N E W S
`
`Buzz around Campath proof-of-concept trial in Ms
`
`when it was approved. The notion
`that Campath might also work as
`a treatment for MS was pioneered
`in 1991 by Alistair Compston, at
`Cambridge University, UK, also the
`lead investigator in the recent New
`England Journal of Medicine study
`(N. Engl. J. Med. 359, 1786, 2008). He
`speculated that the antibody might
`work by destroying the mature T
`and B lymphocytes that drive the
`autoimmune attack against nerves
`and brain tissue in MS patients.
`After treatment, the immune sys-
`tem would be replenished, but this
`time, without the auto-reactive
`lymphocytes.
`The strategy is indeed promising.
`Results from the latest study, funded
`by Cambridge, Massachusetts–
`based Genzyme and partner Bayer
`Schering, of Leverkusen, Germany,
`look “extremely attractive,” says Jerry
`Wolinsky, who directs the Multiple
`Sclerosis Research Group at the
`University of Texas Health Science
`Center in Houston.
`In the phase 2 trial, known as
`CAMMS223, Campath was adminis-
`tered once yearly to 334 previously untreated
`individuals with early relapsing-remitting
`MS. This regime cut patients’ risk of relapse
`by 74% and reduced the rate of sustained
`accumulation of disability by 71%, compared
`with patients treated with the standard treat-
`ment Rebif, a high-dose interferon β-1a from
`
`Mehau Kulyk/science Photo Library
`
`An MRI brain scan shows lesions attributable to multiple sclerosis,
`which were reduced in people taking the experimental drug
`Campath.
`
`When news broke in October that
`an approved cancer therapy had, for
`the first time, halted the progress of
`multiple sclerosis (MS), excitement
`was tangible among clinicians and
`patient groups. The phase 2 study’s
`results are certainly unprecedented
`in MS. But whether Campath (alem-
`tuzumab), a monoclonal antibody
`(mAb) already approved to treat
`leukemia, actually ‘reverses’ MS, as
`some news stories in the mainstream
`media trumpeted, and how it works
`remain unresolved. The next two
`years are expected to reveal much
`about not only Campath in MS, but
`also the competitive landscape for
`this indication where the tradeoff
`between efficacy and safety remains
`a tough hurdle for drug developers.
`Campath was the first humanized
`mAb to be developed as a therapy. It
`has a long, illustrious history, dat-
`ing back over two decades to anti-
`lymphocyte rat antibodies first
`raised by Herman Waldman and
`Geoffrey Hale (Mol. Biol. Med. 3,
`305–319, 1983). The name Campath
`derives from the pathology depart-
`ment at Cambridge University, UK, where
`the academics worked.
`The monoclonal was raised to target
`B and T cells and was initially pursued as
`treatment for graft-versus-host disease.
`However, Campath took off as a therapeu-
`tic only when Greg Winter and colleagues,
`
`also at Cambridge University, humanized the
`recombinant DNA-derived antibody, which
`became known as alemtuzumab.
`Campath targets the cell surface glyco-
`protein CD52 present on all mature lym-
`phocytes and has been used to treat B-cell
`chronic lymphocytic leukemia since 2001
`
`SeleCTeD research collaboration
`
`Partner 1
`ImmuPharma (London)
`
`Partner 2
`Cephalon (Frazer, Pennsylvania)
`
`$ (millions)
`500
`
`Shenzhen Neptunus Interlong Bio-Technique (China)
`
`GlaxoSmithKline (GSK, London)
`
`Dyadic International (Jupiter, Florida)
`
`Codexis (Redwood, California)
`
`Galapagos (Mechelen, Belgium)
`
`MorphoSys (Planegg, Germany)
`
`78
`
`10
`
`*
`
`*Financial details not disclosed.
`
`6
`
`volume 27 number 1 january 2009 nature biotechnology
`
`©2009 Nature America, Inc. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1109 PAGE 1
`
`

`
`N E W S
`
`Status
`BLA
`Phase 3
`
`Phase 3
`
`Phase 3
`Phase 3
`
`Phase 3
`
`Phase 3
`
`MBP8298 (dirucotide), synthetic peptide ver-
`sion of a portion of human myelin basic protein
`Campath (alemtuzumab), targets CD52
`
`Cladribine (oral), purine analog, anti-neoplastic Phase 3
`
`Fingolimod, targets sphigosine 1-phosphate
`receptor
`Laquinimod, targets T lymphocytes
`Teriflunomide, targets DNA synthesis
`
`Phase 3
`
`Phase 3
`Phase 3
`
`Table 1 Selected MS therapies in late-stage development
`Developer (location)
`Drug
`Rebif (interferon β-1a), new formulation
`Merck (Darmstadt, Germany)
`Accentia Biopharmaceuticals
`Revimmune (cyclophosphamide)
`(Tampa, Florida)
`Acorda Therapeutics (Hawthorne,
`New York)
`Biogen Idec
`
`Fampridine SR (4-aminopyridine), targets
`potassium channels
`Panaclar (dimethylfumarate), targets NF-κB
`Rituxan (rituximab), targets CD20
`
`BioMS Medical (Edmonton,
`Alberta, Canada)
`Genzyme (Cambridge,
`Massachusetts)
`Merck (Whitehouse Station,
`New Jersey)
`Novartis (Basel, Switzerland)
`
`Teva Pharmaceutical (Jerusalem)
`Sanofi-Aventis (Paris)
`BLA, biologics license application.
`
`Merck Serono. Patients were followed for
`three years; those on Campath scored higher
`on a standard disability scale than before
`starting the treatment, whereas patients on
`Rebif deteriorated. The benefits were long
`lived, lasting at least three years.
`Even more striking, perhaps, are the mag-
`netic resonance imaging scans that suggest
`the drug may be reversing the symptoms of
`the disease. Imaging data revealed that peo-
`ple in the Campath arm increased brain vol-
`ume after a year, whereas the brain volume
`in the group receiving standard interferon
`experienced a decline.
`“We’re not saying people are cured,” cau-
`tions neurologist David Margolin, Genzyme’s
`lead medical monitor in the phase 2 and
`
`ongoing phase 3 program. But Campath
`patients’ disability scores improved dra-
`matically “within a few months, and this is
`not driven by just a few individuals,” adds
`Margolin, who has an MS specialty practice
`at Massachusetts General Hospital and the
`Brigham and Women’s Hospital in Boston.
`“Clearly, there is some recovery occurring,
`only in the [Campath] population as a group.
`Thirty percent of Rebif patients improved,
`but more of them worsened,” whereas
`Campath achieved “remarkable stabilization”
`of disease. The other benefit of Campath is
`its once-yearly administration.
`“It’s not reversing MS,” says Lauren Krupp,
`neurologist at Stony Brook University
`Hospital in New York and director of the
`
`Details
`Cephalon will pay a $15 million upfront payment to obtain an exclusive, worldwide license to ImmuPharma’s
`Lupuzor now in a phase 2b study for systemic lupus erythematosus. As part of the agreement, ImmuPharma
`will receive a one-off license fee, milestone payments and royalties that may total $500 million. Cephalon
`will assume all expenses for phase 3 studies and subsequent commercialization for Lupuzor, an immuno-
`modulating spliceosomal peptide recognized by lupus CD4+ T cells.
`The two companies have inked a formal cooperation agreement leading to a joint venture (JV) company worth
`$78 million in assets. The JV will seek to co-develop seasonal and pre-pandemic influenza vaccines, initially
`targeting viral strains specific to China, Hong Kong and Macau. GSK expects to contribute $31 million in
`return for a 40% stake in the JV, whereas Neptunus will contribute $47 million in assets.
`Codexis, a company developing improved biocatalysts, obtained a license to use Dyadic’s C1 expression system
`for large-scale production of enzymes utilized in biofuels and pharmaceutical intermediate production. The
`agreement includes an upfront payment by Codexis of $10 million subject to certain performance criteria.
`MorphoSys and Galapagos will co-develop novel antibody therapies to treat bone and joint diseases, includ-
`ing osteoporosis, osteoarthritis and rheumatoid arthritis. Galapagos will provide antibody targets using its
`adenoviral target discovery platform. MorphoSys will contribute its HuCal antibody technologies to generate
`fully human antibodies directed against these targets. Under the terms of the agreement, the companies will
`share R&D costs and future revenues equally.
`
`nature biotechnology volume 27 number 1 january 2009
`
`7
`
`©2009 Nature America, Inc. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1109 PAGE 2
`
`

`
`N E W S
`
`in brief
`Myriad wins BRCA1 row
`After seven years of dispute, the European
`Patent Office (EPO) has decided to uphold
`Myriad Genetics’ patent on the BRCA1 ‘breast
`cancer gene’ but in a limited form. In 2001
`patents were granted to Salt Lake City, Utah–
`based Myriad for using the genes BRCA1 and
`BRCA2 to diagnose women’s predisposition to
`breast and ovarian cancers. But international
`research institutes and genetics societies filed
`an opposition to the patents. “It became clear
`that the patent owners did not intend to offer
`licenses [to other institutions], or at least not
`at a reasonable price,” says Gert Matthijs from
`the Center for Human Genetics, University of
`Leuven, Belgium. “This [pricing issue] has
`angered the genetic community, even more than
`the idea that genes and diagnostic tests could
`be patented.” As a result, EPO revoked the
`patent for BRCA1. Myriad then filed an appeal
`requesting that the patent be maintained in a
`revised form. The November 19 ruling gives
`the patent owners the right to collect royalties
`on tests carried out across Europe, although
`the patent’s original scope has been reduced
`to cover only frameshift mutations, not BRAC1
`itself. EPO says the patent cannot be contested
`at the European level; however, it is still possible
`for opponents to go to national courts to further
`reduce the scope of the patent. Myriad’s William
`Hockett says the company is pleased with EPO’s
`decision.
`—Nayanah Siva
`
`Value-driven price deal
`Small companies and patients stand to benefit
`from the recently renegotiated Pharmaceutical
`Price Regulation Scheme (PPRS). Rather
`than the 5% across-the-board price cut to
`medicines proposed in June, the finalized deal
`recommends a pricing scheme that staggers
`and delays price cuts. PPRS is a voluntary
`agreement between government and industry
`on pricing of branded drugs supplied to the
`National Health Service (NHS). The finalized
`PPRS recommends a 3.9% price cut in
`February, followed by a 1.9% cut in January
`2010, and for small companies with sales
`up to £25 ($37.5) million in 2007, the first
`£5 ($7.5) million sales will be exempt from
`the price cut. For the first time, the UK’s
`Bioindustry Association (BIA) has been involved
`in PPRS negotiations, working closely with the
`Association of British Pharmaceutical Industry
`on aspects affecting small companies. As part
`of the agreement, companies that supply the
`NHS will be allowed to introduce drugs at lower
`initial prices with the option of negotiating
`higher prices at later stages if the clinical value
`of a product is proved. This flexible pricing
`scheme agreed upon in November will ensure
`patients have faster access to novel medicines,
`and encourage industry innovation. “This is a
`definite plus,” says Nick Scott-Ram, the BIA’s
`strategy consultant on this issue. “The PPRS is
`now taking a more value-based approach
`to everything. We have come out of 18 months
`of negotiation in a reasonable position.”
`
`—Susan Aldridge
`
`“None of these drugs are
`going to fix neurons that
`are dead and gone, but
`some probably will help to
`slow the neurodegenerative
`processes,” Margolin says.
`
`Pediatric Multiple Sclerosis Comprehensive
`Care Center, who is nonetheless guardedly
`optimistic. “You have patients with relapses
`and remissions. If you get rid of the relapses,
`then over time, it’s going to look like there
`is less [of a] persistent neurologic deficit.
`It’s just a function of the drug’s effects on
`the relapses, rather than turning the disease
`around.”
`The claims of disease reversal regarding
`Campath are still “a big stretch,” says Wolinksy,
`who points out that the extrapolations are
`made by hopeful onlookers and boosters
`and not by the drug makers Genzyme and
`Bayer Schering. “The absolute good news is,
`if we treat early and
`aggressively, we can
`expect remarkable
`outcomes, but at a
`cost for a fair per-
`centage of patients.”
`Clinicians
`and
`regulators worry
`over
`side effects,
`particularly the risk
`of developing a rare
`neurological condition progressive mul-
`tifocal leukoencephalopathy (PML), the
`brain infection that bedevils the α-4 inte-
`grin antagonist Tysabri (natalizumab), co-
`marketed by Biogen Idec, of Cambridge,
`Massachusetts, and Dublin-based Elan.
`Thus far, no cases of PML have shown up
`in MS patients exposed to Campath. Years
`of experience using Campath for chronic
`lymphocytic leukemia treatment may not
`be informative as patients with this form of
`leukemia can develop PML, independently
`of Campath.
`Despite the troubles associated with
`Tysabri, people with MS may still retain “an
`overall positive view” toward the treatment,
`says David Williams, head of business devel-
`opment for PatientsLikeMe, an online health
`community for patients with life-changing
`conditions including MS. “Campath will be
`the same way, if it’s approved,” Williams pre-
`dicts, though the risks as known so far are
`hardly identical.
`With Campath, safety issues could arise
`over a potentially fatal autoimmune disorder.
`In the phase 2 trials, 20% of Campath-treated
`patients developed thyroid disorders com-
`pared to 3% on Rebif. Krupp notes, however,
`that thyroid trouble seems to occur with MS
`anyway, for reasons that are not well under-
`stood. More serious is the development of
`immune thrombocytopenic purpura (ITP).
`Three patients in the Campath group devel-
`oped this complication and one of them died.
`“Some people would suggest management
`
`of ITP is easy, but if it were straightforward
`and easy, they wouldn’t have had the first one
`die,” Wolinsky says. Margolin notes that the
`fatal case of ITP—the first to arise —“took
`everyone by surprise,” whereas the others
`fully recovered with treatment, and one did
`so spontaneously. Krupp, for her patients,
`“would consider [Campath] in patients
`where all of those things, as bad as they
`sound, are ‘not as bad’ as what’s happening
`with their MS.”
`Other promising mAbs in late-stage
`development for MS include Rituxan (ritux-
`imab), an approved therapy for rheumatoid
`arthritis and non-Hodgkin’s lymphoma
`from Biogen and
`S. San Francisco,
`California–based
`Genentech, in phase
`3 trials (Table 1).
`Another drug cur-
`rently in phase 2
`studies is Zenapax
`( d a c l i z u m a b ) ,
`an
`immunosup-
`pressant mAb for
`organ transplants from Biogen and PDL
`Biopharma of Fremont, California. Leerink
`Swann analyst William Tanner wrote in a
`September research report that consultants
`were “not overly impressed” with Zenapax,
`holding out hopes for other compounds,
`though the safety profile of Campath may be
`of concern. Still in the game, but just barely,
`is Basel–based Novartis’ S1P1 modulator
`FTY720 (fingolimod), which has run into
`serious safety issues in pivotal testing.
`For Campath, efficacy could win over
`safety concerns. One phase 3 trial aims to
`enroll 525 patients like those in phase 2 with
`early, relapsing, remitting disease; the other
`will test relapsing MS patients and intends
`to enroll 1,200. Campath could be filed for
`approval with the FDA as early as 2011, prob-
`ably as a monotherapy. “With the findings to
`date, I don’t see any reason to add another
`drug,” Margolin says, though some neurolo-
`gists speculate that Campath might be used
`as induction therapy, to be followed by inter-
`feron or Copaxone (glatiramer).
`An ongoing debate in MS therapy is how
`the disease’s inflammatory and neurodegen-
`erative aspects overlap and what this means
`for drug developers. “None of these drugs
`are going to fix neurons that are dead and
`gone, but some probably will help to slow the
`neurodegenerative processes,” Margolin says.
`“We hope our trials will establish Campath
`as the treatment of choice, if patients are
`relapsing.”
`Randy Osborne Mill Valley, California
`
`8
`
`volume 27 number 1 january 2009 nature biotechnology
`
`©2009 Nature America, Inc. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1109 PAGE 3