Drugs, Drugs and more Drugs for MS

[Guest guest]

This is from the FDA internal documents. I did not post the link

because one cannot see it since it is internal. This has many of the

MS drugs that are being used or are on the horizon. My personal

opinion is that non of these drugs will cure MS. Roe

New drugs to battle multiple sclerosis

By n Borrell

Multiple sclerosis remains a cruel medical mystery. It strikes in the

prime of life and runs an unpredictable course that can end in total

disability. Scientists are a long way from halting the disease

entirely, but several promising drugs are in late-phase clinical

trials and experts anticipate better lives for patients in the near

future.

" We will see many new drugs on the market and many new options for

patients, " says Dr. Diego Centonze, a neurologist at Tor Vergata

University in Rome, who is running clinical trials for three new

experimental compounds, including one called fingolimod that is the

first oral MS drug to move to Phase 3 clinical trials.

In the early 1990s, there were no Food and Drug

Administration-approved therapies for MS on the market. Today, there

are at least half a dozen, and Centonze expects as many as eight or

nine by 2010.

But there are still many challenges, says Dr. Ari Green, assistant

director of the multiple sclerosis center at UC San Francisco, which

also is running drug company-sponsored trials. None of the approved

drugs is ideal, and each of the new experimental drugs has significant

adverse side effects.

MS is an autoimmune disease: The body's immune system attacks some of

its own tissues. The common form, known as relapsing-remitting, begins

when disease-fighting lymphocytes launch an attack on the brain and

spinal cord. These relapses cause short-term inflammation and symptoms

such as numbness, but eventually lead to a progressive decline of the

nervous system.

The less common form of MS -- primary progressive -- doesn't manifest

itself with acute attacks, although patients still exhibit

neurodegeneration, leading to fatigue, pain, problems with walking and

balance, dizziness and bladder and bowel dysfunction.

Currently approved drugs primarily work by reducing the activity of

lymphocytes or reducing their ability to travel from the blood into

the nervous system. Some of the new ones do that too -- while others

function in different ways.

The first drugs to gain approval in the mid-1990s were interferon

beta-1b (Betaseron), interferon beta-1a (Avonex or Rebif) and

glatiramer acetate (Copaxone). Because they have minimal side effects

(such as flu-like symptoms) they are used as a first line of defense.

But they are only moderately effective, says Dr. Rhonda Voskuhl,

director of the UCLA multiple sclerosis program. Patients " fail them,

and then move on " to more powerful drugs such as natalizumab (Tysabri)

and mitroxantrone.

Mitroxantrone, approved in 2000, is a chemotherapeutic drug that

suppresses the immune system and can lead to leukemia or heart damage.

Natalizumab (Tysabri), which received accelerated FDA approval in 2004

and is considered the most effective drug available today, was taken

off the market in February 2005 after three patients in clinical

trials developed progressive multifocal leukoencephalopathy, a fatal

viral disease. After an FDA review, it has been available under a

special program in which patients are closely monitored for

opportunistic infections.

On the horizon

There's clearly a lot of room for improvement, which is one reason why

doctors are excited about options on the horizon.

Fingolimod, originally developed to prevent organ rejection in

transplant patients, blocks a signal that allows T-cell lymphocytes to

cross into the brain. At the American Academy of Neurology meeting

this year, researchers reported that 173 patients with a relapsing

form of MS showed a decline in the relapse rate over 36 months from

0.31 relapses per year to 0.20, a 30% decrease in their relapse rate

when they took fingolimod. In just six months, the number of patients

with brain lesions decreased from an average of 2.2 per patient when

taking the placebo down to 1.29. In addition, after 36 months, brain

scans revealed that 89% of patients had no evidence of inflammation.

Fingolimod is promising not only for effectiveness but because it

comes in pill form, Centonze says. " For patients that must receive

injections every other day or every single day, the quality of life is

really affected. Taking pills can change this. "

Another compound on the horizon is alemtuzumab (Campath), a monoclonal

antibody designed and FDA-approved for fighting leukemia. In a trial

of 334 patients published in October in the New England Journal of

Medicine, researchers reported that the drug could reduce the relapse

rate in early-stage MS patients by two-thirds relative to the standard

MS drug interferon beta-1a.

UCSF's Green says the findings are impressive because this is the

first MS trial to compare a new drug to an approved compound rather

than a placebo and yet " it still had a remarkable effect on reducing

disease activity. "

Rituximab, an antibody that was designed for treating rheumatoid

arthritis, is also being studied, in a clinical trial headquartered at

UCSF. Rituximab is directed at the immune system's B cells, rather

than T cells that have been targeted by MS researchers since the 1970s.

Biology of MS

In February, a team led by Dr. Hauser of UCSF reported in the

New England Journal of Medicine that in a 48-week trial of 104

patients, rituximab halved the number of patients experiencing

relapses relative to a placebo. " It's led to a whole new understanding

of the biology of MS, " Green says. " There are now a ton of potential

therapies that are going to be B-cell directed. "

But the downside of taking powerful modulators of the immune system

are their serious side effects, including making patients more

susceptible to infections and other chronic diseases. Two patients

died after taking fingolimod, one with a brain infection and the other

with shingles.

And in the alemtuzumab trial published in October, researchers

reported that one-quarter of the patients developed an autoimmune

disease attacking the thyroid and three developed an autoimmune

disease of the blood platelets.

" Drugs like this are toxic, " Voskuhl says. " It's a hard sell to people

who are very young to expose them to drugs that have dramatic side

effects. "

A larger problem with the current slate of therapeutics is that they

address only the inflammation side of the disease. " But we now know

for sure that neurodegeneration is not just caused by inflammation, "

Centonze says.

As excited as he is about the burgeoning treatment options, he says,

" Before judging the real quality of these drugs, you must treat many,

many patients for several years. "