Boehringer Ingelheim and the broken social contract

The twoday symposium, aimed at launching Boehringer Ingelheim’s new protease inhibitor, Aptivus, took place outside of Rome, Italy, and included an overview on AIDS treatment evolution with an emphasis on antiretroviral resistance.

The Role of Industry in AIDS Drug Development and the Broken Social Contract

It would be inappropriate for an activist speaking at a drug company symposium not to address the role of industry in research, treatment, access, and scale-up towards universal access. Since this symposium is sponsored by Boehringer Ingelheim I will address therole that company has played and should play in AIDS treatment research and access initiatives.

First, I should make it clear that I believe the R&D based pharmaceutical industry has an indispensable role to play in discovering and developing diagnostics, drugs, and vaccines to improve human health. Industry plays a vital role in taking the discoveries made in fundamental research supported by public agencies such as the National Institute of Health (NIH) and taking them to develop lead compounds and to bring new drug compounds and classes to market.

A classic example of this process is the NIH-funded discovery in 1995-96 of the role of CCR5 and CXCR4 as HIV co-receptors and the role of industry in taking this scientific breakthrough and developing lead compounds and candidate drugs and testing them pre-clinically and in humans.

Second, I believe that pharmaceutical companies are entitled to make a reasonable return on investment. If they do not make a profit they will not be able to stay in business. But drug companies must be part of a larger social contract to ensure that all people who need the benefits of new therapies receive them, regardless of whether they live in rich or poor countries or which kind of health system they have access to. And currently the drug companies are part of the broken social contract, rather than part of the solution.

Third, in spite of the detailed criticism which follows, I believe that Boehringer Ingelheim has made important contributions to HIV treatment, has the potential to make further discoveries, and can improve its performance by designing more informative clinical trials, responding more rapidly and effectively to scientific and community concerns, and assuring access to all who will need its therapies.

Boehringer Ingelheim and the Privileges of Privately-Held Pharmaceuticals
Boehringer Ingelheim developed and brought to market the first non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (Viramune®), approved by FDA in 1996, and the tenth protease inhibitor tipranavir (Aptivus®), approved by FDA in summer 2006. Boehringer Ingelheim is a privately-held, family-owned global R&D pharmaceutical company with its headquarters in Germany.

According to a company press release quoted in yesterday’s Financial Times, last year, Net sales grew by 17% to 9.5 billion euros (2004: EUR 8.2 billion). The number of employees worldwide rose by some 1,900 to total 37,400 (+5.3%). Dr Alessandro Banchi, Chairman of the Board of Managing Directors, with responsibility for Pharma marketing and Sales, said the financial year 2005 was clear confirmation ‘that Boehringer Ingelheim has entered the group of leading international pharmaceutical companies, not only in terms of sales growth, but also in terms of profits’.

According to figures from the market analysts IMS, which all pharmaceutical companies use, Boehringer Ingelheim was last year the fastest growing company among the major international pharmaceutical groups. Boehringer Ingelheim grew by 23% (sales in constant euros), while the pharmaceutical market average could only add 6%. The company, which for the sixth time in a row has grown faster than the pharmaceutical company average, has in the meantime secured a world market share of around 2%, ranking it as No.14 internationally. Dr Banchi expects distinctly faster than average pharmaceutical market growth again in 2006. ‘We trust in our own strengths and are confident that we can extend our position further in our market segments, “ the Chairman said. Simultaneously, Dr Banchi underlined that successful growth and good profits are no end in themselves, but are the ”preconditions for developing innovative medicines to benefit people’...

The highlight of the last year was the market launch of the AIDS drug Aptivus®, a novel protease inhibitor which offers additional treatment options for patients with multiple resistance to other HIV drugs...

For years, the company’s biopharmaceutical production has here been particularly successful, with net sales last year growing by 40% to 550 million euros...“

As its 4 April 2006 press release indicates:

The most important regions for Boehringer Ingelheim last year were once again both American continents with 4.6 billion euros net sales. Europe contributed 3.1 billion euros to sales and Triple A (Asia, Australasia, Africa) 1.9 billion euros... The good development of net sales led to markedly higher income after taxes. This amounted to 1.5 billion euros, corresponding to an increase of almost 70% compared to the previous year. However, this result contains only part of the overall tax burden. The position regarding the taxation of partnerships in Germany – and the family-owned company Boehringer Ingelheim is such a partnership – includes only the trade tax, but not the income tax also incurred. This has to be shown on the balance sheet as ‘capital withdrawn’, said Professor Marbod Muff, responsible at Boehringer Ingelheim for the Corporate Board Divisions Finance and Human Resources.

In Germany, the families who own BI must, alas, pay income taxes on their profits.“ Since BI does not have to report to public shareholders, or comply with legal and regulatory requirements which apply to publicly-listed companies, it benefits from the current system without having to play by rules which affect publicly- traded companies. Dr Banchi and Prof. Muff drew attention to Boehringer Ingelheim’s peculiarity as a company independent of the capital market. ‘We can plan really long term,’ said Dr Banchi. ‘The development of our business is characterised by stability and continuity.’ This also has a decisive influence on our vibrant corporate culture.

For the future, the company presents a positive picture. The product pipeline contains a number of promising candidates in various therapeutic areas. In 2005, almost 1.4 billion euros was invested in Research & Development + Medicine. That is 10% higher than the previous year. However, due to the very positive development of net sales the R&D+M expenditure as a share of net sales in Prescription Medicines slightly declined to 18.2% (2004: 19.3 %). Many of Boehringer Ingelheim’s successful products will be patent-protected or will enjoy exclusivity for a significant number of years. New market launches and indication extensions are to come in 2006, including pramipexole (Sifrol®/Mirapex®) in the indication restless legs syndrome – RLS. For Dr Banchi the goals for 2006 are clearly defined: ‘We will maintain our dynamic growth in 2006 too.’ BI’s independence from capital markets and its ability to plan for the long-term may well benefit people suffering from restless legs syndrome.

Vagaries of nevirapine (Viramune®)
BI played a critical role by keeping the development of nevirapine alive despite discouraging early results which demonstrated that when used as monotherapy nevirapine could promote the outgrowth of NVP resistant HIV within one week. Another set of studies from Harvard prematurely claimed victory in a series of papers marred by laboratory errors followed up by clinical trials which did not combine all three anti-HIV drugs – in this case AZT, ddI, and nevirapine – simultaneously in people without previous treatment experience. Luckily, some inside and outside the company realized this potential Achilles heel – which had already emerged with the nucleoside analogue RTIs AZT, ddI, ddC, 3TC, and d4T – could be delayed or prevented by the simultaneous introduction of three ARVs to individuals who had not previously received antiretroviral therapy. BI’s INCAS study, presented at Vancouver in 1996, showed that HAART did not require a protease inhibitor, and could also include an NNRTI as the anchor drug. Viramune® was approved in 1996, but sales were never as robust as for the more potent protease inhibitors.

Nonetheless the drug achieved a niche; by 2002, it was awkwardly wedged no. 8 between two forms of abacavir (Trizivir® and Ziagen®) in IMS health’s list of the top ten U.S.antiretrovirals by sales. Perhaps more important from a global perspective, the NIH-sponsored HIVNET 012 study, completed in 1998, was the first study to show that singledose nevirapine, administered during childbirth, could dramatically reduce the transmission of HIV from mother to child. While previously ACTG 076 showed that twelve weeks of AZT had greater effects, singledose NVP obviously had greater public health implications for prevention of mother-to-child transmission (PMTCT) in resource-poor settings, and indeed it provided the first impetus for previously treatment averse United Nations agencies such as UNAIDS and UNICEF to begin sluggishly advocating for a more treatment-oriented approach to AIDS in poor countries.

While HIVNET 012, conducted in Uganda by NIH and without full regulatory support from BI to meet standards for FDA approval, had some deficiencies with respect to recordkeeping and other administrative matters, numerous scientific reviews and rigorous retrospective analyses, as well as other controlled studies, have demonstrated that the underlying scientific conclusion is correct.

By Durban in mid-2000, activism to demand nevirapine access for pregnant HIV-positive women was a core demand for South Africa’s Treatment Action Campaign (TAC). Perhaps it was just a coincidence then – or more likely the presence of the global media and AIDS research elite – that elicited BI’s announcement on 7 July 2000 of a five year free nevirapine donation program for PMTCT in developing countries. The program generated oceans of good publicity for BI, while actual supplies of free nevirapine slowly trickled to poor countries, hampered by logistical difficulties at every turn.

In addition the findings of the early Richman study of rapid development of resistance to nevirapine were followed by the evidence for the rapid emergence of resistance to even single-dose nevirapine.

Ultimately, despite the development of generic forms of nevirapine by many companies around the world, its price as the lowest of any generic NNRTI either as a single drug or in fixeddose combinations (FDCs), seven years of promises by BI, UNAIDS, UNICEF, and others, and massive increases in resources for HIV/AIDS prevention and care programs through GFATM, PEPFAR, and others, uptake of nevirapine for PTMCT remains pathetic.

According to the 28 March 2006 WHO 3x5 update, ”In most low- and middle-income countries ... less than 10% of pregnant women living with HIV/AIDS [are] estimated to be receiving antiretroviral prophylaxis. As a result, 1800 infants are infected with HIV every day...“

Clearly, while victory has a thousand parents, defeat is an orphan. It is not Boehringer Ingelheim’s fault, or that of GFATM, PEPFAR, UNAIDS, UNICEF, or WHO that uptake of PMTCT is so pathetic – it is all of their responsibility, and that of governments that do not take care of their people. And it demonstrates the need for better infrastructure, human resources for health, robust supply chain management systems, and all the rest – but it is striking that eight years after its discovery, PMTCT appears to be progressing even more slowly than ART scale-up, which is much more complicated.

Meanwhile further complications of nevirapine when used as therapy (rather than in single dose PMTCT) emerged in 2004-2005. These concerns centered around sometimes fatal hepatotoxicity associated with NVP, which had always been a known side-effect, but received renewed concerns after several women died in a clinical trial of emtricitabine (FTC) being conducted by Triangle (later bought by Gilead), which included AZT and nevirapine in both arms and was comparing FTC to its established cousin FTC.

The FDA asked Boehringer Ingelheim to conduct intensified reviews of the post-marketing database. BI sponsored a special supplementon ”Hepatic Safety and HAART“ in the 2 March 2004 Clinical Infectious Diseases, and the title page noted, ”This supplement is sponsored by Boehringer Ingelheim International.“ The editors of CID published an unusual disclaimer stating, ”The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or to the publisher, editor, or editorial board of Clinical Infectious Diseases“. A lead article by guest editor Douglas Dieterich and colleagues reviewed cohort studies (rather than randomized trials or post-marketing FDA safety reporting.) This comparison looked at elevations in liver function tests (LFTs) rather than at the severe, lifethreatening hepatotoxicity observed with NVP (but not with all other ARVs). The rate of severe hepatotoxicity, ALT and/or AST levels >5 times the upper limit of normal (ULN), during therapy with NNRTIs is relatively low but may be significantly higher in patients with concurrent chronic viral hepatitis (hepatitis B or C). A comprehensive analysis of 17 randomized clinical trials of nevirapine demonstrated that 1% of all nevirapine-treated patients developed elevated levels of ALT and/or AST >5 times the ULN; however, almost two thirds (6.3% of nevirapine-treated patients) of these elevations were asymptomatic. Symptomatic hepatic events were seen in 4.9% (3.2% 8.9%) of nevirapine-treated patients. The article leaves one with the impression that all ARVs have similar hepatic toxicity profiles at least when it comes to elevated LFTs. However, it did not look at comparative rates of severe, life-threatening, or fatal hepatotoxicity.

In the meantime, the FDA, after a post-marketing safety database review, required BI to change the Viramune package insert, which now begins with a prominent black box. The revised prescribing information was released on 11th January 2005, just nine months after the misleading coverage in the March 2004 CID, and was followed by an ”FDA Public Health Advisory for Nevirapine (Viramune)“.

Unfortunately the politics of HIV denialism in South Africa and elsewhere seized on the newly clarified safety concerns – as they had previously on the unrelated issues regarding record-keeping in the HIVNET 012 study – to cast doubt on the underlying safety and efficacy of nevirapine for either PTMCT or on ART regimens.

Nonetheless BI’s support for the CID supplement and what some have suggested was its less than forthright response to safety considerations raised by FDA and others in the decade since the licensing of nevirapine clearly provide an opportunity for the company to reflect on its behavior and commit to addressing future safety concerns in a more proactive, transparent fashion. This means taking an aggressive approach to studying the toxicities associated with their drugs in well-designed long-term safety studies, investigating the interactions between their drugs and other commonly used treatments, trying to understand the pathogenesis of hepatotoxicity, providing clinicians and patients with clear, accurate information about the detection and management of severe adverse events, and fulfilling their postmarketing commitments to FDA and other regulatory authorities. In many places where nevirapine is now used as the most common anchor drug in first-line ART regimens in countries scaling up ART programs, lab and clinical capacity needs to be made available to monitor liver function tests (LFTs) when possible, and people on ART, providers, and the health system need to be trained and encouraged to be vigilant for clinical symptoms which may suggest NVP hepatotoxicity. Nothing is ever simple in HIV treatment.

More Complications –The Tortured Tipranavir Tale
Which brings us to tipranavir. Perhaps no approved antiretroviral has had a more tortuous development course. First introduced into the literature in 1997 as PNU140690, tipranavir (TPV) was initially developed by Pharmacia & Upjohn, a company soon swallowed up in the wave of pharmaceutical mergers which dramatically slowed down development of a number of HIV drugs, the former PNU140690 compound included.

Tipranavir got a reprieve – just barely; in 2001, Boehringer Ingelheim decided to take up PNU140690 for Development.

Tipranavir is structurally different from other protease inhibitors and hence exhibits activity against most PI-resistant HIV. On the downside, tipranavir has a daunting pill count. The tipranavir data presented in Argentina were somewhat confusing, as the formulation changed midstudy. In addition, tipranavir was given in combination with low-dose ritonavir in order to boost the drug’s less than overwhelming pharmacokinetics...

Boehringer held a spirited community meeting where they were questioned aggressively on these results, although some of the problems with the development plan were the legacy of the previous sponsor. For example, the dose-ranging study included efavirenz, which is likely to affect the drug’s pharmacokinetics. Despite its intriguing resistance profile, the combination of high pill count, bizarre pharmacokinetics and significant toxicity poses a trinity of major obstacles for this drug.

Over the subsequent years BI conducted two studies of tipranavir in highly treatment experienced patients, RESIST-1 and RESIST-2. The studies allowed participants to use T-20 (enfuvirtide) and generally those who added both TPV and T-20 to their regimen did better. However the results of the RESIST studies were difficult to interpret due to the complex nature of the patients and their HIV in the studies, because of early treatment switches, and other confounding variables.

In June 2005, the United States Food and Drug dministration’s Antiviral Drugs Advisory Panel voted to recommend a twice daily dose of 500mg of tipranavir boosted by 200mg of ritonavir, as studied in phase III trials of the drug. Although the panel voted to approve tipranavir, they expressed caution and asked for further studies to be carried out to guide use of the drug.

In particular the FDA highlighted problems with potential drug interactions and liver toxicity. They noted that interaction studies looking at a wide range of cytochrome p450 enzymes and drugs metabolised through those pathways have not yet been carried out, despite the fact that tipranavir also inhibits CYP1A2, CYP2C9, CYP2C19 and CYP2D6. Grade 3 or 4 liver toxicity was noted in 10% of tipranavir treated patients, and emerged significantly more quickly in both RESIST studies. The same was true for triglyceride and cholesterol elevations.

A higher rate of rash was also seen in women than men treated with tipranavir in phase I and phase II trials, but no difference between the tipranavir group and the control group was seen in the RESIST studies. However the FDA says that the small number of women included in these studies makes it impossible to draw definitive conclusions.

Thus, four years after the first BI meetings with the community on TPV, the ”trinity of obstacles“ remained of concerns and the FDA approved labeling for Aptivus included a now-familiar black-box warning on tipranavir’s hepatic side-effects. It is fortunate that FDA is requiring such detailed and extensive postmarketing studies under its accelerated approval authority; however, past experience shows that many companies do not fulfill their postmarketing commitments. A recent FDA study showed that 154 drug sponsors had 1,231 open postmarketing commitments. By 30th September 2005, two thirds (797, 65%) were still ”pending“, 231 (19%) ”ongoing“, 28 (2%) ”delayed“, 3 (<1%) ”terminated, and just 172 (14%) “submitted“. This is a rather dismal performance by industry and reflects the need for stronger FDA authority to compel sponsors to fulfill their commitments, as well as the need for more robust post-marketing pharmacovigilance.

Hence, FDA and the community must be vigilant in ensuring that BI fulfills its promises here. Thus, it is hard to know how useful TPV will really be in the clinic. With its plethora of side effects, serious liver toxicity, and bizarre pharmacokinetics, it may be reserved for individuals able to tolerate it and who need a stopgap protease inhibitor before the introduction of possibly more forgiving alternatives such as Tibotec’s forthcoming protease inhibitor darunavir, or – still speculatively as they are in earlier phases of study –the Pfizer or Schering CCR5 inhibitors, the Gilead or Merck integrase inhibitors, or other potential new ARV candidates.

Perhaps fearing that its brief moment in the sun would quickly be eclipsed by these rapidly advancing alternatives, BI decided to price Aptivus at a record $13,410 per year wholesale in the United States, the highest price for any protease inhibitor. This certainly betrayed, at the very least, a dismaying indifference to the plight of U.S. HIV-infected people who might fall between the cracks in the fragmented health system, or even a more cynical urge to gorge on excess profits as quickly as possible due to fears of a vanishingly small window of opportunity to obtain market space. The AIDS Treatment Activists Coalition (ATAC) responded to BI’s unprecedented pricing move with a public warning that drug companies were engaging in a ”steady onslaught of unreasonable, unacceptable, and unjustified’ increases in the prices of therapies to treat HIV...

On 23rd February 2006, BI held a conference call with US treatment activists to announce that it was dropping the 500/200 mg tipranavir/ritonavir arm from the ongoing 1182.33 study in ARV naives which was comparing two doses of TPV/rtv (500/200 and 500/100) to Kaletra. BI refused to disclose the number of events which occurred, the relative risks between study arms, or to describe in any detail the reasons other than what they stated in their press release, saying fuller disclosure had to wait until an unspecified future scientific conference.

This continuing evasive behaviour stood in stark contrast to Pfizer’s detailed disclosure regarding a single, severe adverse event in its ongoing maraviroc study in ARV naïve individuals. The fact that the dose combination which is FDA approved for use in treatment experienced individuals was now deemed too toxic for treatment naive ones indicates the alarming degree to which BI has failed to clearly define a dose which is both safe and effective for use in diverse HIV infected individuals.

Conclusion
In conclusion, Boehringer Ingelheim has failed to live up to the best practices which should be expected for the world’s fifteenthlargest R&D based pharmaceutical company. In its interactions with treatment activists in the US or Europe, BI clings behind the excuses of being small, family owned, and privately held, to justify its small studies, inadequate research into side effects or resistance, and failure to fulfill post-marketing study commitments. Similarly, when activists or from developing countries or NGOs such as MSF implementing ART and PMTCT programs in developing countries complain about difficulties accessing BI, obtaining regulatory information, or obtaining promised discounted or free drug donation programs, BI claims that it lacks the capacity to respond to the myriad of requests coming from places where it is understaffed or relies on intermediates. Yet at the same time, in its annual reports to investor, BI trumpets its unparalleled growth, intention to join the big leagues, commitment to groundbreaking innovative research, and brags that being privately-held enables it to plan long-term, while simultaneously complaining its profits are doubly-taxed in Germany.

BI needs to decide which role it intends to play. If it really wants to be a global player, it must be more accountable, transparent, scientifically rigorous and respectable, and let community activist networks have access to the most timely and accurate scientific information. It must make its products accessible to all who need them without pricing entire countries or populations out of its markets. It must meet and exceed its commitments to FDA. It must conduct solid research into the reasons for drug toxicities and how to manage them in diverse population groups affected by HIV, HBV, HCV, drug substitution therapy, and other combinations.

Mark Harrington

EATN - European AIDS Treatment News, Volume 15, I – Spring 2006

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