Servier presents its Research and Development programmes · Servier presents its Research and...

1

Press folder

Annual Conference

Servier presents its

Research and Development

programmes

Thursday 1st December 2016

9 – 11 am

4 bis passage Landrieu, Paris 7ème

In the presence of:

- Emmanuel CANET, Executive Vice-President of R&D

- Eric FALCAND, Vice-President of Business Development and Licensing

- Isabelle Tupinon-Mathieu, Director of Cardiovascular and Metabolism Innovation

Divisions, Vice-President of R&D

- Olivier Geneste, Director of Oncology Research

- Hans-Martin Schneble, Director of Neurology Project

2

I. Research and innovation: main axis of development for the group

A long tradition and recognised experience

The Servier group has always been strongly committed to research and development. The

Suresnes Research Centre opened in 1960, only six years after the creation of the initial

laboratory in Orléans.

In 1988, Servier was named the most creative laboratory worldwide by the Scrip magazine

and in 2002, the group received the Galien prize, which rewards its creative research.

The group's areas of excellence are cardiology and diabetes, but Servier has also always had

research teams in neurosciences, rheumatology and oncology, in order to meet the growing

medical needs in these areas.

Servier has always been committed to the therapeutic advances for the benefit of patients.

A) The strategic directions of the group in terms of Research and Development

As an average sized group (21,200 collaborators, turnover of 4 billion euros), choices must

be made on which diseases to specialise in so as to develop a very high level of expertise.

In 2015, Servier redefined its strategic directions in terms of research and development in

order to better use its expertise while meeting medical needs that have not been fulfilled.

Aim: to strengthen the group's leadership in cardiovascular diseases and diabetes,

and play a leading role in the fight against cancer, immunoinflammatory diseases and

neurodegenerative diseases.

Therefore, in cooperation with its R&D teams, Servier established academic collaborations

and partnerships to more effectively meet the needs of patients and to build a balanced risk-

taking portfolio of projects.

B) Building a portfolio, the outcome of long-term reflection

Today, to meet the requirements for specialisation, innovation and speed of marketing new

drugs, laboratories can no longer go it alone. Given the complexity and rapid evolution of

areas such as oncology or neurodegenerative diseases, it is no longer possible to master all

the recent knowledge and technologies alone. Working within a network is essential. For

two thirds of its drug candidates, Servier has partners but the emphasis is placed on

collaboration and joint participation in the different stages of development. The aim is to

best use the competencies of each partner and to benefit from their strengths for making

new drugs available to doctors and patients. These partnerships can therefore consist of

taking approved molecules or entrusting Servier molecules to other groups, as both actions

3

can be done with the same partner. It may also entail collaborations on scientific or

technological approaches.

However, the success of these partnerships is related to the competences of the internal

teams, recognised for their know-how and capable of identifying the most innovative

projects.

These approaches, for example, have allowed European patients to access the anti-cancer

drug Lonsurf in 2016.

C) Some key figures

23 drug candidates in clinical development, including 17 new molecular entities.

CARDIOVASCULAR

DISEASES

Heart failure

DIABETES

Type 2

diabetes

CANCERS

Solid tumours

and malignant

haemopathies

IMMUNOINFLAMMATORY

DISEASES

Autoimmune diseases

NEURODEGENERATIVE

DISEASES

Neurodegenerative

diseases

25% of Servier turnover invested in R&D

2,200 collaborators, 9th investor of the European Union in R&D in the pharmaceutical

sector

3 research centres, including 2 in France

One ambitious objective: to launch one new molecular entity every 3 years

4

II. A historical leader position in cardiovascular diseases and diabetes

1) Cardiovascular diseases

Hypertension and vascular disease

In the area of hypertension, Servier is the only pharmaceutical laboratory to have a fairly

extensive range, making it the 1st player in Europe and the 2nd worldwide.

A) General information

Hypertension is a major public health problem for a country like France. It is in fact the most

common of chronic illnesses with an estimated number of hypertensive patients between

14 and 16 million. The risk of hypertension increases with age: one in three French people

over the age of 35 years is hypertensive but after 65 years, it is one in two French people.

This condition is defined simply with blood pressure figures beyond a set threshold of

140/90 mmHg (14/9 when your doctor informs you of your pressure).

According to the World Health Organisation (WHO), hypertension is today the number one

cardiovascular risk factor worldwide. Out of 100 diagnosed hypertensive patients, it is

estimated that 20 are not treated and that 50 among those who are treated do not meet the

treatment objective. It is essential to inform a hypertensive patient of the dietary and

lifestyle measures, but in most cases, medical treatment will be necessary. This treatment

will need to be personalised by taking into account the patient’s specific characteristics.

B) Positioning of the Servier group and portfolio

Positioning

The product portfolio in the cardiovascular field offers prescribing physicians the most

extensive choice of treatment solutions, so as to offer each patient a treatment that is

adapted to their risk profile and their main comorbidities (diabetes or dyslipidaemia

particularly), and if necessary, fixed-dose combinations (up to 3 active ingredients) within a

same tablet to facilitate a patient's treatment compliance.

Existing Servier portfolio

9 products are currently on the market:

Coversyl: treatment for hypertension and heart failure

5

Cosyrel: for hypertensive patients suffering from coronary heart disease

Coveram: treatment for essential hypertension and/or stable coronary heart disease

Natrilix: diuretic

Natrixam: for elderly hypertensive patients

Preterax: for hypertensive patients with diabetes or following a stroke

Triplixam: fixed-dose combination, hypertension treatment

Triveram: for hypertensive patients with dyslipidaemia (cholesterol level too high)

Viacoram: for newly diagnosed hypertensive patients

Servier also markets a major product in the field of venous disease. Daflon is a venotonic

agent, which increases the tonicity of venous walls, and a vasoprotective agent, which

improves small blood vessels resistance. It is indicated in the treatment of symptoms related

to venous and lymphatic insufficiency (heavy legs, pain, restless leg syndrome) and in the

treatment of functional signs related to haemorrhoid attacks.

Heart failure


Heart failure is a common disease (around 500,000 patients in France), on the increase,

incapacitating and serious since an average of one in two patients will die within five years

following the first hospitalisation for heart failure.

Heart failure has therefore become the first cause for hospitalisation in France in patients

over 60 years old, with a total of 210,490 hospitalisations concerning 160,092 patients in

2010 (because of repeated hospitalisations for some). Intrahospital mortality was 8.2% in

2009, much more than for myocardial infarction. Prognosis after a first hospitalisation still

remains bleak today with 30% of patients hospitalised for heart failure dying the year

following the event.

There are two major risk factors for heart failure: myocardial infarction and hypertension.

B) Portfolio


5 products currently on the market:

Procoralan: indicated in the management of angina and chronic heart failure with systolic

dysfunction

6

Implicor

Vastarel: for angina pectoris

Carivalan: pending marketing authorisation

In the portfolio:

Cardioskin: a “connected t-shirt” developed in collaboration with Bioserenity, scheduled to

launch in 2017. It will help detect heart rhythm disorders more easily without restricting to

the use of electrodes or limiting the recording time due to an intelligent clothing item fitted

with sensors.

With ivabradine, Servier introduced a “first in class” drug to the market, included since 2012

in the guidelines of the European Cardiology Society for the treatment of heart failure

patients whose heart rate at rest is higher than 70 beats per minute and ejection fraction is

less than 35%.

In the cardiovascular field, Servier has 3 molecules in development and 7 research

programmes directly targeting heart failure or reducing the size of the myocardial infarction

so as to avoid the onset of heart failure.

Focus on

AMGEN partnership Servier has agreements with Amgen to benefit from the best expertise of both groups and to

make innovative treatment available to patients quickly.

On the one hand, Servier has granted Amgen the United States marketing rights of

ivabradine for the treatment of heart failure. The FDA approved this drug in April 2015.

On the other hand, Servier signed an exclusive option agreement with Amgen for the

marketing of omecamtiv mecarbil (OM) in Europe. OM is a selective activator of cardiac

myosin, developed jointly by Amgen and Cytokinetics, for potential use in the treatment of

heart failure in patients presenting with systolic dysfunction.

In September 2016, Servier and Amgen announced a stronger collaboration. Servier has

decided to exercise its option on omecamtiv mecarbil by including Russia, and the countries

within the Community of Independent States and Ukraine. The two companies have also

stated their aim to continue the development programme of omecamtiv mecarbil in Phase 3,

in collaboration with Cytokinetics.

The decision to continue the Phase 3 programme for omecamtiv mecarbil was taken

following the positive results from the COSMIC-HF study (Chronic Oral Study of Myosin

7

Activation to Increase Contractility in Heart Failure), a Phase 2 trial which evaluated this

treatment in patients with chronic heart failure and which showed significant cardiac

function improvement in these patients. These results were presented as a Late-Breaking

Clinical trial at the scientific session of the American Heart Association (AHA) in November

2015. Data from the OM Phase 2b (COSMIC-HF study) will soon be published.

This collaboration helps promote the common values of both companies, both committed

worldwide to playing a major role in the treatment of cardiovascular diseases.

C) Diabetes


According to the latest estimate from the Institut de Veille Sanitaire [French health

monitoring institute], the prevalence of diabetes treated pharmacologically in France was

5.0% in 2015, namely more than 3.3 million people treated for diabetes. Among these

patients, 85% presented with type 2 diabetes.

Besides gestational diabetes, there are two main types of diabetes:

Type 1 diabetes: around 10% of all diabetics. This diabetes more often sets in during

childhood or adolescence. It is caused by the more or less rapid destruction of

insulin-producing pancreatic cells by the immune system. Its treatment relies on

insulin from the outset.

Type 2 diabetes: around 90% of diabetic patients. Diabetes specialists have warned

about the very significant increase in the number of patients affected by type 2

diabetes worldwide. This increase is related to rising longevity, the start of the illness

in increasingly younger patients and the increase in the two major risk factors

(obesity and growing sedentary lifestyle).

In 2015, there were 415 million diabetics (type 1 and 2) worldwide, namely one adult in 11.

And if there is no major shift in lifestyles or new treatment during the next 10 to 15 years,

642 million people will be diabetic in 2040, a 50% rise in only a quarter of a century.

The definition is the same for both types of diabetes: a chronic excess of sugar (glucose) in

the blood, defined by a fasting glucose level (glycaemia) more than or equal to 1.26 grams

per litre (or 7 mmol/l).

Diabetes is the 7th cause of death, related mainly to cardiovascular complications. It is also

the main cause of renal failure, of blindness in adults and of amputation of lower limbs.

8


The Servier group has been a major player in diabetology for many years. It was in 1971 that

Diamicron® (gliclazide) was granted its first marketing authorisation. This oral antidiabetic,

registered by the World Health Organisation on the list of essential drugs, is now amongst

the most widely prescribed oral antidiabetics. Throughout the world and all formulations

included, no less than 7.5 million patients receive Diamicron treatment (2015 data).

Servier participates in the European programme called “Innovative Medicines Initiative”,

which is the result of an ambitious partnership between the European Commission and the

pharmaceutical industry represented by the EFPIA (European Federation of Pharmaceutical

Industries and Associations). It aims to encourage access to innovation in the field of

diabetes.

Within this context, Servier participates om 3 IMI programmes: DIRECT, IMIDIA and

RHAPSODY, with the intention of better understanding why some diabetic patients have a

more active illness than others. These approaches should enable to provide further accurate

insight into the physiopathology of the illness and to give rise to more homogeneous groups

of patients for whom an adapted and personalised treatment strategy is required, therefore

allowing to better meet treatment needs.


Diamicron: is indicated in the treatment of non-insulin-dependent diabetes (type 2) in adults

when diet, physical exercise and weight loss alone are not sufficient to obtain glycaemic

balance.

In development: ITCA650 is in phase 3 (see focus below).

In earlier research phase: 4 programmes in the field of diabetes and its complications.

Focus on

INTARCIA partnership

The strategic partnership announced in November 2014 between the American biotech

Intarcia and Servier should soon enable the first GLP-1 agonist, ITCA 650, to come onto the

market, dispensed for a duration of 3 months and then 6 months, thanks to an osmotic mini-

pump the size of a matchstick, placed under the skin during a simple medical procedure

performed under local anaesthesia within a few minutes by qualified medical staff. The

registration application to the FDA for the US was submitted on 21 November 2016 by

Intarcia.

9

III. A development strategy to become a leader in oncology and in the

neurodegenerative and immunoinflammatory diseases

1) Oncology


Cancers are among the main causes of morbidity and mortality in the world, and are

considered the 21st century diseases. In 2012, according to the World Health organisation,

14 million new cases of cancer were diagnosed and cancers cause 8.2 million deaths. In

about twenty years, this figure may number 22 million new cases of cancer per year

throughout the world, a 50% increase.

In France, the estimate number of new cases of cancer in 2015 was 385,000, while the

number of deaths attributed to cancer was 150,000. Within the European Union, these

figures are 2.45 and 1.23 million, respectively.

With an estimated 42,152 new cases in 2012 of which 55% in men, colorectal cancer is rated

the 3rd most common cancer in France. The stage of the illness at the time of diagnosis is the

most relevant prognostic factor. The survival rates at five years vary from 93% at stage I to

less than 10% at stage IV (metastatic). Between 20% and 25% of patients have a stage IV

illness at the outset and up to 50% will develop towards this stage during the course of the

illness. The rate of survival at five years varies from 5% to 15% in patients with a generalised

metastatic illness (HAS source).

The prognosis of patients with a metastatic colorectal cancer after failed standard

chemotherapy including fluoropyrimidines combined with anti-VEGF and anti-EGFR

depending on tumour status remains poor, and the median overall survival is generally less

than 6 months. Therefore, therapeutic need is only partially met.

A cancer originates from a cell that became abnormal due to its DNA changes, i.e. from its

genetic heritage.

Today, in addition to improving the accuracy of both radiotherapy and chemotherapy,

researchers endeavour to identify the physical, chemical and/or biological means of more

selectively reaching the cancerous cell to ensure total destruction while sparing the healthy

cells.

Among these new means, three are used in the Servier R&D programmes: targeted

therapies, restoration of apoptosis and immuno-oncology.

10


Positioning

Servier has made oncology one of its main research & development themes. Thus, the R&D

oncology share, which was 14% two years ago, is currently 35% and should read 50% within

two years. Hence, the progression of the oncology portfolio is significant as witnessed by the

number of products on the market or in preclinical or clinical development.

A development focused on the 3 new avenues options envisaged for fighting cancer:

Targeted therapies

The targeted therapies aim at the different signals to which cells are submitted and which

command phenomena such as cell proliferation, apoptosis, angiogenesis or the capacity for

tissue invasion and metastatic diffusion.

Apoptosis

Apoptosis is this natural phenomenon called programmed cell death, by which the body

destroys cells that have become useless or abnormal.

Immuno-oncology

The aim of immuno-oncology is to restore the body’s immune defences so they are aimed at

the malignant cells to destroy them.

In oncology particularly, Servier is convinced that effective research relies on an open

partnership policy as well as on academic structures, drug companies and the extraordinary

field of biotechnologies.

Servier took on this challenge many years ago by developing a partnership policy with

Inserm and the CNRS, or more specifically in oncology with the Curie Institute (Paris) and the

Gustave Roussy Institute (Villejuif).

This opening was also done internationally for all therapeutic fields with partnerships agreed

in Asia, with the Shangai Institute of Materia Medica or the Singapore Immunology Network,

and in Australia with the Walter and Eliza Hall Institute.

The opening also included multiple partnerships signed with both major pharmaceutical

groups like Amgen, Novartis and Pfizer, and companies from the biotechnologies world.


3 products were registered and made available to physicians and patients:

Muphoran: is indicated for disseminated malignant melanoma (including brain localisations)

and primary malignant brain tumours.

11

Pixuvri: developed by CTI BioPharma, this molecule resulted in a partnership with Servier in

2014. Pixuvri is currently undergoing clinical investigation in combination with rituximab for

the treatment of lymphoma.

Lonsurf: in June 2015, Servier concluded an exclusive license agreement with Taiho

Pharmaceutical for the joint development and marketing of LONSURF® in Europe and

worldwide except for the United States, Canada, Mexico and Asia. LONSURF® is an

anticancer drug for the treatment of colorectal cancer.

9 molecules in development

19 ongoing partnerships

Focus sur

NOVARTIS partnership In 2014, the Servier group finalised a worldwide collaboration agreement with Novartis for

the joint development and marketing of new drug candidates in oncology, originating from

the Servier research programme focused on apoptosis. This collaboration concerns the joint

development worldwide of S 55746, a Bcl-2 selective inhibitor, that is currently undergoing

Phase 1 clinical trials in Europe and Australia for the treatment of malignant haemopathies

and for which Phase 1b clinical trials were launched in July 2015 in the United States. This

agreement will also apply to two other targets, not yet divulged, subject to Novartis

exercising its options.

The proteins from the Bcl-2 family are key regulators of apoptosis. Disorders to this family of

proteins play a major role in the abnormal survival of tumour cells.

Servier remains responsible for the research activities and shares responsibility with Novartis

for conducting a clinical development programme aimed at resulting quickly in a first

therapeutic indication for the benefit of patients.

The marketing rights of products generated from this collaboration will be distributed

between the parties on a geographic basis.

In December 2015, following the purchase option by Novartis, the agreement was extended

to include anti-Mcl-1 drug candidates, the results of Servier research in collaboration with

Vernalis (UK).

12

2) Neurological and psychiatric illnesses


The Servier group has been an expert in the neuropsychiatry field for more than 40 years,

and particularly in the depression field.

Among the most common or most incapacitating conditions in this area, the following can be

cited:

Depression

Major depression is a common and serious condition that affects 11% to 15% of the

population depending on the countries. It is two times more common in women than in men

(Bromet, 2011; Kessler, 2013).

The WHO considers that it is one of the most incapacitating conditions and would be the

3rd cause of disability worldwide (WHO, 2008).

Parkinson’s disease

Parkinson’s disease is a neurodegenerative condition that is characterised by gradual

degeneration of the nigrostriatal dopaminergic neurons. It is the second most common

neurodegenerative disease in France after Alzheimer’s disease. It affects around

120,000 people in France, and as it is age-related, will not stop increasing with life

expectancy. It affects both genders, with a slight predominance in men. The disease starts at

a median age of 60 years and mean average period between diagnosis and death is 15 years.

Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia and affects 2% to 4% of the

population from the age of 65 years and 15% of those over the age of 80 years. Today, in

France, it affects 900,000 people and this should rise to 1.3 million in 2020. Women who

have a longer life expectancy are more widely affected than men. In 2013, 44 million people

suffered from dementia worldwide. In 2030, it is expected that 75 million people will be

affected by dementia.

Multiple sclerosis

Multiple sclerosis is an autoimmune disease in which the individual’s immune system

becomes deregulated and considers the myelin sheath as a foreign body. It is a multifactorial

disease in which both genetic and environmental factors are involved (exposure to sun,

tobacco, obesity, etc).

In France, the disease affects more than 100,000 individuals. This number is 400,000 in

Europe and more than 2 millions worldwide.

The mean age of onset of the disease is between 25 and 35 years. However, paediatric forms

exist (age of onset before 18 years) and other forms develop after the age of 40 years.

13

Today, in France, 4,000 to 6,000 new cases of MS are diagnosed every year. And among

those people affected, 3 in 4 are women.

Strokes

Strokes are common in France and one stroke occurs every four minutes. It involves the

interruption of vascularization in one area of the brain that may be caused either by an

obstructed vessel or by a ruptured vessel. In France in particular, 80% of strokes are of

ischaemic origin, caused by the occlusion of a cerebral artery. The main causes of brain

infarcts are atherosclerosis and some cardiac diseases responsible for emboli that intervene

in the brain circulation. Less than 20% of strokes in France are of haemorrhagic origin while

more than 80% are of ischaemic origin. Rupture often concerns an already fragile artery due

to a cardiovascular risk factor, such as hypertension or a malformation, such as an aneurysm.

The onset of brain haemorrhage may also be triggered by a coagulation disorder.


Positioning

To better enhance its expertise and fulfil its mission, which is to make innovative products

available to patients quickly, Servier decided to focus its research activities on

neurodegenerative diseases. At both the academic level and through its private

partnerships, the group decided to work and invest in these diseases whose frequency is

forever increasing and that currently do not benefit from any satisfactory therapeutic

responses.


4 products are currently marketed by the group:

Arcalion (salbutiamine): a psychostimulant

Trivastal (pirebidil): a dopaminergic agonist that stimulates dopamine receptors and the

cerebral dopaminergic pathways. It is indicated for the treatment of Parkinson’s disease.

Stablon (tianeptine): a modulator of the AMPA glutamate receptors with effects on

neuroplasticity. It is indicated for major depressive episodes.

Valdoxan (agomelatine): has antidepressant and anxiolytic properties. It is indicated for the

treatment of major depressive episodes.


3 ongoing partnerships

14

Focus on

GENEURO partnership

GeNeuro was established in 2006 within Eclosion, the life sciences incubator in Geneva, as a

spin-off of the bioMérieux company where the technology was initially discovered.

The agreement signed on 28 November 2014 between GeNeuro and Servier concerns a

license option for GNbAC1, a monoclonal antibody developed for the treatment of multiple

sclerosis. GNbAC1 is a humanized monoclonal antibody that neutralizes MSRV-Env, a viral

toxin that can lead to neuroinflammation and demyelination.

This approach is innovative as it addresses a potential underlying mechanism that causes the

disease and particularly neurodegeneration, while treatments currently available mostly

target flare-ups as symptoms of this disease.

The results of a Phase 1 and a Phase 2a trial have already shown a promising safety profile.

According to the terms of this agreement, GeNeuro is responsible for the development of

GNbAC1 until the end of Phase 2b, after which Servier will be able to exercise the product

license option for all markets with the exception of the United States and Japan.

The Phase 2b study, CHANGE-MS, is currently ongoing. The first results of CHANGE-MS are

expected end 2017.

3) Immunoinflammatory diseases


Among the most common or most incapacitating immunoinflammatory diseases, in which

Servier is invested, the following can be cited:

Systemic lupus erythematosus

It represents a significant medical need with around 142,000 SLE patients in the 5EU, of

which 13,000 involve lupus nephritis. Around 10% of cases are severe and do not respond to

any type of conventional treatment.

Systemic scleroderma

It represents around 30,000 patients in Europe. The survival rate at 10 years is 60% to 80%

due to the high risk of life-threatening complications: renal crisis, severe digestive disorder,

severe pulmonary fibrosis and sometimes severe cardiac disorder and pulmonary

hypertension.

15

Sjögren’s syndrome

It affects around 189,000 patients in Europe. It is the 2nd most common autoimmune disease

after rheumatoid arthritis. A third of patients have a systemic condition. There is an

increased risk of B cell lymphoma and pulmonary fibrosis (due to lymphocytic infiltration).

Today, the treatment of theses diseases is limited to corticosteroids that have some efficacy

but carry enormous side effects. Immunosuppressants and biotherapies with anti-TNFs have

revolutionised everything but failed treatments and medical needs not yet met are a reality.

In addition, all patients do not yet have access to all these treatments.

A new approach lies in the biotherapies for which many laboratories are developing

neutralizing auto-antibodies.


Positioning

The main illnesses in which Servier is invested have been chosen for their yet unmet high

medical need, i.e. for which patients require innovative treatments to manage their illness.


Protelos: for the treatment of severe osteoporosis in menopausal women with a high

fracture risk


3 current partnerships

Servier presents its Research and Development programmes · Servier presents its Research and...

Documents

Transcript of Servier presents its Research and Development programmes · Servier presents its Research and...