New research reveals one of the HIV virus’s many complex mechanisms for evading the immune system. Published in the March issue of 

, a study shows that a protein produced by HIV negative factor or Nef, could inhibit the way infected people’s bodies produce two specific antibodies necessary for fighting invading agents.

    Nef has long been known to have several roles in HIV infection, particularly the early stages, explained lead author Andrea Cerutti. But until now, most studies have focused on Nef’s effect on T cells. Cerutti and his lab look at Nef’s affect on B cells.

    Their research showed that Nef accumulates in germinal centers, which are clusters of B cells inside the lymph nodes. Even though HIV does not infect B cells, Nef still penetrates the B cells, Cerutti said. The mechanism by which the protein enters these B cells is unknown.

    All B cells produce antibodies, but the B cells in germinal centers are able to produce especially specific versions of antibodies called IgG and IgA, according to Cerutti. These highly specific antibodies are particularly effective at targeting infectious agents. 

    “They work like molecular bullets,” Cerutti said.

    Antibody production is turned on when the B cells receives chemical signals from a T cell that has been activated by an invader. The germinal center’s B cells first produce less specific antibodies, called IgM, Cerutti said. 

    Through a process called class switching, IgM is altered into the more specific IgG and IgA. B cells inside and outside of the germinal centers can produce IgG and IgA. But inside the germinal centers, the antibodies undergo a second step called somatic hypermutation, which allows them to more specifically target the foreign object they were designed to fight.

    HIV-positive people are less capable of producing specific antibodies than uninfected individuals, Cerutti explained. As a result they are not as capable of responding to pathogens, including the HIV virus, opportunistic infections, and vaccines. IgA is especially important for helping bodies fight the HIV virus, because it’s structure makes it especially capable of targeting foreign agents that enter the body through mucous membranes in the mouth, intestinal tract, and genital region.

 paper shows that after invading the germinal centers, Nef is able to inhibit the B cells ability to create IgG and IgA. So Nef works to inhibit class switching, at least in the laboratory, Cerutti explained. Based on his results, it looks like Nef accomplishes this by hijacking the body’s own mechanism for regulating class switching. 

    Class switching is inhibited through a negative feedback loop at a certain point in the immune response, in order to prevent the body from reacting too strongly. When the immune response is too strong it can attack healthy cells, resulting in autoimmune disorders.

    Cerutti’s research demonstrated that Nef enhances molecular expression of two proteins that are involved in this negative feedback pathway for class switching. Eventually, this interference might prevent the class-switching process from ever getting turned on, he said.

    According to Cerutti, Nef is a good drug target, because it is involved in several aspects of HIV infection. If agents that block Nef were discovered, among other things, they could stop the class switching process from being shut down. 

    “This could improve the quality and magnitude of antibody responses to the virus and other pathogens,” Cerutti said.

    Since Nef is known to be involved in the early stages of infection, a Nef blocker might someday be used to prevent infection in high-risk individuals, he speculated.

Articles

A new study indicates that a protein produced by HIV invades uninfected B cells and inhibits a mechanism that makes certain antibodies very good at targeting invading agents.

HIV-produced Protein Decreases Antibody Specificity

At a March 22 meeting, FDA’s Pediatric Advisory Committee recommended that the labels for all drugs to treat attention hyperactivity disorder (ADHD) be changed to acknowledge a risk of cardiovascular or psychotic events. 

    But the committee did not follow in the footsteps of another advisory board, the Drug Safety and Risk Management Committee, which recommended a black box warning for cardiovascular risks to adults be added to the labels of ADHD drugs that are stimulants. The FDA usually follows advisory committee recommendations.

    Even if the label changes go forward, industry analysts predict that they would have only a minimal impact on the market for ADHD drugs. 

    “From a physicians perspective, it isn’t going to change prescribing habits that much,” said Anathea Waitekus, an analyst at market research firm Decision Resources, adding that doctors are very familiar with these drugs because they have been on the market for so long.

    Waitekus predicted that parental hesitation due to new labels could have a slight effect on the market. Warnings about an increased suicide risk for teens taking anti-depressants have had little impact on prescribing, she said.   

    Lisa Kelly, an analyst at Wood Mackenzie, noted that the market share of Adderall XR’s (amphetamine/dextroamphetamine) has not suffered since a warning for people with heart conditions was added to its label in 2004.

    Kelly credited her predictions of continued market strength to ADHD drugs’ effectiveness.

    “The drugs available to treat ADHD are the most effective of the psychiatric drugs,” Waitekus said.

    But Kelly added that there is a market opportunity for an ADHD drug that is not categorized by the Drug Enforcement Agency as an addiction risk. Shire has a product, NRP-104, in development that it believes will not receive a “scheduled” designation.

    Lilly’s Strattera (atomoxetine) is the only ADHD treatment that is not designated a controlled substance by DEA. But it also has a warning about suicidal behavior among children in its label.

    In a November 2005 report, Waitekus predicted that NRP-104 would achieve blockbuster sales by 2014, driven in large part by the adult market. The next wave of growth in the ADHD market will come from adults, Waitekus said in an interview. 

    A recent report from pharmacy benefit manager Medco Health Solutions shows that use of ADHD drugs among people age 20 to 44 grew 139 percent between 2000 and 2005. Growth among those 19 and under was 82 percent during the same period.

    The company estimates that last year 1.7 million adults and 3.3 million children used ADHD drugs.

    But Kelly remains cautious about the adult ADHD market. 

    The adult ADHD market has only been 5 percent penetrated, compared with 40 percent penetration for the pediatric market, explained Wood Mackenzie analyst Alex Grosvenor. In spite of this, Kelly explained, awareness of ADHD as an adult problem is not very high. 

    The biggest impact to the ADHD market this year will probably come from generic competition, Kelly predicted. She believes that some form of generic Adderall will be available by the end of 2006.

Experts say proposed label changes or black box warnings would not significantly decrease ADHD drug prescriptions. But they see potential market opportunities for new products and generics.

Label Changes Would Have Minimal Impact on ADHD Market

In what may become a national class-action lawsuit, a New Jersey union welfare fund alleged that Pfizer marketed its blockbuster cholesterol-lowering drug, Lipitor (atorvastatin), to patients who did not need it. The suit charges that the company tried to expand the market for Lipitor by convincing doctors to prescribe it for patients whose cholesterol count was lower than what is specified in the prescription guidelines on the drug label. The lawsuit does not claim that patients were harmed.  The aggrieved parties are insurance companies and drug benefit plans -- like the New Jersey union -- that paid for off-label prescriptions that, the suit claims, might not have been written if Pfizer had marketed the drug legally. 

The suit relies on the federal Racketeer Influenced and Corrupt Organizations Act (RICO) to build a national class of defrauded third-party payers. In case the RICO class fails, the plaintiffs’ lawyers are filing additional state lawsuits. 

We talked about the lawsuit with Geoffrey Jarvis, a partner at Grant and Eisenhofer, P.A., the plaintiffs’ attorneys, and with Bryant Haskins, a Pfizer spokesman. 

What is it that you are accusing Pfizer of doing, and who are you accusing Pfizer of harming?

Geoffrey Jarvis, partner at Grant and Eisenhofer:

What we are claiming that Pfizer has done. Let’s back up a minute.

This is about the low-risk people. Those that have less than a 10 percent chance of contracting coronary heart disease in the next five years. For that group of people, according to the drug label, unless their cholesterol is above 160, statin drug therapy is not recommended. You are not supposed to use it. You are supposed to use therapeutic lifestyle changes.

The NCEP [National Cholesterol Education Panel] report says that there are two reasons for this. First, the benefits for people with low risk of heart disease and relatively low cholesterol -- under 160 -- are not that great. And there are, of course, risks associated with using statin drugs -- liver complications, for instance. I don’t think they are very common, but they exist.  And second, the course of the drug is very expensive -- $1500 or $1800 a year, or whatever it is. And it’s a lifetime commitment. So the trade-off the government has made is that for this group of people, based on the medical and other evidence available at this time, they don’t believe that statins are worth it. Those guidelines are on the label.

Where does it say on the label that there is a lifetime commitment?

It doesn’t say that. But when you start a statin drug, it only works if you use it forever. Once you stop using it, then you don’t get the benefit of the lower cholesterol to the extent you have risk for heart disease.

Okay, that’s the background. Now give me the brass tacks of what you accuse Pfizer of doing.

We claim that Pfizer is -- through marketing programs to doctors-- trying to get physicians to prescribe this drug to people who are at low risk of heart disease and whose cholesterol level is below 160. There are about 15 million people in that group. Basically, they are trying to expand the market of the drug to people who really ought to not be on it.

The people who are paying for it: your insurance company. Insurance companies traditionally do not check if a patient meets the guidelines. If a doctor prescribes Lipitor, the companies don’t check to see the person’s cholesterol. Is it really above 160? Do they really have a greater than 10 percent risk? The system isn’t set up to have that kind of Big Brother aspect to it.

And Pfizer is taking advantage of the that fact companies will pay for whatever is on the formulary for the label indication of the drug.

But aren’t we underestimating the knowledge and critical-thinking capacities of doctors? If somebody comes and tells me to write a story that I think is a dumb story, I don’t write it. In fact, PR people do that all day long, and I ignore them. Don’t doctors do the same thing when companies come and tell them to prescribe a drug for somebody it’s not indicated for?

They may. But doctors might not be as familiar as they could be with balancing all the factors: risk, benefit, and cost. For the doctors’ perspective, it’s probably about risk of liver disease versus any benefit at all from the drug. But the ATP III guidelines go one step further. [ATP III guidelines are found in the third report of the Adult Treatment Panel, developed by the National Cholesterol Education Panel, which is a panel of the National Heart, Lung, and Blood Institute.] They go to the cost side. Well the doctor ain’t paying for it. And in 99 percent of the cases the patient ain’t paying for it. So the cost-benefit side doesn’t play a role in the doctor’s thinking. The drug company, we claim, is trying to talk doctors into prescribing it for people who it’s not indicated for, but the real burden falls on somebody else entirely.

But really, isn’t some of this up to the doctor? Can’t he say, maybe Lipitor is a good idea for you, even if it’s off label? 

Yes. The complaint makes that clear. You can prescribe an FDA-approved drug for any purpose whatsoever. But does that mean that somebody else has to pay for it? Here, the concern is what kind of system we want to have to maintain the doctor’s discretion. Should people, to get their Lipitor prescription, have to turn in all of their medical records to the insurance company to get it approved? We don’t want that system. But we would like, at least as a prophylactic measure, to prevent the drug companies from advertising the drug to the physicians. To prevent them from trying to get doctors to prescribe it to people who it’s not appropriate for.

You call this RICO, Racketeering Influenced and Corrupt Organizations Act, if I remember right? 

That’s basically a way of pleading a nationwide fraud. It’s just a way to build a nationwide class of people. Fraud is a common-law claim in the United States. There is no national fraud law; every state has its own. In the event that a court claims that it’s not RICO, we’ve also set up state complaints. We filed in New Jersey, you saw that, and we are going to file complaints in other states to take advantage of their state laws. 

So you’re not calling Pfizer a bunch of racketeers.

Tell me a little more about what you call Pfizer’s scheme to promote the off-label use of Lipitor. 

They would make presentations to doctors and try to take the focus off the guidelines set up in NCEP III or ATP III and promote what they call the get-to-goal message. That was their mantra. The goal for everyone, even the patients who are low risk, was cholesterol of 130. So what they suggested was that if you’re above 130, you should get to goal. But that’s not what the guidelines call for. They say that if you are above 160, and it’s called for, then we try to treat you to make sure you are at 130. What Pfizer is trying to do is promote this get-to-goal message for everybody. They want to cloud the message that if you are above 160 you take it, and if you are below 160 you don’t.

Not indicative of the marketing they did, but of the overall scheme: When they are speaking to investors and they talk about the size of the Lipitor market, they include the people who are in the 130-to-160 category –- the low risk people who clearly should not be part of the market. But their slides of how they put the market together include those people among patients who ought to be taking Lipitor. It shows the corporate goal. It shows that they did have an overall plan to include the people who were low risk and had cholesterol between 130 and 160 in the market.

What do you think this cost your clients?

It’s hard to say. Nationally, we think this is a multibillion-dollar-a-year problem. Our clients have some percentage of that. They’ve all paid for a substantial number of Lipitor prescriptions. I’m not at liberty to tell you what their prescription payments are. It’s not an insignificant amount. We talked about what we think the percentages are. But we didn’t put it in the complaint on purpose. We don’t want to go out with a number we aren’t sure of.

*************************************************************************

Our lawyers are looking at it. We can’t comment on specific points. We take very seriously our responsibility to provide appropriate information to physicians and patients and to comply with all federal laws and regulations regarding the promotion of our medicines. But based on the information that we have, we believe there is absolutely no merit to the claims that the suit makes regarding the promotion of Lipitor.

They basically say in a nutshell that you are promoting the use of Lipitor for cholesterol levels that are below those specified in the label, which is taken from the ATP III guidelines [Third report of the Adult Treatment Panel, developed by the National Cholesterol Education Panel, which is a panel of the National Heart, Lung, and Blood Institute]. 

Well I think the ATP III are guidelines. And we always recommend that patients consult with their doctors and determine what is the best approach for them to take regarding any of our drugs, and particularly for Lipitor for cholesterol reduction. That’s a decision to be made between them and their doctors. Are they claiming that the doctor has no position as far as prescribing medicine to patients?

No. Quite the opposite, I think. They are saying that you are trying to influence doctors to prescribe at levels lower than the label recommends. 

They’re basically saying that Pfizer goes out and hires a lot of consultants and invites doctors to fancy meetings in nice hotels, where the company tells them to prescribe Lipitor when patient’s cholesterol levels are lower than specified in the ATP III guidelines on the label.

Our position has always been that patients should consult with their doctors to determine the appropriate treatment for them as individuals.

But they would say, fine, instead of influencing patients you decided to influence doctors. 

They’re not giving much credit to the doctors, are they?

No, they’re not. But that’s what they’re saying. I think I owe it to both sides to ask the question. Pfizer recognizes that the doctor-patient relationship is a very powerful one, and that doctors influence their patients. So Pfizer sets out this big elaborate -- the attorneys call it a scheme -- to influence doctors. And you do spend a lot of money influencing doctors. They’re your customers, right?

Yes. But that doesn’t mean we’re influencing them unduly. And I can’t get into addressing specific allegations of this lawsuit. Other than to say that we would strongly disagree with many, if not most or all, of the points that they make in the lawsuit. But beyond that, we’re not going to get into talking point by point. We never do that with litigation that’s in progress.

I’m grateful that you talked about it as much as you did.

A Q&A with Geoffrey Jarvis, counsel for the plaintiffs, with a response from Pfizer.

Lawsuit Alleges Pfizer Marketed Lipitor Too Broadly

The Supreme Court heard arguments March 21 in a case that could influence the legal definition of what can and cannot be patented, or at least the language of patent claims.

    The suit, which pits Laboratory Corp. of America Holdings against Metabolite Laboratories Inc., involves Metabolite’s patent on a diagnostic test for the amino acid homocysteine. An excess of homocysteine is linked to cardiovascular disease, according to the National Institutes of Health. And because homocysteine is broken down by vitamin B, an excess of homocysteine is also linked to a deficiency of certain types of vitamin B.

    In the lower court cases, LabCorp asserted that one section of the patent, claim 13, was too broad. This claim states that the patent covers all tests that detect high levels of homocysteine and correlate this with decreased levels of vitamin B. LabCorp, which lost both the initial suit and the appeal, said this could include other homocysteine assays, not just the one in the patent, explained George Hovanec, an attorney at Buchanan Ingersoll PC, who is not involved in the case.

    But when it reached the Supreme Court, the case took on larger implications. The case addressed the issue of whether or not this claim crosses the line of trying to patent a natural law or phenomenon, which everyone agrees is not allowed, Hovanec continued.

    The concern, explained Ron Daignault, partner at Jenner & Block LLP’s New York office, is that a doctor could infringe on the patent by simply thinking or suggesting that elevated levels of homocysteine could indicate a vitamin B deficiency. Daignault is not involved in this case.

    “They’re trying to patent a law of nature,” Daignault said.

    An extreme example, Daignault said, would be a medical school professor infringing the patent by explaining the correlation between homocysteine and vitamin B to students.

    But Stephen Maebius, partner at Foley and Lardner LLP, said the main issue of contention in this case is the language of Metabolite’s patent, not the intent.

    “The language is responsible for making this a questionable case, in what otherwise did not need to be,” he said.

    In patent litigation each claim is considered separately. The goal of writing a patent, Maebius explained, is to have some claims that are broad enough to increase the likelihood of infringement, but to also have at least one of the infringed claims be strong enough to be upheld. The stronger claims should be directed at commercial ways of using the patented product. The broader claims should be worded very carefully to avoid problems.

    When writing claims, companies always try to look at possible future methods and applications, Hovanec indicated.

    “Nobody wants to cover the doctor’s thought processes,” Maebius said.

    Although this case has caused a lot of worry, the court will probably not make any drastic changes to what is considered patentable subject matter, experts agree.

    If the Supreme Court addresses this issue at all, it will probably be a matter of fine-tuning or remanding the case to the lower courts, said Cono Carrano, a partner at Dewey Ballantine LLP.

    If they do set precedent about patentable subject matter, Maebius said, it will probably be in a nuanced opinion that sets forth a general framework. This would be similar to the 

    But the high court may decide not to address this issue at all, according to Carrano, because it was not raised in the two lower court cases.

    Section 101 of the patent code sets the limits of what is patentable subject matter. This section was not addressed in the previous cases, which focused on other parts of the code.

    Because Metabolite’s compliance with section 101 was not previously argued, it makes this case a difficult vehicle to address the issue, Maebius indicated.

    The court could simply focus on compliance with section 112 of the patent code, Carrano explained. In this case, section 112 deals with how the company described and claimed its product beyond natural phenomenon, he said.

    But the fact that the court took the case indicates that at least some of the justices are interested in refining what is patentable material, according to Hovanec.

    “The Supreme Court was waiting for the opportunity to speak on this issue,” he said.

The high court could fine-tune the definition of what is patentable in deciding LabCorp v. Metabolite. Legal experts weigh-in on the nuances of the case.

Pharmaceutical Executive-03-29-2006

HIV-produced Protein Decreases Antibody Specificity

Label Changes Would Have Minimal Impact on ADHD Market

Lawsuit Alleges Pfizer Marketed Lipitor Too Broadly

Supreme Court Hears Arguments in Patent Case