The biggest MS meeting in the world

Well, it’s been a busy year, but I have saved up some topics for the blog.

ECTRIMS 2013 was a plethora of presentations, many of which were not unexpected, and a few that were a surprise.

Lifestyle issues in MS continue to increase in importance for the health and management of the severity of MS. 

ITS THE SALT STUPID

Most surprising is the first clinical paper supporting earlier animal studies in EAE (and suspicions in related autoimmune diseases), namely that  sodium intake is a key regulator of the aggressiveness of the inflammatory response in MS.

Mauricio Farez, MD, from the Institute for Neurological Research, Buenos Aires, Argentina presented an MRI and clinical study of individuals with results stratified to dietary sodium intake.     Exacerbation rate was threefold higher with moderate and fourfold higher with high sodium intake relative to a low sodium diet. Individuals with high sodium intake had on average 8 more lesions and more than threefold risk of new lesions on MRI.

Sodium intake is an astonishingly important and heretofore unappreciated environmental risk factor for the severity of MS, and a very attractive approach in the adjunctive therapy of the disease. It may also explain the increasing prevalence of MS in populations with a Western diet. Even if repeat studies show a much smaller effect, the insights which such a mechanism offer into control of the disease have implications for every physician who sees multiple sclerosis.

Other lifestyle issues continue to be reviewed. Vitamin D3 deficiency is now recognized as a fundamental cause and exacerbating factor of MS. Tobacco use has been seen also to be an important factor in the cause and severity of MS.

GELINYA IS REALLY GOOD

Many presentations on existing therapies and investigational agents nearing approval continue to support the  previously recognized efficacy of these MS immunotherapies.

Gelinya (fingolimod) long-term studies support a robust, long-term, treatment effect on slowing and preventing brain atrophy, as well as enduring suppression of relapse rate and protection against   disability in a 5 year follow study from the original TRANSFORMS and FREEDOMS cohorts.

Important data regarding the transition of patients from Tysabri (natalizumab) to Gelinya (fingolimod) was presented by several groups, making this transition a straightforward and palatable option for the management of PML risk for the majority of MS patients.

LEMTRADA IS EVEN BETTER

CAMPATH (the old name) or likely to be called Lemtrada (alemtuzumab), which is recently approved in Europe, and likely to have approval imminently in the USA, represents the most potent and effective therapy yet seen for multiple sclerosis, has robust effects at three years, with an expectation of improvement (not simply slowed progression) with 45% improved and 25% stable in disability at 3 years. The effect clearly continues beyond the treatment cycle years into the year where fewer patients receive a cycle. A new endpoint, 12 month sustained reduction in disability, was introduced which 27% of the subjects met.

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We are on pins and needles waiting on new medications for MS!

SFH Headshot

Most people know me as a huge cheering fan, but sometimes critical, of the pharmaceutical industry. Yes, I am a fan of capitalism and all the great innovations it produces for us. However, they are regulated by the government, which is in the habit of making us wait a long time. Nevertheless,  this has been the most eventful period of development of new medications for MS, and we are waiting for some tremendous advances.

Three new and completely different medications are likely to be approved within the next year.

First up any day now: teriflunomide “Aubagio” is a daily pill which is closely related to an established and widely used drug for rheumatoid arthritis known as leflunomide “Arava.” In fact it is essentially the same (leflunomide becomes teriflunomide in the body). This medication has undergone extensive testing in MS, and at generally lower doses than in rheumatoid arthritis, with less other immunosuppressive medications, produces a satisfactory decrease in disability, relapse, and MRI activity. It is not spectacular, but it is fairly simple. It will be marketed by Genzyme which is owned by Sanofi. The upside it works, the downside is that it is complicated to use in women who become pregnant, and immediate action is required to get the drug out of the body to reduce the risk of birth defects; about 1/2 of children exposed in the first two months of pregnancy have multiple minor defects (these are not usually serious). It is also important to monitor for depressed white blood cells “neutropenia” which is an established and not rare complication of the drug. Liver complications are much less significant. Serious infections were not a problem at the doses used in the trials. Unfortunately, a significant fraction of patients become allergic to the drug (as many as 10-15%) and cannot take it further. Some hair loss can also occur.

All in all this good. It is an immunosuppressive medication which hits rapidly dividing cells, and whether long term there is more risk is not clear. MS patients generally have less of these complications due to the factor they do not take multiple immunosuppressive medications like RA patients.

I think Genzyme/Sanofi has a challenge. If they price it too high, it won’t be used, and leflunomide is still out there and is essentially the same drug (really, for practical purposes it is the same drug). If you want to know more about this drug, go to the prescribing information for Arava/leflunomide. The active metabolite, which is discussed at length, is teriflunomide.

Up second by 1st qtr 2012 is a real game changing drug. Alemtuzumab/”Lemtrada”, formerly known as CAMPATH. Also being marketed by Genzyme/Sanofi and copromoted with Bayer Healthcare. This is the most powerful drug ever seen in MS. It also has some significant medical risks, but the vast majority of people treated do not have a major complication. This a bioengineered targeted “magic bullet” monoclonal antibody for which TWO Nobel prizes have already been awarded. It has been researched in MS for over 20 years and the therapy was invented by the brilliant professor Alastair Compston at Cambridge University. I think he deserves a Nobel as well. It will save the lives of many, many people with worse than average MS.

Alemtuzumab basically makes the immune system reboot by wiping clean a great fraction of the immune cells “lymphocytes” which are the dysfunctional, misbehaving cells causing MS. It induces wonderful remissions after two once-yearly treatments (IV 5 days the first and 3 days the second). It stomped a very good MS medication (high dose interferon-beta or Rebif). Most people do not need further MS treatment for years. Mild-moderate infections, mostly minor nuisance infections (yeast, ringworm, shingles) can occur in the months following treatment, but the immune system is amazingly intact.

The down side–people feel run down a few weeks after the annual cycle. A large amount of surveillance blood testing is needed because a large fraction (25%) will develop some kind of thyroid problem, usually overactive (hyperthyroid). A few percent have this severely and feel bad for an extended period of time and need  radiation therapy (radioiodine) to treat a severely overactive thyroid. A few percent also can get a temporary bleeding disorder called acute ITP, which if detected early on a blood test is simple to treat with prednisone. Both of these illnesses, and a few milder and rarer ones occur, because the immune systems of people with MS are capable of generating immune cells which react against many of the bodies organs. About 1/3 of MS patients develop thyroid disease in their lifetime anyway.

So trading severe MS for an annoying minor thyroid problem is a good deal. Moreover, alemtuzumab is the first medication which reliably IMPROVES disability in MS patients.

Our clinic has been a leading center in research worldwide in this treatment. It seems to work for even the most severe MS.

Last of all, coming 3rd qtr 2013,  there is the medication with a sexy name “BG-12” (doesn’t have a brand name yet), but is dimethylfumarate, owned by the little engine er company that could, Biogenidec, the powerhouse of MS research. This drug is a simple chemical, used for decades for psoriasis in Germany, which seems to have two fascinating properties- it trips the sensor cells use to tell they are being stressed by oxygen, and this turns on the systems (nrf2) which quelch damage from oxygen and chemicals, which helps in MS because the inflammation is doing this harm. An added bonus is it throws the circuit breaker on the inflammation by blocking a powerful inflammation inducing signal (NFkappaB). So, this is a completely new class of drug. The closest thing to it, believe it or not, is broccoli (mostly the sprouts), which contains a chemical called sulfurophane, which also does this. You don’t want to have to eat enough broccoli (pounds a day).

The data on dimethylfumarate evoked a “WOW” last fall at the ECTRIMS meeting, and again at AAN this spring, where it stomped Copaxone, besting it by another 50%. This drug seems to have very little toxicity (none), except it causes a bellyache which doesn’t go away in about 10% of people, and those folks can’t take it. There is occasionally some nuisance flushing which decreases with aspirin. We don’t have more than about 3 years of data though. That said, it looks pretty safe. The only other drawback..it will be a twice a day pill.

Having been involved from early in the development of this dimethylfumarate, I like this drug very much. It could fundamentally change how we treat MS, provided the manufacturer prices it appropriately and the long term data continues to look safe.

All these medications will have a role. Alemtuzumab will have the biggest impact as it adds a nuclear weapon to our arsenal, literally making it the last medication someone may ever need. It is not a cure, but the closest we will see in the next 10 years. Patients and doctors will have to swallow hard and accept the risks in order to get the benefits, but the vast majority will get off without anything more than inconvenience.

The other pills will have to see both longterm risk, and how the manufacturers price them. Hopefully, they will not make the mistake drug giant Novartis made pricing their products in the stratosphere, which made it impossible for people to get them in many cases.

The existing medications will be used. For a substantial number of people they are safe, reliable, and already doing the job.

People with MS are going to be switching treatments more, and their paths and options are going to be more individual.

Samuel F. Hunter, M.D., Ph.D. is a neurologist specializing in neuroimmunology and neuroimaging, and has a remarkably broad background in pharmacology, image analysis, medicine, and neurosciences. He directs the Advanced Neurosciences Institute, Novel Pharmaceutics Institute, and NeuroNexus Center for research and education in Franklin, Tennessee, a suburb of Nashville. He participates and directs a multiple sclerosis clinic and many research trials for multiple sclerosis and its related conditions. He consults or performs contract research and consults for many pharmaceutical companies. Dr. Hunter has previously been a consultant for many pharmaceutical companies.

Copyright 2012, Dr. Samuel F. Hunter

Why do new medications cost so much?

In response to a reader’s request, I will address the cost of medications for MS. She asked specifically about Obamacare causing this, but the issue is much bigger and more complex.

What do you pay for when you buy a brand name medication? Why do they go up in price so dramatically? How can we get them cheaper?

To provide a definitive “white paper” to explain all this would be hundreds of pages. If you will permit me, I will instead outline for you in a more understandable fashion, although you must give me the leeway to make some statements which are not explained in more detail.

First, let it be said that I am a great admirer of the pharmaceutical industry and capitalism in general. No other industry has performed for humanity in this way. The fact that you have at your disposal thousands of very cheap medications is due to enormous investments in scientific research and plain hard work to show these drugs work. These costs are mostly manpower and factories. Once feared conditions are now routine – hypertension, diabetes, arthritis, ulcers, pneumonia, cardiac disease, and many types of cancer. Moreover, you are likely to get these medications at pennies on the dollar of what they originally cost.

The current cost to bring a new medication to market is about $1 billion, give or take a few hundred million. Why so much? Manpower, safety testing, and almost all government regulation. All major companies require extremely rigorous testing with thousands of people over many years, and all this data is carefully collected in a rigid setting using somewhat expensive and out of date methods (required by the governments). And it takes 7-10 years to get to market. About 50% of drugs which enter phase III testing will fail for safety or efficacy. To get approval, there must be both. So more or less a new drug has to clear several billion dollars of revenue. What amazes me is that so many companies will place enormous amounts of capital at risk. Very few blockbuster profits have been made, but the system produces continual innovation. In a large number of cases, the brand name drugs are superior to, or have no comparable drug, in the generic market place.

How do drugs become generic? Patent law specifies a monopoly on a new product (an involved process on it’s own) for a minimum of 17 years, and in some cases 20 years. So after this time, other companies are free to try to produce their own versions. Since many drugs are chemicals which can be made in large bulk and packaged using available technologies, there is a huge economy to competition and scale.This results in pharmacies giving them away to get you and come in and shop for milk , cheese, and butter, and over the counter cough and cold remedies, which make much more money.

So why are brand name drugs expensive – we said monopoly is one reason, but that money in large part goes to reward the risks and investment taken to produce the drug. About 1/3 of revenues go into production costs, 1/3 back into research and development, and 1/3 marketing/distribution/profits. Sounds reasonable? Well why then does the cost keep going up? There is the problem.

Any good business charges what the market will bear. But is healthcare really a market? Yes and no. Insurers and consumers have influence by choosing products, but if products are limited, or if they are quite different, these are not as powerful. Moreover, a large part of the cost is borne by a third party – insurance, or ultimately governmental funding. So only a percentage is passed on to the consumer.

How do drug companies increase profits? Well, they can either sell more drug, or raise the price. Market is limited and there is competition. They sell more drug by providing incentives to patients to use their product, e.g. copay rebates. These rebates may expire. Insurance companies may force someone to change products.

How does increasing the price help? Well in some cases they get many times more money from the insurance than from the consumer. Some companies like Bayer (Betaseron), have adopted this strategy to provide a 100% rebate of copay to the consumer. Other companies like Pfizer/Serono (Rebif) try to get insurance companies to do the work for them and sell their drug to the pharmacy/insurance at a lower cost and don’t provide the consumer assistance.

What about people on Medicare Part D, TRICARE, Medicaid? Well, the manufacturer is not permitted by the government to give you assistance unless you meet some economic criteria (near poverty). The insurer wants to, but the government calls it a “kickback” (corrupt practice).

So what was behind the recent run up in drug prices? In 1993, when Betaseron came to market it cost about $17000 a year. Now that drug is $47000 a year. Did costs go up? No. The same factories have been making the drug for 20 years. But new drugs came to market, and when they did they needed to recover their costs of development, and had some advantages, and no competition, so they set their prices higher. What happened then? Well, those companies with older products were able to raise their prices because now the market would bear it.

The most dramatic examples have occurred when the US government instituted Medicare Part D prescription coverage. Previously, many of these patients were given subsidized or free drug. Since now the government would foot the bill, this is the greatest bonanza a company would hope for, and because the government was promising with one hand to help pharma, and the other hand to beat them if they did not control costs, Pharma took the initiative and dramatically raised costs for fear in the future government would not permit them to do so.

The other major recent event was the advent in late 2010 of a new and improved therapy known as Gilenya by giant Novartis. Novartis priced this drug at a highly criticized and outlandish cost of nearly $50,000, and subsequently jacked it up even higher. Why? they only have 6 years to recover the costs of a 20 year research program, and the drug is twice as good as many of the drugs on the market. This was nearly twice the cost of the other drugs. So everyone else raised their drug prices too.

One last factor driving costs is that the patent on Copaxone is expiring in 2013, and three other companies are lined up to knock it off. It is a very cheap to make, 1960s technology, and TEVA pharmaceuticals has been wildly profitable due to the recent increased revenues, low production costs, and captive market, since unlike interferon-beta, no glatiramer products compete in the market. The actions of TEVA can only be described as nonadmirable and most would consider it an abuse. At the same time, they started provided much less assistance. Most of my colleagues have interpreted it as greed, pure and simple, the worst of capitalism. TEVA also embarked on a landmark course of suing other companies to stop them from doing what is legally permitted. Ironically, in the past, TEVA has usually been the one knocking off other drugs and getting sued. Both US Food and Drug Administration and the European counterpart have stated that Copaxone can be simply knocked off as a generic drug. TEVA has unfortunately suffered a major failure in drug development of laquinimod (another subject to blog about).

So my advice is that if Rebif is costing you too much, go talk to Bayer about Betaseron. You’ll likely get a better deal. Bayer has been rebating everyone’s copay and the other companies don’t do this.

Beginning 2013, the advent of multiple competing versions of generic glatiramer acetate (Copaxone) will mean you will have pressure to use this drug instead of Rebif, Betaseron, Extavia, Avonex, Gilenya, and Tysabri, since the cost will be much lower. Patients new to MS will be required to do glatiramer and “fail” regardless of whether your doctor thinks this is right for you.

I am of the opinion that Copaxone (glatiramer) does not work well for many MS patients, so I do not relish this development. I do however have faith that our capitalistic system will continue to perform for people with chronic disease. However, the excesses which occur along the way will likely result in more regulations, which will simply be passed on to the consumer and taxpayer.

Obamacare? Well it is the government taking over healthcare. How well do you think that is going to work?

Samuel F. Hunter, M.D., Ph.D. is a neurologist specializing in neuroimmunology and neuroimaging, and has a remarkably broad background in pharmacology, image analysis, medicine, and neurosciences. He directs the Advanced Neurosciences Institute, Novel Pharmaceutics Institute, and NeuroNexus Center for research and education in Franklin, Tennessee, a suburb of Nashville. He participates and directs a multiple sclerosis clinic and many research trials for multiple sclerosis and its related conditions. He consults or performs contract research and consults for many pharmaceutical companies. Dr. Hunter works for many pharmaceutical companies, does research for them, and patient education under their auspices.

Copyright 2012, Dr. Samuel F. Hunter