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Spotlight On... Multiple Sclerosis, Sep. 2010 -- Pharma Matters Report
 

Spotlight On... Multiple Sclerosis, Sep. 2010 -- Pharma Matters Report

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Oral drugs will soon revolutionize treatment of multiple sclerosis. Until recently, the only disease-modifying agents available were the interferons, ...

Oral drugs will soon revolutionize treatment of multiple sclerosis. Until recently, the only disease-modifying agents available were the interferons,
a highly competitive drug class, but with the disadvantage of administration by injection. This report observes how this key drug franchise is evolving, and evaluates the strengths and weaknesses of the current and future players. Development of the deals landscape during this time of change is discussed, highlighting recent activity as industry heavyweights pair up for commercialization of the leading products, but also make significant investments in developmental candidates that show promise. Extracting consensus data from Thomson Pharma® Partnering Forecast, the report assesses the present market and reveals the future dynamics and competitive positioning of therapeutics in this exciting therapy area as it diversifies and transforms.

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    Spotlight On... Multiple Sclerosis, Sep. 2010 -- Pharma Matters Report Spotlight On... Multiple Sclerosis, Sep. 2010 -- Pharma Matters Report Document Transcript

    • Image CopyrIght: REUTERS/Tim WimborneSpotlight on...Multiple ScleroSiSA phArMA MAtterS report.JULY-SEPTEMBER 2010 Expert therapy area review of the key market players and deals highlights for leading areas of industry investment and development. These insightful reviews are based on the strategic data and insights from Thomson Pharma® and Thomson Pharma® Partnering Forecast. AWARDED TO THOMSON SCIENT FIC LIMITED (THE SCIENTIFIC BUS NESS OF THOMSON REUTERS)
    • ABSTRACT Oral drugs will soon revolutionize treatment of multiple sclerosis. Until recently, the only disease-modifying agents available were the interferons, a highly competitive drug class, but with the disadvantage of administration by injection. This report observes how this key drug franchise is evolving, and evaluates the strengths and weaknesses of the current and future players. Development of the deals landscape during this time of change is discussed, highlighting recent activity as industry heavyweights pair up for commercialization of the leading products, but also make significant investments in developmental candidates that show promise. Extracting consensus data from Thomson Pharma® Partnering Forecast, the report assesses the present market and reveals the future dynamics and competitive positioning of therapeutics in this exciting therapy area as it diversifies and transforms. Sales figures are correct as of July 16, 2010 For more information on Thomson Pharma and Thomson Pharma Partnering Forecast visit go.thomsonreuters.com/commercial or email scientific.lifesciences@thomsonreuters.comPHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • SECTION IAN EvOLvING MULTIPLE SCLEROSIS MARkET:THE ORAL REvOLUTIONWith impending launches of the first oral drugs for multiple sclerosis(MS), the MS market is entering an exciting phase of evolution, which will There has been a significant expansion of thesignificantly impact patients’ lives and transform the competitive landscape MS market, driven primarily by price increases,of this therapy area. new patient diagnoses in the US, and by higher penetration rates in EU markets.Since 1993, the only disease-modifying options for MS have been a rangeof interferon-based products, which are administered intravenously,intramuscularly or subcutaneously, typically with considerable discomfort.Competition has been intense between the interferon products, and wascompounded by the entry of two new injectable therapies (Copaxone andTysabri) over the last decade. Competition across the market is now expectedto further escalate as the race for the first oral MS drug approval intensifies.According to Thomson Pharma Partnering Forecast, the MS market is setto rise from $8.9 billion in 2008, to $15.6 billion in 2014, based largely onthe expected entry of several new oral therapy options, although the betainterferon brands and Tysabri will also see some growth.This rapidly evolving market is also expected to further diversify as companieswith no previous involvement enter the sector. The MS market until now hasbeen dominated by an oligopoly; Biogen Idec, Teva, Merck Serono and BayerSchering have been the leading competitors globally. However, companieslike sanofi-aventis, AstraZeneca, Novartis and Glenmark, with some ofthe most technologically advanced products in their pipeline portfolio, areexpected to start to attract the most investor attention as the market beginsto change. Indeed, Novartis is employing several strategies to enter the fieldof MS therapeutics, including in-house development, early- to mid-stagepartnering, and development of biosimilars.MULTIPLE SCLEROSIS WORLDWIDE (US$) 2008 REPORTED SALES AvONEx 25% REBIF 22% NATALIZUMAB 9% GLATIRAMER ACETATE 25% BETASERON 19%MULTIPLE SCLEROSIS WORLDWIDE (US$) 2014 CONSENSUS FORECASTS BETASERON 9% AvONEx 15% ALEMTUZUMAB 2% REBIF 14% NATALIZUMAB 9% GLATIRAMER ACETATE 26% FINGOLIMOD 7% FAMPRIDINE (ORAL, SUSTAINED RELEASE, MS / SPINAL CORD INjURy, ACORDA/BIOGEN 6% ExTAvIA 2% CLADRIBINE (ORAL, MS), MERCk SERONO 3% OTHER 7% PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • MULTIPLE SCLEROSIS: THE CURRENT MARkET The MS market has changed very little over the past 10 years. Four There is a demand for oral therapy given injectable disease-modifying drugs monopolized the landscape, with three the inconvenience of dosing of existing formulations of beta interferon (Biogen Idec’s Avonex, Merck Serono’s Rebif, injectable therapies. and Bayer/Novartis’ Betaseron) and one complex immunomodulatory peptide (Teva’s Copaxone). Copaxone became the best selling MS drug in 2008, driven primarily by the drug’s tolerability and status as the only non-interferon front-line agent. Copaxone gained its dominant market share largely through data from the REGARD and BEyOND trials, which supported efficacy equal to that of the interferons, without the associated tolerability issues. In july 2008, Momenta/Sandoz and Mylan filed ANDAs for Copaxone, which are currently being litigated and could threaten sales going forward. Copaxone is a mixture of chemically synthesized polypeptides, and although not approved as a biologic, because the multiepitopic sequences in Copaxone are not completely characterized, Teva has argued that biosimilar manufacturers will not be able to demonstrate their drug is a precise copy of Copaxone. Although the FDA considers these contentions unpersuasive, Copaxone is not expected to lose its bestseller position until 2013, even as the market starts to radically diversify with the expected entry of oral therapies in 2010. Even in the face of this competition, sales for Copaxone are expected to rise from $2.26 billion in 2008 to $3.872 billion in 2013. Avonex had been the best-selling MS drug until 2008, but despite being overtaken by Copaxone, it still remains the top-selling interferon, having performed well in the face of competition from the higher-dose interferons. Steady market share and aggressive US pricing are supporting moderate sales growth, and the product is expected to maintain its number one interferon product status to 2013, with sales rising from $2.03 billion in 2008 to $2.342 in 2013. In a further effort to support the franchise, Biogen Idec is also developing PEGylated Avonex, which prolongs the drug’s half- life and improves its ease of use to twice-monthly injections; phase III trials are ongoing. Despite Avonex’s status as the top interferon, Rebif is the fastest-growing interferon product in the franchise. Sales grew 15% in 2008 to $1.958 billion, although the total was impacted by currency. Rebif has benefited from data from the EvIDENCE trial, which established superiority for high-dose Rebif over Avonex over 12 months. According to Thomson Pharma Partnering Forecast, Rebif will see continued strongest growth within the three interferon products in the period up to 2013, rising to $2.183 billion. REPORTED AND CONSENSUS FORECAST REvENUE (MILLION US$) Copaxone Avonex Rebif Betaseron 4000 3500 3000 SALES IN US $ 2500 2000 1500 1000 2008 2009 2010 2011 2012 2013 YEAR* REPORTED CONSENSUS * Data is derived from Thomson Pharma Partnering ForecastPHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • TYSABRI: GAINING MARkET SHARE,BUT PML RISk SIGNIFICANTIn late 2004, Biogen Idec and partner Elan received first approval for Tysabriin the treatment of MS. Seemingly destined for blockbuster status, thedrug’s commercialization was halted less than three months into its launchfollowing two cases of severe progressive multifocal leukoencephalopathy(PML) reported in clinical trial patients treated with a combination ofTysabri and Avonex for more than two years. A third confirmed case wasthen reported in a Crohn’s disease patient receiving intermittent Tysabrimonotherapy over 18 months. At that time, Biogen Idec and Elan completeda full review of Tysabri’s safety throughout its entire clinical trial programand found no additional cases of PML in 3000 patients who had receivedthe drug.Tysabri remained withdrawn from the market until further analyseshad been presented to the FDA, at which point a positive FDA panelrecommendation led to its relaunch in the US in july 2006, under theTOUCH risk management program. The FDA had reviewed the impressiveefficacy data for Tysabri, and concluded the risk/benefit was acceptablewhen other therapies had failed.The drug’s approval was based upon data from the AFFIRM (Tysabrimonotherapy versus placebo) and SENTINEL (Tysabri plus Avonexcombination versus Avonex) studies. In these trials, Tysabri induceda dramatic reduction in relapse rate versus either placebo or Avonexmonotherapy. In AFFIRM, patients experienced a 66% reduction in relapserates after one year, with annualized relapse rates of 0.25 for Tysabri versus0.74 on placebo. At two years, AFFIRM demonstrated a 42% reductionin the risk of disability progression for the Tysabri treatment arm versusplacebo, eclipsing reported risk reductions for Avonex (37% reduction) andRebif (30% reduction), while Betaseron and Copaxone have never shown animpact on disease progression.Since its relaunch, Tysabri has steadily gained market share, and thedrug surpassed $1 billion in sales for the first time in 2009. By june 2010,regulators had linked the drug to 11 deaths and 55 cases of PML since it wasreintroduced in 2006, although were still recommending it remain on themarket. However, the drug’s sales will inevitably be closely linked to its rateof association with PML, and another 12 months of commercial experiencemay be required before Tysabri’s true association with PML becomes clearer,possibly with data from the TyGRIS trial. In the meantime, Biogen Idec is Avonex, with its convenient dosing and lowerevaluating whether earlier diagnosis followed by plasma exchange might side effects, may benefit from a large-scaleimprove patient outcomes, and is also seeking to identify factors that might phase III trial examining the combined use ofpredispose certain patients to PML. Sales are forecast to rise from $831 Avonex and Copaxone that is due to completemillion in 2008 to $1.517 billion in 2013, according to Thomson Pharma in july 2012.Partnering Forecast, which could be its peak year of sales. PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • THE FIRST ORAL THERAPIES Despite the relative lack of options for MS over the last decade, significant Rebif is clinically superior to Avonex after 24 research is ongoing into newer targeted immune therapies for MS, including weeks, despite being chemically identical, the monoclonal antibodies daclizumab, alemtuzumab and ocrelizumab, and according to data from the EvIDENCE trial. the T-cell vaccine Tovaxin. However, it is the success in trials of the oral MS These data allowed the drug to gain FDA therapies which has created the greatest excitement among investors, and it approval, despite Avonex holding Orphan is these which are the most anticipated new treatment options. Drug exclusivity. Merck Serono’s cladribine (Mylinax) and Novartis’s fingolimod (FTy- 720), both in regulatory filing, and sanofi-aventis’s teriflunomide, Biogen Idec’s BG-12, and Active Biotech’s laquinimod, all currently in phase III development, are the most keenly watched oral pipeline products. These are at the most advanced stages of development, and have demonstrated induction of remyelination, reduction in lesions and relapses, and reduced side effects. Between the two most advanced drugs, Novartis has edged ahead of Merck Serono in the race to get the first oral MS treatment to market, having now filed for approval of fingolimod in the US and Europe. The FDA will conduct a priority six-month review, which could bring it to market by year-end. Merck Serono filed its US application for cladribine first, in September 2009, but the FDA rejected the filing two months later as incomplete, which means that although the filing was resubmitted in june 2010, Novartis will most likely be the first company to get an oral therapy registered in the US with fingolimod. FINGOLIMOd: STRONG EFFICACY BUT CONCERNING SIdE EFFECTS Novartis filed fingolimod for approval at the lowest dose studied in trials (0.5 mg), which had the best benefit-risk profile. Data published from two late-stage trials have showed fingolimod is effective in reducing relapses, disability progression and lesions. In the one-year TRANSFORMS study, involving 1292 patients, the lower dose of fingolimod reduced relapses by more than 50% compared with Avonex. Robust efficacy was also confirmed by the FREEDOMS study, in which fingolimod (1.25 mg) reduced the relapse rate by 60% compared with placebo. However, questions about the tolerability of fingolimod persist. While efficacy appeared impressive in TRANSFORMS, the trial highlighted a potentially concerning side-effect profile. There were two fatal herpes infections, and one death from a progressive neurological condition of unclear etiology. While the lower dose appeared to be associated with less risk of infection, opportunistic infections were still observed in this relatively short-term study. Almost as concerning was that eight patients on fingolimod (six on the low dose, two on the high dose) developed melanoma and two developed breast cancer. Transient reductions in heart rate, increases in blood pressure (1 to 3 mmHg), elevations in liver enzymes, and increased rates of macular edema were also seen in fingolimod-treated patients. As long as these side effects do not worsen with time, it is anticipated that physicians and patients may be willing to accept the risks, given the significant demand for oral dosing, and sales are forecast to ramp quickly upon launch, reaching $853.7 million in 2013. Nonetheless, the threat to the existing major players in the franchise may be somewhat tempered by the need for a stringent risk evaluation and mitigation strategies (REMS) program involving a broad group of specialty physicians.PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • MYLINAx – PROLONGEd LYMPHOPENIA MAY BE AN ISSUE Oral cladribine (Mylinax) is a new formulation of the intravenous chemotherapeutic cladribine, currently approved for the treatment of hairy Tysabri displays very low rates of relapse with cell leukemia. Positive data from the phase III CLARITy trial showed a 58% radiographic progression in the real-world setting. reduction in relapse rate over two years with Mylinax treatment, which while not as great as the reductions seen with Tysabri, place it above the first-line interferons. However, the reduction in disability associated with Mylinax (33%) in CLARITy did not quite match reductions seen with Avonex (37%) and Tysabri (42%+), although reductions in lesion activity were evident. As with fingolimod, the biggest question at this stage is cladribine’s safety profile and its potential to cause elevated incidences of infection. The drug works by causing moderate-to-severe prolonged lymphopenia, the longer- term consequences of which are unclear. In addition, CLARITy featured four cases of cancer and one death from tuberculosis possibly related to the drug. There may also be some question over whether the drug is suitable for use in women of childbearing age. On the positive side, cladribine is viewed as easy to use (as few as 10 days dosing per year), relatively well tolerated, and strongly efficacious. Should the clinical sequelae associated with lymphopenia be manageable, oral cladribine could become a first-line drug with strong clinical potential; sales are forecast to reach $358.7million in 2013. REPORTED AND CONSENSUS FORECAST REvENUE (MILLION US$) Mylinax Fingolimod 900 800 700 600SALES IN US $ 500 400 300 200 100 0 2008 2009 2010 2011 2012 2013 YEAR* REPORTED SALES * Data is derived from Thomson Pharma Partnering Forecast PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • FURTHER ALONG THE ORAL PIPELINE Sanofi-aventis’s teriflunomide is a pyrimidine synthesis inhibitor with Fingolimod’s oral convenience may be immunomodulatory properties. Development has been protracted, with the offset by demands for multidisciplinary initial phase III trials beginning in September 2004, first as a monotherapy monitoring, including liver, dermatology and and then in combination with interferon. Phase II data have been positive, infection screening. with reductions seen in MRI lesions, and a trend towards reduced disability/ number of relapses. However, some degree of immunosuppression was seen in 49% of patients. The first phase III data, from the TEMSO study, are expected in 4Q10. Biogen Idec’s oral second-generation fumarate derivative BG-12 has completed a 257-patient European phase II dose-ranging trial; data showed that the drug reduced brain lesion activity at six months versus placebo; the highest dose (720 mg) reduced the mean number of lesions by 69% between weeks 12 and 24 and led to a 48% reduction in newly enlarging T2-hyperintense lesions. There was a trend toward reduction in relapse rate (32% reduction versus placebo), although this was not significant. While liver enzyme elevations were observed in 2 to 8% of patients, no opportunistic infections occurred in patients on BG-12. Two phase III studies, DEFINE and CONFIRM, have completed enrollment. Teva’s laquinimod has received fast-track status from the FDA, and the company believes it could enter the market as soon as late 2011. However, so far, phase II data have suggested only modest efficacy. Two phase III trials have completed enrollment. Looking to earlier-stage drugs, Tysabri has validated blockade of the alpha4-β 1 integrins as a therapeutic approach for the treatment of MS, and a number of alpha4 integrins are now progressing through trials, including GlaxoSmithkline’s firategrast (licensed from Tanabe in December 2000); a Biogen Idec molecule (CDP-323), part of a collaborative global deal with UCB signed in October 2006, with the same mechanism of action was discontinued in 2009 due to lack of efficacy. AdJUNCTIvE THERAPY Effective oral disease-modifying agents for MS will address the treatment goal of preventing long-term disability, and their arrival will herald a sea change in treatment of the disease. However, the scope for oral treatment has not stopped there, and effective symptom management for MS may mark another radical change in the dynamics of the market. The first of these treatment options, Acorda Therapeutics’ sustained-release fampridine (Ampyra), was approved in january 2010 to improve walking ability in patients with MS; launch took place in March 2010. Ampyra successfully completed two SPA-supported phase III trials, which included patients with primary-progressive, secondary-progressive, relapsing-remitting and progressive-relapsing disease. The first study yielded results in 2006; data were strong, and Ampyra met all three predefined efficacy hurdles. Compared to placebo, a greater proportion of patients on Ampyra showed a consistent improvement in walking speed and were classified as responders, the study’s primary outcome (34.8% versus 8.3%). This effect was maintained throughout the 14-week treatment period, and there was a significant improvement in the 12-Item MS Walking Scale for responders versus non-responders. In june 2008, Acorda reported positive data from a further phase III trial, in which Ampyra demonstrated a consistent increase in walking speed across all types of MS. The trial’s primary endpoint was met convincingly, with 42.9% of Ampyra patients responding to therapy versus 9.3% on placebo. The average increase in walking speed over the 8 weeks of treatment compared to baseline was 24.7% for the responders compared to 7.7% for placebo.PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • However, despite favorable efficacy data, prescriptions may be limitedby price concerns, given that the drug is likely to be prescribed alongsidethe high-cost disease-modifying agents. Additionally, a dose-relatedrisk of seizures was observed in trials, which could further temper sales.Ampyra addresses an important need in terms of reducing symptoms andconsequently the drug is expected to reach sales of $639.6 million in 2013. SECTION IIdEALS HIGHLIGHTSThe impact of the economic downturn has dramatically influenced the focusand needs of pharmaceutical companies in recent months. As the financialmarkets show early signs of a slow recovery, licensing activity betweencompanies has been unpredictable but still prevalent and in some cases,profitable. It is clear that the emphasis on ensuring a signed deal sustainslongevity is rooted at the relationship between companies. The increasedattendance at annual partnering conferences has been a well-observed trend.Thus, confirming that business development representatives understand theneed to identify potential partners with expertise and knowledge within aniche field and/or territory, in order to achieve the ideal partnering model ofsustainable agreements and pioneer novel therapeutics.The major companies in the MS market that have emerged as prominentdeal-making figures include Biogen Idec, Merck Serono and TevaPharmaceutical. It is important to note that the concurrent licensing activityconducted by these parties also emphasizes the competitive need tomaintain partnered agreements.BIOGEN IdEC: A FAvOREd PARTNER FOR MULTIPLESCLEROSIS THERAPEUTICSBiogen Idec became the exclusive non-US partner for the development of “We believe that Biogen Idec’s internationalAcorda Therapeutics’ Ampyra in july 2009 (see Table 1). This late-stage dealexemplifies a company realizing the commercialization capabilities of an expertise in MS and neurology also will helpestablished major player in the worldwide MS therapy market. While the drug us optimize future development of Ampyrais not expected to achieve blockbuster status, its significant potential was and maximize its value in markets outsiderealized by Biogen. As such, the parties agreed to a cost-sharing arrangement, the US.“with Biogen committing a large upfront payment of $110 million, regulatory ron Cohen, mD, president and Ceo of acordaand sales-based milestone payments of up to $400 million and double-digitroyalties on ex-US sales to Acorda. By December 2009, Biogen expected toreceive an additional payment of $45 million in expenses.Incidentally, Acorda will grant a proportion (7%) of those payments tothe drug’s originator, Elan. This was significant, considering that during3Q09, Elan and Biogen were locked in a separate legal dispute regardingblockbuster drug Tysabri.Elan and Biogen had been collaborating on the program (originallydeveloped by Elan) since August 2000, as part of a deal worth over $125million (see Table 1). However, Biogen claimed Elan had breached contractby signing a Strategic Financing and Collaboration Agreement relatedto the drug with a johnson & johnson (j&j) affiliate. In September 2009,the United States District Court for the Southern District of New yorkruled in favor of Biogen’s claim and Elan terminated the relevant portionof its transaction with j&j. Despite this unintentional breach, it was clearthat the market clout of Biogen proved to be too valuable an asset tolose. The companies continue to collaborate under a cost/profit-sharingarrangement, with no additional milestone payments required; for theyear ending December 31, 2009, $215.9 million was reflected in the twocollaborators’ recorded profit-sharing line for Tysabri. PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • Biogen demonstrated its aptitude in the MS arena after acquiring BG-12 (dimethyl fumarate) from Swiss firm Fumapharm in October 2003 (see Table 1); the company was acquired by Biogen in july 2006. The drug was originally developed for the potential treatment of psoriasis, reaching phase III of development. However, the partners had agreed to withdraw a marketing authorization application for psoriasis in Germany by September 2007. Given the strength of BG-12’s anti-autoimmune activity, Biogen continued to pursue the program for MS and rheumatoid arthritis (RA). Enrollment of a phase III trial involving 1237 patients was completed in March 2009. PARTNER DEAL DEAL vALUE DRUG COMPANy START DATE (US $)* fampridine Acorda july 2009 510 million (Ampyra) Therapeutics (plus royalties) natalizumab Elan August 2000 125 million (Tysabri) (plus royalties) dimethyl Fumapharm October 2003 Undisclosed fumarate (BG-12) Table 1: SUMMARy OF BIOGEN IDEC’S MS-RELATED DEvELOPMENT AND COMMERCIALIZATION AGREEMENTS * Approximate values based on the achievement of all milestones for the principal components included in the deal. BIOGEN FINdS MARkETING PARTNERS FOR AvONEx Biogen has a widely recognized marketing and distribution network for its recombinant interferon β-1a –based program Avonex, including Latin American, Australian, Indian and Nepal, Spain and Nordic regions. The drug, originally formulated using Inhance drug delivery technology licensed from Nektar Therapeutics, is marketed by Abbott Laboratories in Latin American countries, CSL in Australia, Piramal Healthcare in India and Nepal, and distributed by AstraZeneca in Nordic regions and Schering- Plough in Spain (see Table 2). TERRITORIES PARTNER COMPANy DEAL START DATE COvERED Abbott Laboratories February 1998 Latin America CSL june 1999 Australia Piramal Healthcare December 2003 India and Nepal AstraZeneca August 1996 Nordic region (distribution only) Schering-Plough August 1996 Spain (distribution only) Table 2: SUMMARy OF BIOGEN IDEC’S MARkETING AND DISTRIBUTION DEALS FOR AvONEx MERCk SERONO dEvELOPS COMPETITOR PROdUCT TO AvONEx Merck kGaA’s subsidiary Merck Serono has developed Rebif, another recombinant interferon β-1a, which was launched in the US in March 2002 after demonstrating superiority to Avonex. Both were designated Orphan Drug Status for fast-track approval. However, at the time, the FDA informed Biogen that the drug’s approval letter specifically prohibited labeling with broad claims of clinical superiority. Merck Serono originally licensed rights to the drug from the Weizmann Institute of Science (see Table 3). Following its US launch, Merck Serono enlisted the commercial weight of pharma giant Pfizer to copromote Rebif. The drug is also comarketed in Italy with Italfarmaco, under an agreement signed in 1992 with Ares-Serono (see Table 3).PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • MERCk SERONO ANd TEvA JOIN FORCES AGAINSTMULTIPLE SCLEROSISMerck Serono is also developing Mylinax (oral cladribine), licensed ona worldwide basis from IvAx in October 2002 (see Table 3). FollowingTeva’s acquisition of IvAx in january 2006, Teva decided to discontinue itsdevelopmental involvement but continue to offer financial support to theMerck Serono-led program.IvAx exclusively licensed oral and intravenous formulations of the drugfrom Scripps Research Institute in December 2000, following Scripps’demonstration of the candidate’s ability to eliminate brain lesions normallyassociated with MS observed from patient magnetic resonance imaging(MRI) scans. DEAL DEAL PARTNER TyPE START vALUE DRUG COMPANy OF DEAL DATE (US $)* Recombinant Weizmann Development/ By Undisclosed interferon Institute of commercialization December β-1a (Rebif) Science worldwide 1992 Recombinant Pfizer Copromotion july 2002 Undisclosed interferon in the US β-1a (Rebif) Recombinant Italfarmaco Comarketing By Undisclosed interferon in Italy December β-1a (Rebif) 1992 cladribine Teva Development/ October Undisclosed (oral; Pharmaceutical commercialization 2002 milestone Mylinax) worldwide and royalty paymentsTable 3: SUMMARy OF MERCk SERONO’S MAjOR MS-RELATED AGREEMENTS* Approximate values based on the achievement of all milestones for the principal components included in the deal.TEvA’S MAJOR MULTIPLE SCLEROSIS dEALS “After working with Teva since 2004 on developing laquinimod we believe that TevaTeva’s non-interferon-based MS therapy Copaxone has been launched in the is the optimal marketing and distributionUS since 1997. The active compound was discovered at the Weizmann Instituteof Science and subsequently licensed to Teva for commercial development. partner in our territory.“ tomas Leanderson, president & Ceo, active BiotechWhile Teva retained the majority of MS development rights, the companywas comarketing the drug in the US with Marion Merrell Dow (MMD),through the joint venture Teva Marion Partners. In December 1995, Tevaoutlicensed worldwide (excluding the US) marketing rights to Frenchconglomerate sanofi-aventis. Teva acquired sanofi-aventis’ stake in thejoint venture in February 2001; sanofi-aventis continued to receive revenuesfrom North American sales until March 2008, when Teva reacquired NorthAmerican distribution rights.Currently, Teva and sanofi-aventis continue to jointly commercialize thedrug in major European markets. The two parties copromote the drug inGermany, Uk, France, Spain, Netherlands and Belgium. sanofi-aventis hassole marketing rights in other European markets, as well as Australia andNew Zealand (see Table 4).It was reported that Teva is in the process of reacquiring rights to allterritories by the first quarter of 2012, effectively terminating the agreement;sanofi-aventis would be eligible to receive predetermined terminationpayments in the meantime.Finally, one of Teva’s most lucrative licensing agreements in the MS arenastems from its june 2004 deal with Swedish firm Active Biotech for itsphase III autoimmune suppressant laquinimod. The original deal, in which PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • Active Biotech could earn up to $97 million in upfront and milestone payments plus royalties, granted Teva exclusive rights to develop, register and commercialize the candidate worldwide (excluding Nordic and Baltic regions). These terms were amended in February of this year, granting Teva Nordic and Baltic territory rights. Active Biotech agreed to receive a higher royalty rate on eventual sales of the drug (see Table 4). DEAL PARTNER TyPE DEAL vALUE DRUG COMPANy OF DEAL START DATE (US $)* glatiramer sanofi- Comarketing january 1996 Undisclosed acetate aventis in Europe (Copaxone) Marketing in Australia/ New Zealand laquinimod Active Development/ june 2004 97 million (SAIk-MS) Biotech commercialization (plus worldwide royalties) Table 4: SUMMARy OF TEvA PHARMACEUTICAL’S MAjOR MS-RELATED AGREEMENTS * Approximate values based on the achievement of all milestones for the principal components included in the deal. SUMMARY While the ultimate goal of neuroprotection and repair of damaged areas of the nervous system remains distant, the addition of new agents to an interferon or Copaxone backbone may enhance efficacy. However, the true blockbuster potential lies with a safe and effective oral agent, which will constitute a new platform therapy. The avoidance of injections and potentially greater tolerability may also lead to significant increases in the number of patients with MS who begin and remain on treatment, thus expanding the market. So far, licensing activity surrounding MS therapeutics with promising scientific backing has borne several deals individually worth more than $100 million, and the future also appears solid. At the R&D end of the spectrum, novel animal disease models are being evaluated and companies are collaborating on the development of several promising next-generation candidates: Merck Serono is investigating orally active tetracycline derivatives, as part of a development deal with Paratek, and Teva has partnered with vaccinex on the development of the human monoclonal antibody vx-15, which Teva is investigating for MS. Lastly, using Dyax’s proprietary phage display technology, a demyelinating disease program targeting the Nogo-66 receptor/p75 signaling complex was discovered from a long-standing collaboration between Biogen and Dyax. The strategic partnering activity in the market also indicates that not all pharma companies are collaborating with the well-known major players. Instead, some firms are actively seeking partners with specific experience and an established commercial strength. The prospect of potentially novel oral MS therapeutics also heightens the necessity to utilize companies’ specific formulation expertise. These first oral therapies are likely to be offered in the very near future, although physicians will begin to use these without long-term plans for their use, and careful monitoring of the longer-term effects of more effective immunomodulation will be required. However, in a decade from now, there could be ten or more oral therapeutic options for MS, and the revolution in the treatment of this enigmatic disease may be complete.PHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
    • NOTESPHARMA MATTERS | SPOTLIGHT ON... MULTIPLE SCLEROSIS
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