APPLICATION FOR INCLUSION OF DIHYDROARTEMISININ PLUS PIPERAQUINE (DHA/PQP) FIXED DOSE COMBINATION TABLETS IN THE 21st EDITION OF THE WHO MODEL LISTS OF ESSENTIAL MEDICINES

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TABLE OF CONTENTS General items

1. Summary statement of the proposal for inclusion

2. Name of WHO technical department and focal point submitting or supporting the application (where relevant)

3. Name of the organisation(s) consulted and/or supporting the application

4. International Non-proprietary Name (INN, generic name) of the medicine and Anatomical Therapeutic Chemical (ATC) code of the medicine

5. Formulation and strength proposed for inclusion; including adult and paediatric

6. Whether listing is requested as an individual medicine or as an example of a pharmacological class

Treatment details, public health relevance and evidence appraisal and synthesis

7. Treatment details (requirements for diagnosis, treatment and monitoring)

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population, likely impact of treatment on the disease)

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings  Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)  Summary of available data (appraisal of quality, outcome measures, summary of results)  Summary of available estimates of comparative effectiveness

10. Review of harm and toxicity: summary of evidence on safety  Estimate of total patient exposure data  Description of adverse effects/reactions and estimates of their frequency  Summary of available data (appraisal of quality, summary of results)-  Summary of comparative safety against comparators  Identification of variation in safety that may relate to health systems and patient factors

11. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group:

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 Range of costs of the proposed medicine  Comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained)

Treatment details, public health relevance and evidence appraisal and synthesis

12. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well)

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia)

14. Reference List

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ACT Artemisinin Combination Therapy AE Adverse Event AMF-m Affordable Medicine Facility-malaria A/L Artemether/Lumefantrine AS/AQ Artesunate - Amodiaquine AS+MQ Artesunate plus Mefloquine AS+SP Artesunate plus Sulfadoxine–Pyrimethamine CI Confidence Interval DHA Dihydroartemisinin; Artenimol ECG Electrocardiogram EMA European Medicines Agency FCT Fever clearance time FDC Fixed-Dose Combination ICH International Conference on Harmonization ITT Intention-To-Treat Kcal Kilo-calories MMV Medicines for Malaria Venture PCT Parasitaemia Clearance Time PP Per Protocol PQP Piperaquine Phosphate P. falciparum, P. vivax, P. ovale, P. Plasmodium falciparum, Plasmodium ovale, malariae and P. Plasmodium malariae, Plasmodium knowlesi knowlesi QTc Corrected QT segment length SmPC Summary of Product Characteristics STEAE Serious Treatment-Emergent Adverse Event TEAE Treatment-Emergent Adverse Event TF Treatment Failure USD United States Dollar

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1. Summary statement of the proposal for inclusion

Malaria remains a major cause of morbidity and death in endemic areas and substantial numbers of travelers from non-endemic areas are exposed to the risk of malaria each year.

The most severe form of malaria, which is responsible for the great majority of malaria-related deaths (most of which occur in children aged < 5 years who reside in endemic areas), is associated with infection due to the species Plasmodium falciparum (P. falciparum). Of the five Plasmodium species that infect man P. falciparum has the shortest exo-erythrocytic phase (7-10 days) and the merozoites released after asexual reproduction of sporozoites in hepatic cells are able to invade erythrocytes at any stage of their development.

Because of the relentless increase in resistance of P. falciparum to drugs such as chloroquine, sulfadoxine–pyrimethamine and mefloquine, new agents have had to be developed. The World Health Organization (WHO) has recommended that artemisinin combination treatment (ACT) should be regarded as the “policy standard” for treatment of malaria in areas where P. falciparum is the predominant infecting species. In developing ACT regimens the aim is to achieve rapid schizontocidal activity by means of the selected artemisinin compound together with a longer antimalarial effect associated with the different mechanism of action and longer half-life of the selected partner agent.

The latest version (19th ed., updated November 2015) of the WHO Model Essential Medicines List (1) states that it “currently recommends combinations according to treatment guidelines.” Currently, the fixed-dose combinations (FDC) ACT included in the 19th edition are: artemether/lumefantrine, artesunate/amodiaquine and artesunate/mefloquine.

It is noteworthy that the 3rd edition of WHO’s Guidelines for the Treatment of Malaria datedApril 2015 (2) recommends, dihydroartemisinin plus piperaquine (DHA/PQP), as an ACT option for the “first-line treatment of uncomplicated P. falciparum malaria worldwide”. This addition was categorized as a “Strong Recommendation” and was included due to “High Quality Evidence.”

Comparative benefits: As a once-a-day FDC taken over the course of three days, DHA/PQP will offer a simpler dosing burden for patients compared to the pill burden of twice-per-day treatment over three days for artemether/lumefantrine. This diminished burden will benefit patients and enhance the likeliness of improved treatment compliance in settings where patients are administered treatment with limited or no medical oversight. In addition, the longer half-life of this companion non-artemisinin component compared to all the others partner drugs of the ACTs (lumefantrine, amodiaquine, mefloquine) confers longer patient protection from reinfection, a critical consideration in areas of high malaria transmission. Based on these considerations, DHA/PQP has been recently utilized for large Mass Drug Administration trials as well as for Seasonal Malaria Chemoprevention campaignes.

The fixed combination (DHA/PQP) subject of this application obtained a Marketing Authorisation Approval by EMA for all EU countries on 27 October 2011 (trademark Eurartesim).

On 9 October 2015, the product obtained the WHO prequalification status (MA093-094)

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Following the EMA approval, since 2012, marketing authorisation applications have been submitted by the Applicant in many endemic countries. Currently, the product is already approved in some African and Asian countries while registration is in progress in others.

Eurartesim is currently commercialized in some EU, African and Asian markets. In addition, the Product has been sold through Governmental Agencies or no-profit organizations.

A detailed status of the countries where product is approved and/or commercialized/sold is reported in sections 11 and 12.

As of today, there are six countries that have officially listed DHA/PQP as their National first-line treatment for uncomplicated P. falciparum malaria following WHO’s guideline recommendation: Vietnam, Indonesia, Myanmar and Cambodia, Ghana, Senegal.

The inclusion of this product in the Essential Medicines List will hopefully facilitate its inclusion in the malaria National guidelines of the African countries.

Summary of the Efficacy Data The main efficacy results which were part of the EMA registration dossier are two Phase III clinical trials conducted by Sigma-tau in patients with uncomplicated P. falciparum malaria. The first one was conducted in children and adult Asian patients and the second one in African children (≥6 months, ≤5 years).

The Asian Phase III (3) trial was a randomised, active-controlled, non-inferiority trial, to assess the efficacy and safety of DHA/PQP in comparison with Artesunate+Mefloquine (AS+MQ) in children and adult patients affected by uncomplicated P. falciparum malaria.

A total of 767 patients received DHA/PQP and 381 AS+MQ. Results in the two co-primary populations for analysis showed a Day 63 PCR-corrected cure rate of 97.0% for DHA/PQP and 95.3% for AS+MQ (modified-ITT population) and 98.7% for DHA/PQP and 97.9% for AS+MQ (Per Protocol population), demonstrating similar good results in terms of efficacy for both the two treatments. In addition, the analysis of the 63 days of follow up showed that DHA/PQP significantly reduced the risk of new infections (Kaplan-Meier estimates of the proportions of patients with new infections on day 63 were 22.7% for DHA/PQP and 30.3% for AS+MQ, ITT population).

The African Phase III trial (4) was carried out in children affected by uncomplicated P.falciparum malaria. The study was designed as a randomised, active-controlled, non-inferiority trial, to assess the efficacy and safety of DHA/PQP in comparison with Artemether/Lumefantrine (A/L, Coartem™).

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The randomized population consisted of 1039 children treated with DHA/PQP and 514 with A/L. The results showed a Day 28 PCR-corrected cure rate of 92.7% for DHA/PQP and 94.8% for A/L (m-ITT population) and of 95.7% for both DHA/PQP and A/L (PP population). The study demonstrated that both ACTs had similar efficacy to cure uncomplicated P. falciparum malaria. In addition, the analysis of the 42 days of follow up showed that DHA/PQP significantly reduced the risk of new infections.(Kaplan-Meier estimates of the proportions of patients with new infections on day 42 were 13.6% for DHA/PQP and 24.0% for A/L, ITT population). This effect is attributable to the long half life of PQP and is expected to have a major impact to improve the health care system of the countries were malaria is endemic.

Efficacy data have been also collected in two pharmacokinetics trials carried out in patients with uncomplicated P. falciparum malaria. One trial was carried out in Burkina Faso, where 32 children (≥1 year, ≤5 years) have een treated with DHA/PQP. The Day 28 PRC-corrected cure rate was 87.5% in the ITT population and 93.3% in the PP population. A similar PK trial was carried out in Thailand, where 25 adult patients with uncomplicated P. falciparum malaria have been treated with DHA/PQP. The Day 90 PCR-corrected cure rate was 100% in the ITT population.

Similar good results have been obtained with DHA/PQP in many other clinical studies reported in literature (see section 10).

It can be concluded that treatment with DHA/PQP for uncomplicated P. falciparum malaria is effective.

Summary of Safety Data In the Asian phase III study (3), the proportion of patients experiencing at least one treatment- emergent adverse event (TEAE) was slightly lower in the DHA/PQP group compared with the AS+MQ group; 69.4% (DHA/PQP) vs. 72.4% (AS+MQ). The most frequently reported TEAEs (related and unrelated) in the DHA/PQP and AS+MQ groups, respectively, were headache (18.9% vs. 20.7%), malaria (14.5% vs. 22.6%), P. falciparum malaria (13.4% vs. 15.2%) and pyrexia (10.6% vs. 11.3%). The adverse event profiles for both DHA/PQP and AS+MQ were similar in terms of type and frequency of adverse events (AE). There were 12 serious TEAEs (1.6%) in the DHA/PQP group and three serious TEAEs (0.8%) in the AS+MQ group, including one case of encephalitis that was probably related to MQ. There were no deaths.

At enrolment, patients were mildly thrombocytopenic and showed signs of haemolysis. During the study laboratory changes were consistent with recovery from malaria.

Mild QTc interval prolongation was reported as a TEAE in 5.6% (DHA/PQP) vs. 3.2% (AS+MQ) patients. The change in QTc from baseline to Day 2 between treatments was statistically significant; by Day 7, the QT prolongation was completely resolved.

In the African phase III study (4), the proportion of patients experiencing at least one TEAE was similar between treatment groups; 79.3% (DHA/PQP) vs. 80.6% (A/L). Pyrexia (29.1% vs. 32.0%) and P. falciparum infections (19.0% vs. 25.9%) were reported more frequently in the Coartem group. The adverse event profile for both DHA/PQP and A/L was very similar in terms of type and frequency of events and was consistent with malaria expectations. There were

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similar STEAEs in the DHA/PQP group compared with the Coartem group; 1.7% vs. 1.0% (p = 0.249), respectively, as were also the related STEAEs: 1.5% vs. 0.8% (p = 0.332). There were two deaths in the study, one in the DHA/PQP group (judged unlikely related to study treatment by the investigator), and one in the Coartem group (judged possibly related by the investigator).

At recruitment, patients were anaemic and mean platelet counts were at the lower end of the normal range. The anaemia and platelet counts improved and a mild eosinophilia was observed, particularly in the Coartem-treated group.

Mild QTc prolongation (all preferred terms) was reported as a TEAE by 26 (2.5%) DHA/PQP- treated and 13 (2.6%) Coartem treated patients in the study. No arrhythmias were reported during the study.

Following the results of the phase III studies, a study properly designed for addressing the QTcprolongation has been carried-out. This study has shown that the prolongation in QTc observedat the end of the treatment with Eurartesim administered with a high or a low Kcal diet issignificantly reduced when the drug is administered in fasting conditions with water.

The safety and efficacy of Eurartesim in children aged <6 months and in children weighing <5kg has not yet been evaluated. No data are available for these pediatric subsets.

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2. Name of the focal point in WHO submitting or supporting the application

Dr. Peter Olumese, Dr A. Bosman - WHO Global Malaria Programme.

3. Name of the organisation(s) consulted and/or supporting the application

Medicines for Malaria Venture (MMV), Geneva, Switzerland.

4. International Non-proprietary Name (INN, generic name) of the medicine

Dihydroartemisinin (DHA) and Piperaquine Tetraphosphate (PQP)

ATC Code: P01BF05

Artenimol (DHA) rather than dihydroartemisinin is the correct INN for DHA therefore EMA, as an outcome of product renewal assessment (13 September 2016) recommended to use this term in the SmPC/PIL/labelling for EU markets.

5. Formulation proposed for inclusion

Film-coated tablets of a fixed-dose combination of:

 Dihydroartemisinin (DHA)  Piperaquine (PQP), as tetraphosphate

Two strengths are proposed for the above formulation:  40 mg DHA + 320 mg PQP  20 mg DHA + 160 mg PQP

6. Whether listing is requested as an individual medicine or as an example of a therapeutic group

DHA/PQP will be listed as an individual medicine.

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7. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostic or treatment facilities and skills)

Proposed indication Eurartesim is indicated for the treatment of symptomatic, uncomplicated P. falciparum malaria in adults, children and infants ≥ 6 months and/or ≥5 kg. Appropriate guidelines should be followed when treating malaria.

Proposed posology and method of administration

Eurartesim is a FDC formulated as tablets for oral administration in two strengths and the following pack sizes:  160 mg/20 mg tabs – packs of 3 tabs  320 mg/40 mg tabs of PQP/DHA – packs of 3, 6, 9, and 12 tabs

Eurartesim can be administered to adults, children and infants ≥ 6 months.

Eurartesim should be administered over three consecutive days for a total of three doses taken at the same time each day. Dosing should be based on body weight as shown in the table below.

Body Daily dose (mg) weight Tablet strength and number of tablets per dose (kg) PQP DHA 5 to <7 80 10 ½ x 160mg / 20mg tablet 7 to <13 160 20 1 x 160mg / 20mg tablet 13 to <24 320 40 1 x 320mg / 40mg tablet 24 to <36 640 80 2 x 320mg / 40mg tablets 36 to <75 960 120 3 x 320mg / 40mg tablets 75 to 100 1,280 160 4 x 320mg / 40mg tablets >100 There are no data on which to base a dose recommendation in patients weighing >100kg.

If a dose is missed, it should be taken as soon as realized and then the regimen continued until the full course of treatment has been completed.

Eurartesim should be taken with water without food. Each dose should be taken no less than 3 hours after the last food intake. No food should be taken within 3 hours after each dose. For patients unable to swallow the tablets, such as infants and young children, Eurartesim may be crushed, mixed with water and administered as slurry. If a patient vomits within 30 minutes of taking Eurartesim, the whole dose should be re- administered; if a patient vomits within 30-60 minutes, half the dose should be re- administered.Re-dosing with Eurartesim should not be attempted more than once. If the second dose is vomited, alternative antimalarial therapy should be instituted.

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No special diagnostic or treatment facilities or skills are needed.

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

Epidemiology

Malaria is a widespread disease, endemic in tropical and subtropical climates. It is caused by protozoan parasites of the genus Plasmodium which are transmitted by infected bites of the Anopheles mosquitoes. There are 5 species of Plasmodium capable of infecting humans (P. falciparum, P. vivax, P. ovale,P. malariae and P. knowlesi).

Globally It is estimated that a cumulative 1.2 billion fewer malaria cases and 6.2 million fewer malaria deaths occurred globally between 2001 and 2015.

Of the estimated 6.2 million, about 5.9 million (95%) were in children aged under 5 years.

By 2015, it was estimated that the number of malaria cases had decreased to 214 million (range: 149–303 million), and the number of deaths to 438 000 (range: 236 000–635 000).

It is also estimated that 15 countries accounted for 80% of cases, and 15 countries accounted for 78% of deaths. The global burden of mortality is dominated by countries in sub-Saharan Africa, with the Democratic Republic of the Congo and Nigeria together accounting for more than 35% of the global total of estimated malaria deaths. Decreases in case incidence and mortality rates were slowest in countries that had the largest numbers of malaria cases and deaths in 2000 (5).

Assessment of current use

Current antimalarial therapy simultaneously employs two or more blood schizontocidal drugs with independent modes of action. This improves therapeutic efficacy and also delays the development of resistance to the individual components of the combination.

To combat the development of resistance, in 2006 WHO (6) has recommended that monotherapy be banned from the markets and that malaria should be treated with a combination of an artemisinin derivative and another anti-malarial with a different mechanism of action. This is referred to as ACT. Artemisinin derivatives rapidly decrease the parasite biomass, while the presence of a second anti-malarial with a different mechanism of action reduces the probability of the emergence of resistant strains. WHO encourages the development of FDC versions of ACTs, vs co-blistered presentations which can be misused to facilitate de-facto the monotherapy use of artemisinin.

Five specific ACTs have been recommended over time by the WHO for treatment of P. falciparum

 Arthemether + lumefantrine (A/L) - FDC

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 Artesunate + amodiaquine (AS/AQ) - FDC  Artesunate + mefloquine (AS/MQ) - FDC  Artesunate + sulfadoxine-pyrimethamine (AS+SP): it is only co-blistered, no FDC version is available).  Dihydroartemisinin – piperaquine (DHA/PQP) - FDC: it was approved by the European Medicines Agency (EMA) in 27 October 2011 (trademark: Eurartesim) and included in the WHO Prequlification list on 9 October 2015. It is noteworthy that, since the 2nd edition, the WHO’s Guidelines for the Treatment of Malaria (March 2010) (7) expanded to include DHA/PQP as an ACT option for the “first-line treatment of uncomplicated P. falciparum malaria worldwide”. This addition was categorized as a “Strong Recommendation” and was included due to “High Quality Evidence.

The choice of therapy is influenced by local parasite susceptibility as well as by cost considerations, even though data from literature have shown that the use of effective therapy leads to overall cost-benefits (8).

Target population

The target population for treatment with Eurartesim includes infants aged six months or more (and with a body weight of at least 5 kg), children and adults.

Eurartesim has not been evaluated in patients with severe renal or hepatic impairment. In addition, clinical studies of Eurartesim did not include subjects aged 65 years and over or weighing more than 100 kg. Caution is needed when administering Eurartesim to these patients.

Likely impact of treatment on the disease Successful malaria control depends greatly on treatment with efficacious anti-malarial drugs. Countries have a National Malaria Treatment Policy that specifies drugs for treatment of both uncomplicated and severe malaria, malaria in pregnancy and what to do if first line treatment fails.

As drug resistance develops to existing drugs, new ones need to be introduced. For plasmodium falciparum use of two or more drugs with different modes of action in combination is now recommended to provide adequate cure rate and delay development of resistance.

Currently artemisinin-based combination therapy (ACT) is recommended for the treatment of P. falciparum malaria. Fast acting artemisinin-based compounds are combined with a drug from a different class. Companion drugs include lumefantrine, mefloquine, amodiaquine, sulfadoxine/pyrimethamine and piperaquine. Artemisinin derivatives include dihydroartemisinin, artesunate and artemether.

Implementation of the recommendation to use ACTs is widely accepted.

The malaria WHO guideline third edition (2) recommends to use ATCs to treat pregnant women with uncomplicated P. falciparum in the second and third trimester. Due to the limited data on the

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safety of artemisin-derivatives in early pregnancy (first trimester), quinine + clindamycin is recommended in this condition.

The benefits of ACTs are their high efficacy, fast action and the reduced likelihood of resistance developing. In order to make best use of them, it is critical to address issues of delivery, access and cost.

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings

Efficacy results

A total of twelve clinical studies have been conducted by Sigma-tau in humans using DHA/PQP and other two studies are currently ongoing. All of them were compliant with the requirements of the most stringent regulatory authorities. Among them, eight were PK studies to investigate the DHA and PQP pharmacokinetics and the safety of the product and two were phase III trials to demonstrate efficacy and safety of DHA/PQP in adults and children suffering from acute, uncomplicated P. falciparum malaria. Out of the eight PK studies, two were conducted in patients (so also efficacy and safety data were obtained in these studies) and six in healthy volunteers.

Both the Phase III studies were designed as open-label, randomized, active-controlled studies to demonstrate the non-inferiority of DHA/PQP in terms efficacy and safety toward the standard reference therapy which currently is AS+MQ in South East Asia and A/L (Coartem™, Novartis) in Africa.

The primary objective of both the phase III studies was to demonstrate that the PCR-corrected cure rate of DHA/PQP is non-inferior to that of the comparator. The non-inferiority margin was set at 5%. This margin was tight so that only a very small loss of efficacy was allowed in comparing the new treatment with the reference one.

The African study was focused on monoinfections from P. falciparum, while the Asian study allowed also enrolment of patients with mixed infections, i.e. P. falciparum and other forms of Plasmodia. This difference is justified on the basis of a different epidemiology of malaria in the two countries.

Phase III Asian Study (ST3073+ST3074 DM040010)

This study enrolled both male and female, adult and paediatric patients aged between 6 months and 62 years inclusive with a body weight of at least 5 kg and who had microscopically confirmed P. falciparum malaria or mixed infection and a history of fever (temperature at  37.5°C).

A total of 1150 patients were randomised in the study, according to an allocation ratio of 2:1 in favour of the DHA/PQP group. The dosing regimen was based on body weight as reported above. AS and MQ were used in accordance with WHO policy for ACT. The primary efficacy endpoint was the PCR-corrected cure rate at Day 63.

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The secondary efficacy endpoints of the study were as follows:  PCR corrected cure rates at Days 28 and 42  Uncorrected cure rates at Days 28, 42, and 63  Proportion of patients with treatment failure (TF) as defined by WHO  Proportion of aparasitaemic patients and time to parasitaemia clearance (PCT)  Proportion of afebrile patients and time to fever clearance (FCT)  Proportion of patients with gametocytes

The treatment comparison as for the safety profile was an important goal of the study (safety results are described in section 11).

Efficacy analyses were performed on the pure Intention-To-Treat population (ITT, defined as all randomised patients who received at least one dose of the study treatment), modified ITT population (m-ITT, defined as the pure ITT population with the exclusion of those patients lost-to- follow up for unknown reasons before Day 63) and the Per Protocol population (PP, defined as all randomised patients who showed no major protocol violations). The m-ITT and the PP populations were chosen as co-primary populations for analysis. Safety analyses were performed on the Safety Population, which was the same as the ITT.

Demographic characteristics of the study population are summarised in the table below. Summary of demographic characteristics in the Phase III Asian study

DHA/PQP AS+MQ Demographic Characteristic Safety & Safety & m-ITT PP m-ITT PP Pure-ITT Pure-ITT N 767 726 668 381 361 336 582 549 506 295 276 257 Males (75.88%) (75.62%) (75.75%) (77.43%) (76.45%) (76.49%) 185 177 162 86 85 79 Females (24.12%) (24.38%) (24.25%) (22.57%) (23.55%) (23.51%) Mean Age (Years) 25.44 25.39 25.23 25.79 25.87 25.96 Median Age 24.83 24.80 24.51 25.26 25.40 25.45 (Years) 0.68- 0.68- 0.68- 1.03- 1.03- 1.03- Age Range (Years) 61.58 61.58 61.58 62.43 62.43 62.43 767 726 668 381 361 336 Race: Asian (100%) (100%) (100%) (100%) (100%) (100%) Mean Weight (kg) 44.34 44.08 43.87 44.61 44.37 44.35 Median Weight 49.00 49.00 48.75 49.00 49.00 49.00 (kg) 6.50- 6.50- 6.50- 7.00- 7.00- 8.50- Weight Range (kg) 90.00 90.00 90.00 80.50 80.50 80.50

The PCR-corrected cure rates at Day 63 are summarised in the table below.

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PCR-corrected and uncorrected cure rates at Day 63 in the Phase III Asian study Treatment Difference DHA/PQP AS+MQ (DHA/PQP - AS+MQ) Study Lower Limit of one- Population Cure Rate sided 97.5% CI Chi- (n)* n % n % ∆ Without With square Continuity Continuity test, p Correction Correction PCR- 674 87.87 330 86.61 1.26% -2.87 % -3.06% 0.544 Pure-ITT corrected (n=767, 381) Uncorrected 516 67.28 227 59.58 7.70% 1.75 % 1.56 % 0.010

PCR- 704 96.97 344 95.29 1.68% -0.84% -1.04% 0.161 m-ITT corrected (n=726, 361) Uncorrected 516 71.07 227 62.88 8.19% 2.22% 2.01% 0.006

PCR- 659 98.65 326 97.02 1.63% -0.39% -0.61% 0.074 PP corrected (n=668, 336) Uncorrected 504 75.45 223 66.37 9.08% 3.07% 2.84% 0.002

In the m-ITT, the PCR-corrected cure rates at day 63 were 96.97% for DHA/PQP group vs. 95.29% for the AS+MQ group (p = 0.161). The lower limit of the 97.5% one-sided CI of the difference (DHA/PQP-AS+MQ) was -0.84%. In the PP population, the PCR-corrected cure rates at day 63 were 98.65% for the DHA/PQP group vs. 97.02% for the AS+MQ group (p = 0.074). The lower limit of the 97.5% one-sided CI was -0.39%. Both the two mentioned CIs have lower limits above the non-inferiority margin of -5%, demonstrating that DHA/PQP is non-inferior to AS+MQ. This finding was confirmed by the results on the pure ITT population and the results of all sensitivity analyses. The performance of AS+MQ was comparable with the expectations from previous studies, therefore the trial was proved to have good assay sensitivity

The estimate of the true failure rate, defined in accordance with the WHO criteria, was less than 5% (the currently “revised” WHO threshold) for both treatment groups at all considered time- points (Days 28, 42, and 63) and in any case always in favour of DHA/PQP group. When dividing these treatment failures between early (ETF) and late (LTF), at Day 63, there were no statistically significant differences between treatments, in either of the considered populations. On the contrary, at Days 28 and 42, there was a statistically significant difference between treatments in the proportion of patients with LTF in all efficacy populations. These differences were in favour of DHA/PQP.

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The difference between uncorrected cure rates at day 63 in the DHA/PQP group compared to AS+MQ was statistically significant in the two co-primary populations. In the m-ITT population, the rates were 71.07% for the DHA/PQP group vs. 62.88% for AS+MQ (p=0.006). In the PP population, the rates were 75.45% for DHA/PQP vs. 66.37% for AS+MQ (p=0.002). The lower limit of the CI of the difference (DHA/PQP - AS+MQ) was 2.22% in the m-ITT and 3.07% in the PP populations. The results in the pure ITT population were similar.

There was no statistically significant difference between treatment groups in the proportion of both aparasitaemic patients and afebrile patients up to Day 3 in either the m-ITT or PP populations (at Day 3, the proportions of aparasitaemic patients (DHA/PQP vs AS+MQ) were 69.97% vs 71.19% in the m-ITT population and 69.46% vs 70.83% in the PP population). The median time to parasite clearance (Kaplan-Meier estimate) was 2 days for both DHA/PQP and AS+MQ, in all three study populations.

In the m-ITT and PP populations there was a statistically significant difference (up to Day 28 and 21, respectively), between treatments in the proportion of patients with gametocytes. Overall, gametocyte prevalence in the DHA/PQP group was twice the one in the AS+MQ group: 9.69% vs. 4.80%, respectively (m-ITT population). Similar results were seen in the PP population. These data indicate that DHA/PQP has less gametocytocidal effect than AS+MQ. However, an ad-hoc study, in which the viability of the gametocytes is tested, would be needed to verify whether the gametocytes surviving the DHA/PQP treatment are still infectious. Anyway, ACTs are known to reduce gametocyte carriage markedly, and thus to reduce transmission, so even though DHA/PQP is apparently less gametocydal than AS+MQ, it is still likely to be better than other anti-malarial drug classes.

Phase III African Study (ST3073+ST3074 DM040011)

This study enrolled both male and female paediatric patients, aged between 6 and 59 months inclusive, with a body weight of at least 5 kg and who had microscopically confirmed P. falciparum malaria and a history of fever (auxiliary temperature at  37.5°C).

A total of 1553 patients were randomised in the trial with an allocation ratio of 2:1 (DHA/PQP : A/L). The dosing regimen was calculated by body weight as shown above. A/L (Coartem™) was used in accordance with its Summary of Product characteristics (Novartis, 2007).

The primary and secondary efficacy endpoints were the same as the Asian study with the exception of timing: the primary time-point was Day 28 while the secondary time-points were Days 14 and 42. Efficacy analyses were performed on the pure ITT, m-ITT, and the PP populations, that were defined as in the previously described study.

Demographic characteristics of the study population are summarized in the table below.

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Summary of demographic characteristics in the Phase III African study

DHA/PQP A/L Demographic Characteristic Safety/ Safety/ m-ITT PP m-ITT PP Pure-ITT Pure-ITT n 1038 1027 951 510 497 462

525 517 483 281 277 261 Males (50.58%) (50.34%) (50.79%) (55.10%) (55.73%) (56.49%)

513 510 468 220 201 Females 229 (44.9%) (49.4%) (49.66%) (49.21%) (44.27%) (43.51%)

Mean Age (Years) 2.42 2.42 2.43 2.43 2.44 2.45

Median Age (Years) 2.28 2.28 2.31 2.33 2.34 2.34

Age Range (Years) 0.51-6.99 0.51-6.99 0.51-6.99 0.49-4.98 0.49-4.98 0.49-4.98

1036 1036 949 497 462 Black 510 (100%) (99.81%) (99.81%) (99.79%) (100%) (100%)

Asian 1 (0.10%) 1 (0.10%) 1 (0.10%) 0 0 0

Other Race 1 (0.10%) 1 (0.10%) 1 (0.10%) 0 0 0

Mean Weight (kg) 11.19 11.19 11.21 11.28 11.29 11.31

Median Weight (kg) 11.0 11.0 11.0 11.0 11.0 11.0

Weight Range (kg) 6.07-25.50 6.07-25.50 6.07-25.50 6.00-21.00 6.00-21.00 6.00-21.00

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The PCR-corrected and uncorrected cure rates at Day 28 are summarised in the table below. PCR-corrected and uncorrected cure rates at Day 28 in the Phase III African study

Treatment Difference DHA/PQP Coartem™ (DHA/PQP - Coartem™)

Study Lower Limit of one- sided 97.5% CI Population Cure Rate Chi- (n)* n % n % ∆ Without With square Continuity Continuity test, p Correction Correction PCR- 938 90.37 459 90.00 0.37% -2.80 % -2.94% 0.820 Pure-ITT corrected (n=1038, 510) 910 87.67 391 76.67 11.0% 6.82 % 6.68 % <0.001 Uncorrected

PCR- 952 92.70 471 94.77 -2.07% -4.59 % -4.74% 0.128 m-ITT corrected (n=1027,497) 910 88.61 391 78.67 9.94% 5.84 % 5.69 % <0.001 Uncorrected

PCR- 910 95.69 442 95.67 0.02% -2.24 % -2.40 % 0.988 PP corrected (n=951,462) 884 92.95 376 81.39 11.56% 7.67 % 7.50 % <0.001 Uncorrected

* (n= DHA/PQP, A/L) In the m-ITT population, the PCR-corrected cure rates at Day 28 were 92.70% for DHA/PQP and 94.77% for A/L (p = 0.128). The lower limit of the 97.5% one-sided CI of the difference (DHA/PQP-A/L) was -4.59%. In the PP population, these rates were 95.69% and 95.67% for DHA/PQP and A/L, respectively (p = 0.988). The lower limit of the 97.5% one-sided CI of the difference (DHA/PQP-A/L) was -2.24%. The CIs for the two co-primary populations have lower limits above the non-inferiority margin of -5% and therefore demonstrate that DHA/PQP was non-inferior to A/L. This finding is confirmed by the results on the pure ITT population and the results of all sensitivity analyses. Furthermore, the behaviour of the comparator is as expected from literature and this allows the conclusion that the study is valid.

As for the estimate of the true failure rate, defined in accordance with the WHO criteria, it was less than 5% for both treatment groups, at Day 28. Therefore, the conclusions are the same of the Asian trial, i.e. the efficacy definition of WHO is met. The overall treatment failure was 8.76% for DHA/PQP and 18.71% for Coartem, in the m-ITT, and 5.99% vs. 17.10%, respectively, in the PP population. This treatment unbalance is explained by the difference in LTF rates between treatments, which was in favor of DHA/PQP. However, there were more ETFs in the DHA/PQP group compared with the Coartem group (1.17% vs. 0.40%, respectively, in the m-ITT). The most frequent reason for ETF was persistent vomiting at Day 0 with the use of quinine or i.v. artesunate at Day 0 (n = 9 vs. n = 2, for DHA/PQP and A/L, respectively).

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Further analysis of the data showed that the uncorrected cure rate at Day 28 was substantially higher for DHA/PQP compared with A/L. In the m-ITT population, the uncorrected cure rate at Day 28 was 88.61% for DHA/PQP vs. 78.67% for A/L, with a treatment difference of 9.94% (p < 0.001). In the PP population, the same estimate was 92.95% for DHA/PQP vs. 81.39% for A/L, with a treatment difference of 11.56% (p < 0.001). These results are confirmed in the pure ITT population.

Since the rate of recrudescence is comparable between the two treatment groups, the treatment difference observed in the uncorrected cure rate was mainly due to fewer new infections with DHA/PQP as compared to A/L. These data indicate that DHA/PQP confers more protection from acquiring new P. falciparum infections than A/L. This added protection is a tremendous advantage in Africa where malaria is hyper-endemic with an associated high morbidity, especially in young children.

In the m-ITT, 36.03% of DHA/PQP treated patients were aparasitaemic on Day 1 (24h after starting treatment) compared with 28.57% of A/L -treated patients. This difference between treatments was statistically significant (Chi-square test, p = 0.003). By Day 3, 97.66% and 98.39% of DHA/PQP and A/L treated patients respectively were aparasitaemic (Chi-square test, p = 0.279). Very similar patterns were observed in the ITT and PP populations. The median time to parasite clearance (Kaplan-Meier estimate) was 2 days for both DHA/PQP and A/L, in all three study populations.

No difference was observed between the two compared treatment groups on the results for overall fever clearance.

The proportion of patients with gametocytes at enrolment was similar between treatment groups (m-ITT population: 11.78% in DHA/PQP vs. 13.28% in A/L, p = 0.403; PP population: 11.36% in DHA/PQP vs. 12.99% A/L, p = 0.374). However, by Day 2, it was noted that the percentage of patients with gametocytaemia was greater in the DHA/PQP group compared with the A/L group: 16.65% vs. 9.26% respectively, in the m-ITT population and 16.09% vs. 9.09% respectively, in the PP population (Chi-square test, p < 0.001). This difference persisted and was statistically significant until Day 21 in both study populations. These data confirm that DHA/PQP could have less gametocydal effect than A/L.

Phase I/II Studies (ST3073+ST3074 DM04008 and DM04009)

Efficacy data have been also collected in two pharmacokinetics trials carried out in patients with uncomplicated P. falciparum malaria.

One trial (Study ST3073+ST3074 DM04008) was carried out in Burkina Faso, where 32 children (≥1 year, ≤5 years) have been treated with DHA/PQP. The Day 28 PRC-corrected cure rate was 87.5% in the ITT population and 93.3% in the PP population.

The other trial (Study ST3073+ST3074 DM04009) was carried out in Thailand where 25 adult patients with uncomplicated P. falciparum malaria have been treated with DHA/PQP. The Day 90 PCR-corrected cure rate was 100% in the ITT population.

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Efficacy Findings from Other Clinical Trials Reported in the Literature A full literature search was done, covering the period from marketing authorization of Eurartesim® (27/10/2011) up to the initial application for marketing renewal (27/10/2015). A total of 123 publications have been identified during this period. By excluding review articles, citations related to abstracts presentation to congresses/conferences, mathematical models, description of study protocols, general tolerability and pharmacokinetic studies conducted in healthy volunteers, 38 articles have been selected (9-46). Seven studies were related to clinical trials conducted with Eurartesim® (14824 treated patients) while the remaining articles to studies conducted with DHA/PQP fixed-dose combinations equivalent to Eurartesim® (6621 patients). Among the latter ones, eleven articles investigated efficacy issues (1792 patients), two explored malaria transmission (492 patients), five focused on artemisinin resistance (917 patients), four on Plasmodium vivax (419 patients) two on pregnant women (535 patients) and seven on chemoprevention (2466 patients).

Six of the seven trials conducted with Eurartesim® are relevant to patients affected by P. falciparum malaria and main efficacy results are summarized here below. The other one is relevant to treatment of patients affected by P. vivax malaria and results are reported in a subsequent section.

The 4ABC Study (10) reported a comparison of four ACTs for treating uncomplicated P. falciparum malaria in African children. Between 2007 and 2009, a non-inferiority trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine phosphate (Eurartesim®), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 months old with uncomplicated P. falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with Eurartesim®), actively followed up until day 28 and then passively for the next 6 months. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: Eurartesim® (97.3%) versus AL (95.5%) (Odds Ratio [OR]: 0.59, 95% CI: 0.37- 0.94); Eurartesim® (97.6%) versus ASAQ (96.8%) (OR: 0.74, CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, CI: 0.28-0.92). CD+A was significantly less efficacious than the other three treatments. For the PCR-uncorrected cure rates, AL was significantly less efficacious than Eurartesim® (72.7% versus 89.5%) (OR: 0.27, CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, CI: 0.30-0.53) while Eurartesim® (92.2%) had higher efficacy than ASAQ (80.8%). Day 63 results were similar to those observed at day 28. This large comparison of most available ACTs in sub-Saharan Africa showed that Eurartesim®, AL and ASAQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for Eurartesim®, followed by ASAQ and then AL.

The INESS Study (9). After the first publication appeared on Malaria journal, captured by the literature search in the above stated time interval of search, a second article appeared beginning of January 2016 (47), presenting more details on the efficacy data obtained in this trial. In order

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to provide the full data generated in this trial, results from this latter publication have been added in this description. The study was an independent observational study which was completed after recruiting 11028 patients with malaria in Burkina Faso, Mozambique, Ghana and Tanzania. Aim of the study was to evaluate the effectiveness/safety of Eurartesim® when used simulating the real life condition of use of the drug in endemic countries, for treatment of uncomplicated P. falciparum malaria. A sub-set of 1305 patients constituted the Nested group, in which intensive ECG monitoring and laboratory analyses were performed. The overall compliance to the study treatment (i.e. three doses assumed) was satisfactory: 98% (9532 patients out of 9723) for the Main group and 97.2%, (1268 patients out of 1305) for the Nested one. The baseline analyses showed that the two groups, Main and Nested, were well balanced. Most of the patients were children. The mean (SD) age of the population in study was 11.3 (13.5) years, 47.3% of patients were male. Patient distribution according to different classes of age is reported in the following table: Age characteristics in of participants who took all the three doses of Eurartesim®

Age groups (yrs) Main Study Nested Coohort Total (n (%)) N = 9598 N = 1002 N = 10591

< 6 4654 (48.5%) 331 (33.0%) 4985 (47.1%)

6- < 13 2612 (27.2%) 398 (37.7%) 3010 (28.4%)

13- < 18 753 (7.8%) 112 (11.2%) 865 (8.2%)

> 18 1570 (16.4%) 161 (16.1%) 1731 (16.3%)

The mean weight for the main group and the nested group were 26.0 kg and 28.7 kg respectively while the height was 112 cm and 125.5 cm. A total of 10591 participants successfully completed the study and were included in the analysis. Almost all the patients had a diagnosis of P.falciparum mono-infections while 90 cases had mixed infection with microscopic findings of P. falciparum and P. malariae and 4 cases of P. falciparum and P. ovale. By day 28, the unadjusted risk of recurrent symptomatic parasitaemia was 0.5% (51/10591). Of these, 47% (24/51) were seen within two weeks of treatment. Of the 51 patients who tested positive during the unscheduled visit, 22% (11/51) were not treated with an antimalarial treatment. The reason for the non-treatment of these patients, the majority (73%) of whom were within 2 weeks of treatment and still tested positive RDT, was because of the long clearance time of the RDT’s used. They were treated for other presenting conditions (ARI and gastroenteritis) and recovered. A limitation of the study was the lack of microscopically confirmation of all the recurrent symptomatic cases. Most patients (39/51) with recurrent symptomatic parasitaemia were <5 years.

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In conclusion, this large phase IV study in sub-Saharan Africa confirmed the good efficacy of Eurartesim® and its tolerability for the treatment of uncomplicated cases of Malaria.

The PREGACT Study Data provided by the Sponsor and recently published (11) The trial was performed in four African countries (Ghana, Burkina Faso, Zambia and Malawi) to determine the safety and efficacy of four distinct Artemisinin Combination Treatments (ACTs) when administered to pregnant women with uncomplicated P. falciparum malaria during the second and the third trimester of pregnancy. A total of 3,428 pregnant women with confirmed P. falciparum infection were randomized to the different study treatments, i.e. 881 to artemether-lumefantrine (AL), 843 to amodiaquine- artesunate (ASAQ), 855 to dihydroartemisinin-piperaquine (DHA/PQP, Eurartesim®) and 849 to mefloquine-artesunate (ASMQ). The Intent-To-Treat (ITT) analysis included 3423 women (880 in the AL, 842 in the ASAQ, 853 in the DHA/PQP and 848 in the ASMQ arms) while the Per Protocol (PP) analysis included 3000 women (810 in the AL, 742 in the ASAQ, 720 in the DHA/PQP and 728 in the ASMQ arms). Baseline characteristics were comparable between treatment arms. The majority of women were included in the second trimester of pregnancy and about half of them were primigravidae. Symptoms of malaria were found in 30-40% of women though only a few had fever at time of recruitment. By PP analysis, the overall PCR adjusted cure rate on day 63 was 94.8% (748/789)(95%CI: 93.0-96.1) for AL, 98.5% (718/729)(95%CI: 97.3-99.2) for ASAQ, 99.2% (701/707)(95%CI 98.2- 99.6) for DHA/PQP and 96.8% (693/716)(95%CI: 95.2-97.9) for ASMQ. The ITT analysis gave similar results. There was no significant difference between ASAQ, DHA/PQP and ASMQ. AL showed significantly lower cure rates, although the difference was smaller than the 5% non- inferiority limit. The unadjusted cure rates were significantly lower for AL (52.5%, 425/810) than for ASAQ (82.3%, 611/742), DHA/PQP (86.9%, 626/720) and ASMQ (73.8%, 537/728). AL cure rates were significantly lower than the other two tested treatments. The ITT analyses and adjustment with covariates further supported these efficacy results. At day 2, nearly all women (>99.5%) had a negative blood slide. However, parasite clearance seemed slower in women treated with AL as at day 1 24.8% (217/875) were still infected as compared to 6.9% (57/828) for ASAQ, 8.0% (67/837) for DHA/PQP, and 13.5% (113/837) for ASMQ (p<0.001). Haemoglobin changes between day 0 and day 7, day 14, day 28 and day 63 did not differ between treatment arms. In conclusion, AL showed the lowest efficacy and the shorter post-treatment prophylactic period. Considering the higher occurrence of AEs in both the ASAQ and ASMQ groups, DHA/PQP has been evaluated as the most suitable treatment for African pregnant women with P. falciparum malaria as it performed well in all countries where it was tested, with PCR-adjusted cure rates close to 100%.

Borrmann (12) investigated the responsiveness of Plasmodium falciparum infection to artemisinin-based combination treatments on the Kenyan coast from 2005 to 2008. The treatment responses of Eurartesim® versus AL in 474 children 6-59 months old with uncomplicated P. falciparum malaria was evaluated in a randomized controlled trial. As results,

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the proportion of patients with residual parasitaemia on day 1 rose from 55% in 2005-2006 to 87% in 2007-2008 (OR: 5.4, 95% CI, 2.7-11.1; P<0.001) and from 81% to 95% (OR: 4.1; 95% CI, 1.7-9.9; P = 0.002) in the Eurartesim® and AL groups, respectively. In parallel, no statistically significant increased risks (Kaplan-Meyer) of recrudescent infection by day 84, from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with Eurartesim® and AL, respectively, was estimated. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitaemia (defined as absence of fever) declined between 2005-2006 and 2007-2008 (OR body temperature >37.5°C: 2.8, 95%CI, 1.9-4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof. The authors concluded that the small decline through time of parasitological response rates to ACT treatment might be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both.

Moore (13)studied the effect of co-administered fat on the safety and efficacy of Eurartesim® in Papua New Guinean children with uncomplicated malaria. The tolerability, safety, efficacy, and pharmacokinetics of Eurartesim® administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated P. falciparum malaria. Three daily doses of Eurartesim® were given with water (n=14, group A) or milk (n=16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography- mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC0–∞) for PQ (median, 41,906 versus 36,752 µg • h/liter in groups A and B, respectively; P=0.24) or DHA (4,047 versus 4,190 µg • h/liter; P=0.67). As a conclusion, the authors stated that a small amount of fat does not change the bioavailability of Eurartesim® in children.

Desai (15) compared an intermittent screening and treatment (IST) or intermittent preventive treatment (IPT) with Eurartesim® versus IPT with sulfadoxine–pyrimethamine (SP) for the control of malaria during pregnancy in western Kenya. The study was an open-label, three-group, randomized superiority trial at four sites in western Kenya with high malaria transmission and SP resistance. The primary outcome was malaria infection at delivery, defined as a composite of peripheral or placental parasitaemia detected by placental histology, microscopy, or rapid diagnostic test. Between 2012 and 2014, 1546 women were randomly allocated to receive IST with Eurartesim® (n=515), IPT with Eurartesim® (n=516), or IPT with SP (n=515); 1368 (88%) women comprised the intention-to-treat population for the primary endpoint. Prevalence of malaria infection at delivery was lower in the IPT with Eurartesim® group than in the IPT with SP group (15 [3%] of 457 women vs 47 [10%] of 459 women; relative risk 0.32, 95% CI 0.18-0.56; p<0.0001), but not in the IST with Eurartesim® group (57 [13%] of 452 women; 1.23, 0.86-1.77; p=0.26). Compared with IPT with SP, IPT with Eurartesim® was associated with a lower incidence of malaria infection during pregnancy (192.0 vs 54.4 events per 100 person-years; incidence rate ratio [IRR] 0.28, 95% CI 0.22-0.36; p<0.0001) and clinical malaria during pregnancy (37.9 vs 6.1 events; 0.16, 0.08-0.33; p<0.0001).

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However, IST with Eurartesim® was associated with a higher incidence of malaria infection (232.0 events; IRR 1.21, CI 1.03-1.41; p=0.0177) and clinical malaria (53.4 events; IRR 1.41, CI 1.00-1.98; p=0.0475). The authors concluded that at current levels of rapid diagnostic test sensitivity, IST is not a suitable alternative to IPT with SP in the context of high SP resistance and malaria transmission. However, Eurartesim® represents a promising alternative drug to replace SP for IPT.

Efficacy of Eurartesim in P. vivax Uncomplicated Malaria Several published trials investigated the efficacy or effectiveness of ACTs for the treatment of the uncomplicated P. vivax malaria in chloroquine-resistant areas. The most commonly investigated combinations have been DHA/PQP, A/L, AS/AQ and AS+SP. Among them, the DHA/PQP combination appeared to be the most promising therapy in terms of efficacy, safety and prophylactic effect against relapses.

The third edition of the WHO Guidelines for the treatment of malaria (2) indicate that “ACT containing piperaquine, mefloquine and lumefantrine are the recommended treatment although artesunate + amodiaquine may also be effective in some areas. In the systematic review of ATCs for treating P. vivax malaria, dihydroartemisinin + piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (artemeter + lumefantrine, artesunate + amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up (RR, 0.57; 95% CI, 0.40-0.82, three trials, 1066 participants). The half-life of mefloquine is similar to that of piperaquine but use of dihydroartemisin + piperaquine in P.vivax mono-infections has not been compared directly in trials with use of artesunate – mefloquine. In the first trimester of pregnancy, quinine should be used in place of ACT”

More recently, one publication presented the results of a comparative study (14) investigating the efficacy of primaquine against relapse when administered with quinine or Eurartesim® for the treatment of the acute P. vivax infection. The study was a randomized, open-label trial for the radical cure of P.vivax malaria. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute P. vivax malaria were eligible for the study. One hundred sixteen enrolled subjects were randomized to receive artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or Eurartesim® daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered Eurartesim® plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for Eurartesim® plus primaquine. The improvement observed in the Eurartesim® plus primaquine group confirmed the previous data showing a higher prophylactic effect of Eurartesim® plus primaquine, against malaria relapses, related to the longer half-life of DHA/PPQ.

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Summary of available estimated of Comparative Effectiveness

Similar results as those observed in the Asian and African Phase III trials have been reported in the literature. From the 38 identified articles published during four years after the date of marketing authorization of Eurartesim®, it is shown that full courses of Eurartesim® or other equivalent DHA/PQP fixed-dose combinations have been administered to more than Twenty-thousand patients. Overall, the published data highlight comparable cure rates of Eurartesim® with respect to the other ACTs (e.g. not inferior to AL and ASAQ in the treatment of P. falciparum malaria). In addition, the treatment with DHA/PQP confers better protection against parasite re-infection due to the longer half-life of piperaquine with respect to other partner drugs of ACTs. For this property, Eurartesim® and other DHA/PQP combinations are useful as preventive therapy and are still under investigation in several trials of malaria chemoprevention. Eurartesim® is also shown to be effective for blood-stage parasite clearance of uncomplicated P. vivax malaria and highly efficacious, when combined with primaquine, for the radical cure of this infection. Regarding the use of ACTs in pregnancy, the published papers show that DHA/PQP treatment in the second and third trimesters is safe and highly effective. Moreover, Eurartesim® represents a promising alternative drug to replace sulfadoxine-pyrimethamine for intermittent preventive treatment during pregnancy. In accordance to the publications mentioned above, the last edition of WHO guidelines for the treatment of malaria (2) includes the dihydroartemisinin/piperaquine combination in the list of recommended ACTs for first-line treatments of uncomplicated P. falciparum and P. vivax malaria. Furthermore, the guidelines recommends DAH/PQP and other ACTs for the treatment of pregnant women with uncomplicated malaria during the second and third trimesters of pregnancy and for the treatment of non-immune travellers with uncomplicated P. falciparum malaria returning to non-endemic settings.

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10. Review of harm and toxicity: summary of evidence on safety

Patient Exposure

The safety database for exposure of patients to DHA/PPQ consists primarily of data from four completed clinical studies sponsored by sigma tau, and two ongoing trial for a total of 2175 adult and paediatric patients with malaria. Furthermore, data from eight studies in 401 healthy volunteers are also included.

Information about the two ongoing Sigma-tau sponsored clinical trials are reported here below:

• A phase II clinical trial on a new paediatric formulation of Eurartesim (ST3073-ST3074- DM12-002): “A Phase II, open label, multicenter, pharmacokinetic, pharmacodynamics and safety study of a new paediatric Eurartesim dispersible formulation and crushed film-coated Eurartesim tablet in infant patients with Plasmodium falciparum malaria”.

• A proof of concept study on the efficacy of Eurartesim® in imported P. vivax malaria cases (ST3073-ST3074-DM13-001): “Proof of Concept Study of Eurartesim® in Patients with Imported Uncomplicated Plasmodium vivax Malaria”.

The first study is a PK/PD study involving 300 children aged from 6 to 12 months. 200 children were treated with a new paediatric formulation, i.e. Eurartesim dispersible tablets, and the remaining 100 children were treated with the Standard Eurartesim® formulation, administered as crushed tablets. The enrolment of the 300 infants has been completed but the final report is not yet available.

The second study is a multi-centre, single-arm study to collect preliminary data on efficacy of Eurartesim® in adult patients with uncomplicated Plasmodium vivax malaria. One hundred adult (age >18 years) patients are to be recruited in 13 European and one Israelian sites. Thirteen patients have been enrolled from study start to October 2015 (the DLP of this analysis).

Finally, a third study was started in India to evaluate safety and tolerability of Eurartesim® in Indian children affected by uncomplicated malaria. No patients have been recruited till the DLP of the present analysis.

The cumulative number of subjects exposed to Eurartesim® from Sponsored Phase I-III Clinical Trials from DIBD to October 27th, 2015 is reported in the following table:

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Cumulative Subject Exposure to Eurartesim® from Sponsored Phase I-III Clinical Trials from DIBD to October 27th, 2015

Number of subjects Treatment Patients Healthy Total

Eurartesim® 2175 401 2576 Comparators 891 130 1021

Considered studies on patients: ST3073-ST3074 DM040011 (Eurartesim: N=1038; Coartem: N=510) ST3073-ST3074 DM04008 (Eurartesim: N=32) ST3073-ST3074 DM040010 (Eurartesim: N=767; Artesunate & Mefloquine: N=381) ST3073-ST3074 DM04009 (Eurartesim: N=25) ST3073-ST3074 DM12002 (Eurartesim: N=300, ongoing study) ST3073-ST3074 DM13001 (Eurartesim: N=13, ongoing study)

Considered studies on healthy volunteers: ART-DFM 05002 (Eurartesim: N=16) – PK study on healthy volunteers ST3073-ST3074 DM09006 (Eurartesim: N=152; Riamet: N=68; Izilox: N=62) – QTc study ST3073-ST3074 DM09007 (Eurartesim: N=80) – Study on Asian/Caucasian subjects ST3073-ST3074 DM09008 (Eurartesim: N=37) – Food Effect study ST3073-ST3074 DM11001 (Eurartesim: N=18) – DDI study on Midazolam ST3073-ST3074 DM11002 (Eurartesim: N=36) – DDI study on Clarithromycin ST3073-ST3074 DM11003 (Eurartesim: N=26) – DDI study on oral contraceptive ST3073-ST3074 DM12001 (Eurartesim: N=36) – Relative bioavailability study

The following table report the cumulative subject exposure to Eurartesim® according to age and sex.

Cumulative Subject Exposure to Eurartesim® from Sponsored Phase I-III Clinical Trials by Age and Sex (Trials from DIBD to October 27th, 2015) Number of subjects Age range Male Female Total Patients Healthy Patients Healthy

<1 y 208 0 224 0 432 1-2 y 149 0 160 0 309 2-5 y 353 0 333 0 686 5-12 y 34 0 34 0 68

12- 18 49 0 27 0 76 18-64 500 289 104 112 1005 Total 1293 289 882 112 2576

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All exposed subjects received DHA and PPQ in the same 1:8 ratio, adjusted by body weight according to the table presented in section 7.

Given the very limited numerical contribution of the pediatric patient population from the Asian pivotal study, they were not integrated with the data coming from the African studies on children. A cumulative tabulation of the SAEs occurred in Pediatric Population (African Patients) from the DIBD up to the DLP of this analysis (27 October 2015) is reported in the following table.

SAEs in the Safety Population from DIBD (Pediatric Population - African Patients) MedDRA version(s): 8.1, 17.0, 17.1 Eurartesim® Coartem® Patients patients System Organ Class Primary Preferred Term N=1370 N=510 n % n % Blood and lymphatic system disorders Anemia 1 0.07% 1 0.20% Gastrointestinal disorders Intussusception 1 0.07% 0 0.00% General disorders and administration site conditions Pyrexia 3 0.22% 0 0.00% Sudden death 1 0.07% 1 0.20% Hepatobiliary disorder Hepatitis 2 0.15% 0 0.00% Jaundice 0 0.00% 1 0.20% Infections and infestations Bacterial infection 1* 0.07% 0 0.00% Bronchiolitis 1 0.07% 0 0.00% Gastroenteritis 1 0.07% 0 0.00% Malaria 1* 0.07% 0 0.00% P. falciparum Infection 5 0.36% 0 0.00% Pneumonia 3 0.22% 0 0.00% Nervous system disorder Convulsion 1 0.07% 1 0.20% Febrile convulsion 1 0.07% 0 0.00% Respiratory, thoracic and mediastinal disorders Asthma 0 0.00% 1 0.20% Considered studies: ST3073-ST3074 DM040011 (Eurartesim: N=1038; Coartem: N=510) ST3073-ST3074 DM04008 (Eurartesim: N=32) ST3073-ST3074 DM12002 (Eurartesim: N=300, ongoing study) *This SAE is from an ongoing study.

The following table summarizes the related SAEs occurred in African Children patients:

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Related SAEs in the Safety Population from DIBD (Pediatric Population - African Patients) MedDRA version(s): 8.1 Eurartesim® Coartem® patients patients System Organ Class N=1370 N=510 Primary Preferred Term n % n % Blood and lymphatic system disorders Anemia 1 0.07% 1 0.20% Gastrointestinal disorders Intussusception 1 0.07% 0 0.00% General disorders and administration site conditions Pyrexia 2 0.15% 0 0.00% Sudden death 1 0.07% 1 0.20% Hepatobiliary disorder Hepatitis 2 0.15% 0 0.00% Jaundice 0 0.00% 1 0.20% Infections and infestations Bronchiolitis 1 0.07% 0 0.00% Gastroenteritis 1 0.07% 0 0.00% P. falciparum Infection 3 0.22% 0 0.00% Pneumonia 3 0.22% 0 0.00% Nervous system disorder Convulsion 1 0.07% 0 0.00% Febrile convulsion 1 0.07% 0 0.00% Respiratory, thoracic and mediastinal disorders Asthma 0 0.00% 1 0.20% Related SAEs = Serious adverse events for which the investigator classifies the relationship to drug as 'unlikely', 'possible', 'probable', 'definitely related', or whose classification is missing

Considered studies: ST3073-ST3074 DM040011 (Eurartesim: N=1038; Coartem: N=510) ST3073-ST3074 DM04008 (Eurartesim: N=32) ST3073-ST3074 DM12002 (Eurartesim: N=300, ongoing study)

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Similar cumulative tabulations for the SAEs occurred in Adult Population are reported in the following tables.

SAEs in the Safety Population from DIBD (Adult Patients Population) MedDRA version(s): 8.1 Eurartesim® AS+MQ patients patients System Organ Class N=805 N=381 Primary Preferred Term n % n % Blood and lymphatic system disorders Anemia 2 0.25% 1 0.26% Cardiac disorders Wolf-Parkinson-White Syndrome 1 0.12% 0 0.00% Infections and infestations P. falciparum Infection 3 0.37% 0 0.00% Pyelonephritis 1 0.12% 0 0.00% Pyelonephritis acute 1 0.12% 0 0.00% Viral infection 1 0.12% 0 0.00% Nervous system disorder Convulsion 0 0.00% 1 0.26% Encephalitis 1 0.12% 1 0.26% Grand mal convulsion 1 0.12% 0 0.00% Respiratory, thoracic and mediastinal disorders Pneumonia aspiration 1 0.12% 0 0.00% Considered studies: ST3073-ST3074 DM040010 (Eurartesim: N=767; AS+MQ: N=381) ST3073-ST3074 DM04009 (Eurartesim: N=25) ST3073-ST3074 DM13001 (Eurartesim: N=13, ongoing study) AS+MQ=Artesunate & Mefloquine

Related SAEs in the Safety Population from DIBD (Adult Patients Population) MedDRA version(s): 8.1 Eurartesim® AS+MQ patients patients System Organ Class N=805 N=381 Primary Preferred Term n % n % Blood and lymphatic system disorders Anemia 2 0.25% 1 0.26% Cardiac disorders Wolf-Parkinson-White Syndrome 1 0.12% 0 0.00% Infections and infestations Viral infection 1 0.12% 0 0.00% Nervous system disorder Convulsion 0 0.00% 1 0.26% Encephalitis 1 0.12% 1 0.26% Grand mal convulsion 1 0.12% 0 0.00%

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Related SAEs = Serious adverse events for which the investigator classifies the relationship to drug as 'unlikely', 'possible', 'probable', 'definitely related', or whose classification is missing

Considered studies: ST3073-ST3074 DM040010 (Eurartesim: N=767; AS+MQ: N=381) ST3073-ST3074 DM04009 (Eurartesim: N=25) ST3073-ST3074 DM13001 (Eurartesim: N=13, ongoing study) AS+MQ=Artesunate & Mefloquine

No SAEs occurred in healthy volunteers.

Description of Adverse Effects/Reactions in pivotal Phase III trials

There were 2 deaths in the pivotal study programme (both occurring in Study DM04011: one in DHA/PPQ and one in A/L). No concerns arise from the incidence of such a number of deaths in the respective treatment groups, or from a detailed consideration of the individual narratives.

The incidence of the serious treatment-emergent adverse events (TEAEs), plus the serious TEAEs related to the study drug, in the pivotal studies is summarised in the table below:

Serious Treatment-Emergent Adverse Events in Pivotal Studies

Total Related Total Related Total Study STEAEs STEAEs STEAEs STEAEs STEAEs (DHA/PPQ) (DHA/PPQ) (Comparator) (Comparator) DM040010 15 12 6 3 3 (Asia) (1.3%) (1.6%) (0.8%) (0.8%) (0.8%) DM040011 21 18 15 5 4 (Africa) (1.4%) (1.7%) (1.5%) (1.0%) (0.8%)

There were no statistically significant differences in the number of serious TEAEs or drug-related serious TEAEs between treatment groups, in either studies. Two serious TEAEs of “anaemia” in the Eurartesim group of Study DM04010 are in fact likely to have been due to disease pathology rather than to drug treatment. In addition, one case of Wolf-Parkinson-White syndrome was recorded as a serious TEAE: since this is in fact a congenital condition, this assignment of relatedness appears incorrect.

Overall, the nature of serious TEAEs is in line with expectations for this patient population. The distribution of serious TEAEs between treatment groups gives no cause for concern.

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The most common adverse events in the pivotal studies are shown in the table below: Common TEAEs (5% in Any Treatment Group) in Pivotal Studies

Proportion of patients (%)

TEAE Study DM04010 (Asia) Study DM04011 (Africa) DHA/PPQ AS+MQ DHA/PPQ A/L Headache 18.0 20.2 Malaria 14.5 22.6 P. falciparum Infection 13.4 15.2 19.0 25.8 Pyrexia 10.6 11.3 29.1 32.0 Eosinophilia 8.5 10.0 Cough 8.0 10.0 39.8 38.0 Anaemia 7.3 6.6 Myalgia 6.0 5.8 Arthralgia 5.5 5.5 ECG QT corrected prolonged 5.4 4.2 Abdominal Pain 5.2 5.3 Asthenia 5.0 7.6 Anorexia 5.0 5.5 5.8 7.7 Nausea 2.9 6.8 Vomiting 2.5 6.3 6.8 6.9 Dizziness 1.4 6.3 Influenza 21.0 18.6 Diarrhoea 13.7 12.0 AS+MQ: artesunate+mefloquine; A/L: arthemether/lumefantrine (Coartem) Five common events were recorded in both pivotal studies.The most notable finding is the incidence of P.falciparum infection. The between-group differences were 1.8% and 6.9% (both in favour of Eurartesim). The apparent reduced rate of new falciparum infection following treatment with Eurartesim is certainly of relevance to any patient who remains in a malaria endemic area. The larger treatment difference observed in the African study probably reflects the fact that this is an area of stable transmission (and therefore the risk of new infection is inherently higher). Pyrexia, anorexia and vomiting occurred with similar or lower frequency in the Eurartesim groups than in the comparator groups. Incidence of cough was higher for Eurartesim in the Asian study and higher in the African study, but in each case the difference was no more than 2%.

Adverse events occurring at any frequency and for which a between-group frequency difference of 2% was observed are shown in the table below:

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TEAEs with Between-group Differences 2% in Pivotal Studies

Proportion of patients (%)

TEAE Study DM04010 (Asia) Study DM04011 (Africa)

DHA/PPQ AS+MQ ∆ (%) * DHA/PPQ A/L ∆ (%) * Sinus bradycardia 4.2 1.3 2.9 Nausea 2.9 6.8 3.9 Vomiting 2.5 6.3 3.8 Asthenia 5.0 7.6 2.6 Malaria 14.5 22.6 8.1 Dizziness 1.4 6.3 4.9 Headache 18.0 20.2 2.2 Pyrexia 29.1 32.0 2.9 Influenza 21.0 18.6 2.4 P falciparum infection 19.0 25.9 6.9

AS+MQ: artesunate+mefloquine; A/L: arthemether/lumefantrine (Coartem) *: Values on the left of the column indicate an excess in the DHA/PPQ group; numbers on the right of the column indicate an excess in the comparator group.

The key observations are:  Only 2 events in the pivotal studies (sinus bradycardia and influenza) registered an excess of 2% in the DHA/PPQ group.  Far more events (8 events) were more frequent in the comparator arms. These included malaria (8.1% excess in the Asian study) and P. falciparum infection (6.9% excess in the African study).

Assessments of relatedness concluded that nausea, asthenia, dizziness, influenza, P. falciparum infection and anorexia were the only TEAEs related to treatment. Of these, only influenza occurred more frequently in the DHA/PPQ groups. The remaining drug-realated TEAEs were all less common on DHA/PPQ than on comparator.

The overall picture with regard to the incidence of TEAEs is therefore highly reassuring. Very few events were recorded at higher frequency for DHA/PPQ than in comparator groups; even here, the excesses were modest and the events themselves are not of major clinical concern. In general, excesses in the comparator groups were also modest, with the important exceptions of new malaria infections. These occurred with very considerably higher frequency in comparator arms, strongly implying an advantage of real clinical importance for DHA/PPQ.

In addition to adverse events, the following parameters were examined in the pivotal studies sponsored by Sigma-tau:

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1. Physical examinations and vital signs: Changes in vital signs from baseline to end-of- study were all directly attributable to recovery from malaria and were apparent irrespective of treatment allocation. 2. Laboratory values: Haematology and biochemistry evaluations (both pivotal studies) plus urinalysis results (Study DM04010 only) showed changes from baseline to end-of-study. These changes were all directly attributable to recovery from malaria and were apparent irrespective of treatment allocation. There was no evidence of any unwanted effect of DHA / PPQ treatment on any laboratory parameter. 3. ECGs: A rigorous evaluation of cardiac safety was undertaken in the pivotal studies. ECGs were taken on Days 0, 2 and 7 and centrally read; the QTc prolongation potential was analysed according to the ICH E14 guideline. The analyses showed that:  At baseline, a QTc prolongation is associated with the malaria infection state;  On Day 2, a higher proportions of patients with borderline and prolonged QTc values were present in the DHA/PPQ group with comparison to the comparator groups;  By Day 7, differences in the proportions of patients with borderline and prolonged QTc had resolved;  No patients with QTc >500msec were present in either study at any timepoint.  This short-term QTc prolongation does not translate into a tangible risk of suffering clinically significant TEAEs that are known to be associated with QT interval prolongation.

Description of Other relevant safety information from other clinical trials

To clarify the relevance of the ECG findings observed in the pivotal trials, Sigma-tau agreed with EMA’s request to perform a specific thorough QTc study. The study enrolled healthy volunteers being administered DHA/PPQ either in fasting conditions (n=40), or following a low (n=64) or high (n=40) Kcal meal. Control subjects were administered A/L after a low Kcal meal (n=64 subjects), or placebo plus moxifloxacin (n=40 subjects).

The results of this study showed that there was a food-dependent effect of Eurartesim on the QTc prolongation, which correlates with the plasma levels of PPQ, while it is quite independent of DHA plasma concentrations. Specifically:  In fasting condition, DHA/PPQ causes a mean QTcF prolongation of 21.0 ms (95% CI: 15.7-26.4 ms) over placebo. This change is similar to that reported in patients (Mytton OT, 2007) were the prolongation for QTcF was 29 ms. If we consider about 10 ms the QTcF prolongation given by placebo (not used in this trial), the “true value” should be around +20 ms. The Authors concluded that “at therapeutic doses, DP does not have clinically significant effects on the electrocardiogram.”  No subject in the DHA/PPQ fasting arm had a maximum time-matched actual value of QTcF greater than 480 ms, nor a maximum time-matched change from baseline greater than 60 msec, both being thresholds of concern. Due to these findings, DHA/PPQ dosing conditions have been modified in the Summary of Product Characteristics (SmPC), which now states that Eurartesim should be administered with water without food.

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Generally speaking, all the Phase 1 studies in healthy volunteers did not show any significant adverse event related to the study drug.

The drug drug interaction study, aimed to evidence possible Eurartesim® interaction with other drugs metabolized by the CYP3A4, investigated the effect of Eurartesim® on the pharmacokinetics of a clinically relevant dose of midazolam, a well-recognised CYP3A4 substrate, in 18 healthy male volunteers. The results showed that the concomitant administration of Eurartesim® with a drug that is a substrate for the CYP3A4 induces an increase of rate and extent of exposure of 21% for Cmax and 65% for AUC0-t and AUC0-inf of the midazolam and a decrease of about 40% in midazolam clearance. The exposure to midazolam observed one week after last administration of Eurartesim® was similar to that observed when midazolam was administered alone, demonstrating that the effect of Eurartesim® on CYP3A4, one week after the administration, is not present anymore.

According to this results, Eurartesim® can be classified as a mild inhibitor of CYP3A4 as it caused a 1.25 to 2 fold increase of midazolam exposure. This mild inhibiting effect of CYP3A4 exerted by Eurartesim® can have a clinical significance only in case of concomitant administration of drugs having a narrow therapeutic regimen and being mainly metabolised throughout CYP3A4.

The second drug-drug interaction study was aimed to assess the effect of clarithromycin on piperaquine metabolism since piperaquine is also metabolized by CYP3A4 and clarithromycin is a potent CYP3A4 activity inhibitor. The concomitant administration of the two drugs led to an increase of geometric mean PQ Cmax of about 45% and AUC0-t and AUC0-24 of about 40%.

The 90% CI of PQ rate of absorption and extent of exposure geometric mean ratio (clarithromycin + Eurartesim® /placebo + Eurartesim®) were partly excluded from the bioequivalence reference range (0.80-1.25), the upper limit of the 90% CI being higher than 1.25.

In conclusion, based on this study results, clarithromycin, a potent inhibitor of CYP3A4 activity, mildly inhibited PQ metabolism, leading to a less than 2-fold increase of the geometric mean PQ exposure (i.e., increase of about 40% of GM AUC0-24).

The result of this study confirmed the contraindication that had been already reported in the SmPC. The last drug-drug interaction study was conducted in order to investigate the Potential interaction of Eurartesim® on the pharmacokinetics of oral contraceptives (based on ethinyl estradiol/levonorgestrel). It investigated the impact of a full treatment course of Eurartesim® on the pharmacokinetics and the efficacy of ethinylestradiol and levonorgestrel, taken as contraceptive treatment in 24 healthy female volunteers of childbearing potential. The co-administration with Eurartesim® showed that geometric mean exposure of ethinyl estradiol was increased by about 5.5%. The 90% CI of geometric mean ratio of AUC0-t was within the bioequivalence range [0.80-1.25]. Differently, an increase of ethinyl estradiol rate of absorption ® (expressed by Cmax) of about 28% was observed after the co-administration of Eurartesim with oral contraceptive. For ethinyl estradiol Cmax, the upper bound of 90% CI was excluded from the bioequivalence range.

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One week after the Eurartesim administration no significant interaction between the two drugs have been evidenced. These results suggest that the inhibitory effect of PQ on the pre-systemic metabolism of ethinyl estradiol, principally mediated by CYP3A, was not present one week after last administration of Eurartesim®. In the meantime, it appears unlikely that, the about 28% increase of ethinyl estradiol rate of absorption observed when oral contraceptive dose was coadministered together with Eurartesim® could have a negative impact on the efficacy of oral contraception, since this difference lasted a limited period of time and a transient increase in ethinyl estradiol is unlikely to reduce its activity. Moreover, the evaluation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels also suggest that Eurartesim® did not modify the activity of oral contraception.

The co-administration of Eurartesim® with oral contraceptive did not modify significantly levonorgestrel Cmax; its exposure was slightly increased by 11% when coadministration was given. Levonorgestrel exposure and rate of absorption (expressed by geometric mean of AUC0-t and Cmax, respectively) decreased of about 12% and 11%, respectively one week after last administration of Eurartesim® compared to when oral contraceptive was administered alone. The 90% CI of geometric mean ratio of both PK parameters was within the bioequivalence range. Progesterone plasma concentrations were not quantifiable in both periods except for one subject in the period of oral contraceptive administration. The results of this study show that Eurartesim® does not exert any significant drug-drug interaction with oral contraceptive containing ethinylestradiol and levonorgestrel.

Safety of DHA/PPQ from completed non interventional studies

In the INESS study (9, 47), a total of 11,028 patients with a diagnosis of uncomplicated malaria were treated with Eurartesim®: 9,723 were enrolled in the Main group and 1,305 composed the Nested group which was assessed more closely with laboratory analyses and ECGs at several time points.

In the Main group, 404 patients experienced a total of 592 AEs, out of whom 33 patients reported 51 serious AEs. In the Nested group 135 patients experienced 187 AEs, out of whom 9 patients experienced 11 serious AEs. In both the Main and the Nested groups the most frequent SAEs were infections and infestations, gastrointestinal disorders, general disorders and administrative site conditions, and respiratory thoracic and mediastinal disorders. Under cardiac disorders, there were only two cases of palpitations. The related SAEs were 12, experienced by 7 patients in the Main group, and 5, experienced by 3 patients in the Nested group. There were six cases of deaths, all of them judged not study related.

All the analyses on the QT interval prolongation have been performed considering the 960 patients of the Nested group having the central ECG readings (CARDIABASE laboratory). Both Fredericia (QTcF) and Bazett (QTcB) corrected QT values were recorded but QTcF values were given primary focus

No patient had QTcF>500 msec prior to the Day 3 pre-dose. Two patients had QTcF>500 msec after having received the last dose of the study drug. They returned to QTcF<500 at the Day 7 observation. On Day 3 post-dose, 80 patients had QTcF increased with respect to Baseline by more than 60ms. Only six of them did not return to the Baseline values on Day 7, i.e. they still had a delta from Baseline above 60 msec, but all of them had QTcF below 450 msec.

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Safety from ongoing Non-Interventional Study

Safety Registry (Protocol No. 3381) The study is conducted in seven European countries: Belgium, France, Germany, Italy, The Netherlands, Spain and the UK. One hundred eighty-one patients have been included up to the 27th of October (DLP of the present document).

At the DLP of the present document, 15 SAEs and 3 AESIs (QTc prolongations) were reported. They are summarized in the tables here below.

SAEs from the Safety Registry at the DLP (27 October 2015) Date First Reporter's Sponsor's Causality for # Case Receipt Preferred Term Causality Causality the analysis ST2013.0896 03JUL2013 Hepatitis Suspected Suspected Suspected Nausea Possible Suspected Suspected Vomiting Possible Suspected Suspected ST2014.1633 04NOV2014 Headache Not Related Probable Suspected Vomiting Not Related Probable Suspected ST2014.1956 10NOV2014 Atypical pneumonia Unsuspected Possible Suspected Headache Unsuspected Possible Suspected Pyrexia Unsuspected Possible Suspected Vomiting Unsuspected Possible Suspected ST2014.2226 17DEC2014 Pneumonia bacterial Not Related Not Related Unsuspected ST2015.0591 12JAN2015 Malaria Not Related Not Related Unsuspected ST2015.1073 09JUN2015 Hepatitis acute Unsuspected Suspected Suspected ST2015.1150 24JUN2015 Acute kidney injury Unsuspected Doubtful Suspected ST2015.1471 19AUG2015 Haemolysis Suspected Suspected Suspected ST2015.1752 13OCT2015 Anaemia Suspected Suspected Suspected

AESIs from the Safety Registry at the DLP (27 October 2015)

Date First Reporter's Sponsor's Causality for # Case Receipt Preferred Term Causality Causality the analysis ST2013.0913 02JUL2013 Electrocardiogram QT prolonged Suspected Suspected Suspected (patient 330001/1) ST2015.0956 13APR2015 Electrocardiogram QT prolonged Suspected Suspected Suspected (patient 320001/8) ST2015.0964 13APR2015 Electrocardiogram QT prolonged Suspected Suspected Suspected (patient 390001/9)

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Safety data on Reproductive Toxicity

Four IICTs were conducted in pregnant women. Recently, the results of the PREGACT and the ISTp Malawi studies have been published and are presented here below.

PREGACT study (11)

The PREGACT study was performed in four African countries (Ghana, Burkina Faso, Zambia and Malawi) to determine the safety and efficacy of four distinct Artemisinin Combination Treatments (ACTs) when administered to pregnant women with uncomplicated P. falciparum malaria during the second and the third trimester of pregnancy. A total of 3,428 pregnant women with confirmed P. falciparum infection were randomized to the different study treatments, i.e. 881 to artemether-lumefantrine (AL), 843 to amodiaquine- artesunate (AQAS), 855 to dihydroartemisinin-piperaquine (DHA/PQP, which was actually Eurartesim®) and 849 to mefloquine-artesunate (MQAS). The Intent-To-Treat (ITT) analysis included 3423 women (880 in the AL, 842 in the AQAS, 853 in the DHA/PQP and 848 in the MQAS arms) while the Per Protocol (PP) analysis included 3000 women (810 in the AL, 742 in the ASAQ, 720 in the DHA/PQP and 728 in the MQAS arms). A total of 72 SAEs occurred during the 63-day follow up, including one death in the MQAS arm, approximately one month after having received the study treatment and probably due to meningitis. There were 10 SAEs reported as treatment-related, 5 in the ASAQ arm (2 anaemia cases, one with upper abdominal pain and 2 women with malaise), 4 in the MQAS arm (one abdominal pain, 2 vomiting cases and one woman with malaise), and 1 in the DHA/PQP arm (one possible adverse drug reaction). The latter case was a woman who complained of vomiting, headache and general weakness 2 days after the completion of treatment. She was hospitalised for 2 days and recovered completely. Patients in the MQAS (84.9%, 722/850) and the ASAQ (79.0%, 665/842) arms had a significantly higher incidence of any Adverse Event (AE) compared to the AL (72.8%, 641/881) and DHA/PQP (70.4%, 602/855) arms (P<0.001). Similarly, drug- related AEs were significantly more frequent in the MQAS (50.6%, 430/850) and ASAQ (48.5%, 408/842) arms than in the DHA/PQP (20.6%, 176/855) and AL (11.5%, 101/881) arms (P<0.001). Such differences were mainly due to the significantly higher occurrence of asthenia, decreased appetite, dizziness, nausea, and vomiting among women treated with MQAS or ASAQ. In conclusion, AL had the best tolerability profile but the lowest efficacy and the shorter post- treatment prophylactic period. Considering the higher occurrence of AEs in both the AQAS and MQAS groups, DHA/PQP has been evaluated as the most suitable treatment for African pregnant women with P. falciparum malaria as it performed well in all countries where it was tested, with PCR-adjusted cure rates close to 100%.

ISTp study (48)

The ISTp Malawi study was performed in three Malawian sites with high SP resistance in order to evaluate, as an alternative strategy to IPTp-SP, the efficacy and safety of scheduled intermittent screening with malaria Rapid Diagnostic Tests (RDTs) and treatment of RDT- positive women with dihydroartemisinin-piperaquine (ISTp-DP). A total of 1873 women at 16.18 weeks of gestation were recruited (paucigravidae=1155; multigravidae=718) of whom 923 in the IPTp-SP arm and 920 in the ISTp-DP arm. 1,722

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(91.9%) women were seen at delivery. Ultimately, 1,689 (90.2%) contributed to the primary morbidity outcome and 1,636 (87.3%) to the primary outcome of malaria infection at delivery. The baseline characteristics were well balanced, within each gravidity strata and overall. At baseline, about half of the women were infected with malaria parasites. In both arms, the median (IQR) follow-up time was 4.0 (3.2-4.7) months and median (range) number of scheduled visits was 4 (1-4). In the ISTp-DP arm, 38.5%, 42.7%, 17.3% and 1.4% received 0, 1, 2, 3, courses of DP respectively. Among paucigravidae, the prevalence of SGA/LBW/PT (Small-for-Gestational-Age/Low-Birth- Weight/Preterm) was similar in the ISTp-DP (33.8%) and IPTp-SP (30.5%) arms (RR=1.11, 95% CI 0.93-1.32, p=0.261). The prevalence was also similar between arms among multigravidae. Among multigravidae, the risk of malaria at delivery was significantly higher in the ISTp-DP (34.8%) than in the IPTp-SP (27.3%) arm (RR=1.27 (1.01-1.61), p=0.044). This was also evident among paucigravidae and all gravidae. In absolute terms, the risk of malaria was increased in multigravidae by 7.5% (0.3-14.7) and amongst all gravidae by 7.2% (2.4-12.0). Following enrolment, 45.8% of women had >=1 episode of malaria infection prior to delivery (PCR or microscopy) and 11.4% had >=1 episode of clinical malaria and these were similar in both arms. At delivery, 22.3% of women had peripheral malaria detected by PCR, RDT or microscopy and this was higher in the ISTp-DP arm (RR=1.33 [1.11-1.60], p=0.002). The overall prevalence of placental malaria detected by histology, PCR, RDT or microscopy was 38% and higher in the ISTp-DP arm: RR=1.14 (1.01-1.29), p=0.036. Congenital malaria was common (12.0%) in both groups. At delivery, the mean haemoglobin concentration was higher, and the prevalence of anemia (Hb<11g/dL) lower in paucigravidae in the ISTp-DP arm relative to the ITPp-SP arm. LBW was more common in the ISTp-DP arm (RR=1.31 [0.98-1.73], p=0.067). Overall DP was well tolerated. There was no difference between arms in the number of maternal SAEs or deaths. There were no severe cutaneous reactions. Foetal loss was highest in the ISTp-DP arm (2.6% vs 1.3%). Further stratified analysis within the ISTp-DP arm showed that this was highest among women who had never received DP (i.e. pregnancies who remained RDT- negative throughout) (3.1% vs 2.2% in DP recipients). Perinatal, neonatal and infant (by 6-8 weeks) mortality were also higher in the ISTp-DP arm (not statistically significant). Overall, fetal loss or infant death by the end of the follow-up period at 6-8 weeks occurred more often in the ISTp-DP (4.0%) than in the IPTp-SP (2.3%) arm (RR=1.76 [1.04-2.98], p=0.036). One case of neonatal jaundice was detected in the ISTp-DP arm (non DP-recipient) and none in the IPTp-SP arm. The frequency of congenital malformations was 1.5% and 1.0% in the ISTp-DP and ISTp- SP arm respectively (RR=1.44 (0.62-3.35), p=0.398) (1.5% vs 1.6% in non-DP vs DP-recipients within the ISTp-DP arm). In conclusion, scheduled screening for malaria parasites with RDTs provided 3 to 4 times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in areas with high SP resistance in southern Malawi and was associated with higher foetal loss and more malaria at delivery. The results should be equally relevant to other areas in east and southern Africa with similar or lower levels of parasite SP resistance. In super-resistant settings, where alternative drugs that can replace SP for IPTp are lacking, ISTp-DP could be a potential interim solution.

Safety of DHA/PPQ in Spontaneous Studies

In total, the MAH provided Eurartesim® for 18 interventional IICTs; twelve studies have been completed and six are still ongoing. A summary table is presented here below.

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Ongoing and Completed IICTs

Study Acronym/ Institution Patient N. Expected Title Countries Trial status Protocol ID (sponsor) DHA-PQP end WANECAM/ A Phase IIIb/IV comparative, randomised, multi-centre, open label, Mali, Burkina University of 1300 adults Ongoing 2016 IP_07_ 31060_002 parallel 3-arm clinical study to assess the safety and efficacy of Faso, Guinee Bamako, Mali and children repeated administration of ACTs in children and adults with falciparum (MMV) malaria ACTia Programmatic implementation of ACTs in Malawi: safety and Malawi Liverpool School 650 children Completed 2015 NCT01038063 effectiveness of combination therapies with repeated treatments for of Tropical uncomplicated P. falciparum malaria over a 3 years period Medicine (Gates Foundation ) ISTp Malawi/ Scheduled intermittent screening and treatment in pregnancy (ISTp) Malawi Liverpool School 830 pregnant Completed 2015 NHSRC#916 versus intermittent preventive treatment (IPTp) in women protected by of Tropical women insecticide treated nets for the control of malaria in pregnancy in Medicine Malawi (EDCTP) STOPMIP Kenya/ Intermittent Screening and Treatment (IST) or Intermittent Preventive Kenya Liverpool School 1036 pregnant Completed 2015 KEMRI Treatment (IPT) with dihydroartemisinin-piperaquine, versus IPT with of Tropical women SSC2179 sulfadoxine-pyrimethamine for the control of malaria in pregnancy in Medicine - CDC Kenya Kenya STOPMIP Indonesia/ Intermittent Screening and Treatment or Intermittent Preventive Indonesia Liverpool School 3198 pregnant Ongoing 2016 ISRCTN 34010937 Therapy for the Control of Malaria in Pregnancy in Indonesia: An of Tropical women Open Label Cluster-Randomized Controlled Superiority Trial Medicine PREGACT/ Safe and efficacious artemisinin-based combination treatments for Burkina Faso, ITM-Antwerp 870 pregnant Completed 2014 NCT 00852423 African pregnant women with malaria Ghana, (Gates Found., women Malawi, EDCTP, MRC Zambia UK) CDC Malawi/ Efficacy and safety of the dispersible formulation of A-L, co-packaged Malawi Malaria Branch 166 Completed 2013 NCT 01326754 AS-AQ and co-formulated DHA-PQP for the treatment of CDC - University uncomplicated falciparum malaria in Machinga District, Malawi of Malawi Karolinska Guinea/ Improving anti-malarial treatment options in Guinea-Bissau Guinea-Bissau Karolinska StepB: 237 Ongoing 2016 NCT 01704508 Institute children

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Study Acronym/ Institution Patient N. Expected Title Countries Trial status Protocol ID (sponsor) DHA-PQP end Vivax in soldiers/ Randomized, open-label trial of the safety, tolerability and efficacy of Indonesia Oxford University 60 adults Completed 2014 OXTREC 179-12 primaquine against relapse when combined with pyronaridine- (MMV) artesunate or dihydroartemisinin-piperaquine tetraphosphate for radical cure of acute plasmodium vivax malaria in soldiers ADJusT-Malawi Antimalarial Dose Justification and Tolerability Study of DHA- Malawi Liverpool School 200 children Prematurely 2016 PACTR201303000506 Piperaquine in the 5–24 kg Weight Band in Malawi of Tropical stopped due 302 Medicine to lack of (EDCTP) funding ARV-ACT ADAPT Pharmacokinetics studies of interactions between ACTs and Malawi Liverpool School 84 adults Completed 2013 (phase A) Antiretroviral therapies in Malawi of Tropical Medicine (EDCTP) ADAPT (phase B) Efficacy and safety of Artemisinin-based Combination Therapies in Malawi Liverpool School 163 Ongoing 2016 PACTR201311000659 people with plasmodium falciparum malaria receiving antiretroviral of Tropical 400 Therapy Medicine(EDCTP

INESS Observational study to evaluate the clinical safety after introduction Burkina Faso, Gates Found 10000 Completed 2014 INESS 02/2012 Eurartesim in public health districts of Burkina Faso, Mozambique, Mozambique, VERSION 2.0 Ghana and Tanzania Ghana, 25/03/2013 Tanzania

Primaquine-DP Open label study to evaluate potential pharmacokinetic interaction of Thailand Mahidol 16 healthy Completed 2014 NCT01525511 orally administered Primaquine and DHA-PQP in healthy adults University, volunteers Thailand Primaquine-The Primaquine’s gametocytocidal efficacy in malaria asymptomatic The Gambia Medical research 1200 children Ongoing 2016 Gambia PRINOGAM carriers treated with dihydroartemisinin-piperaquine in The Gambia Council - The and adults SCC 1321 Gambia ARCO-Tanzania Safety, tolerability, pharmacokinetics and efficacy of fixed Tanzania Ifakara Health 60 adults and Completed 2014 NCT01930331 artemisinin/naphthoquine (ARCO®) and dihydroartemisinin/ Institute children piperaquine (Eurartesim®) therapies in adults and children with uncomplicated P. falciparum malaria in Tanzania MSF-Niger Efficacy of three artemisinin combination therapies for the treatment of Niger Medicins Sans 221 children Completed 2015 NCT01755559 uncomplicated Plasmodium falciparum malaria in children aged 6 to 59 Frontieres months

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Study Acronym/ Institution Patient N. Expected Title Countries Trial status Protocol ID (sponsor) DHA-PQP end Eurartesim_GSK A Five-cohort, Randomized, Open-label, Parallel-group Study to US GlaxoSmithKline 48 healthy Completed 2015 Evaluate the Pharmacokinetics of a Single Dose of Tafenoquine volunteers (SB252263) 300mg when Co-administered with the Artemisinin-based Combination Therapies (ACT) Artemether + Lumefantrine (AL) and Dihydroartemisinin + Piperaquine tetraphosphate (DHA+PQP)

Page 42 of 54 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

Sigma-Tau has provided Eurartesim® to all the above listed IICTs free of charge. A Pharmacovigilance agreement for the exchange of the safety information has been signed in all these cases. Each study Sponsor is committed to provide, on ongoing base, expedited SAE reports and AESIs, and on a periodic base (quarterly or half-yearly), updated information about the enrolment status of the study (i.e.: number of enrolled patient to date) and line-listings of all SAEs and any other relevant information about the study progress.

It must be considered that these trials are often large interventional studies that mimic very closely the marketing experience. The MAH considers this a practical and realistic assessment of the benefit-risk analysis, given the nature of the product and the countries in which it is mostly utilised.

Tabulation of the AEs (by seriousness and relationship) received from these studies is summarized in the table here below. It is to be noted that AEs from INESS, PREGACT and ISTp Malawi studies are also included in this tabulation.

AEs from IICTs from IBD to DLP Serious Non Serious System Organ Class Preferred Term R NR T R NR T Blood and lymphatic system disorders 10 26 36 0 0 0 Angina unstable 0 1 1 0 0 0 Cardiac arrest 1 0 1 0 0 0 Myocardial ischaemia 1 0 1 0 0 0 Cardiac disorders Palpitations 0 0 0 10 2 12 Pericardial effusion 0 1 1 0 0 0 Sub-Total 2 2 4 10 2 12 Congenital, familial and genetic disorders 26 17 43 0 0 0 Eye disorders 0 0 0 1 0 1 Gastrointestinal disorders 8 7 15 6 0 6 General disorders and administration site conditions 14 8 22 3 1 4 Drug-induced liver injury 2 0 2 0 0 0 Hypertransaminasaemia 3 0 3 0 0 0 Hepatobiliary disorders Jaundice 1 0 1 0 0 0 Sub-Total 6 0 6 0 0 0 Immune system disorders 1 0 1 0 0 0 Infections and infestations 43 153 196 2 0 2 Injury, poisoning and procedural complications 1 5 6 0 0 0 Electrocardiogram QT 0 0 0 26 0 26 prolonged Investigations Haemoglobin decreased 0 1 1 0 0 0 Weight decreased 0 1 1 0 0 0 Sub-Total 0 2 2 26 0 26

Page 43 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

Serious Non Serious System Organ Class Preferred Term R NR T R NR T Metabolism and nutrition disorders 1 6 7 0 0 0 Musculoskeletal and connective tissue disorders 1 0 1 0 0 0 Neoplasms benign, malignant and unspecified… 1 1 2 0 0 0 Nervous system disorders 6 3 9 24 0 24 Pregnancy, puerperium and perinatal conditions 111 56 167 0 0 0 Psychiatric disorders 1 0 1 0 0 0 Renal and urinary disorders 5 0 5 0 0 0 Reproductive system and breast disorders 2 2 4 0 0 0 Respiratory, thoracic and mediastinal disorders 20 12 32 0 0 0 Skin and subcutaneous tissue disorders 2 1 3 20 1 21 Surgical and medical procedures 19 9 28 0 0 0 Vascular disorders 0 2 2 0 0 0

TOTAL 280 312 592 92 4 96 R = Suspected, NR = Non suspected

Page 44 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

Variation in Safety due to Patient Factors The possible impact of intrinsic factors (age, gender, body mass index, parasite density at baseline and liver abnormalities) or of extrinsic factors (dose/kg of treatment received and use of selected concomitant medication) on the safety profile of DHA/PPQ was assessed: no clinically significant effects were found. The occasional statistically significant results obtained can be regarded as random and most probably unrelated to DHA/PPQ administration.

QTc prolongation was the most variable and sensitive parameter but, as already discussed, it was asymptomatic. Interestingly, DHA/PPQ treatment did not worsen the AE profile in patients with ECG abnormalities at baseline, irrespective of age, gender and parasite density at baseline; in addition, there did not appear to be a correlation between the total dose/kg of treatment received and QTc interval.

Preliminary published data shows that DHA/PPQ does not negatively affect pregnancy during the second and third trimester. Since there is no direct experience with DHA/PPQ in pregnancy in Sponsored clinical trials, the warnings on use in pregnancy present in the SmPC are in line with the WHO guidance on the use of artemisinins in pregnancy.

Summary of Comparative Safety against Comparators

See above for a discussion of the safety profile of DHA/PPQ, when compared to other drugs in pivotal studies (A/L and AS+MQ).

Conclusions on Safety

The number of patients treated with DHA/PPQ in the Sigma-tau clinical programme and in observational clinical trials and IICT is large and it is also comprehensive with respect to age range. The observed safety profile is in line with expectations from published literature.

In the pivotal studies, DHA/PPQ was generally associated with fewer TEAEs than comparators in most system organ classes, with the exception of the cardiovascular system, where a small excess of TEAEs was seen in the DHA/PPQ group. The most noticeable safety signal relates to the potential for QTc prolongation, which occurred with slightly higher frequency and somewhat greater intensity than it did for comparators. However, these changes were largely asymptomatic – there was no increased rate of AEs associated with QTc prolongation, and occurred in a PQP and food- dependent fashion. The SmPC provides prescribers with more than adequate warnings and advice relating to this potential risk, which is largely offset by PQP’s benefit of preventing resistance to artemisinins, and of providing a secondary prophylaxis to new P. falciparum infections.

In conclusion, Eurartesim® is well tolerated at the tested doses and regimens.

Page 45 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

Comparative Effectiveness and Overall Conclusions

Currently there are only two other ACT’s registered on the EU market:

Eurartesim® proved to be as effective as Artemether + Lumefantrine and Artesunate + Mefloquine.

For all these drugs the therapeutic success in the treatment of uncomplicated P. falciparum malaria exceeded the threshold of 95%.

The expected advantages of Eurartesim® compared to Artemether + Lumefantrine are:  Favourable compliance: body weight being equal, a patient weighing 60 kg must take 24 Coartem tablets in 48h vs. 6 of Eurartesim®.  Lower incidence of re-infections (a very important advantage in endemic areas).  In addition, Eurartesim® should be administered with water in between meals, while Artemether + Lumefantrine requires co-administration with a fatty meal or milk.

With regard to the combination of Artesunate and Mefloquine, the expected advantages of Eurartesim® is a better safety profile. Artesunate + Mefloquine may cause a greater number of adverse events. Mefloquine causes psychiatric reactions such as depression, mood changes, anxiety, confusion, hallucinations, panic attacks, restlessness, forgetfulness, psychosis, paranoia, emotional instability, aggression, and agitation (cfr: FDA and AIFA Drug Safety communicatons regarding mefloquine and the associated risk of serious psychiatric and nerve side effects (49, 50).

Eurartesim® causes a longer QTc prolongation as compared with the two above described drugs. However, the intensity and frequency of the QTc prolongation associated with Eurartesim®, when administered with water without food, appears modest (in terms of mean increases from baseline) and transient (completely resolves by day 7).

With regards the QTc pronlongation of DHA/PQP the WHO malaria guidelines state:

“…….”Piperquine prolongs the QT interval by approximately the same amount as cloroquine but by less than quinine. It is not necessary to perform and electrocardiogram before prescribing dihydroartemisinin + pipearquine but this ACT should be used in patients with congenital QT prolongation or who have a clinical condition or are on medications (see Annex 5.14) that prolong the QT interval. There has been no evidence of piperaquine-related cardiotoxicity in large randomized trials or in extensive deployment.”

Overall, Eurartesim® offers an effective solution to uncomplicated P.falciparum malaria when compared to the other existing options.

Page 46 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

11. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group

Here below reported is an overview of the Eurartesim in Europe and in Africa and Asia markets (prices in the private and public sector), as well as a cost comparison with the prices of other products containing DHA/PQP in Africa.

Eurartesim® is a FDC formulated as tablets for oral administration in two strengths and several pack sizes :

 160 mg/20 mg tabs – packs of 3 tabs  320 mg/40 mg tabs of PQP/DHA – packs of 3, 6, 9, and 12 tabs

Eurartesim® should be administered over three consecutive days for a total of three doses taken at the same time each day. Dosing should be based on body weight as shown in the table reported in section 7. In Europe the only pack size that is on the market is the 12 tabs of 320mg/40mg that covers up to one treatment for the range of bw of 75 to 100 Kg (cfr section 7).

The European prices are below reported.

Eurartesim® Prices

Since the EMA approval, the product has been launched in the following EU countries

AUTHORISATIO LAUNCH TRADE Ex-factory COUNTRY N Pack size launched DATE NAME(S) price DATE 12 packs (€) 12 film-coated tabs 320 mg/40 Belgium 27 Oct 2011 21 Jun 2012 Eurartesim® mg (PQP/DHA) 40 12 film-coated tabs 320 mg/40 28.56 France 27 Oct 2011 25 Jun 2012 Eurartesim® mg (PQP/DHA) United 12 film-coated tabs 320 mg/40 35 27 Oct 2011 25 Jun 2012 Eurartesim® Kingdom mg (PQP/DHA) 12 film-coated tabs 320 mg/40 33.67 Portugal 27 Oct 2011 02 Jul 2012 Eurartesim® mg (PQP/DHA) 12 film-coated tabs 320 mg/40 41.59 Ireland 27Oct 2011 01 Sep 2012 Eurartesim® mg (PQP/DHA) 12 film-coated tabs 320 mg/40 38.43 Spain 27Oct 2011 03 Sep 2012 Eurartesim® mg (PQP/DHA)

13 Sep 2012 12 film-coated tabs 320 mg/40 35 Italy 27 Oct 2011 Eurartesim® mg (PQP/DHA) The 12 film-coated tabs 320 mg/40 40 27 Oct 2011 01 Oct 2012 Eurartesim® Netherlands mg (PQP/DHA) 12 film-coated tabs 320 mg/40 37.04 Germany 27 Oct 2011 01 Feb 2013 Eurartesim® mg (PQP/DHA) 12 film-coated tabs 320 mg/40 33.96 Greece 27 Oct 2011 Eurartesim® mg (PQP/DHA)

Page 47 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

Moreover, Eurartesim® has been authorized in the following extra EU countries and marketed in the private sector as well as in the public sector (through Governamental Agencies or no-Profit Organisation). The commercial partner of Sigma-Tau in the African countries is Pierre Fabre.

In most countries the product is registered with all the presentations and on the market with the 9 tabs pack that covers up to one treatment for the range 36 - <75 range of bw..

Registered presentations in the Extra EU markets with relevant ex-factory prices for the private market (where available) are reported in the following table:

FIRST FIRST Ex-Factory price TRADE COUNTRY AUTHORISATION LAUNCH Pack size authorized (€) NAME(S) DATE DATE (*) 12 film-coated tabs 320 mg/40 mg 9 film-coated tabs 320 mg/40 mg 3.7 (9’s) Burkina Faso 23 March 2013 March 2016 Eurartesim® 6 film-coated tabs 320 mg/40 mg 3 film-coated tabs 320 mg/40 mg 3 film-coated tabs 160 mg/20 mg

12 film-coated tabs 320 mg/40 mg 9 film-coated tabs 320 mg/40 mg Cambodia 07 August 2012 Sep 2012(**) Eurartesim® 6 film-coated tabs 320 mg/40 mg 3 film-coated tabs 320 mg/40 mg 3 film-coated tabs 160 mg/20 mg

12 film-coated tabs 320 mg/40 mg 4.36 (12’s) 9 film-coated tabs 320 mg/40 mg 10 December 2.99 (9’s) Congo March 2016 Eurartesim® 6 film-coated tabs 320 mg/40 mg 2015 2.34 (6’s) 3 film-coated tabs 320 mg/40 mg 1.17 (3’s) 3 film-coated tabs 160 mg/20 mg 0.83 (3’s)

12 film-coated tabs 320 mg/40 mg 4.37 (12’s) 9 film-coated tabs 320 mg/40 mg Last trimester 3.5 (9’s) Gabon 30 June 2016 Eurartesim® 6 film-coated tabs 320 mg/40 mg 2016 2.35 (6’s) 3 film-coated tabs 320 mg/40 mg 1.18 (3’s) 3 film-coated tabs 160 mg/20 mg 0.83 (3’s)

12 film-coated tabs 320 mg/40 mg 4.37 (12’s) 9 film-coated tabs 320 mg/40 mg 1st semester 3.5 (9’s) Ghana 04 January 2013 Eurartesim® 6 film-coated tabs 320 mg/40 mg 2017 2.35 (6’s) 3 film-coated tabs 320 mg/40 mg 1.18 (3’s) 3 film-coated tabs 160 mg/20 mg 0.83 (3’s) 18 February Guinea April2016 Eurartesim® 9 film-coated tabs 320 mg/40 mg 2016 3.5 (9’s)

12 film-coated tabs 320 mg/40 mg 3.62 (12’s) 9 film-coated tabs 320 mg/40 mg September 2.9 (9’s) Ivory Coast 17 June 2016 Eurartesim® 6 film-coated tabs 320 mg/40 mg 2016 1.95 (6’s) 3 film-coated tabs 320 mg/40 mg 1.17 (3’s) 3 film-coated tabs 160 mg/20 mg 0.83 (3’s)

12 film-coated tabs 320 mg/40 mg

9 film-coated tabs 320 mg/40 mg 06 November December 2.8 (9’s) Kenya Eurartesim® 6 film-coated tabs 320 mg/40 mg 2014 2016 3 film-coated tabs 320 mg/40 mg 3 film-coated tabs 160 mg/20 mg

1st trimester Madagascar 05 October 2016 Eurartesim® 9 film-coated tabs 320 mg/40 mg 3.5 (9’s) - proposed 2017

1st semester Mauritania 21 October 2016 Eurartesim® 9 film-coated tabs 320 mg/40 mg 3.5 (9’s) 2017

Page 48 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

FIRST FIRST Ex-Factory price TRADE COUNTRY AUTHORISATION LAUNCH Pack size authorized (€) NAME(S) DATE DATE (*)

12 film-coated tabs 320 mg/40 mg 4.37 (12’s) 9 film-coated tabs 320 mg/40 mg 23 February 3.5 (9’s) Niger April 2016 Eurartesim® 6 film-coated tabs 320 mg/40 mg 2016 2.35 (6s’) 3 film-coated tabs 320 mg/40 mg 1.18 (3’s) 3 film-coated tabs 160 mg/20 mg 0.84 (3’s) 12 film-coated tabs 320 mg/40 mg 2.8 (9’s) 9 film-coated tabs 320 mg/40 mg Nigeria 06 May 2014 June 2016 Eurartesim® 6 film-coated tabs 320 mg/40 mg 3 film-coated tabs 320 mg/40 mg 3 film-coated tabs 160 mg/20 mg

12 film-coated tabs 320 mg/40 mg 9 film-coated tabs 320 mg/40 mg 4.37 (12’s) 1st semester RDC 07 May 2016 Eurartesim® 6 film-coated tabs 320 mg/40 mg 3.5 (9’s) 2017 3 film-coated tabs 320 mg/40 mg 2.35 (6s’) 3 film-coated tabs 160 mg/20 mg 1.18 (3’s) 0.84 (3’s)

14 February 12 film-coated tabs 320 mg/40 mg 2013 9 film-coated tabs 320 mg/40 mg Tanzania Not marketed Eurartesim® 6 film-coated tabs 320 mg/40 mg 3 film-coated tabs 320 mg/40 mg 3 film-coated tabs 160 mg/20 mg 06 June 2013 12 film-coated tabs 320 mg/40 mg 9 film-coated tabs 320 mg/40 mg 02 September Thailand Not marketed Eurartesim® 6 film-coated tabs 320 mg/40 mg 2015 3 film-coated tabs 320 mg/40 mg 3 film-coated tabs 160 mg/20 mg

14 September 1st semester Togo Eurartesim® 9 film-coated tabs 320 mg/40 mg 2016 2017 2.9 (9’s)

12 film-coated tabs 320 mg/40 mg 9 film-coated tabs 320 mg/40 mg Zambia 08 January 2015 Not marketed Eurartesim® 6 film-coated tabs 320 mg/40 mg 3 film-coated tabs 320 mg/40 mg 3 film-coated tabs 160 mg/20 mg (*)Not all pack sizes/strengths may be launched (**) Sold through Governative Agencies or no‐profit organizations.

Cost Comparison of DHA/PQP products in the private market

Here below is a table containing the average exfactory prices (IMS data) of DHA/PQP products (presentation pack of 9 tabs) commercialized in the 12 French East African Countries.

AVERAGE ex‐factory € IMS prices (MAT Aug.'16) – 9 tabs MALACUR (Salvat) 3,28 RIDMAL (Ajanta) 2,96 D‐ARTEPP (Guilin) 2,74 DUO COTECXIN (Bejing Cotec) 3,98 EURARTESIM (Sigma-tau) 3,42

Page 49 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

Regarding the sales through Governmental Agencies or no-profit organizations, ST makes the Product available for distribution in Malaria Endemic Countries at a price which is lower than FBMC (Fully Burdened Manufacturing Cost) plus a mark-up of no greater than 45% of FBMC calculated on quantities delivered. Such a price should preferably, be no greater than USD 1,00 per adult course of treatment and USD 0,60 per pediatric course of treatment.

On the above basis, Eurartesim has been sold in Myanmar, Kenya, Senegal, Sierra Leone, Uganda through Global Found at the price reported in the following table:

Eurartesim® Floor Prices EUR USD

Per pediatric treatment – 3 tablets 20mg DHA 160mg PQP 0.50 0.66

Per adult treatment – 3 tablets 40mg DHA 320mg PQP 0.70 0.93

Per adult treatment – 6 tablets 40mg DHA 320mg PQP 1.10 1.46

Per adult treatment – 9 tablets 40mg DHA 320mg PQP 1.50 1.98

Per adult treatment – 12 tablets 40mg DHA 320mg PQP 1.91 2.52

Conclusion

Clinical trial Phase III evidence has demonstrated that DHA/PQP provides the best protection against reinfection, compared to other qualified FDC ACTs. In the African Phase III trial the proportion of new infections up to Day 42 was 13.55% (95% CI: 11.35%–15.76%) for DHA/PQP vs 24.00% (95% CI: 20.11%–27.88%) for A/L (p<0.0001).

This sizeable difference in diminishing reinfections by nearly 50% compared to Artemether + Lumefantrine will yield significant cost effectiveness benefits.

Page 50 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

12. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well)

Eurartesim® has been approved through Centralized Procedure by EMA on 27 October 2011. Product registration renewal (unlimited) was awarded on 15 September 2016.

The product is, since 2012, on the market in the country of origin (Italy) as well as in some EU markets. Since 2012, the Applicant submitted the marketing authorisation application in many African and Asian countries directly or, through its commercial Partner, Pierre Fabre.

Additionally the Product has been sold in some endemic market through Governmental Agencies or no-profit organisation. For the detailed status where the product is registered and/or commercialized/sold, see section 11 of this document.

Product obtained the WHO prequalification status on 9 October 2015.

Complete overview of the Eurartesim regulatory status in reported in section 11.

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia)

Sigma-tau started in 2010 a collaboration with the International Pharmacopeia and the United States Pharmacopoeia on DHA/PQP. The target is to define an International standard of DHA/PQP based on the most recent findings by Sigma-tau mainly in the area of stability related Impurities both in Drug substances and Drug product. In particular, the International Pharmacopoeia should be upgraded with a new monograph for PQP drug substance and with a new monograph for the drug product DHA/PQP, reporting methods able to detect the principal DHA degradation products and to assess the shelf life of the drug combination.

Page 51 Sigma-tau SpA Dihydroartemisinin/Piperaquine Application for inclusion in the 21sth WHO Model List of Essential Medicines 5 December 2016

14. REFERENCES

1. WHO. Model Essential Medicines List. 19th ed. Updated November 2015. 2. WHO. Guidelines for the Treatment of Malaria. 3rd ed. April 2015. 3. Valecha N, et al. - An Open-Label, Randomised Study of Dihydroartemisinin-Piperaquine Versus Artesunate-Mefloquine for Falciparum Malaria in Asia - PLoS ONE. 2010;5(7): e11880. 4. Bassat Q, et al. Dihydroartemisinin-Piperaquine and Artemether-Lumefantrine for Treating Uncomplicated Malaria in African Children: A Randomised, Non-Inferiority Trial. PLoS One. 2009; 4(11): e7871. 5. WHO. World Malaria Report. 2015. 6. WHO. Facts on ACTs. January 2006. 7. WHO. Guidelines for the Treatment of Malaria. 2nd ed. March 2010. 8. Whiteman V, et al. Cost-effectiveness study of three antimalarial drug combinations in Tanzania. PLoS Med. 2006 3(10): e373.

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