Wednesday, March 23

MS article: A New Era: New Drugs, New Options, New Risks

Melissa Losasso had her first MS symptom 12 years ago, but wasn't diagnosed until an attack paralyzed her right side in 2004. It didn't take much for the Maryland resident with two young kids at home to opt for treatment. In fact, she volunteered for a clinical trial comparing two standard MS meds head to head. For three years she took both a daily and a weekly injection. For research purposes, she had no clue if one or both of the drugs she took were real, and, in fact, she doesn't know today. But she certainly experienced side effects.

"The daily injection left my skin tough and dimpled. I'd have swollen red marks that itched and burned," she said in testimony before an FDA advisory committee considering a new MS drug. Her weekly shot was worse. The "flu-like" side effects that abate in time for many others ruined every single weekend for three years.

"I would start to become agitated and depressed I long before I needed to take it. I would sit holding » the needle for 30 minutes or more trying to make 2 myself inject, knowing I was going to have body £ aches, fever and pain within hours. Mentally, I was wearing down, angry at my disease and angry with myself for putting my family through this."

She soldiered on and completed the trial as promised but then couldn't bring herself to continue on either of the two drugs. "I had to have a break," she said. Although many people stop their MS med with no obvious effect, Losasso had an attack just a few weeks later.

An oral option

Unlike others who have dropped treatment-and gone without protection from mostly silent MS damage-Losasso was offered an out. She was eligible for a clinical trial of an MS medication in a capsule. The trial was designed to explore the best dosages, so all the volunteers were given active medication. The weekend bouts of aches and fever were gone, and with them her depression, anxiety and fear. And her MS was controlled. The experimental drug was fingolimod, approved last September under the brand name, Gilenya.

"Having the option of an oral drug has truly made a difference in my outlook on life," she told the FDA advisory committee.

The MS drug pipeline

An oral MS disease modifier has been urgently sought ever since the first injectables were approved in the early 1990s. We listed 14 oral drugs "in the pipeline" in the Summer 2009 issue of Momentum. Some have since been ejected as ineffective, a few others are stalled at this writing, one has emerged into the marketplace and several seem headed for an FDA review sometime this year. In addition to tablets and capsules, some are "infrequent dosing" treatments delivered as periodic IV infusions or as a short series of injections every few months or only once a year.

We now have a powerful game changer for people like Losasso whose lives have been marred by unrelenting side effects. We will have some new options for people who have continued to have MS attacks despite conscientiously taking injections. And there is new hope for people with needle fear so severe that they cannot consider self-injection.

Risk-the Catch-22

But more options mean it's going to be complicated-because of the sheer number of drugs and because of a new level of serious risk.

Almost all the coming new drugs, including the just approved Gilenya, carry risks that are fairly new in the MS world. Tysabri could be considered a harbinger of this new situation. Tysabri is powerfully effective but has produced a relatively rare but very serious "adverse event"-PML (progressive multifocal leukoencephalopathy) caused by JC virus infection. PML has caused severe disability and some deaths in Tysabri users, despite careful clinical monitoring.

We asked Dr. Richard Ransohoff, a leading MS researcher at the Cleveland Clinic Foundation and a member of the Society's board of clinical advisors, about drug safety.

"When a new medicine arrives, typically only a few thousand people will have received it for no more than a couple of years. That doesn't tell you what you really need to know about safety. As for efficacy, it's taken forever to get solid data supporting the idea that our standard MS drugs do help some people in a meaningful way, by lowering their likelihood of disability," he said.

Older drugs in new packages

As if considering the new choices weren't tough enough, Dr. Adil Javed, an MS researcher at the University of Chicago, noted at a recent presentation that many current brands will soon emerge out of patent protection. So in addition to the new drugs, we can expect an influx of new names tagged "bioequivalent," "biosimilar" or "biogeneric"-all variants considered equivalent to the older standard MS drugs.

Will competition lower costs, as market models say? How will insurance companies respond to claims? No one really knows. But Dr. Ransohoff suggests it will take some time before good study data support clear choices. Will the lack of evidence for superior or comparative effectiveness give any insurers a reason to deny claims?

Not enough to say about progressive MS

We still seem to be far from effective treatments for primary progressive or advanced secondary progressive MS. Hopes raised for meeting this urgent need have been dashed by discouraging results. A recent large clinical trial of ritux-imab in primary progressive MS had poor results although reviews are in progress to see if some subgroups experienced benefits. A clinical trial of Gilenya for progressive MS is just beginning.

Taking a different tack, a number of investigators are pursuing therapies that can protect or repair damaged nerve cells, rather than reduce inflammation since inflammation is less prominent in progressive MS.

Safe, but not always producing results

Over the past two decades, the gray unknowns initially surrounding the first generation of MS disease modifiers have slowly receded. The standard therapies are supported by robust data and years of clinical experience. Betaseron (and its equivalent, Extavia), Avonex, Copaxone and Rebif are all remarkably safe. Their side effects are not always trivial, but not generally life threatening. For example, depression (sometimes linked to interferons) is treatable. Copaxone users may face something called lipoatrophy, a scarring or hardening of fat tissues under the skin. Most of the time, elevated liver enzymes (from the interferons) mean rather little. Injection site infections-which can be quite nasty-are treatable.

The worst aspect of all the standard drugs is that they are only partially effective. For some individuals they fail to work at all. "Copaxone is moderately good for almost everyone," Dr. Ran-sohoff opined. "The interferons are quite effective for some and almost ineffective for others and we don't know why. We urgently need a way to determine who is a good candidate for interferon and who is not. This is a highly biased opinion, of course. My research team is working on it now."

Tolerability is almost as big an issue as safety, according to long-time MS clinician and clinical researcher, Dr. Bruce Cohen, at the Comprehensive MS program at Chicago's Northwestern University. "I have patients who skip doses because of the injection. And others who are hanging on, waiting and waiting for a way to stop. No drug is effective if people don't take it."

Risky, but producing results

Some of the new drugs appear to have advantages in terms of markedly increased effectiveness in both preventing new brain lesions from forming and in controlling MS attacks. And because they are taken by mouth or, like Tysabri, are delivered as periodic infusions or injections-some only once a year-they dramatically change the tolerability issues.

At the same time Dr. Cohen pointed out that people have a very reasonable sense of caution, because of the sheer newness. So do many healthcare professionals. Moreover Dr. Cohen comments, "When someone doesn't need therapy again for a year, we'll have to be sure they will really come in for follow-ups in between so we can monitor for possible side effects. In addition, the impact of what we call 'co-morbidity'-another condition, like hypertension, asthma or diabetes along with MS-could also be magnified," he continued.

"The dream that we do this intervention and a person can forget about MS for a year-well, we just aren't there yet."

Dr. Loren Rolak, who heads the MS program at Wisconsin's venerable Marshfield Clinic, agreed. "I'm in a very conservative rural community. Many are farmers. And I have only a handful of patients who have accepted my suggestion to take Tysabri. They refuse because of the risk.

"My center wasn't in on the fingolimod (Gilenya) studies, so I've called up some of the principal investigators to get their personal take," Dr. Rolak continued. "I got a wide range of opinion. Some are ready to roll and will use this new drug as a first line treatment. Others want to wait and see how it plays out once many more people are taking it."

Hanging in, doing well

Basically, if one is doing well, why fix what ain't broke, as Dr. Ransohoff remarked.

Lynette Steinmetz was 34 with a husband and two young kids when debilitating vision problems slammed her. As a lab technician at the Marsh-field Clinic, she had enough medical background to suspect a cerebral aneurysm. The diagnosis of MS was almost a relief. Still, she had a number of relapses that first year, her balance deteriorated and her vision didn't improve. She started taking daily injections 11 years ago.

"It's mainly a nuisance today," she said. "It's much easier now the drug is delivered in a pre-filled syringe. I just grab one and go." In the intervening years, her vision did improve, her kids have grown up, she wrote two how-to books on quilting, served as a 4-H club leader, and continued working part time at the clinic. When her husband lost his job in 2009, the Steinmetzes took the plunge and bought a restaurant/bar in Marshfield. Lynette then upped her hours at the clinic to qualify for health insurance-as her coverage was lost with her husband's job. She also took on being a weekend hostess, handling decorations, doing the restaurant's Web site and looking after the books. She belongs to an MS support group in town as well.

"I'm stable," she reported. "Yes, I'd like to get done with the needles, but I'm not sure I'll go there. This is my safety net."

The bottom line: Are you doing well?

A lot of people with MS will say it's hard to tell. The disease-modifying drugs may have little impact on how a person feels day to day. The treatment can be doing a good job modifying the ongoing course of MS, without changing the bouts of fatigue, spasticity, bladder problems, pain, constipation, low libido and more. Can a person who feels crummy really be doing well?

"Professionals grapple with the same question," Dr. Rolak said recently. "I've been to a number of national meetings where we MS professionals tried to set guidelines or indicators that a patient is or is not doing well. Is it the number of MS lesions seen on MRI? Is it the number of recent attacks? Is it a drop in mobility (reflected in scores on the EDSS scale)? We haven't been able to agree."

Dr. Ransohoff looks at it this way: "How do you know if you're doing well financially? If you take every penny you earn and spend on stuff that's fun, you might say I'm doing great, I have a car, I go to clubs, I have a big house. But you're in debt ... and the debt keeps getting bigger. A person with MS might feel reasonably well, but their MRI shows they're developing T2 lesions. That can translate into a higher risk of secondary progression later on and I believe it requires some attention now. A person's quality of life has to be good, but a professional appraisal of the evidence of disease control is also needed. MRIs may not say much about today-but they are predictive of the future."

Dr. Rolak isn't quite so sure. "MRI findings can be very confusing. Some people with bad MRIs have done quite well. For me, MRI is important but it's just one of the indications to be factored in. I'd be likely to correlate one or more MRIs with other findings before making a recommendation."

Symptoms need to be managed

Many of the things people with MS go through need symptom management approaches, not a change of the disease-modifying drug, Rolak pointed out. "Maybe the person needs more baclofen for their spasticity, or meds to get their bladder under control."

A range of options, a range of opinion, a range of responsibility

It should be noted that three of the doctors who spoke to Momentum for this article are members of the National MS Society's Clinical Advisory Board. The questions they raise here are being raised in professional meetings, at the Society and elsewhere, and there will be more seminars and blue-ribbon panels.

All three doctors know that what people say about their own health is of primary importance. "If someone has a feeling that they are just not doing as well as they should, they need to say so and tell their doctor," Dr. Rolak advised. "They need to ask if their expectations are realistic. How that's dealt with may depend on their doctor's point of view. There are a lot of different opinions."

Dr. Rolak sees the new era as similar to what women with breast cancer or men with prostate cancer have faced for years. There is no one standard treatment. The choices have to be made patient by patient. The individual and the doctor have to go over all the factors. "And now, in MS, we have a similar situation," he said.

Dr. Cohen sees a learning curve for everyone in the MS world. He hopes people will take on the challenge to:

▪ Educate themselves using sources that are reliable, scientifically valid and not biased by commercial interests.

▪ Recognize that treatment decisions are individual. Patient and doctor need to go over the pertinent issues, with a hard look at how that individual feels about taking risks or going into the unknown.

▪ Be prepared emotionally for the likelihood of new side effects from the new drugs. "Things may emerge in a wider population that just weren't seen in the clinical trials," he said.

▪ Take special note of treatment choices if planning a pregnancy.

▪ Learn more about MRIs. There are limits to what conventional MRIs can tell and no consensus on how often to have one. There are also concerns about quality. An MRI needs to be designed to reveal MS lesions and done in exactly the same way each time so the results can be compared.

Martha King is the editor of Momentum

Unusual Sunrise

At least for me, because this morning in a very long time, I was actually awake and up before the sun rose. So of course I took a couple of pictures and this was the best one. Good morning!


March 2011 sunrise