@ © 1998 Nature Publishing Group http://www.nature.com/naturebiotechnology
`COMMENTARY
`
`THERAPEUTICS
`
`Genentech is poised for an anti-cancer breakthrough
`
`Russ Hoyle
`
`Ever since the freewheeling G. Kirk Raab was
`forced to step down three years ago as head of
`Genentech (S. San Francisco, CA), his succes-
`sor Arthur D. Levinson has been under pres-
`sure to beef up the company’s research and
`development programs and produce exciting
`new product lines.
`Levinson has gotten off to a good start.
`Genentech, which was bought out by
`Hoffman-LaRoche (Basel)
`in 1990, began
`marketing Rituxin,
`the
`only
`federally
`approved monoclonal antibody for the treat-
`ment of cancer,
`last November. With the
`announcement
`this September that a US
`Food and Drug Administration (FDA;
`Rockville, MD) advisory committee voted to
`approve Genentech’s experimental Herceptin
`monoclonal
`antibody,
`Levinson
`and
`Genentech are now poised for another
`impressive therapeutic breakthrough for
`late—stage treatment of breast cancer. The
`FDA is expected to approve Herceptin by the
`end of the year.
`For Levinson, the timing could not be
`more serendipitous. When he took over the
`company in 1995, what was then known as
`Her2 was among the hottest new properties
`in Genentech’s pipeline. It was also believed
`that Levinson’s fate would probably depend
`on
`how successfully
`he
`beefed
`up
`Genentech’s flagging research programs and
`brought
`innovative new pharmaceutical
`products to market. Under the terms of the
`buyout, Hoffman-LaRoche, which owns
`67% of Genentech,
`is due to exercise its
`option to purchase 100% of the company
`next year.
`The development of an effective mono-
`clonal antibody targeting the HER2 onco—
`gene, a marker for the fatal spread of late-
`term breast cancer, has been a result of deter-
`mined and exacting scientific research that
`began on Raab’s watch. Under Levinson’s
`leadership, Genentech has also developed a
`knack for cooperation with the cancer com—
`munity and a cool capacity for taking advan-
`tage of a changing regulatory climate.
`As early as the mid—19805, attempts to use
`monoclonal
`antibodies
`to treat
`cancer
`
`seemed promising. Early efforts to make
`monoclonal antibodies involved injecting
`antigens into mice on the theory that the
`resultant antibodies would block cancerous
`
`cell growth. These attempts failed due to the
`unanticipated fact that bits of protein mole-
`cule from the mice acted as antigens in
`humans, triggering immune responses that
`destroyed any therapeutic effects.
`
`For the better part of a decade, the excite-
`ment over monoclonal
`therapies cooled.
`Then researchers figured out how to replace
`the problematic mouse-contaminated por-
`tions of molecules with replacement material
`from human proteins. Genentech’s new
`“humanized”
`experimental monoclonal
`antibody therapy targeted the growth factor
`receptor gene HER2/hen, which was known
`to proliferate on the surface of cancerous
`breast tissue cells in deadly late-stage cases of
`the disease. The antibody worked by attach-
`ing itself to the HER2 receptor, blocking the
`genetic signals that cause diseased cells to
`reproduce and in some cases killing off the
`cancer cells.
`
`The potential market was small, but in
`dire need. Some
`1.6 million American
`
`women currently have breast cancer. There
`are 180,000 new cases in the US. each year.
`Of the roughly 164,000 metastatic cases,
`some 25—30% involved overexpression of the
`HER2 gene. As early as 1995, Genentech was
`swamped by demand for the highly targeted,
`yet—to-be-approved new drug and teamed up
`with patient advocacy groups to design a lot—
`tery system to equitably distribute a limited
`supply of the investigational drug to severely
`affected patients.
`But it wasn’t until 1996, less than a year
`after Levinson had taken the reins from Raab,
`that Genentech announced favorable results
`
`of the initial tests of its experimental therapy.
`At an April scientific meeting, Genentech
`clinical researcher Thomas Twadell reported
`that 5 of 44 women treated with the new anti—
`
`HERZ antibody alone experienced significant
`tumor reduction. In combination with other
`
`chemotherapy, positive responses occurred in
`nine out of 36 cases, or 25% of those treated.
`More than a year later, in December 1997,
`Genentech announced “favorable” prelimi-
`nary results of phase III clinical
`trials.
`Levinson declared that
`the studies “have
`shown that the Herceptin monoclonal anti-
`body may result in both slowing the progres-
`sion of the cancer and increasing the percent-
`age of woman who experience tumor shrink-
`age.” He was careful to add that Herceptin
`was “not a cure,” but emphasized that the
`encouraging results suggested that “better
`control of the disease is possible.” In short
`order the company announced that it would
`file with the FDA for fast track approval of
`Herceptin, taking advantage of a new law
`passed by Congress earlier that year.
`From that point on, the pace picked up
`considerably. This past March, Genentech
`
`announced a deal with DAKO AIS (Glostrup,
`Denmark) to develop a diagnostic kit
`to
`screen patients for overexpression of the
`HER2 receptor for FDA approval. In May, the
`FDA granted fast track status to Herceptin.
`The fast track application, said Levinson,
`marked “a massive effort on the part of
`Genentech, the clinical trial investigators and
`staff, breast cancer advocates, researchers and
`the FDA to evaluate this novel treatment as
`
`rapidly as possible.”
`Two weeks later, on May 17, the prelimi-
`nary data from the phase III clinical trials
`were reported at the annual meeting of the
`American Society on Clinical Oncology.
`They were
`impressive
`(Nat. Biotechnol.
`16:615, 1998). The randomized, controlled
`study of 469 women with metastatic breast
`cancer showed that 28% of women treated
`
`with Herceptin showed no progression of the
`disease for 7.6 months after treatment began,
`compared with 4.6 months for chemothera-
`py alone-a dramatic 65% increase.
`Combining Herceptin with chemothera-
`py resulted in tumor shrinkage of 50% or
`more in 49% of the patients, compared to
`32% in patients who underwent chemother-
`apy alone. The results were particularly
`encouraging
`in
`combination
`with
`chemotherapy using paclitaxel, a form of
`taxol. A second study of 222 patients found
`that 16% of women, who had been previous-
`ly treated with conventional chemotherapies,
`showed major tumor reductions for nine
`months after using Herceptin alone.
`Although last month’s favorable recom—
`mendation by the FDA’s Oncologic Drugs
`Advisory Committee is not binding, most
`observers
`expect
`the FDA to approve
`Herceptin
`for
`commercialization
`by
`November. Right now,
`the reality is that
`breast cancer patients who Overproduce
`HER2 can now expect to live some 10 to 12
`months after metastasis begins, a horribly
`rapid progression compared to six or seven
`years for HER2—normal patients. Genentech
`has teamed up with the National Cancer
`Institute to expand its Herceptin access pro-
`gram across the nation and has vowed to pro—
`duce an “adequate” supply of the drug by this
`fall anticipating FDA approval.
`As anyone familiar with terminal cancer
`knows, a few extra months of coherent, pain—
`free life is tantamount to the Holy Grail.
`Barring any surprises, Genentech’s Levinson
`should be credited for showing the pharma-
`ceutical biotechnology industry how to get
`the job done.
`M
`
`NATURE BIOTECHNOLOGY VOLUME 16 OCTOBER 1998
`
`Celltrion v. Genentech
`
`887
`
`IPR2017—01122
`
`Genentech Exhibit 2018
`
`