Open Access

MMV in partnership: the Eurartesim® experience

Malaria Journal201312:211

https://doi.org/10.1186/1475-2875-12-211

Received: 26 February 2013

Accepted: 11 June 2013

Published: 19 June 2013

Abstract

Background

This case study describes how a public-private partnership between Medicinesfor Malaria Venture (MMV) and Sigma-Tau Industrie Farmaceutiche Riunite SpAachieved international regulatory approval for use of the fixed-doseartemisinin-based combination therapy dihydroartemisinin-piperaquine(Eurartesim®) for the treatment of malaria, enablingmore widespread access to the medicine in malaria-endemic countries.

Case description

The combination of dihydroartemisinin and piperaquine demonstrated success inclinical trials for the treatment of malaria in Asia and Africa in the2000s. However, as it had not been developed to international regulatorystandards it was out of the reach of the majority of patients indisease-endemic countries, particularly those reliant on public healthcaresystems supported by international donor funding. To overcome this, as of2004 MMV worked in partnership with Sigma-Tau, Holleykin, Oxford University,the Institute of Tropical Medicine Antwerp, and the National Institute ofMalaria Research India to develop the dihydroartemisinin-piperaquinecombination to international standards. In 2011, the European Commissiongranted full marketing authorization to Sigma-Tau for Eurartesim.

Discussion and evaluation

The partnership between MMV, Sigma-Tau, and numerous other academic andindustrial partners across the world, led to the successful development toEMA regulatory standards of a high-quality and highly efficaciousanti-malarial treatment that otherwise would not have been possible. Thedossier has also been submitted to the WHO for prequalification, and asafety statement to guide correct use of Eurartesim has been produced. InJuly 2012, the first delivery to a disease-endemic country was made toCambodia, where the medicine is being used to treat patients and helpcounter the emergence of artemisinin resistance in the area. A paediatricdispersible formulation of Eurartesim is being developed, with the objectiveto submit the dossier to the EMA by the end of 2014.

Conclusions

The development of Eurartesim to international regulatory standardsexemplifies the strengths of the product development partnership model inutilising the individual skills and expertise of partners with differingobjectives to achieve a common goal. Successful uptake of Eurartesim bypublic health systems in malaria-endemic countries poses new challenges,which may require additional partnerships as we move forward.

Background

Eurartesim® (dihydroartemisinin-piperaquine phosphate; DHA-PQP) is anartemisinin-based combination therapy (ACT) that received regulatory approval fromthe European Medicines Agency (EMA) on 27 October 2011. With this high-quality stampof approval in hand, the medicine is now being used safely and effectively and canbe brought to many more malaria patients than earlier versions of the samecombination. In July 2012, the first shipment of Eurartesim was despatched inCambodia, where its use will help to stem the development of artemisinin drugresistance emerging in the region. This case study describes the partnership betweenMedicines for Malaria Venture (MMV) and Sigma-Tau Industrie Farmaceutiche RiuniteSpA, and ultimately many other partners, that enabled this objective to become areality.

Malaria places a huge burden on disease-endemic countries of the developing world,both economically and in terms of human suffering. High-quality affordableanti-malarial drugs must continue to be developed to ensure that patients receiveadequate treatment and to slow the development of drug resistance. Theanti-malarials market in disease-endemic countries is flooded with poor quality orcounterfeit medicines, often with fatal repercussions for patients, and so qualityis key [1]. In recent decades, however, the increased costs of developing andregistering pharmaceutical products, coupled with the prospect of inadequatecommercial returns, resulted in the withdrawal of the majority of research-basedpharmaceutical companies from research and development (R&D) investment inmalaria. Moreover, public sector government agencies and the not-for-profit privatesector are not individually equipped with all the skills and resources necessary todiscover, develop, and commercialize new anti-malarial drugs.

International realization of the deteriorating situation with regard to the discoveryand development of new high-quality treatments for malaria and other neglecteddiseases in developing countries led to the emergence of the public-private productdevelopment partnership (PDP) model. In 1999, specifically for malaria, the modelwas brought to life in the form of a not-for-profit partnership, MMV that receivesfunding from governments and philanthropic organizations. The PDP model, as appliedby MMV, offers an alternative approach to conventional drug discovery anddevelopment that brings together partners from the public sector (e.g., governmentagencies and international institutions such as the World Health Organization[WHO]), the for-profit private sector (e.g., pharmaceutical and biotechnologycompanies), and civil society (e.g., academia, the not-for-profit private sector,and philanthropic institutions). MMV’s strength lies in the complementarity ofskills and resources provided by its individual partners, its extensivecommunication networks, and in-house malaria R&D expertise, which accelerate thediscovery, development, and delivery of new medicines.

PDPs such as MMV frequently do not have the infrastructure themselves to undertakeresearch and development projects in-house. Instead, they work in partnership withinstitutions or companies with existing facilities and expertise to conductresearch, such as laboratories or clinical sites. The partners provide in-kindcontributions and/or financing to their specific projects, while PDPs manage thecomplete project portfolio, focusing on allocating resources, inputting scientificexpertise and coordinating partner activities throughout the complete R&Dprocess. MMV manages a complete project portfolio, bringing dedicated sources offunding and expertise to committed researchers to enable the discovery, developmentand delivery of new medicines for malaria.

MMV has forged over 287 successful partnerships across almost 50 countries since itsinception. Today, the project portfolio includes approximately 65 anti-malarialprojects. The WHO-recommended treatment for uncomplicated Plasmodiumfalciparum malaria is fixed-dose ACT [2]. In line with this recommendation in 2004 a partnership was formedbetween MMV, Holleykin (comprising the Chinese Holley group and Guangshou Universityof Traditional Chinese Medicine), the Italian pharmaceutical company Sigma-TauIndustrie Farmaceutiche Riunite SpA and Oxford University. The objective was todevelop and gain international regulatory approval for use of the fixed-dose ACTDHA-PQP (brand name Eurartesim®). The combination of DHA-PQP (underother brand names from other manufacturers) had been used widely and demonstratedusefulness as a key treatment against malaria in the private sector in certaincountries in Asia and Africa [38]. With the emergence of resistance to artemisinin and its derivatives insouth-east Asia, WHO’s Global plan for artemisinin resistance containment(GPARC) calls for improved access to quality-assured diagnostics and treatment withACT [9]. Since 2008, DHA-PQP has been the first-line drug of choice in Cambodia,one of the key countries leading the fight to contain artemisinin-resistant strainsof malaria [10]. However, the EMA approval of Eurartesim in 2011, the public sector hadno access to it as it had not been approved by a stringent regulatory authority andthus could not be procured using international donor funds. MMV and Sigma-Tau workedtogether to develop the combination to high regulatory standards in order to changethat and help bring the medicine to more vulnerable patients.

Case description

Early development of dihydroartemisinin-piperaquine

Initially, PQP and DHA were developed and tested separately as monotherapies.PQP, a bisquinoline anti-malarial, was first synthesized in the 1960s atRhone-Poulenc in France and, independently, developed and tested at the ShanghaiResearch Institute of Pharmaceutical Industry in China. Due to the increasingprevalence of chloroquine (CQ)-resistant parasites in China, PQP was adopted asthe first-line treatment between 1978 and 1994 [11]. PQP monotherapy was used broadly for both malaria prophylaxis andtreatment, with the equivalent of 140 million adult doses manufactured anddistributed [12]. However, resistance to PQP began to emerge in the late 1980s onward [13]. At the same time, in Thailand, it was discovered that by combiningmefloquine, which had largely failed as monotherapy due to resistance, withartesunate, it was possible to restore effective anti-malarial activity. Such acombination also required less artesunate than monotherapy with artesunate– an expensive and rare drug at the time. These factors, together with thedesire to have a presence in the international pharmaceutical industry, sparkedthe interest of the Chinese scientific community in developing ACT, and they puta number of combinations to the test (Figure 1).
Figure 1

Timeline of key events in the development ofEurartesim ®  to international regulatorystandards.

Professor Li Guoqiao of Guangzhou University of Traditional Chinese Medicineinitially developed the combination of DHA-PQP in the late 1990s. At that time,his goal was to develop a highly affordable medicine, and so he opted for theless expensive DHA rather than artesunate; its production involves one syntheticstep less than artesunate, and it is, therefore, more cost-effective yet stillvery efficacious against malaria. In 2001, clinical development of the drugcombination commenced through a collaboration with Professor Tran Tinh Hien ofthe Hospital for Tropical Diseases (HTD) and the Wellcome Trust Major OverseasProgramme in Vietnam. An important randomized controlled study of a fixed-dosecombination of DHA-PQP was undertaken at the HTD, and the drug combination wasfound to be safe and highly efficacious [6].

Following Professor Hein’s trial, other clinical investigations of DHA-PQPwere also carried out in Thailand and Cambodia, all confirming the excellentsafety and efficacy of the combination [35, 7].

In 2002, the Holley group, a Chinese company involved in the production ofartemisinin-based anti-malarial drugs, formed a joint venture with GuangzhouUniversity of Traditional Chinese Medicine named Holleykin. This brought theDHA-PQP combination product into the Holley group portfolio. Clinicaldevelopment work continued on DHA-PQP, and in 2003, the product achievedregistration in China under the name of Artekin®. The name,however, was later abandoned in favour of Eurartesim, owing to its similarity tothe name of another anti-malarial combination treatment,Artequin®, which contained artesunate and mefloquine.

The first contacts – East meets West

The combination of DHA-PQP caught the attention of the WHO in early 2001 [2]. Later that year, MMV was invited by the WHO Western Pacific RegionalOffice to participate in a meeting convened in Shanghai on how best tofacilitate uptake of DHA-PQP and other forms of ACT by public health systems inmalaria-endemic countries. The United States Pharmacopeia (USP) was alsoinvited, and other meeting participants included members of the scientificcommunity and Chinese government, as well as representatives of Chinesecommercial interests. Through the highly successful use of dihydroartemisinin,piperaquine, primaquine, and trimethoprim combined into one tablet in Vietnam inthe 1990s (under the names China-Vietnam drug number 4 and 8; CV4/CV8 orArtecom®), the DHA-PQP combination had already demonstratedsignificant potential as an anti-malarial treatment capable of positivelyimpacting public health and reducing the malaria burden [6, 14, 15]. MMV recognized this potential. Participants of the 2001 Shanghaimeeting concluded that although DHA-PQP demonstrated significant efficacyagainst malaria, its production using Chinese Good Manufacturing Practice (GMP)laws at that time did not match the regulatory standards of Europe and the USA.This meant that further development of the product would be needed in order tomeet international regulatory standards to facilitate its uptake by publichealth systems in malaria-endemic countries. International regulatory approvalwould allow the product to be purchased using international donor funds. At thetime, Chinese GMP bore a number of differences to EU and US GMP in terms of thelevel of detail of its quality control requirements, meaning that specificimplementation of the requirements could significantly vary between productionplants. (Chinese GMP has since evolved, and the new Chinese GMP 2010 (effectivesince March 1, 2011) contains many more detailed requirements on key aspects ofthe drug manufacturing process, bringing the key provisions of Chinese GMP intoalignment with EU and US GMP [16].)

Drawing on its strong regulatory expertise, MMV proceeded to hold discussionswith Holleykin about how best to develop DHA-PQP to international standards. In2003, a non-disclosure agreement was signed between MMV and Holleykin to worktowards this goal. MMV commenced an analysis of the elements that would benecessary for a potential dossier on DHA-PQP suitable for submission to aninternational regulatory authority.

The USP Drug Quality and Information Program was also engaged at this time toexamine the GMP capabilities of the Guangdong Medi-World Pharmaceutical Company,responsible for manufacturing Artekin within the Holley group. They consideredthat it should be possible for the pharmaceutical company to establishsufficient controls and capabilities to consistently manufacture the productaccording to international GMP standards, without any major upgrade of theexisting facilities.

The partnership comes together

In 2003, Dr Claudio Cavazza (Founder and then President of Sigma-Tau) and DrGirolamo Sirchia (then Italian Minister of Health) held discussions about theimportance of continuing Italy’s scientific contribution in the field ofmalaria and possible ways this could be achieved. Dr Sirchia suggested the ideaof a collaboration between Sigma-Tau, MMV, Holleykin, and the University ofOxford (UK). The University of Oxford (through its unit in Bangkok, the MahidolOxford Tropical Medicine Research Unit [MORU]) had played a leading role inresearching ACT and had done some pioneering work on the combination of DHA/PQPfrom China [17]. Contact was made between Sigma-Tau and the Holley group, facilitatedby representatives of the WHO Tropical Disease Research programme and MMV. In2004, a four-way agreement was signed between Sigma-Tau, the Holley group,Oxford University and MMV to develop a DHA-PQP combination product tointernational quality standards.

The partnership also drew on MMV’s extensive network of world-classpartners, including the Institute of Tropical Medicine Antwerp (Belgium) and theNational Institute of Malaria Research (NIMR) in India. All partners workedtowards the same goal of developing DHA-PQP to stringent standards in order togain international regulatory approval for the product. The Oxford scientistswere able to provide a wealth of clinical background and know-how on conductingclinical trial in malaria endemic countries and of DHA-PQP, as they had workedwith the combination for a number of years through their south-east Asiancollaborations. They were also able, in addition to the scientists from Antwerpand NIMR, to offer access to their dedicated clinical trial sites in Asia andAfrica to advance the development process, which were considered centres ofexcellence. This included sites in Thailand, Laos, and Kenya.

Both MMV and Sigma-Tau possessed different skill sets and expertise, whichenabled them to maximize their individual strengths in a complementary manner.MMV was able to provide strong regulatory and clinical expertise and guidance,as well as in-house experience in malaria R&D [18], while Sigma-Tau possessed high-level fully compliant European GMPpharmaceutical laboratories and production facilities, as well as expertise indrug development.

In 2006, recognising the threat of drug resistance to artemisinin, the goldstandard anti-malarial treatment, the WHO urged governments to ban the use ofartemisinin monotherapy [19]. At that time, the Holley group’s sole source of pharmaceuticalrevenue came from an artemisinin monotherapy product namedCotecxin®. When faced with the WHO demand, the Holley groupagreed to progressively stop producing its DHA monotherapy. However, the grouphad to move quickly to replace this product and subsequently pulled out of theagreement to develop Eurartesim and commercialized their existing version ofDHA-PQP, Duo-Cotecxin®.

MMV and Sigma-Tau remained in partnership and continued their effort by firstexamining the existing quality, clinical, and non-clinical data on DHA-PQP heldby the Holley group. It became clear that much of the existing product datawould be insufficient for the requirements of a stringent regulatory authority;data had been collected from diverse drug production batches of differingquality and from diverse research settings, and the active compounds originatedfrom a variety of sources and had been manufactured using different methods.Moreover, little of the available documentation could have been considered tohave been produced under the internationally recognized conditions of GMP, GoodLaboratory Practice, and Good Clinical Practice.

The development plan

MMV and Sigma-Tau worked together to create a clinical development plan able todeliver all the necessary data for submission of a dossier on Eurartesim to astringent regulatory authority. They drew on the malaria expertise of Oxford andthe Institute for Tropical Medicine in Antwerp, while using the tools of moderndrug development to maintain the highest regulatory standards. The partnershipjointly determined the timeframes for each section of the development plan,while working together with scientists who had previously tested the combinationto discover the optimal dosing schedule. They drafted a clinical developmentplan, which included three pharmacokinetics studies and two pivotal Phase IIIrandomized trials (Table 1).
Table 1

Studies of Eurartesim in patients

Study

Dose

Test regimen

Comparator

Total no. of subjects

Subject type

Main efficacy endpoint

Countries

ST3073+ST3074 DM09006 Phase I

Dose range: 1.6-2.5 mg/kg/day DHA and 12.4-20.3 mg/kg/dayPQP

40 mg DHA/320 mg PQP tablet. 3 oral doses in 48 hrs.

Placebo, Riamet,(AL), moxifloxacin

268

Adult healthy volunteers

To evaluate the effect of multiple oral doses of DHA and PQPon the QT/QTc interval compared to AL, placebo andmoxifloxacin in healthy male and female volunteers

France

ST3073+ST3074 DM09007 Phase I

Dose range: 1.6-2.7 mg/kg/day DHA and 12.4-21.8 mg/kg/dayPQP

40 mg DHA/320 mg PQP tablet. 3 oral doses in 48 hrs.

Not Applicable

72

Adult healthy volunteers

DHA and PQP PK in healthy male and female Asian and Caucasianvolunteers after single and repeated dose of Eurartesim

Australia

ST3073+ST3074 DM09008 Phase I

Dose range: 1.7-2.1 mg/kg/day DHA and 13.9-17 mg/kg/dayPQP

40 mg DHA/320 mg PQP tablet. One single oral dose.

Not Applicable

37

Adult healthy volunteers

To assess the effect of food on the PK of DHA and PQP aftersingle oral administration of Eurartesim in healthy maleadult volunteers

Australia

ST3073+ST3074 DM 04008 (Africa) Phase I/II

Dose range: 1.67-3.08 mg/kg/day DHA and 13.3-24.64 mg/kg/dayPQP

20 mg DHA/160 mg PQP or 40 mg DHA/320 mg PQP tablet. 3 oraldoses in 48 hrs.

Not Applicable

32

Paediatric P. falciparum malaria patients

To assess the PK of DHA and PQP by analysing serial bloodsamples during and after a therapeutic course in childrenwith malaria

Burkina Faso

ST3073+ST3074 DM04009 (Asia) Phase I/II

Dose range: 1.6-3.64 mg/kg/day DHA and 12.8-29.12 mg/kg/dayPQP

40 mg DHA/320 mg PQP tablet. 3 oral doses in 48 hrs.

Not Applicable

25

Adult P. falciparum malaria patients

To assess the pharmacokinetics of DHA and PQP by analysingserial blood samples during and after a therapeutic coursein adults with malaria.

Thailand

ST3073+ST3074 DM040010 (Asia) Phase III

Dose range:1.67-3.33 mg/kg/day DHA and 13.3-26.7 mg/kg/dayPQP

20 mg DHA/160 mg PQP or 40 mg DHA/320 mg PQP tablet. 3 oraldoses in 48hrs.

50 mg AS + 250 mg MQ AS 4 mg/kg/day for 3 days + MQ 25 mg/kgdivided into two doses

1150

Adult and paediatric P. falciparum malariapatients (even in combination with other Plasmodia)

To demonstrate that the PCR-corrected cure rate of DHA-PQP atDay 63 is non-inferior to that of AS+MQ (non-inferioritymargin=5%)

Thailand, India, Laos

ST3073+ST3074 DM040011 (Africa) Phase III

Dose range: 1.6-3.64 mg/kg/day DHA and 12.8-29.12 mg/kg/dayPQP

20mg DHA/160mg PQP or 40mg DHA/320 mg PQP tablet. 3 oraldoses in 48 hrs

20 mg A/120 mg L 2-6 tablets per day over 3 days dependant onbody weight

1553

Paediatric P. falciparum malaria patients

To demonstrate that the PCR-corrected cure rate of DHA-PQP atDay 28 is non-inferior to that of AL (non-inferioritymargin=5%)

Burkina faso, Kenya, Uganda, Mozambique, Zambia

Clinical trial supplies were produced by Sigma-Tau at their EuropeanGMP-compliant plant in Pomezia, Italy, initially using active pharmaceuticalingredients (APIs) from the Holley group in China. A plan was then executed toqualify the API and develop acceptable specifications, as well as to minimizeimpurities, and, where needed, to perform regulatory non-clinical qualificationof them. Sigma-Tau and MMV eventually took the decision to move production ofthe APIs from China to the Indian pharmaceutical company Arch Pharmalabs. ArchPharmalabs possessed current GMP-compliant manufacturing facilities that hadbeen inspected and approved by global regulatory agencies.

The pharmacokinetics of piperaquine were largely unknown in 2001. As the drug wasknown to have an extremely long half-life, it was decided that it would beimportant to carry out stringent analysis of the pharmacokinetic profile ofDHA-PQP in different populations. This served the purpose of defining thepossibility of accumulation of piperaquine, which might be considered a safetyand regulatory risk for the combination. As it turned out, the information thatwas gathered proved vital in achieving the registration later on. The clinicalpharmacokinetics studies conducted were as follows: (i) a Phase I single-dosestudy carried out in 2005 in Switzerland in healthy volunteers; (ii) a PhaseI/II study carried out during 2005 and 2006 in adult patients in Asia; and (iii)a Phase I/II study carried out in 2006 in paediatric patients in Africa.

Eurartesim clinical trial programme

Two pivotal Phase III trials were carried out in Asia and Africa, respectively,to account for the differences in baseline immunity and transmission risks formalaria in differing endemic regions. Both were multicentre, randomized, openlabel, two-arm, parallel group studies. The Asian study was conducted betweenJune 2005 and April 2007 at 10 study sites across India, Laos, and Thailand,with the objective of determining whether DHA-PQP was non-inferior to the loosecombination of artesunate + mefloquine as well as assessing the efficacy andsafety of DHA-PQP in Asian patients with acute uncomplicated P.falciparum malaria [2022]. The main efficacy measure was the proportion of patients who werecured 63 days after treatment (determined using polymerase chain reaction (PCR)genotype-correction). The African study was conducted between August 2005 andJuly 2006 at five study sites in Burkina Faso, Kenya, Mozambique, Uganda, andZambia. The objective of the study was to determine whether DHA-PQP wasnon-inferior to artemether-lumefantrine and to assess its safety andtolerability in African children with acute uncomplicated P. falciparummalaria [23, 24]. The main efficacy measure was the proportion of patients cured 28days after treatment, (determined using PCR genotype-correction). Patients were,however, followed up to day 42 as a secondary endpoint. In total, 2,703 patientswere included in the Phase III studies.

Both Phase III studies were guided by a clinical development committee thatprimarily addressed the scientific conduct, ethical integrity, and regulatoryacceptability of the trial programme [25]. The clinical development committees each comprised onerepresentative from MMV, two representatives from Sigma-Tau, and thestudy’s Coordinating Investigator. In addition, both studies included adata monitoring committee responsible for performing an interim analysis forsample size reassessment, monitoring safety data during the study, and revisingthe primary efficacy data [25]. The data monitoring committees each included one statistician andfour clinicians with malaria expertise who were independent of Sigma-Tau andMMV.

The results of the Eurartesim clinical trial programme confirmed theproduct’s safety and high level of efficacy. In the Asian Phase III trial,97% of patients were cured 63 days after treatment compared with 95% of patientswho received the comparator artesunate + mefloquine. Additional,country-specific analysis of the Phase III data from India led the study authorsto suggest DHA-PQP could be considered for the first-line treatment in country [26]. In the African Phase III trial, 93% of patients were cured 28 daysafter treatment compared with 95% of patients treated withartemether-lumefantrine (differences between treatment groups werenon-significant and percentages are based on modified intention to treatpopulations) (Table 2). Both studies also found thatthe occurrence of new infections during the follow-up period after treatment wassignificantly lower with DHA-PQP than the comparator treatments, indicating thatDHA-PQP has a comparatively longer prophylactic effect after treatment [20, 23].
Table 2

Results of the two Phase III open-label clinical trials

Study

PCR-corrected cure rate (mITT)

 

Eurartesim

AS+MQ

A+L

DM040010 (n=1087)

97.0%

95.3%

-

DM040011 (n=1524)

92.7%

-

94.8%

A+L: artemether+lumefantrine; AS+MQ: artesunate+mefloquine; mITT:modified intention-to-treat (defined as all randomized patients whoreceived at least one dose of study treatment, with the exclusion ofthose patients lost to follow-up for unknown reasons); PCR:polymerase chain reaction.

MMV and Sigma-Tau took the decision not to carry out extensive non-clinicalstudies with Eurartesim other than the aforementioned pharmacokinetic analysisof piperaquine, on the basis that between 1976 and 1994 the equivalent of 140million adult doses of piperaquine had been used in China [11, 12, 27]. As such, PQP would have qualified as a ‘well-establishedsubstance’, as defined in the EU regulations [28]. Nonetheless, the documentation for this use proved less thanconvincing for the EMA. This regulation on well-established substances was thenrevised in 2007 by the EMA [29] and, therefore, additional non-clinical testing was required.

Regulatory decisions

Initially, MMV and Sigma-Tau had made the decision to seek Italian regulatoryapproval for Eurartesim. Sigma-Tau already possessed strong Italian regulatoryexpertise, so an application for regulatory approval through the national routewould enable them to use this expertise. In 2005, an Italian Investigational NewDrug application was filed with the National Institute of Health (IstitutoSuperiore di Sanità), which allowed Phase I studies to begin. After furtherextensive evaluation drawing upon MMV’s own strong regulatory expertise, adecision was made to apply for European centralized registration via an orphandrug application, rather than Italian national registration. As an orphan drugapplication, the dossier would benefit from an accelerated review process.Moreover, the regulatory seal of approval from the EMA for Eurartesim as anorphan drug would enable the product dossier to be filed and accepted morequickly in disease-endemic countries. It would also allow Sigma-Tau to marketthe product in Europe, where they already had a commercial presence. On 3 August2007, orphan designation (EU/3/07/468) was granted by the European Commission toSigma-Tau Industrie Farmaceutiche Riunite SpA, Italy, for DHA-PQP for thetreatment of malaria.

In July 2009, MMV and Sigma-Tau submitted their completed dossier on Eurartesimto the EMA for marketing authorization. In July 2010, a list of questions wasreceived from the Committee for Medicinal Products for Human Use (CHMP) inresponse to the submission. Among the questions, the CHMP noted a potential riskfor QTc interval prolongation with Eurartesim. Over the next six months, MMVworked closely with Sigma-Tau to produce the response to the CHMP questions,which necessitated three further clinical trials and 25 new non-clinicalstudies. In collaboration with MMV, Sigma-Tau pulled together all of itsresources to work intensively to produce the necessary data and responses to thequestions, and in June 2011, the CHMP of the EMA adopted a positive opinion,recommending the granting of marketing authorization in Europe for Eurartesimfilm-coated tablet for the treatment of uncomplicated P. falciparummalaria in adults, children, and infants aged 6 months and over and weighing 5kg or more. On 27 October 2011, the European Commission granted full marketingauthorization in 27 member states, making it the first ACT to be approved by theEMA for the treatment of uncomplicated P. falciparum malaria using acentralized procedure.

Eurartesim product and safety

Eurartesim is generally well tolerated and has a simple dosage regimen thatinvolves weight-based administration once daily (up to four tablets per dose)for three days [30]. This makes the drug more patient friendly and could increasecompliance over other currently-available forms of ACT requiring twice-dailyadministration. Owing to the long half-life of piperaquine, Eurartesim alsoprovides better and longer protection from new malaria infections than otherforms of ACT, as demonstrated during its clinical development programme [20]. This is an important advantage, particularly for children in hightransmission areas who are often affected by a second life-threatening malariaepisode after recovering from their original infection [23]. Moreover, the formulation of Eurartesim means that it has a two-yearshelf life in disease-endemic countries. A recent study reported Eurartesim tobe the most stable form of the six DHA-based formulations investigated [31]. Eurartesim is available in two different packs (one for adults andone for children) with different quantities of the active ingredients in thetablets: each film-coated tablet contains either 160 mg piperaquinetetraphosphate (as the tetrahydrate; PQP) and 20 mg DHA, or 320 mg PQP and 40 mgDHA [30].

Following EMA registration, MMV and Sigma-Tau worked together to produce a safetystatement on Eurartesim to guide correct prescription of the product [seeAdditional file 1 for complete safety statement]. TheCHMP considered that the current safety database on Eurartesim was notsufficiently large to determine whether the QTc effect of Eurartesim wouldtranslate into arrhythmias, and if so, how frequently these might occur(although they did consider that the non-clinical data suggested thetorsadogenic potential of Eurartesim is lower than chloroquine and similar toartemether-lumefantrine) [32]. To enable the optimal deployment and use of Eurartesim, arepeat-dose study is underway in West Africa (The West African Network forClinical Trials of Antimalarial Drugs: WANECAM) and a safety and effectivenessstudy is due to commence in Ghana, Burkina Faso, Mozambique and Tanzania in 2013(INDEPTH Effectiveness and Safety Studies of Antimalarials in Africa:INESS).

Discussion and evaluation

This case study illustrates how a strong PDP collaboration between partners withdiverse skills, expertise, and motivations can lead to success. The development ofEurartesim to international regulatory standards, thereby enabling the medicine toreach many more patients, would simply not have been possible without thesepartnerships. Although the drug combination DHA-PQP was already in existence andavailable in the private sector, and had been used extensively in China, Vietnam,and certain other countries in Asia, the formulation had not previously beenmanufactured according to internationally recognized GMP. Consequently, it could notbe purchased with international donor funding and therefore accessed by the publichealth systems of the majority of malaria-endemic countries in the developingworld.

Recognition of the potential of DHA-PQP to positively impact public health inmalaria-endemic countries initially arose at the WHO and through visionary nationalmalaria control programmes such as that of the Vietnamese HTD. A strong partnershipexisted between MMV and health experts at the WHO, which meant that MMV was in aposition to collaborate with the WHO at an early stage to explore the potential ofDHA-PQP. MMV was also able to draw on the input of other world-class partners duringthe clinical development programme, including researchers from the University ofOxford, the Institute of Tropical Medicine Antwerp, and many other institutionsacross south-east Asia, India, and Africa. This ability to forge researchpartnerships around the world was critical to the success of the clinicaldevelopment programme.

In 2004, when MMV, Sigma-Tau, the Holley group, and the University of Oxford firstsigned a contract to cover the clinical development of DHA-PQP to international GMPstandards, their partnership was perceived as unlikely to succeed because of thediverse and sometimes conflicting priorities of the individual partners.Nevertheless, a not-for-profit PDP foundation and a mid-sized Italian pharmaceuticalcompany successfully combined their respective strengths to respond to an urgentpublic health need for new anti-malarial treatments of high quality. Clearly, notall of the objectives of the individual partners were the same, but through thiscommon goal, both partners possessed the resolve to work together to overcome thehurdles encountered along the way to achieving EMA registration for Eurartesim, andthey produced a partnership that was greater than the sum of its individualparts.

The development of Eurartesim, co-funded by MMV and Sigma-Tau, is a goodexample of critical research driven by generosity and vision, both in terms of theindividual partners involved, and the broader malaria community. It represents animportant innovation for patients in resource-poor settings, especially wheretransmission is high. Poor-quality anti-malarial drugs can lead to drug resistanceand inadequate treatment, and they pose an urgent threat in such patient populations [1]. In addition to Eurartesim, several other forms of ACT are available foruse by public health systems in malaria-endemic countries. This is important, as byproviding a range of therapies to treat malaria, disease-endemic countries can adaptcontrol strategies to their specific needs. The use of multiple first-line therapiesagainst malaria may also delay drug resistance [33, 34].

Additionally, studies have demonstrated that DHA-PQP is efficacious against theblood-stage of P. vivax malaria [35], however, to date it has only been approved for treatment of P.falciparum. Preliminary evidence also indicates that DHA-PQP is one of twocurrently available formulations of ACT potentially able to improve the anti-relapseeffect of primaquine [36, 37]. Further studies will be required to confirm these two indications.

Achievement of EMA marketing authorization for Eurartesim does not guarantee itsaccess. In fact, the next objective is to ensure successful uptake of Eurartesim bypublic health systems in malaria-endemic countries. This poses a number of newchallenges, which include ensuring local registration, successful launch, affordablepricing and distribution in these countries, and operational introduction intonational malaria control programmes. MMV will clearly need additional newpartnerships to address these challenges, the key to which will involve ensuring awin-win solution for partners with differing objectives. MMV has already worked withSigma-Tau’s expert packaging team to design appropriate packaging forEurartesim suitable for use by public health systems in countries with low literacylevels, and both partners have decided to continue their partnership to ensure themonitoring of the long-term safety and efficacy of Eurartesim.

Since July 2012, more than 400,000 packages of Eurartesim have been delivered toCambodia – the first shipments to a malaria-endemic country. This isparticularly significant as Cambodia is situated at the epicentre of emergingresistance to many existing anti-malarials. Cambodia had adopted DHA-PQP asfirst-line treatment for malaria and was awaiting approval by a stringent regulatoryagency to allow procurement of Eurartesim using international donor funds. Cambodiahas now registered Eurartesim. An agreed price of USD 0.66-1.98 per dose (dependingon weight) was accepted by the Global Fund for purchase through The AffordableMedicines Facility–malaria [38]. The first procurement was achieved through a collaboration between theMinistry of Health Cambodia (National Center for Malaria Control, Parasitology andEntomology and the Department of Drugs and Food), Population Services International(PSI; Cambodia and Kenya), WHO (Geneva and Cambodia), Sigma-Tau, and MMV using fundsfrom the Global Fund via the Affordable Medicines Facility–malaria.

Sigma-Tau has recently submitted the Eurartesim dossier for WHO prequalification.Additionally, it has been registered in Ghana Tanzania and Burkina Faso andsubmitted for registration in Mozambique where a multicentre, multicountry Phase IVstudy is planned to monitor the effectiveness and safety of new, approvedanti-malarial drugs in “real-life” settings. This is part of the riskmanagement plan agreed with the EMA and will allow for the long-term follow-up ofthe medicine.

In addition, the MMV–Sigma-Tau partnership is currently developing a paediatricdispersible formulation of Eurartesim suitable for use by children between the agesof six months and five years, which will remain stable in hot and humid conditions.This dispersible formulation will improve ease of use by eliminating the need tocrush the tablets before administration. A recent meta-analysis has indicated that ahigher dose of piperaquine could increase the efficacy of the combination forchildren aged between one and five years [39], however, the safety of an increased dose in this population has not beenevaluated. A complete risk–benefit analysis will need to be made before achange in dosage could be considered. The dosage for the paediatric formulation willbe based on EMA recommendations for this age group. Completion of the developmentprogramme and preparation of the dossier for submission to the EMA is planned by theend of 2014.

Conclusion

Together, MMV and Sigma-Tau have been able to develop a safe and efficacious DHA-PQPcombination medicine to internationally-recognized quality standards, providing asafety statement to guide its correct use. As a result the first shipment ofEurartesim to a malaria-endemic country was made in July 2012 to Cambodia. Thedevelopment of Eurartesim exemplifies the strengths of the PDP model in utilisingthe individual skills and expertise of partners with differing objectives to achievea common goal. The full partnership extended beyond MMV and Sigma-Tau, and includedmany collaborators around the world. Ensuring access to Eurartesim inmalaria-endemic countries will require the formation of new additional partnershipsin order to overcome the challenges involved in successfully launching anddistributing the product, as well as its operational introduction into nationalmalaria control programmes. MMV and Sigma-Tau will continue their work together toachieve EMA registration of the paediatric formulation of Eurartesim in the fastestpossible time.

Declarations

Acknowledgements

We would like to thank our colleagues at Sigma-Tau Industrie FarmaceuticheReunite for their valuable input in writing this article. Editorial assistancewas provided by Christine Kyme (Hinxton Consultants Ltd), with funding fromMMV.

Authors’ Affiliations

(1)
Medicines for Malaria Venture

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© Ubben and Poll; licensee BioMed Central Ltd. 2013

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