Alemtuzumab changes hands

In 1994 Wellcome Biotech abandoned development of Campath-1H.

This was despite having invested 7 years on the project and promising results that were coming through from clinical trials. The decision was made just after the completion of phase II trials with patients suffering from rheumatoid arthritis and non-Hodgkin's lymphoma with associated lymhocytic leukaemia.

Wellcome Biotech's decision to drop Campath, in part, reflected its reorganisation and re-absorption into its parent company, Burroughs Wellcome, in 1994. The executives of Burroughs Wellcome who were most of their energies on the development of HIV therapies, which were directed towards raising T-cell counts in HIV patients, looked upon Campath-1H as unsafe because it depleted T-cells. Furthermore, from their perspective the clinical trial data looked unpromising. While found effective in some types of leukaemia, the drug had proven less positive for rheumatoid arthritis. Particularly concerning was the fact that Campath-1H appeared to suppress immune systems, which heightened patients' risk of infection. Such a complication might be acceptable in the case of cancer, but was unacceptable in an ongoing chronic condition like rheumatoid arthritis. For Burroughs Wellcome's executives the negative trial data from rheumatoid arthritis was disappointing because this disease market was potentially much larger, and therefore much more profitable, than the one for leukaemia.

Burroughs Wellcome's ruling on Campath-1H posed a major dilemma for Waldmann and his team. Their key problem was how to maintain supplies of the drug for use by clinicians conducting BMTs, who were reporting significant benefits with the drug. Indeed, the they receiving requests for the drug every week from physicians around the world. Keeping the commercial development of Campath-1H alive was not only vital to this clinical work, but for transforming the drug from what was currently an exciting research project into one that could become part of widespread use.

Whenever a company terminates the development of a drug, that product receives a black mark. This is based on the assumption that the discontinuing company, already having made significant investment, would only abandon a product if it truly lacked promise. The situation was no different for Campath-1H. The drug's attractiveness to other companies was further hindered by the fact that at this stage a US patent for Campath-1H, covering the world’s largest pharmaceutical market, also looked highly unlikely.

Based on a review of its continuing investment in Campath-1H, BTG agreed to continue supporting its development and launched efforts to re-package it. The drug would have little future if Wellcome merely returned the original rights it had licensed to it. Ideally, BTG needed to gain access to the additional patents, data, materials and expertise Wellcome had gathered over several years in the course of their development of the drug. Such information would help BTG in its presentation of Campath-1H as an attractive commercial opportunity to new partners. Wellcome was naturally wary of such a proposition. The question was how to hand over such material while continuing to protect the confidentiality of the hard-won technology so as to retain it for use in the future development or manufacture of other monoclonal antibody products.

This shows Tim Springer whose work underpinned the original founding of LeukoSite. Funded by the National Institutes of Health, Springer's work focused on cell adhesion molecules located on the endothelial cell surface, a thin lay of cells that line the interior surface of blood vessels and lymphatic vessels, that play a part in the process of inflammation. Credit: Tim Springer.

The complex task of negotiating with Wellcome was undertaken by BTG's Roger Harrison, who was head of BTG's oncology department and responsible for licensing Campath. After some months of discussion, Harrison successfully obtained from Wellcome the necessary clinical data, know-how and other intellectual property for the manufacturing and process development for the production of Campath-1H, as well as patents for additional medical applications.

At the same time as re-structuring the commercial prospects for Campath-1H and strengthening its patent position, Harrison began hunting for a new commercial licensee. He quickly realised that the most suitable partner would be a small biotechnology company, for whom the prospects of a drug addressing a relatively small niche commercial market would be more attractive than for a big pharmaceutical company that was focused on licensing potential blockbuster drugs. If Campath-1H could be first developed in a niche indication, Harrison believed, it could eventually be proven to be of use in other more common diseases, thereby expanding its market potential.

One company Waldmann suggested Harrison approach was LeukoSite. It was a small biotechnology start-up based in Massachusetts, USA, that had been founded in 1993 to commercialise the work of Tim Springer, an American biochemist based at Harvard University. Springer had worked closely with Waldmann at the LMB in the late 1970s, and had invited Waldmann to sit on LeukoSite's scientific advisory board. Helped by seed funding from the venture capital company Healthcare Ventures, LeukoSite was already supporting Waldmann's research, having committed a large proportion of its start-up capital, US$1 million, towards the relocation and building of the TAC in Oxford. In return for its partial funding of the new centre, LeukoSite had licenses to other non-Campath monoclonal antibodies developed at Oxford University and could call on the Centre to help develop their own monoclonal antibodies. Waldmann and the TAC were an invaluable resource for LeukoSite not only in terms of advice, but also provided manufacturing and testing capabilities which it did not possess.

With Harrison's encouragement, Waldmann contacted Christopher Mirabelli, LeukoSite's chief executive officer, to discuss Campath-1H. Mirabelli had little knowledge of the drug because most of the work LeukoSite had done with Waldmann and TAC, up to this moment in time, had been directed towards other monoclonal antibodies. Nonetheless, Mirabelli, on hearing of Wellcome's abandonment of Campath-1H, quickly agreed for LeukoSite to take over the commercial development of the drug. What persuaded him to make this move were the encouraging results reported from the trial using Campath-1H to treat B-cell CLL. Mirabelli's decision was a bold one that was full of risk. Not only had other companies eschewed licensing Campath-1H, but B-cell CLL bore no relation to LeukoSite's own drug development disease portfolio, which at this time was focused on cell adhesion molecules for autoimmune disorders.

Overall, CLL was not a profitable proposition given the small proportion of the population affected by the condition. By the 1990s CLL was the most prevalent form of adult leukaemia, accounting for 25 per cent of all leukaemias, but on average it occurred in only about 120,000 patients annually in the US and Europe. Such a small disease niche area, however, provided certain advantages to LeukoSite. It made Campath-1H eligible for what is known as orphan drug status. Orphan drugs, because they are intended for only a small number of patients and therefore minimal profits, are assigned high priority in many countries. Any companies involved in the development of orphan drugs are not only entitled to reduced taxes, but have access to faster marketing approval from regulatory authorities. The other attraction of Campath-1H, was that it could tap into a potentially a ready market: few alternatives were then available for CLL patients who failed to respond to first and second-line treatments.

Licensing Campath-1H to LeukoSite was a major gamble for BTG. It had no guarantee that LeukoSite would give the drug the sufficient priority needed for furthering its development, nor that it had the resources to develop it adequately. LeukoSite was still a small-start up company and did not have a long track record in drug development. After going through due diligence, however, BTG granted LeukoSite a license to Campath-1H, in April 1997. The license was structured so as to allow LeukoSite to develop the drug for CLL first, with rights to extending it in other disease indications. Among the conditions LeukoSite was entitled to explore, was the use of the drug for multiple sclerosis (MS), organ transplant rejection, rheumatoid arthritis and other cancer conditions. If found effective for such conditions, LeukoSite would gain access to very lucrative markets. The agreement provided LeukoSite with a low-cost route to initiate development, with both parties standing to share the benefit later as confidence in the drug increased.

This shows Christopher Mirabelli, a molecular pharmacologist by training, who was the first and only chief executive officer of LeukoSite. Credit: Christopher Mirabelli.

LeukoSite's decision to prioritise CLL first was done on the basis that this provided the easiest route to generating an approvable drug and the cash it would require to support its development for other diseases. In May 1997, LeukoSite entered a joint venture with Ilex Oncology, a drug development company co-founded in 1994 by an academic oncologist Daniel Von Hoff and Richard Love a biotechnology entrepreneur and chemical engineer. Head-quartered in San Antonio, Texas, Ilex Oncology brought to the partnership the necessary expertise in both cancer and clinical trials that LeukoSite required.

In addition to partnering with Ilex, LeukoSite established a supply contract with the German pharmaceutical company Boehringer Ingelheim for the manufacture of Campath. This was vital, because LeukoSite lacked the appropriate infrastructure for such production. Boehringer Ingelheim had a strong record in the production of biological drugs, having built its first large-scale plant for biopharmaceuticals based on cell culture in 1985. This had been set up with the help of Genentech for the manufacture plasminogen activator tPA for the treatment of heart infarction.

For Boehringer Ingelheim, Campath-1H was just one of a number of monoclonal antibody therapies it was contracted to produce for a variety of companies. With the help of BTG, LeukoSite arranged for Wellcome to transfer all of its manufacturing know-how and cell lines to Boehringer Ingelheim's manufacturing plant in Biberach. From 1994 onwards, Boehringer Ingelheim took responsibility for all the manufacturing and supply of Campath-1H for clinical trials and the market, which it still does to this day.

By 1997 LeukoSite and Ilex had sourced an additional partner to help in the marketing of the drug. This was important as neither company possessed the necessary sales force for promoting and distributing the drug should it win regulatory approval. Creating a sales force internally before the drug had won approval was a highly risky proposition. LeukoSite and Ilex entered a marketing partnership with Schering AG in August 1999. Under the agreement, Schering AG was granted exclusive worldwide rights to the development and distribution of Campath-1H with the exception of Japan and Asia, which was retained by LeukoSite and Ilex. Schering paid US$30 million upfront and provided US$30 million to LeukoSite and Ilex. The transaction marked the first time a major pharmaceutical company was willing to split profits equally between two biotechnology collaborators.

In August 1997, LeukoSite went public, raising approximately US$17 million. The following year, in April, LeukoSite and Ilex initiated the first joint clinical trial of Campath-1H. Involving 20 centres in the US and Europe, by June 1999, the trial had gathered clinical data from 93 patients. Of these, two had experienced a complete recovery and 29 had partially recovered. This represented a positive response rate of 33 per cent. A further 55 patients had experienced a stabilisation of their disease (59 per cent). Based on this, LeukoSite and Ilex started preparing an application to submit for the regulatory approval of Campath-1H.

Click here to see data from the clinical trial.

Soon after starting the process of applying for regulatory approval, LeukoSite was approached with a merger offer by Millennium Pharmaceuticals, a biotechnology company founded in 1993. The proposition offered major advantages to both parties. While LeukoSite now had on its hands a drug with proven efficacy for CLL and positive prospects for market approval, it did not possess the tens of millions of dollars it would need for developing the drug for other indications. By contrast, Millennium possessed a large amount of capital, having net $58 million in 1996 through its initial public offering, but very little in its drug development pipeline. Millennium also had a greater number of staff who could help in extending the development of Campath-1H. While LeukoSite had about 100 employees, Millennium had more than 1,000. LeukoSite's executives and shareholders decided to accept Millennium's offer, realising that combining resources provided an invaluable means to further the commercialisation of Campath-1H.

The merger was finalised in 1999, with Millennium paying US$750 million in stock for the acquisition of LeukoSite. At the time, Campath-1H was expected to have a revenue stream of no more than $150 million per year. Millennium was expected to share the profits from the drug with the two other companies involved in its development. Following the merger, LeukoSite's market valuation increased substantially. At the time of its founding, in 1993, LeukSite had been valued at US$16 million, this had risen to US60 million by 1997 when it went public. Within six months of merging with Millennium, LeukoSite's market value had increased to between US$1 to 1.5 billion. Much of this value rested on the high expectations surrounding Campath-1H.

Following LeukoSite and Millennium's merger, the clinical development of Campath-1H was continued by Millennium together with Ilex. In December 1999, the two companies submitted their Biological Licenses Application to the US Food and Drugs Administration for approval in the treatment of B-cell CLL patients. This was done on the basis of three single arm studies, consisting of 149 patients. One of theses studies, known as 211, was pivotal to the application. Conducted at 22 centres in the US and Europe, this trial involved 93 patients whose previous treatments had failed.

In December 2000, the FDA's Advisory Committee recommended the approval of Campath-1H, which was granted in May 2001 for patients with CLL who had been treated with alkylating agents and had failed dludarabine therapy. A few months later, in July 2001, the drug was approved for use in Europe, to be marketed as MabCampath. The approval was for use as a third-line treatment, that is for patients whose previous therapies had failed to work.

Click here to see Advisory Committee's recommendation and the FDA approval letter, 2001.

Soon after Campath was given market approval for third-line treatment of patients with CLL, Ilex Oncology executives found themselves in negotiations for a merger with Genzyme, a biotechnology company founded in 1981 to develop drugs for patients with rare disorders. One of drivers in Genzyme's bid for Ilex was to gain access to Campath-1H, which its executives believed could boost their then fledgling oncology drug programme. Ever since the 1990s, Genzyme's managers had been looking for a way to diversify the company's disease portfolio and products and had begun investing in, among others, the development of gene therapies and vaccinations for the treatment of cancer. Yet, despite five years of research and an outlay of between US$70 and US$80 million, this internal oncology programme had been largely unsuccessful. None of the oncology products the company had developed internally had progressed beyond phase I clinical trials.

Possessing strong financial resources, Genzyme decided to change direction and started hunting for an oncology portfolio to acquire from outside. To this end, in 2003 its executives undertook a survey of about 300 companies with potentially lucrative cancer treatments. Their decision to acquire Ilex had been born out of this search. Ilex was particularly appealing to Genzyme given that Campath-1H had by now already been on the market for two years for third-line treatment of B-CLL and had an estimated market value of about US$50 million. Moreover, ongoing trials with the drug looked promising for use of the drug in first-line treatment of B-CLL and for other disease indications.

This shows Mark Enyedy, who joined Genzyme in 1996 and was responsible for overseeing corporate collaborations, mergers and acquisitions. From July 2003, Enyedy oversaw Genzyme's oncology division. Credit: Mark Enyedy.

Genzyme's acquisition of Ilex Oncology was finalised in 2004 for US$1 billion. As a result, the development of Campath-1H was passed over to yet another company. Under the agreement, Genzyme was to continue the joint venture started by Ilex with Schering AG for the development of Campath-1H for indications other than CLL, including MS. The collaboration would continue when Bayer and Schering merged in 2006 to become Bayer Schering Pharma. In 2009, Genzyme bought the worldwide rights to Campath-1H from Bayer Schering Pharma.

One of the people in Genzyme who played a pivotal role in the acquisition of Ilex and ensuring the continuing development of Campath-1H was Mark Enyedy. One of his first challenges was to convince clinicians and regulators to move beyond the use of the drug as third-line treatment for B-CLL to its use as a first-line treatment. Positioning the drug as a first-line treatment, he realised would help expand the drug's market potential and profitability. Such a move, however, was not going to be easy. Most clinicians were greatly wary of the drug because of its toxicity and risk of causing patients greater greater susceptibility to infections. Indeed, physicians tended to view the drug as only a last resort in treatment.

In part, the clinicians' negative attitude towards Campath-1H reflected the fact that few of them knew how to manage the infections induced by the drug. Enyedy and his team quickly turned their attention to addressing this issue. What they had on their side was the fact that trial data suggested a patient's susceptibility to infection lessened if Campath-1H was administered earlier in the course of their disease. Any resulting infections had also been shown to be easily controlled with the use of antibiotic prophylactics. Based on the clinical data, Enyedy and his colleagues launched an education programme to teach clinicians about the administration of Campath-1H and management of any infections it induced.

This shows the revenue BTG earned from the license for Campath-1H from the time of its first marketing approval in 2001 through to 2011. Such revenue came from the royalties accrued from sales of the drug. Revenue figures not available for 2008. Credit: BTG, Annual Reports.

Enyedy and his team's efforts to persuade clinicians to prescribe Campath-1H were further enhanced by data collected from an international, multi-centre, randomised, open-label, phase III clinical trial sponsored by Genzyme. Known as the CAM 307 trial, the aim of this study was to study the efficacy of Campath-1H for first-line treatment of B-CLL. Launched in 2001 and completed in 2004, the trial compared Campath-1H with chlorambucil, a standard first-line treatment for the disease. Out of the 297 patients recruited to the study, 147 were randomly assigned Campath-1H and the remaining 148 chlorambucil. Results from the trial, officially reported in 2007, suggested that Campath was more effective than chlorambucil, with Campath-1H reducing the risk of disease progression or mortality by 42 per cent. In summary, the data indicated that while there were significant risks with Campath-1H, particularly in raising patients' susceptibility to infections, the benefits of the drug mitigated the frequency and severity of such risks.

In addition to providing data on how to administer Campath-1H and handle any resulting infections, the CAM 307 trial had conducted genetic profiling of patients which helped determine who would most benefit from Campath-1H. As early as 1999, B-CLL patients who had a defect in their p53 gene, known as 17p deletion, had been observed to be less likely to benefit from cholarmbucil and flurabine, the standard treatment, and that these patients fared better with a high-dose cortiocosteroids. Such patients constituted about a third of all B-CLL patients. Encouragingly, results from the CAM 307 trial suggested that patients with the best response to Campath-1H were those identified as having the 17p deletion. The identification of these patients was helped by a purpose-made diagnostic developed by Peter Hillmen at Leeds University.

Based on the results from the CAM 307 trial, Genzyme applied for a supplementary approval from regulatory authorities for the marketing of Campath as a first-time of treatment for B-CLL. This was granted by the FDA in September 2007 and by the EU regulatory authorities in December 2007.

Click here to see BTG's press releases announcing the results of the trial that resulted in the supplementary approval of Campath-1H.

The new approvals expanded the drug's potential sales substantially. In 2010, the B-CLL therapeutics market in G8 countries was valued at US$437 million and was expected to grow by 13 per cent per year between 2015 and 2020. Campath-1H was reported to be the leading drug on the market for the disease, accounting for 42 per cent of the share. In January 2013, the annual sales of the drug were estimated to be US$76 million.

With Campath-1H having changed so many hands during the course of its development, what had been important was the custodial role taken by BTG to ensure it survived. Throughout the many years of the drug's commercial development and multiple new partnerships, BTG continued to strengthen the drug's patent position, amend license agreements as necessary to reflect changing circumstances, and actively monitor the progress of commercial development to ensure diligent development.

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