Saturday, September 29, 2012

Signals for many immunosuppressant drugs and PML

Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS); Schmedt N, Andersohn F, Garbe E; Pharmacoepidemiology and Drug Safety (Jul 2012)
PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system that has been reported as rare adverse drug reaction (ADR) of immunosuppressive drugs. We aimed to study signals of PML for immunosuppressants using a disproportionality analysis of spontaneous adverse event reports. METHODS: Within the US Adverse Event Reporting System, we analyzed all reports of ADRs submitted to the US Food and Drug Administration between January 1, 2004 and September 30, 2010. We used univariate and multivariate logistic regression analysis to calculate reporting odds ratios with 95% confidence intervals of PML for immunosuppressants according to the Anatomical Therapeutic Chemical classification system (L04), rituximab and cyclophosphamide compared to all other drugs. RESULTS: We identified 635 PML cases in a total of 1 978 706 patients eligible for analysis. Altogether, 21 out of 36 analyzed immunosuppressants were reported at least once with PML. In the univariate analyses, we found a signal for 11 of these drugs (azathioprine, cyclosporine, cyclophosphamide, efalizumab, leflunomide, methotrexate, mycophenolate mofetil, natalizumab, rituximab, tacrolimus and sirolimus). In the multivariate analysis, the signal was no longer present for sirolimus, leflunomide and methotrexate. DISCUSSION: Our study revealed signals of PML for a substantial number of immunosuppressants, including some drugs less considered so far as a risk factor of PML, especially when used for the treatment of autoimmune disorders. These drugs and possible interactions between different immunosuppressants should be studied more closely in future studies. Copyright © 2012 John Wiley&Sons, Ltd.

Saturday, September 08, 2012

Interferon B for SPMS: a systematic review

La Mantia L, Vacchi L, Rovaris M et al.  JNNP 2012

Cochrane analysis of placebo controlled trials 1995-2012. 5 trials, 3082 patients. IFN did not reduce disability progression, there was small decrease in relapses, cognition not studied.  More treated than placebo patients dropped out.  Conclusion: Only use IFN in selected patients with active disease to reduce risk of disabling superimposed relapses.

Comment (blogger).  If patients are relapsing they have RRMS.  SPMS is diagnosed and differentiated from RRMS as an art form.

Tuesday, September 04, 2012

Emerging therapies in MS AAN 2012 Mark Freedman

Random Notes
1.  Tereflunomide- blocks de novo synthesis of pyrimidine synthesis
"Nobody has a clue how these things really work"
2. TEMSO  2 doses used 7 and 14 mg decreased RR, time to attack, and EDSS progression at 2 years and disease activity free measure increased by 60 percent  with higher dose, decreased Gd+ lesions
3. Minor safety issues minor GI , hair thinning (reversible) ; decreased pain (???)
4.  TENERE  -- primary point not efficacy but effectiveness which comparator Rebif.  looked at time to treatment failure due to relapse or AE's leading to stop drug.  RR similar except low dose, but effectiveness was better with tereflunomide.LFT's only thing seen reliably.
5.  Add on therapy to IFN or GA, patients doing well, added on TFN, did not need attack, just stable dose of drug or placebo, added TFN.  Patients doing well, followed with monthly MRI's, half patients had a Gd+ lesions (.57) decreased 80 % when TFN added.  patients doing well were not doing so well, even without relapses.  Keracles is a phase 3 study of combined.  IFN + TFN > GA + IFN
6.  BG 12 blocks NF pathway.  - no effect of BG 12 until got to dose of 240 bid.  bid v tid (240 mg) improved RR , EDSS 9by 30-40 %).  Curves for rr split at 6 months, why ph 2 study (6 month trial) failed, but effect persists and sustains. 
7.  Confirm:  beats GA for RR and MRI. 
8. DEFINE -- 30 % dropout, mostly flushing and nausea.  Used in Germany for years
9.  Laquinomid-- Allegro and Bravo.  23 % reduction RR overall, 36 % reduction risk to progression, modest effect on MRI, well tolerated.  Rare LFT elevations.Did not beat avonex for rr.  EDSS progression "barely significant " for laquinomid.
10. alemtuzumab. 
Care MS I (naive patients).less than 5 years into disease, EDSS < 3. 
.39 RR, much better with alemtuzumab, EDSS progression, only 11 % progressed in IFN arm, not powered to see .  MRI affected positively at 2 years.  AE's: minor infections, infusion reactions. AI disease; Graves, mild to moderate, usually managed effectively with tapazole.  ITP picked up in 4 patients.  May be a biomarkers to predict ITP.
Care MS 2- breakthrough patients with activity. EDSS < 5, years of disease < 10.  2+ attacks in 24 months before entry. 1+ attack during therapy with IFN.  Was 49 % reduction in RR, 42 % risk reduction of sustained disability.
1. Daclizumab-- anti CD 25 effect-
Average duration of disease in initial trials was seven years, so there is a huge difference in timing of treatment

natalizumab Omar Khan AAN 2012 notes

These are random notes of interest
1  Natalizumab was originally used for MS relapses in the 1990s, published in Neurology; negative study but a secondary outcome , on gad enhancement was positive.
2. A later trial by David Miller, sequential trial was also positive and focus changed.  There also was a resurgence of disease activity noted even then when treatment ceased.
3.   Khan open label study sequential failure on GA/IFN then change to NAT with no change with first switch, but dramatic decline in RR after second switch to NAT with significant MRI findings as well. Old study, about to be published.
4.  Suggests usefulness in non aggressive "run of mill " disease.  Tissue repair study with voxel wise MTR imaging, tracking lesions longitudinally
5. Risk management: usually 5 issues: infusion reactions, NAB's, hepatotoxicity, malignancies, opportunistic infections.  Rare cases of toxo, lymphoma but PML is king
PML-- mean duration of dosing was 34.1 months, range 8-67 doses.  Overall incidence is 2.08/1000 (CI 95 % 1.8 to 2.39) 3 risk factors. 
42 patients have died, 159 alive (79 %) but 80 % plus have severe disability among survivors.
3-4 x rise in risk with prior IS use, even one dose, across board therapies.
JCV Ab conversion rate is approximately 2-3 percent per year
6.  "Not a clear path" how to treat patients when they come off natalizumab

Sunday, September 02, 2012

MS notes AAN meeting Gilenya 2012

Jeffrey Cohen on Gilenya
1. O.5 mg daily is only approved dose, lower doses are being tested
2. May take a month or more to completely clear out of system
3. Caution in patients with severe liver disease
4.  Drug interactions occur with inhibitors of liver metabolism, esp ketoconazole; drugs that lower heart rate (beta blockers and calcium channel blockers), drugs that affect QT interval esp amiodarone, other antiarryhtmics which could cause Q onT phenomenon and tachyarrythmias. 
5.  In their center they weight at least three months to switch onto gilenya from natalizumab, etanercept and other antiimmunosuppressants
6.  Freedoms, about 50 % decrease in relapses, slowing brain atrophy, disability v. avonex and placebo
7.  Musculoskeletal side effects including back pain and others is common.
8.  Lymphocyte counts come back within 1-2 months after stopping drugs, although it is longer in some patients.
9.  Relationship between lymphocyte count in blood and infections is tenuous or nonexistant, tend to ignore .
10.  Case of PML reported : details dx ms in 2007, treated with interferon, then natalizumab in 2008, found to be seropositive to JCV antibody in 2011 and changed to Gilenya.  MRI at that time showed one new lesion, which actually was likely first PML episode.  Later treated with steroids for a relapse, no benefit, visual changes led to stopping gilenya after fourteen weeks, PML found, but was there before starting drug.
11.  HR stays abnormal for up to a month and gradually returns to normal.
12.  Holter before hand is useless
13.  Patient death 23 hours after first dose in November 2011: details:  EMA (Europe) and FDA reviewed.  Recommendations are similar.  CHMP recommendations: stronger language for patients with contraindications, including prior cardiac and CVD which require overnight monitoring, not just overnight;caution in patients on certain drugs, liberal use of cardiology consultation.  First dose monitoring should now include VS and EKG prior to dosing, continuous monitoring during dosing.  Extend monitoring until HR has increased at least two consecutive hours, and if concern, monitor overnight. In USA, less tringent changes for first dose monitoring: EKG prior to dosing and prior to discharge; monitor at least six hours, do hourly VS during dosing.  D/C criteria similar to Europe.  Overnight monitoring for those with symptomatic bradycardia, QTc pronlongation or conditions that would predispose to QTc prolongation.
14.  In first two weeks, repeat induction if they skip one day; in second two weeks, if they skip a week; subsequently if they miss two weeks of therapy.
15.  HTN during gilenya beware of.
16.  Macular edema:  half time is symptomatic (blurring), half time asymptomatic.  Usually unilateral, may b bilateral.  Increased in diabetics, (excluded in ph 3 trial), higher dose, and those with uveitis and ? ON.  Reverses within several months if drug is discontinued.
17.  Cases exist of MI, CVA, PRES, others.  HA's seen in trials and is the most frequent reason to discontinue medication:  exacerbation of preexisting migraine.
18.  Sense of SOB or cough
Summary-- his opinion-- used in 800 patients.  Check  LFT's no CBCs, OCT repeated after 3 months
Using in RRMS Approved as first line therapy but actually use less often.