A scathing front-page article published in the January 3 Wall Street Journal (WSJ), outlining strategies by Abbott Laboratories to limit access to Norvir® (ritonavir) for the sake of keeping Kaletra® (lopinavir/ritonavir) sales afloat, has once again raised the ire of treatment activists. According to internal documents provided to the paper, reporter and writer John Carreyrou indicates that Abbott considered three aggressive marketing tactics – including the 400% Norvir price increase that went into effect in December 2003 – to deter the use of competitor protease inhibitors (PIs) that required low-dose Norvir for boosting purposes.

Norvir, approved by the FDA in 1996, was Abbott’s first PI. At its approved dose of 600 mg twice daily, however, the significant side effects of the drug – including upset stomachs, weakness, liver enzyme increases, sharp glucose and lipid (fat and cholesterol) elevations, and numbness/tingling around the mouth – proved too prohibitive for many HIV-positive people.

Soon after it was approved, researchers discovered a beneficial and potentially less toxic use for Norvir. The drug was found to have a profound inhibitory effect on cytochrome P450 enzymes, proteins in the gut and liver responsible for metabolizing numerous medications in the body. Using low doses of Norvir to block these enzymes, researchers were able to combine it with other PIs, effectively making them more powerful and/or easier to take.

Kaletra, Abbott’s second PI approved by the FDA in 2000, is based on this Norvir-boosting concept. Each pill contains lopinavir, the active PI, and a small amount Norvir, which gives lopinavir an effective boost. Following approval, Mr. Carreyrou writes, “Kaletra’s effectiveness and convenience quickly made it the most popular AIDS drug, with 35% of the protease-inhibitor market by 2003 and annual U.S. sales nearing $400 million.”

Meanwhile, Bristol-Myers Squibb’s PI Reyataz® (atazanavir) was generating a lot of buzz in clinical trials and was approved by the FDA in June 2003. Not only were Reyataz’s once-daily dosing and minimal effect on lipid levels attractive selling points – Kaletra required twice-daily dosing in 2003 and is known to cause cholesterol and triglyceride increases – preliminary results from a study comparing Norvir-boosted Reyataz to Kaletra demonstrated equivalency between the medications.

Four months later, in October 2003, GlaxoSmithKline’s PI Lexiva® (fosamprenavir) was approved by the FDA as well. Like Reyataz, Lexiva was showing significant promise as a once-daily Norvir-boosted option.

In response to the threat of Norvir-boosted Reyataz and Lexiva on Kaletra’s sales forecasts, internal documents generated at Abbott outlined potential strategies to take the wind out of the sails of its competition. If the company did not take steps, the documents indicated, Kaletra’s market share would fall by approximately 10% in 2004.

The WSJ article says that on September 6, 2003, Abbott’s HIV marketing director Jeffrey Devlin e-mailed a slide presentation to colleagues discussing two possible strategies to counter the attractiveness of Norvir-boosted Reyataz: quintupling Norvir’s price or, more drastically, withdrawing Norvir pills from the U.S. market and leaving only the unpalatable liquid formulation of the drug. (John Leonard, Abbott’s vice president of global pharmaceutical research and development, has referred to liquid Norvir as “this fluid that has been – I’ll just say it – characterized as tasting like someone else’s vomit.”)

Mr. Devlin ended up supporting the price hike, but Jesus Leal, then vice president of Abbott’s virology franchise, preferred the switch to the liquid formulation.

Mr. Leal, Mr. Carreyrou points out, wrote in an e-mail that a sharp price increase would be difficult to justify, especially if the company was “forced to open books.” The liquid switch, he said, would “minimize any federal investigations regarding price increases.” Plus, according to the slide presentation distributed by Mr. Devlin, U.S. sales of Kaletra would grow by 20% to 30% between 2004 and 2006, while U.S. prescriptions of Reyataz would fall by 28% to 54% over the same period under the scenario. To justify the switch, Abbott would tell the American public that the Norvir capsules “needed to be sent to the developing world (i.e., Africa), as part of a humanitarian effort.”

Another slide set, presented at Abbott on September 24, 2003 – the company says that the slides were prepared by an external public relations firm – added a third option: simply halting global distribution of Norvir altogether. This radical step, the presentation suggested, would remove “pricing from public debate” and render moot any discussion of the liquid’s taste. However, it noted that Abbott’s “corporate reputation” would suffer. What’s more, this decision might have prompted governments to permit the production and distribution of generic Norvir versions, potentially hurting Kaletra sales even more.

Abbott eventually opted for the Norvir price increase, which went into effect in December 2003. Norvir’s U.S. wholesale price rose to $257.10 from $51.30 for 30 100mg capsules. The Abbott slide presentation indicated that this would allow the company to “position Kaletra as a more economical option” and that patients would not be directly harmed, “as nearly all are covered by private insurance, Medicaid, and ADAP.”

According to a December 19, 2003, WSJ article by Vanessa Fuhrmans, AIDS activists and other critics sensed that Abbott’s intention was “to push patients away from using Norvir in drug cocktails and switch to its newer AIDS treatment, Kaletra, instead.” Abbott, however, publicly argued that Norvir’s price increase had nothing to do with Kaletra. The company said that Norvir’s new price was intended to better reflect the drug’s importance in treating HIV and the costs for improving Norvir’s formulation, including a tablet version. (The tablet version, originally scheduled to be available in 2005, has yet to be developed.)

Needless to say, Abbott is not tickled by the latest WSJ article. “The internal documents referred to in the article,” Melissa Brotz, a spokesperson for the company told AIDSmeds, “were taken out of context. The company was looking at a variety of options, not just the three reviewed in the article. Stopping the sale of Norvir was quickly dismissed, as we knew that Norvir still had an important role and this wouldn’t have been good for patients. We ultimately decided to reprice Norvir. That decision was unpopular, but it was ultimately what we did.”

An unpopular decision indeed.

In response to the price increase and Abbott’s apparent dishonesty, activists organized phone and fax “zaps” targeting key company personnel and protested in front of its suburban Chicago headquarters and at its annual meeting of shareholders. What’s more, 300 doctors banded together to boycott Abbott products and barred company sales representatives from entering their offices (one of these doctors was Howard Grossman, MD, the medical editor of AIDSmeds at the time).

In May 2004, the National Institutes of Health (NIH) held a public hearing to consider a request by activists that it authorize cheaper generic copies of Norvir to be made before the drug’s patent expired. According to the WSJ article, the NIH has the legal authority to do this in cases where it has provided funding research for a drug’s development – John Erickson, a former Abbott researcher, testified at the meeting that Abbott received a $3.5 million NIH grant to fund early Norvir research – but did not act on the activists’ requests.

Lynda Dee, a Baltimore-based lawyer, tells AIDSmeds that she was one of the activists to lead the charge against Abbott at the NIH hearing and also helped to get healthcare providers across the country on board. “I also helped to ensure that Abbott’s patient assistance program covered people who couldn’t afford their insurance copayments, and helped to ensure that government payers were charged the price of ritonavir before the 400% increase,” she says. “But I’m sure Abbott had already calculated that these concessions were well worth the profits that would be realized as a result of an increased Kaletra market share, this is to say nothing of the increased Norvir profits. We even went to the Federal Communications Commission in an effort to push them into filing suit against Abbott for unfair trade practices.”

While the FCC did not end up filing a lawsuit against Abbott, the WSJ article says that Illinois Attorney General Lisa Madigan has been investigating Abbott’s price hike for three years, saying it may be an example of unfair pricing that violates the state’s consumer-fraud law. What’s more, a lawsuit has been filed in U.S. district court in California by two HIV-positive people and the Service Employees International Union Health and Welfare Fund alleging that Abbott broke antitrust laws by using its market power to boost Kaletra sales. The California suit is scheduled to go to court in 2008.

“Over time,” Mr. Carreyrou writes, “the outcry faded. Private health insurers took a bigger blow but had little leverage, because they could hardly deny patients a lifesaving drug. Insurer Aetna Inc. sued Abbott but dropped the suit within days. Abbott also settled a suit brought by the AIDS Healthcare Foundation. The company agreed to support programs at the foundation, which provides free medicine to poor and uninsured AIDS patients. Financial terms weren’t disclosed.”

But in light of the WSJ article – and the release of the internal documents – the Norvir price increase and the other proposed Kaletra marketing tactics are once again a leading topic of discussion among activists. “These documents confirm what activists said from the start, that the Norvir price hike was a shocking display of greed and dishonesty,” Mark Milano, a New York City-based activist, told AIDSmeds. “As we learn more about the pharmaceutical industry’s shameless tactics, the need for some form of drug price controls – as exist in almost all other industrialized nations – becomes increasingly urgent.”

Ms. Brotz contends that activist concerns have not fallen on deaf ears. “We hope that we will be judged by the record of what we’ve done over time,” she says. “We’ve worked hard to strengthen communication with patients and doctors since the repricing and we’ve valued their input.”

“It’s been very difficult keeping this issue alive,” says Ms. Dee. “Some things are worth fighting for, no matter how long it takes.”

[Note: Tim Horn, the writer of this story, is also a member of the AIDS Treatment Activists Coalition (ATAC), and was involved with that organization’s response to the Norvir price increase.]

Source:

Carreyrou J. New regimen: Inside Abbott’s tactics to protect AIDS Drug. Wall Street Journal. January 3, 2007.