diagnostic algorithm for the differential diagnosis of new neurologic signs or symptoms

L. Kappos, C.H. Polman, D. Bates, J. King, P.W. O’Connor, R.A. Rudick, H.L. Weiner, S.L. Hauser, T.A. Yousry, E.W. Radue, D. Clifford (Basel, CH; Amsterdam, NL; Newcastle-upon-Tyne, UK; Melbourne, AUS; Toronto, CAN; Cleveland, Boston, San Francisco, USA; London, UK; St. Louis, USA)

In a phase 3 clinical trial (the AFFIRM study), natalizumab monotherapy was shown to reduce disability progression by 42% and annualized relapse rate by 68% over 2 years in patients with relapsing MS. Although natalizumab was well tolerated, three cases (2 in MS and 1 in Crohn’s disease) of progressive multifocal leukoencephalopathy (PML), a rare and often fatal infection of the central nervous system, have been associated with natalizumab use (estimated incidence of 1/1,000; 95% CI, 0.2 – 2.8).

The PML literature and features of the three confirmed cases were reviewed and a panel of experts in neurology, neuroradiology, and PML was consulted. In addition an extensive safety evaluation was conducted to assess patients for PML and to determine the utility of various diagnostic tools.

The goals of the effort were to establish criteria for patient selection and on-treatment management that may lead to improved benefit-risk ratio for natalizumab in patients with MS. From this, guidelines for appropriate patient selection and management during natalizumab treatment were established.

The guidelines emphasize the importance of confirming the diagnosis of MS both clinically and with cranial MRI and the evaluation of patients for factors that may independently place them at risk for PML (e.g., immunocompromise as a result of comorbidities or immunosuppressant use).

The guidelines further emphasize use of a three-step diagnostic algorithm which highlights the importance of clinical vigilance for the early detection and treatment of changes in neurologic status that may present in natalizumab-treated MS patients. Thorough clinical monitoring and early dose suspension whenever PML is suspected may be the best means of improving outcome.

The details of the diagnostic algorithm along with the use of cranial MRI and cerebrospinal fluid as diagnostic tools will be discussed. In addition, MRI features that help distinguish between MS and PML will be described.

[agent107]

Thanks for this amazing collection of data. Much to chew on. Maybe I'll even understand a small bit of it!

agent107

p.s. I'm about to return to Tysabri trial continuation

[Jules A]

Thanks, Mark. I'm so glad Brain Talk is back!!

[*Joy*]

Thanks Mark! I appreciate all you do to bring this important information to us. You're a gem. ;)

agent, good luck with Tysabri!

[Jakaloke]

We had been having a discussion about relative risk reduction vs. absolute risk reduction over at the temporary Braintalk. And in the past I have complained that the drug companies too often overemphasize relative risk reduction while seeming to hide the absolute numbers in the medical papers.

But relative risk is sometimes more important. For example, if a clinical trial lasting two years finds that 40% of the placebo group suffers disability progression, but 0% of the treatment group, then that therapy would be 100% effective relative to placebo. But the absolute number would still be 40%. I would argue that in this case the 100% is more significant.

I would argue that we, as patients and consumers (and our physicians, as our advisors), owe it to ouselves to not be overly swayed by either number. Both figures are neccessary in making an informed decision.

Scott

[lady_express_44]

I would argue that we, as patients and consumers (and our physicians, as our advisors), owe it to ouselves to not be overly swayed by either number. Both figures are neccessary in making an informed decision.

Scott

I agree, Scott.

If there were a risk of say, serious infection, and 3 people were known to have been inflicted while on the drug (zero fom Placebo), the relative risk of death would not be described as 100%.

It's all relative. ;)

Cherie

[mmcc53]

Thanks for all the info, Mark.

I FINALLY get mine in about 10 days!!!!!!!! YEAH!.