Discussion of PML and Therapies like Tysabri next Tuesday
 

Immunomodulating Therapies and Progressive Multifocal Leukoencephalopathy (PML)
Tuesday, November 10, 2009 | 8:00 AM - 5:30 PM
The New York Academy of Sciences

http://www.nyas.org/Events/Detail.as...9-f83b1303698d

Key items from the listed abstracts

"Current presentation will examine the role that some of such viral and host factors play in susceptibility to PML. Specific focus will be given to the role that some mutations in the viral capsid proteinVP1 might play in the development of PML."

"This presentation will provide an update on the status of the programs and key learnings from TYSABRI associated PML cases."

# 32 down.
Usual day.

FDA updated the Tysabri label today
 

Applicable part of the label

"In patients treated with TYSABRI, the risk of developing PML increases with longer treatment duration, and for patients treated for 24 to 36 months is generally similar to the rates seen in clinical trials."

Guess they see the rate as about 1 in 1000 for those between 24 and 36 months.

Oh, I see what they're doing....giving that sub group of 24000, there own statistics..:rolleyes: we're smarter than they give us credit for..:) (for which they give us credit)

I had my 27th infusion yesterday....with my "normal" side effects. I still have a slight headache, a bit of dizziness and the achy feeling all over. But, at least the nausea is gone :)

I even saw the oncologist at the infusion center....it's been almost a year since I've really seen him. We normally wave as he walks through the infusion room. Apparently, the insurance company has informed him he must "see" me at least every 3 months or they won't pay for the infusions.

Rsults/Recommendations from German MS Society(LONG)
 

Translation of pertinent points from the original version in German:

Therapy of Multiple Sclerosis with Monoclonal Antibodies
Results and Recommendations of a Symposium of the Medical Advisory Board of the German MS Society

Autoren R. Gold*, H. P. Hartung*, R. Hohlfeld*, H. Wiendl*, B. C. Kieseier*, R. A. Linker*, S. Schmidt, K. V. Toyka*
für die Arbeitsgruppe Moderne Immuntherapie der MS1


{Page 334/335: Zusammenfassung [below the English version]}
Abstract.
Therapy of relapsing−remitting multiple sclerosis
(MS) has become more effective, but this progress
has unfortunately been associated with more
serious risks. Since 3 years natalizumab has been
licensed as the first monoclonal antibody for the
treatment of a neurological autoimmune disease.
In addition, there is now an increasing off−label
use of rituximab and other monoclonal antibodies
in a variety of immune−mediated neurological
disorders. Experience and insights arising from
applying these therapies will be used to define in−
dications, logistics for monitoring treatment and
adverse events, and some diagnostic and thera−
peutic algorithms for future innovative therapies
for MS and their potential complications. This ar−
ticle is based on deliberations of a symposium
held by an expert group of the German MS society
(DMSG) which had a focus on natalizumab. In the
future, when other novel therapeutic compounds
are to be licensed, this work will be extended, up−
dated and reported. This will help to improve the
practical handling of potential complications of
therapy in both inpatient and outpatient settings.
A structured interaction between different levels
of health−care providers will be an important
part of establishing robust quality standards
aiming at a high level of treatment safety. These
structural aspects are addressed in a back−to−back
article.
{Page 335: Einleitung / Introduction }
...
{Page 335/336: Wirksamkeit und Indikation von Natalizumab / Effectiveness and indication of Natalizumab }
...
{Page 336: Untersuchungen zur Immunkompetenz vor Therapiebeginn }
Verification of the immunecompetence before beginning of therapy.
For the accurate description of the immunecompetence there are, at this time, unfortunately still no evidence-based criteria, but is predominantly based on expert opinion or on similar research into experimental disease models.
The following exclusion criteria were suggested (after [12,13], supplemented):
* systemic fungal infections with Candida and Aspergillus within the last 6 months except [certain] parasytes and skin fungi
* currently active infections (urinary tract infections, pneumonia)
* infections with Herpes (simplex or zoster) and/or their reactivation within the last 3 months
* other opportunistische infections within the last 3 months
* HIV−infection
* chronic virus infections (e.g. Hepatitis)
* chronic or recurring bacteriological infections (e.g. Tuberculosis)
* malignant neoplasm (possible exceptions: treated carcinoma in situ; more than 5 to 10 years remission with treated carcinoma)
* organtransplantation with current immunesuppression

If the MS occurs together with another autoimmune disease, were possible a monotherapy certified for both illnesses or at least well tested substance should be aimed at.
Examples for this are Rituximab with MS (not certified) and Rheumatoid Arthritis, as well as Natalizumab with MS (certified) and Crohn's disease.
Concerning the laboratory values it has been noted that there are no exact (evidence based) guidelines, and that simple default values for blood leukocytes as well as the determination of the CD4/CD8 ratio are probably sufficient.
[i.e. no really specifc guidelines could be found, but if clearly below normal range then ...]
For some pre-defined infections patients should always be tested, before beginning of therapy (or at least when there are indications based on the patient's medical history):
* HIV should be excluded (with each patient and their possible life partner)
* VZV by missing history of smallpox or mssing inoculation (if necessary inoculation before therapy)
* Hepatitis-B- and -C serology because of case history and/or increased liver values.
Chronically active hepatitis and HIV infection have been mentioned as exclusion criteria for a therapy with Natalizumab.

{Page 336/337: Intervalle bei Therapieumstellung }
Washout periods before switching therapies
Here as well there are no evidence-based criteria / laboratory diagnostics, but only empirical data.
Because the biological washout of natalizumab as IgG4 is about 12 ± 14 days, and because there is biologicaly provable blocking of immune cell migration even at very small plasma levels [14,15], it can be estimated how long the antibodies will be present, before a new therapy is to be introduced.
Measurements of the serum concentrations of natalizumab are cumbersome and are at present only conducted at a regular basis by one laboratory in North America.
To be regarded separately is the switch from a previous therapy to Natalizumab and a switch from Natalizumab to a new therapy.
In both situations there is agreement that in addition to the immune status, which should fulfill the same requirements as above defined, minimum time intervals (safety intervals, washout periods) should be respected.
For glatiramer acetate and interferon-b, these intervals are short, ± 2 weeks were considered to be appropriate.
For agents such as azathioprine and MMF 3 months appeared to be appropriate.
For mitoxantrone and cyclophosphamide, however, a longer interval of eg 6 months or even longer (until 12 months) has been contemplated, where the choice of the safety interval in patients with high clinical activity should be carefully balanced in consideration of the risk-benefit ratio.
For some monoclonal antibodies (eg alemtuzumab) an even longer interval is recommended, because of the very long duration of action [of these drugs].
Regarding vaccines, there are no relevant safety signals, neither from studies nor in post-marketing setting.
There is therefore no need seen for a change in the vaccination approach from what is already common practice in MS.
For safety's sake titer controls should be conducted to verify the success of the vaccination.
With respect to exacerbation treatment, there are already many studies and observations from the post-marketing phase.
These allow the following conclusions:
* for acute relapses, steroid pulse therapy is possible
* with the escalation of plasmapheresis in principle also possible
* high relapse rates review of natalizumab indication; possibly lack of effectiveness of this immunotherapy, especially in the presence of neutralizing antibodies (see below)!

The clinical validity of surrogate markers like the ATP Assay of the company Cylex (http://www.cylex.net/technology.html) for functional testing of the immune status is at present not yet sufficient clarified. Thus this test cannot be recommended for routine use, at this time.
While the first cross-sectional data in MS patients and patients with opportunistic diseases are available, the working group sees urgent need for the future validation and establishment of such surrogate markers, especially for the monitoring of the status before and during immune therapy.
{Page 337: Durchführung und Komplikationen der Infusionsbehandlung }
Execution and complications of the infusion treatment
...
{Page 337: Verhalten bei Infektionen und operativen Eingriffen }
What to do in case of infections and surgical intervention
...
{Page 337: Verhalten bei schubförmigen Verschlechterungen }
What to do in case of relapses/exacerbations
...
{Page 338: Diagnostik und Therapie von Infusionsreaktionen und allergischen Reaktionen }
Diagnostics and therapy of infusion and allergical reactions
...
{Page 338/339: Neutralisierende Antikörper gegen Natalizumab }
Neutralizing antibodies against Natalizumab
...
{Page 339/340: Dauer und Beendigung der Therapie mit Natalizumab (Deeskalation) }
Duration and completion of the therapy with Natalizumab (de-escalation / phase out)


{Page 340: Überlegungen zum Thema Therapiepause (¹drug holiday“) }
Considerations about therapy break ("drug holidays“)
Occasionally it has been postulated that a short-term discontinuation of natalizumab ( "Drug Holiday") could possibly positively affect the benefit / risk profile of Natalizumab therapy. This strategy is based on the idea that the immune system could recover during a rest period.
This assumption is so far not supported by any data, and such a study would also not be feasible: to be able to demonstrate an appropriate risk reduction by short-term discontinuation of natalizumab, one would need a 2-year long study involving about 150 000 patients! In addition, there are currently no validated parameters for such an effect.
In addition to the risk of return of disease activity during the drug-free interval,the re-exposure to natalizumab, however, poses other problems, such as a possibly altered immunogenicity of natalizumab after reinitiation.
The consensus of the working group is therefore that the strategy of "Drug Holidays" during natalizumab treatment is not recommended, at this stage.
Should there be new evidence in relation to a cumulative, duration on therepy dependant, risk of PML development, then this will need to be re-evaluated, if necessary.


(thaks go to "teknowiz" for the translation posted to another board)

Biogen, Elan, Roche Forming Brain Infection Consortium
 

By Thomas Gryta
Of DOW JONES NEWSWIRES
NEW YORK (Dow Jones)--Biogen Idec Inc., Elan Corp. Plc and Roche are planning to form a research consortium dedicated to a rare brain infection that has emerged in patients taking a number of their drugs.

The move comes as cases of progressive multifocal leukoencephalopathy, or PML, have risen sharply in patients taking multiple sclerosis treatment Tysabri, sold by Biogen and Elan, prompting a panel of European regulators to review the drug. The infection, also found in users of several other immune system-suppressing therapies, is often deadly, and its emergence has perplexed physicians and researchers as they balance the risk and reward of these drugs.

It has appeared in patients taking some drugs used after organ transplants, as well as arthritis treatment Rituxan, sold by Biogen and Roche, and Raptiva, a psoriasis drug that Roche's Genentech unit pulled from the market earlier this year because of the issue.
Before these drugs, the condition hadn't shown up in patients with MS, or psoriasis, and was most common in patients with AIDS. There have been some reports in cases of arthritis patients, according to a Roche spokeswoman who declined to provide additional details about the consortium because formal agreements haven't been signed.

PML has been most frequent in users of Tysabri, with 24 confirmed cases since its re-launch in 2006, but generally consistent with the 1-in-1,000 patient rate implied by its label. The drug is subject to a rigorous risk management plan and the companies have been researching PML since its emergence in 2005, which led to Tysabri's temporary withdrawal from the market.

Mariska Kooijmans-Coutinho, Biogen's senior director of clinical trial safety and risk management, detailed the plans for the consortium at a meeting covering various aspects of the infection at the New York Academy of Sciences on Tuesday.
The group plans to pool resources related to PML, including the formation of a global database of cases in an effort to predict, prevent and treat the condition, she said.
The effort will also include non-profit organizations and academic institutions, and she invited other drug companies to join the effort. She noted that the consortium will seek financial and time commitments from companies to ensure stability in the group.

PML is caused when JC virus, which most people carry, attacks the central nervous system in people with weakened immune systems, often leading to an irreversible decline in neurologic function and death.
A higher number of Tysabri patients with PML have survived the infection, with only four dying since 2006, because of close patient monitoring and quick removal of the drug from the body. Regardless, the infection's nature often leaves survivors with varying degrees of disability.

Eugene Major, who runs the Laboratory of Molecular Medicine and Neuroscience at the National Institutes of Health, believes that the risk of PML in Tysabri is generally known, but he warns that the condition may be more common than thought in areas not related to Tysabri.
"It is pretty clear that it is underreported," Major said, noting that the NIH and Centers for Disease Control are forming a collaboration to increase the monitoring of PML in the broader population with the hope of gaining a better understanding of its scope.

I'm proud of you bunch of squeaky wheels..:grouphug: