[First revision of this article published 9/7/99]
When LeukoSite Inc., joint venture partner Ilex Oncology Inc., and German pharmaceutical company Schering AG announced plans to distribute and develop Campath-1H in late August, they shone the spotlight on this investigative drug's impressive accomplishments. It's got all the hallmarks of a rising star on the pharmaceutical stage -- in fact, it's proven so effective in treating patients with refractory chronic lymphocytic leukemia (CLL), an often deadly adult cancer, that the drug's sponsors are submitting a BLA based on Phase II data. That's a rare event in the annals of the U.S. drug approval process. The FDA's granted Campath fast-track status, too, so it could be approved and on the market well before this time next year.

But while Campath may be standing center stage today, it wasn't always so. In fact, its life story is filled with as many twists and turns as a good adventure tale -- and the ending hasn't even been written yet. Today it's a major star, but it's had smaller roles throughout its 20-year history. And, though one drug company abandoned it, Campath's always had its champions. And therein lies the tale.



Campath, a humanized monoclonal antibody directed against the CD52 antigen found on B- and T-lymphocytes, started its life in the laboratories of Herman Waldmann, then a professor of pathology at the U.K.'s University of Cambridge (thus the name CAMbridge PATHology). Back in 1979, Campath was the name for a family of antibody molecules, initially raised in rats. Campath-1H, the humanized form, was only one of them (but then, that's another story in itself).

Suffice it to say, studies on this family of antibodies have occupied the last 20 years for Waldmann, his academic collaborators and clinical associates. Waldmann's group has conducted numerous small clinical studies, as have the many clinical collaborators throughout the U.K. and Europe. "My lab was involved in the first leukemia treatment, the use of Campath in bone marrow and kidney transplantation, and in multiple sclerosis," Waldmann said.

According to Geoffrey Hale, who actually characterized the first Campath-1 antibodies in Waldmann's lab, over those 20 years, about 2,000 individuals have been involved in Campath's development -- and another 4,000 patients have participated in the clinical studies. These numbers come from the academic side of the equation, too: They do not include the work conducted or published by drug company sponsors.

Hale is currently the research director at the Oxford Therapeutic Antibody Centre, where Waldmann holds the post of clinical director. (Waldmann is also the head of the pathology department at the University of Oxford). With all these small clinical studies going on, lots more antibody was needed than could be made in the lab. So, in 1990, Waldmann and his group set up The Therapeutic Antibody Centre in Cambridge to produce clinical trial quantities of therapeutic-grade antibody. The Centre was funded mainly by a grant from the MRC, though Wellcome also contributed some funds.

Waldmann's scientific endeavors, including virtually all the early clinical studies, were funded by the U.K.'s Medical Research Council (MRC), the Kay Kendall Trust and other charitable organizations. In the early '80s, universities had no technology transfer offices to facilitate the commercial development of inventions arising from academic labs. But, even earlier, in 1949, the U.K. government had created the National Research and Development Council (NDRC) to act as its tech transfer arm. In the early '80s, the NDRC became the British Technology Group (now BTG plc), which was privatized in 1992 when it was acquired by its staff and management.

"In 1980 or so we offered BTG the opportunity to patent the Campath-1 family of antibodies," Hale said. BTG subsequently licensed several Campath antibodies to the Wellcome Foundation: The first of these were the rat antibodies. "When the humanized version (Campath-1H) came along, we filed a series of patents on them and included them in our license to the Wellcome Foundation," according to Roger Harrison, the head of BTG's oncology business unit.




After BTG licensed Campath to The Wellcome Foundation Ltd., Wellcome took Campath into the clinic, testing it in a broad range of diseases, including rheumatoid arthritis, non-Hodgkin's lymphoma, chronic lymphocytic leukemia and solid organ transplantations. (The monoclonal antibody is directed against an antigen that is expressed almost entirely on lymphocytes, but not on hematopoietic stem cells, making these particular diseases obvious choices. If the leukocytes are destroyed, then the stem cells are critical to restoring normal immune function.)

And Campath does, indeed, deplete lymphocytes. But, as Burroughs Wellcome (a subsidiary of Wellcome) concluded, this could be too much of a good thing. In rheumatoid arthritis, for instance, the Phase I/II trial results suggested that the degree of lymphocyte depletion was too great for chronic therapy. Also, in the Phase I/II non-Hodgkin's lymphoma trial, Burroughs Wellcome detected signs that use of the drug might increase the risk of opportunistic infection and it was apparently not efficacious enough to be used as a stand-alone therapy or first-line treatment. "Wellcome's principal interest was in rheumatoid arthritis (RA)," said Augustine Lawlor, LeukoSite's VP of corporate development and CFO. "It showed efficacy but also had a side effect profile that was acceptable for cancer but less so for RA patients."

By 1994, Burroughs Wellcome had discontinued the trials; the following year, it returned all rights to BTG. This decision was reached well before Wellcome and Glaxo merged in early 1995, explained BTG's Harrison. When BTG regained rights to Campath, however, it got more than it gave: Under the terms of its agreement, it now had clinical data, know-how and other intellectual property originating from Wellcome.


BTG spent considerable effort seeking a new partner for Campath, but finally found a match when it was introduced to LeukoSite by Waldmann. It was LeukoSite's founder, Timothy Springer, also an academic associate of Waldmann's, who had brought the professor on board as one of the original members of LeukoSite's scientific advisory board.

There were stronger ties, though. When Waldmann moved from Cambridge to Oxford, "LeukoSite and the MRC contributed to a facility" similar to the Therapeutic Antibody Centre that had been established in Cambridge, Waldmann said. The aim of the new center was to provide clinical quantities of antibody, but after Wellcome dropped out of the picture, it was in danger of being the only source of Campath-1, "clearly beyond our resources or mandate," added Hale.

The new center needed an industrial partner and it found one in LeukoSite. "In return for their partial funding of the facility, the University [of Oxford] and the MRC agreed that LeukoSite would then have access to information from these studies, which enabled them to approach the University for licenses on other (non-Campath) antibodies," Waldmann explained. One of those is LDP-01, a humanized monoclonal antibody to the b2 integrin on leukocytes, which LeukoSite now has in the clinic for stroke, added Christopher Mirabelli, the biotech company's chairman and CEO.

As to the Campath license? According to Mirabelli, "Waldmann told me that Burroughs Wellcome was likely not to go forward [with the clinical development of Campath]. We saw a real opportunity there." The Cambridge, MA company's principals had already reviewed masses of clinical data -- including the published data from some of Wellcome's clinical trials on Campath in patients with relapsing or refractory CLL. The partial and complete remission rates were high enough to convince LeukoSite of the drug's potential. Plus, this drug would fill an important need, since there is no available therapy to treat CLL patients who have failed first and second-line therapy with chlorambucil and fludarabine.

LeukoSite also received options (which it has now exercised) to license from BTG the rights to use Campath in other disease indications -- multiple sclerosis, organ transplant rejection, rheumatoid arthritis and other (undisclosed) cancers. CLL affects a modest number of individuals -- about 120,000 annually in the U.S. and Europe. If Campath were to be found effective in these additional indications, however, the market opportunities would expand considerably.

"BTG is much more than a licensor; it's been quite a partner," Lawlor said. "All the clinical data, as well as the manufacturing and process information have been transferred to LeukoSite." And that information will play a supportive role in the BLA, he added.



1997 was a busy year for Leukosite: It licensed Campath from BTG in April, formed a joint venture to develop the product with Ilex Oncology in May and completed an IPO in August. It had the money (about $17 million from the IPO), the product and the clinical development partner. And then it went to work.

LeukoSite and Ilex initiated a pivotal clinical trial of Campath in CLL in April 1998. It was designed to enroll 50 to 100 patients in the U.S. and abroad who had failed standard second-line (fludarabine) therapy. (Not coincidentally, several members of Ilex's senior management had been involved directly in the development of fludarabine for treating CLL before they joined Ilex.) This was a small, Phase II trial, but it was designed to build on the earlier body of clinical data generated by Burroughs Wellcome -- and to support a BLA submission.

By June 1999, the partners had the final data from this trial, which they presented at the 4th Congress of the European Hematology Association in Barcelona, Spain. Of 93 evaluable patients, two had complete responses (remissions) and 29 had partial responses, giving an overall response rate of 33 percent. Another 55 patients (59 percent) had disease stabilization. The companies have already submitted sections of the "rolling" BLA to the FDA; the only one left is the clinical section, which should be in the FDA's hands before the end of the year.

If the FDA approves the drug, German pharmaceutical company Schering AG and its U.S. affiliate Berlex Laboratories Inc. will be there to distribute and market it everywhere except Japan and East Asia. Schering will pay up to $30 million for these rights and for regulatory milestones in the U.S. and Europe.

It seems to be a perfect match: The biotech companies get an experienced sales force for the product and Schering gets another CLL drug -- which it can market to the same patient population that's failed therapy with its other CLL drug, fludarabine (Fludara). Moreover, the biotechs will share profits with Berlex on U.S. sales (each gets one-third) and get hefty royalties -- equivalent to the rate of profit-sharing -- from Schering on sales elsewhere

The real excitement behind this deal, however, lies in Campath's future possibilities. Since Leukosite has now gained the rights to develop Campath for multiple sclerosis (MS), solid organ transplantation and other oncology indications, the potential marketing opportunities could mushroom.

That's a winner for all parties. For BTG, which has found first one, then another, drug company to develop Campath into an approved therapeutic, revenues could increase substantially. It's already slated to receive $2.8 million in payments this fiscal year and gets royalties on product sales. But it could get much more. In fact, CEO Ian Harvey predicts that Campath could be as big a money-maker for BTG as BeneFix (Genetics Institute's recombinant factor IX for treating hemophilia B), for which BTG already gets $10 million per year in revenues.

LeukoSite and Ilex will receive funding for new R&D programs, milestones and profit-sharing arrangements similar to those just arranged. Schering gets a greater market presence in multiple sclerosis as well as a deeper oncology portfolio. And patients get more treatment options.




Editor's note: This article has been revised to more accurately portray the role that Professor Waldmann and his academic collaborators and associates have played in Campath's development.

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Model: Loreen de Graves
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