1. A research based specialty pharmaceutical company focused on infectious diseases
Arrozez Sophie, Benchabane Damia, Izoulet Mélanie,
Merlen Sarah, Ouattarra Safiatou
February 16, Master 2 Réglementation du Médicament dans l’Union Européenne

2. Summary I.History II.Financial Analysis III.Xerclear ™ IV.Pipeline
Conclusion

3. I. History
From a Small private research entreprise to a Public research and pharmaceutical company

4. Birth of Medivir … = Medicines + Virus
1988: Spinout of swedish company Astra AB ( now Astrazeneca) antiviral project.
About 20 people involved and 30 collaborating university researchers.
= Medicines + Virus
Swedish Business Development Agency -> SEK 2,7 m loan
1990: Relocates in Huddinge south of Stockholm, Sweden
1996: IPO on the Stockholm Stock Exchange Mid-cap List

5. A new target: polymerases and proteases
First collaboration with Eli Lilly into HIV research
HIV: a big challenge, had been discovered recently! (1983- Françoise Barré-Sinoussi and Luc Montagnier)
Decided to focus their research into polymerases and proteases inhibitors
Many Potential « First in class »
drugs !
Zidovudine (INTI): First anti-HIV
1987
VIIV Healthcare SAS

6. Medivir expands in the UK: Consolidating research ressources
2000
Medivir expands in the UK: Consolidating research ressources
Acquisition of Mimetrix  Medivir Uk Ltd
 High quality portfolio of pre-clinical projects (eg: Cathepsin S, immunological disorders).
Number of employees is now 90
Research now located in 2 centers :
- Cambridge, UK: Construction and preparation of proteins
- Huddinge, Sweden : Cellular biology
5 projets en phase clinique en 2000

7. 2000 Medivir expands in the UK: Consolidating research ressources VZV
Polymerase inhibitors
(MIV-606: valomaciclovir, shingles)
HIV
MIV-150, MIV-310
Polymerases & Proteases inhibitors research program
MIV-160
HSV
( ME- 609,
acyclovir, Oral Herpes)
HCV
HBV
Polymerase inhibitor
(MIV-210)
Immunological disorders
(Cathepsin S)
Osteoporosis (Cathepsin K)
(Proteases inhibitors)
Phase II
Phase II
Phase I
Phase I
Optimization phase

8. Building a new strategy 2003-2005
Research strategy:
Strong know-how in polymerases & proteases.
Bring an in-house developped project to market registration ! (possible in the infectious disease segment : ME-609 -labial herpes- has completed phase II in 2003).
Commercial strategy:
Create partnerships
Outlicense projects
Retain products rights on the Nordic market
Proprietary sales resources in specialists products

9. HCV proteases programme
Building a new strategy
HSV/VZV In-house: ME- 609,acyclovir,labial herpes
HCV proteases programme
VZV
RP-606: valomaciclovir, shingles
HIV
(Polymerases inhibitors: MIV-310-alovudine
MIV 150
MIV 160 MIV 170
HIV/HBV
( MIV-210)
HCV polymerases research programme
Immunological disorders (Cathepsin S) Osteoporosis (Cathepsin K)
Various new collaborations into research programmes
Many outlicensed projects  creates revenues
Diversifying risks: 5 projects in clinical development

10. Osteoporosis/ osteoarthritis
2005
One drug close to the market- Facing difficulties
ME-609 (labial herpes) to phase III
 Medivir is managing a phase III itself!
Commercial potential on the HIV segment becomes difficult
(Changes on the HIV market/ market competition)
Creation of a new subsidiary: Medivir HIV Franchise AB
 Dedicated to divesting or outlicensing projects
HIV
NRTI
Medivir AB
Osteoporosis/ osteoarthritis
HSV (labial herpes)
Autoimmune diseases
HCV
Medivir HIV Franchise AB
RP-606- Valomaciclovir (shingles)

11. Objective : Attain sustainable profitability
Integration of the 2 research units: Medivir UK Ltd and Medivir AB. Research focused in Sweden.  positive financial effects.
Profitability will come from:
Licensing agreements
Regional sales (in-house products + copromotion of external products! )
Market registration
9 new drugs outlicensed (1 ended) : In most cases Medivir retains the rights on the Nordic Market.
Copromotion thanks to a small portion of cash reserve
XerclearTM: first NDA (2008)

12. 2009
First market approval
XerclearTM (ME-609): first product developped in house (acyclovir+ hydrocortisone)
Market approval in the US and in Europe
Collaboration with in the HCV protease programme has gone very far: TMC435 is going through phase III (Chronic hepatitis C). Fast-track status in 2011.
Medivir wins the SwedenBio Award for their success in 2009

13. Today strategy Polymerases and proteases research
More than 75% of the projects into infectious diseases.
Prioritize the best projects: 5 projects discontinued in 2010  10 projects left
From in-house development to market registration
Contribute to innovative changes

14. Challenges developp by Medivir to acquired Biophausia….
2011
Challenges developp by Medivir to acquired Biophausia….
AN INTERESTING DEAL
Medivir reports on 25 august 2010 that the pharmaceutical laboratory Biophausia AB research an agremment to sell its generics business
For the company is a new opportunity to establish a new commercial platform
The deal cost approximarively M SEK
Medivir , will become 90% shareholder if Biophausia accepts the offer

15. What is
Biophausia is a pharmaceutical company develops and sells prescription medecine .
The Company’s operations are concentrated in the Nordic region with a repacking facility in Poland.
Acquires Cross Pharma AB from Meda AB
Acquisition a porfolio medecine from astrazeneca
Acquisition a polish packaging Com
Start to sell generic product
Sold porfolio to Meda AB
2005
2006
2008
2009
2010

16. Biophausia AB sell large number of therapeutic areas
2011
Biophausia AB sell large number of therapeutic areas
Mollipect® (mucolytic)
Citodon® (analgesic)
Laxabon® (laxative)
Egazie ® (antispasmodic)
Suscard ® (psychiatry)
most well-known medicines
www;biophausia;ab

17. Biophausia a compagny in a financial good health in 2011
January – March 2011
Sales for the period amounted to SEK 46 (38) million which is an increase of 19% compared with the previous year..
Revenue
Biophausia net sales for the period were SEK 1 34 million
Biophausia financial report on march 2011

18. BioPhausia acquired operations by Medivir…
11 APRIL 2011
Medivir publicized its offering to acquire all the shares and listed warrants of BioPhausia.
This offering consisted of a combination of cash and new class B Medivir shares, with each BioPhausia share valued at SEK 1.65 and each listed warrant at SEK 0.32, equating to the listed price at the acquisition date.
5 May 2011
Medivir secured shareholder support to issue shares as payment.

19. BioPhausia acquired operations by Medivir…
31 May 2011
The Board of Medivir had decided to execute the acquisition on 31 May 2011.
A total of 2,510,817 class B shares were issued, with an additional SEK m paid in cash for the acquisition.
At the end of the period, Medivir’s holding was 94%.
Medivir financial report on 2011

20. In 31 may 2011 Medivir AB acquires Biophausia AB
Biophausia gives to Medivir
complementary competencies in regulatory affairs ,
logistics ,
distribution marketing
sales
quality assurance
local presence in sweden Denmark and Finland
They include in the deal emergency medecine and include interlia Biophausia portfolio of pharmaceuticals includes disease areas such as gastrointestinal, central nervous systéme
Medivir , have 94% shareholder in Biophausia

21. A new strategy of Medivir…..
2011
A new strategy of Medivir…..
Prior to the acquisition of BioPhausia, Medivir was organized into a single integrated operating segment.
After the acquisition of BioPhausia on 31 May 2011, Medivir’s business operations organize in two busines segment
PHARMACEUTICAL SEGMENT
PARALLEL IMPORTATION
The Pharmaceuticals segment comprises research and development of new products,
The second operating segment consists of the Parallel Import business operation in BioPhausia’s subsidiary Cross Pharma, which imports original pharmaceuticals from EU countries where pricing is lower than in Sweden.

22. What is Medivir interest in this acquisition
2011
What is Medivir interest in this acquisition
The acquisition significantly expands Medivir’s commercial activities in the Nordic countries and creates the platform for the expected launch and commercialization of TMC435, for the treatment of hepatitis C, in the Nordic region where full commercial rights have been retained
Large number of therapeutic areas, and focus in product which can contribute to a positive cash flow
Additionally, BioPhausia gives Medivir, complementary competencies in regulatory affairs, logistics, distribution, marketing, sales and quality assurance, and a local presence in Sweden, Denmark and Finland.

23. II. Financial Analysis

24. Sharing
1 SEK= 0,11€ = 0,15 USD
Medivir: listed in 1996, traded on Nasdaq OMX Stockholm, Mid cap list
Price: SEK
September, 2011 : total number of shareholders= 10,887
Shareholders categories:
Total number of shares =32,030,440

25. Shares evolution
1996
2011/05
1999/12
2009/07

26. Shares evolution 2009, July: SEK=45,34  2010,December= 139,75
1999,December: SEK 65,76 2000, February: SEK 231,47
December 1999: Medivir annonced that clinical Ph II trials with MIV 606 (anti shingle agent) were completed
MIV 606 was effective and as good as acyclovir
Favorable safety profile
WHY?
2009, July: SEK=45,34  2010,December= 139,75
July 2009: Xerclear approval in US
October 2009: approval in UE
WHY?

27. Financial independance ratio
= debt/equity
indicates what proportion of equity and debt the company is using to finance its assets
2006
2007
2008
2009
2010
2011
0,54
0,16
0,29
0,33
0,19
0,23
Medivir is more financed by its equity than by debts
 represents business model of Biotechnology companies

28. Balance sheet analysis : FRNG: Fond de Roulement Net Global
= RESSOURCES STABLES EMPLOIS STABLES
Stockholders equity
Non-current liabilities
Intangible assets
Financial assets
Tangible assets
FRNG calculation (SEK m)
2006
2007
2008
2009
2010
2011
151,5
328,4
232,5
103,8
559,5
567,4
Increase of FRNG since 2010
Variations of Equity

29. Shareholder’s equity 2010/2011 New share issues Conversions of options
Acquisitions of options

30. BFR: Besoin en Fond de Roulement
= ACTIF CIRCULANT – DETTES CIRCULANTES
BFR calculation (SEKm)
2006
2007
2008
2009
2010
2011
128,8
310,3
176 91
337
514,8
Actif circ = creances clients (ce qu’ils nous doient)
Dettes circ = ce qu’on doit à nos fournisseurs
Increase in 2010 – 2011  two solutions:
Business has either increased current assets
Or has decreased current liabilities

31. Current assets evolution (SEK m)
These instruments—often called securities—are contracts which give their owner the right to an asset or the right to buy or sell an asset in the future
Investors purchase these instruments with the goal of earning money by earning dividends, interest, executing the agreement, or selling the security at a higher price.
Increase of current assets are due to :
 Investments in securities : 418,468 SEK in 2010

32. Trésorerie Nette (SEK m)
TN= FRNG – BFR
2006
2007
2008
2009
2010
2011
(9 months)
9,5
17,7 57 13
222
52,6
BFR
FRNG+
Entirely financed by stables shareholders equity & long term liabilities
TN +

33. Income statement analysis Net Sales Evolution
566
249
2007mainly comprised 3 milestone payments totalling SEK 182,3m for HCV protease inhibitors from Tibotec
2011 Due to:
outlicensing and partnership agreements one-off payments (401,2)  MEDA
pharmaceutical sales (63,7)
parallel import sales( 101,2)

34. Net income/ Average stocker’s equity
Return On Equity
Measures the rate of return on the ownership interest of the common stock owners
Measures the firm’s efficiency at generating profits from every unit of shareholer’s equity
2006
2007
2008
2009
2010
2011
(9 months)
- 69,3 %
-10,3 %
-29,5 %
-61,5 %
-35,3 %
19 %
Net income = resultat net
Net income/ Average stocker’s equity
RoE negative!
Net income negative
2011: RoE positive! WHY?

35. Net Income evolution 166,9 SEK m Due to: net sales increase in 2011
Moins negatif en 2007: du au net sales qui ont augmenté ( protease inhibitor licensé a Tibotec)
Due to:
net sales increase in 2011

36. Return On Total Assets = EBIT / TOTAL NET ASSET
An indicator of how effectively a company is using its assets to generate earnings before contractual obligations must be paid
2006
2007
2008
2009
2010
2011
(9 months)
-52,8%
-7,6%
-23,9%
-46,8%
-28,8%
16,2%
NB: EBIT= net income + interest expense+ net taxes
 If net income negative  ROTA negative!!

37. EBITDA = Earnings Before Interest Taxes Depreciation & Amortization:
désigne les revenus avant intérêts, impôts (taxes), dotations aux amortissements et provisions sur immobilisations (mais après dotations aux provisions sur stocks et créances clients).
met en évidence le profit généré par l’activité indépendamment des conditions de son financement (les charges financières), des contraintes fiscales (impôts et taxes), et du renouvellement de l’outil d’exploitation (amortissements)
2009: 129 m sek
2010: m sek
Zonebourse.com

38. (5% acyclovir, 1% hydrocortisone)
III. XerclearTM
(5% acyclovir, 1% hydrocortisone)
Cold Sore Cream
“A major step towards becoming a profitable research-based pharmaceutical company”

39. What is XerclearTM? A Cold Sore Cream; a combination of:
5% Acyclovir  Anti-viral drug (HSV1/2, VZV)
1% Hydrocortisone  Glucocorticoid
• Patent coverage through 2021
why is it different?
• First and only product to have shown reduction in progression of ulcerative cold sores
• Reduction in healing time

40. Cold Sore Stages Latent stage: weeks to months incident-free
Application of antiviral treatments
Latent stage:
weeks to months incident-free
Prodrome stage:
Tingling and bumbling
Inflammation stage:
swelling and redness
Blister and ulcer stage:
Blisters develop and break  ulcer
Crust stage:
Ulcers dry  scab and hard crust disappears
(day0-1)
(day 1)
(day 2-4)
(day 5-8)
(day 9-14)
Antiviral cold sores treatments help ease the symptoms and speed up the healing time, only effective if you apply them as soon as the first signs of a cold sore appear
Herpes Simplex Virus type 1 (HSV-1)
Tingling (prodrome) stage: Itching, burning, tingling, and/or pain signal the start of a cold sore
Redness (erythema) stage: Swelling, redness, and soreness begin
Small bumps (papule) stage: Small bumps develop and swelling may continue
Blister (vesicle) stage: One or more fluid-filled blisters form
Soft crust (ulcer) stage: Blisters break open and form an ulcer
Hard crust stage: Drying of the ulcer results in a scab and the hard crust disappears
Remaining symptoms stage: Swelling, dry skin flakes, and/or redness remain after loss of the hard crust
Normal skin stage: Cold sore disappears and normal skin returns
Latent (weeks to months incident-free): The remission period; After initial infection, the viruses move to sensory nerve ganglia (Trigeminal ganglion),[8] where they reside as life-long, latent viruses. Asymptomatic shedding of contagious virus cells can occur during this stage.
 of eight stages (see viral life cycle):
Prodromal (day 0–1): Symptoms often precede a recurrence. Symptoms typically begin with tingling (itching) and reddening of the skin around the infected site. This stage can last from a few days to a few hours preceding the physical manifestation of an infection and is the best time to start treatment.
Pre-sore (day 2–3): This stage is defined by the appearance of tiny, hard, inflamed papules and vesicles that may itch and are painfully sensitive to touch. In time, these fluid-filled blisters form a cluster on the lip (labial) tissue, the area between the lip and skin (vermilion border), and can occur on the nose, chin, and cheeks.
Inflammation (day 1): Virus begins reproducing and infecting cells at the end of the nerve. The healthy cells react to the invasion with swelling and redness displayed as symptoms of infection.
Open lesion (day 4): This is the most painful and contagious of the stages. All the tiny vesicles break open and merge to create one big, open, weeping ulcer. Fluids are slowly discharged from blood vessels and inflamed tissue. This watery discharge is teeming with active viral particles and is highly contagious. Depending on the severity, one may develop a fever and swollen lymph glands under the jaw.[9]
Crusting (day 5–8): A honey/golden crust starts to form from the syrupy exudate. This yellowish or brown crust or scab is not made of active virus but from blood serum containing useful proteins such as albumin and globulins. This appears as the healing process begins. The sore is still painful at this stage, but, more painful, however, is the constant cracking of the scab as one moves or stretches their lips, as in smiling or eating. Virus-filled fluid will still ooze out of the sore through any cracks.
Healing (day 9–14): New skin begins to form underneath the scab as the virus retreats into latency. A series of scabs will form over the sore (called Meier Complex), each one smaller than the last. During this phase irritation, itching, and some pain are common.
Post-scab (12–14 days): A reddish area may linger at the site of viral infection as the destroyed cells are regenerated. Virus shedding can still occur during this stage.[10]

41. What is XerclearTM? A Cold Sore Cream; a combination of:
5% Acyclovir  Anti-viral drug (HSV1/2, VZV)
1% Hydrocortisone  Glucocorticoid
HSV-1
Zovirax TM
Valtrex TM
Denavir TM
AbrevaTM
Current drugs
XerclearTM
Inflammatory
response
• Patent coverage through 2021
why is it different?
• First and only product to have shown reduction in progression of ulcerative cold sores
• Reduction in healing time
Combination of Acyclovir and Hydrocortisone
control of both viral replication and inflammation
Improve efficacy

42. Acyclovir: Mechanism of Action
N Engl J Med; 1999
After the initial or primary infection, some infected people experience sporadic episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the neuron's axon to the skin, where virus replication and shedding occur and cause new sores.[2]
4.4.1 Mechanism of Action
Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2), and varicella-zoster virus (VZV). The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzymeconverts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
Acyclovir stops replication of HSV-1 DNA via:
Competitive inhibition of viral DNA polymerase
Incorporation into and termination of the growing viral DNA chain

43.  Hydrocortisone suppress the clinical manifestations of the disease
Hydrocortisone: Mechanism of Action
Am J Clin Dermatol; 2008
Hydrocortisone is the main glucocorticoid secreted by the adrenal cortex. It is used topically for its anti-inflammatory effects which suppress the clinical manifestations of the disease in a wide range of disorders where inflammation is a prominent feature.
 Hydrocortisone suppress the clinical manifestations of the disease

44. Market Opportunity
XerclearTM should have a low-risk: based on safe, well-documented and already marketed compounds
Patent protection
Patents protect XerclearTM until 2016 (SCP until 2021)
Formulation technology patented to 2019 (2020 in the USA)
 Cold sore affects 1/3 of the population in the Western world  600 million episodes per year
Approved therapies offer poor results
Market value: $ 170 million in Europe and $ 230 million in North America
Strong annual growth: OTC % and Rx + 9%
There are several topical and systemic options for similar indications regarding treatment of recurrent herpes labialis
Denavir: Penciclovir cream (1%) is indicated for the treatment of cold sores (recurrent herpes labialis) that occur on the face and lips.
• Zovirax: Acyclovir cream (5%) is indicated for the treatment of recurrent herpes labialis (cold sores) in adults and adolescents (12 years of age and older).
• Famciclovir is indicated for treatment of recurrent herpes labialis (cold sores) in immunocompetent patients.
• Valtrex: Valacyclovir is indicated for treatment of recurrent herpes labialis (cold sores) in immunocompetent patients.
North america
Market value estimated to 230 MUSD
• Prescription (Rx) status for all antiviral treatments (aciclovir, penciclovir)
• Main competitors are Zovirax (Rx), Denavir (Rx) and Abreva (OTC)
• Zovirax dominates
• Slow generic penetration to date
• Primary Care Physician sales force
Europe
• Market value estimated to 170 MUSD
• Market dominated by OTC products
• Aciclovir has 75% market share
• Zovirax is market leader in majority of countries
• Generic competition
Biovail has acquired exclusive promotion and distribution rights for the herpes drug Zovirax (aciclovir) Ointment in the USA and Puerto Rico. Under the terms of this agreement, GSK will manufacture and supply Zovirax Ointment and Zovirax Cream to Biovail and will receive $133 million from the Canadian firm for certain rights to the products. The latter will begin promotional efforts related to Zovirax Ointment in January next year and, in the case of Zovirax Cream, GSK said that it will work with the FDA to reinstate an NDA previously filed by the company for the product.

45. XerclearTM XerclearTM
Prescribing Habits Post XerclearTM (2006)
Rapport détaillé sur les ventes!! 2011
Reportlinker Adds Global Herpes Simplex Virus Treatment Industry
Without with
XerclearTM XerclearTM
Prescribe:
Valtrex Another brand
Zovirax Denavir
Xerclear
Primary market research
Base: 225 US physicians who have prescribed cold sore remedies more than 10 times in the last 12 months
Physicians are willing to prescribe a new cold sore remedy
When asked what they would prescribe on the next 10 occasions, Lipsovir claims a 45% share of prescriptions, making it the leading product and drawing users from all 3 principal Rx brands (Zovirax, Valtrex, Denavir)
Topical
Denavir® (penciclovir cream)
Zovirax (acyclovir)
Penciclovir Cream 1%(Denavir®)
Denavir® is a non-greasy cream that works by penetrating the area to block the virus that causes cold sores. It is first topical anti-viral approved in Canada with the indication for cold sores. Denavir® has been found to be most effective when applied during the early signs of a cold sore although it can also be useful in later stages. It helps cold sores heal on average in four and a half days.
Acyclovir Cream/Ointment (Zovirax)
Zovirax has been shown to help reduce cold sore intensity and symptoms (including pain). Zovirax is most effective if used at the first sign or symptom of a cold sore (prodromal stage). Zovirax is applied 4-6 times a day for 10 days
Oral
Famvir (famciclovir)
Valtrex (valacyclovir)
These drugs work only on the replicating virus so they are most effective if taken in the first few days of an outbreak. There are no controlled studies of these drugs been taken after the first 12 hours of symptoms.  Acylcovir (Zovirax) Reduces pain and healing time to scab or crust formation but does not appear to affect or reduce progression, size or healing time of the cold sore. Zovirax oral is most effective if used at the first sign or symptom of a cold sore (prodromal stage). Zovirax oral dosing is 200mg five times a day for 5 days.  Famciclovir (Famvir) Reduces the duration, healing time and pain of a cold sore. Currently this drug is only indicated for treatment of recurrent episodes of HSV infections in HIV-infected patients although new indications for the treatment and prevention of cold sores are being explored. Currently, dosing is 500mg twice daily for 7 days.  Valacyclovir (Valtrex) Reduces duration, healing time and pain of a cold sore. Valtrex may help prevent cold sore outbreak if taken during prodromal stage. Most effective if used at the first sign or symptom of a cold sore (prodromal stage). Valtrex dosing is 2 grams every 12 hours for two doses.
Question:
What would you prescribe on the next 10 occasions?

46.  More than 70% of patients should buy XerclearTM
XerclearTM Consumer Interest (2006)
44%
26% 4%
36%
22%
35% 2% 5%
Definitely would buy Probably would buy Might or might not buy Probably would not buy Definitely would not buy
Strong interest in the concept: 1 in 4 in the UK and 1 in 3 in the USA claim they ‘would definitely buy’
Around three quarters of sufferers express an interest in Lipsovir
 More than 70% of patients should buy XerclearTM

47. Primary end point: Prevention
XerclearTM: Pivotal Clinical Trial
Phase III clinical trials began July 2006
Clinical trials completed December 2007
Primary end point: Prevention
(Proportion of patients with non-ulcerative recurrences)
XerclearTM
1443 subjects with
≥ 3 herpes episodes per year
Randomisation
3:3:1
AcyclovirTM cream
This study was conducted in the USA and Canada. The ITT population was 91% Caucasian, 72% female, with a median age of 44 years old and median frequency of 5 HSV episodes per year. At baseline, 65% of the subjects had only prodromal symptoms, 28% had erythema, and 7% had papules.
The participants are questioned on their cold sores
is the description consistent with herpes?
can the participant feel the early symptoms of a cold sore episode?
is the participant willing to live up to the trial rules?
Approved participants receive a tube with clinical trial material + a key ring container anc can return home and await their next herpes episode
Vehicle cream
symptoms
5 days treatment
Clinic visits until symptom-free
Treatment
commences
within an hour

48. Primary End Point (Prevention) Met
XerclearTM is equivalent to Acyclovir in term of:
Median episode duration (p= 0.38) (XerclearTM shifted ulcerative episodes to slightly longer non-ulcerative)

49. XerclearTM: Approval 2009: Marketing Authorisation Approval
US: NDA in 31 July 2009
EU: MA in October 2009 in 14 MS; (SE/H/882/01/DC)
Strong Label
treatment of recurrent herpes labialis
to reduce the likelihood of ulcerative cold sores
to shorten the lesion healing time (USA)
No product currently marketed for the
treatment of cold sores has a corresponding label

50. Medivir launched XerclearTM itself in Sweden and Finland in March 2010
XerclearTM - Partners
OTC, Q3 2011
Rx, Q1 2011
Rx, Q3 2011
Rx, Q1 2012
Russia
China
February 2011:
Meda launched Xerese TM in USA
February 8, 2012:
GSK has kicked off the first wave of XerclearTM launches  under the trade name of Zoviduo/ Zovirax Duo in Denmark, Czech Republic, Slovakia, Portugal and Poland
:15
Huddinge, Sweden, - Medivir AB (OMX: MVIR), a research-based specialty pharmaceutical company focused on infectious diseases, today announced that it has signed an agreement with Daewoong Pharmaceutical Co. Ltd. to exclusively distribute Medivir’s unique cold sore treatment Xerclear® in China and Hong Kong.  
Under the terms of the agreement, Daewoong will be responsible for conducting clinical studies for obtaining the regulatory approvals, and for marketing, sales and distribution of Medivir’s cold sore product in the territory. In return, Medivir will receive royalties on all product sales.
Daewoong is also responsible for the commercialisation of Xerclear® inSouth Korea.  Daewoong has recently filed for registration with the South Korean authorities and expects the regulatory approval later this year.
Medivir launched XerclearTM itself in Sweden and Finland in March 2010

51. XerclearTM: Remuneration for Agreements
2010:
One-off payment: successful registration on agreed markets:
MEDA: $ 2.5 m of a total of $ 5 m (NDA in USA)
GSK: € 1.1 m of a total of € 3 m (MA in europe)
Partners are responsible for funding commercial development and marketing approval in the remaining territories
The agreement terms for the payments regarding sales and licensing rights will be satisfied when revenue from them will be recognized

52. IV. Pipeline
A leading company in the development of protease and polymerase inhibitors

53. 53
Pipeline 53

54. 54
Infectious Diseases
Hepatitis C Research

55. Hepatitis C virus
Globally ~180 million (3-4% of world population) infected with
hepatitis C virus
Approximately 12 million HCV infected in the US, Europe and Japan
Genotype 1, the most difficult to treat, account for 70% of HCV population

56. Virus cycle life and target
Ribavirine : Après avoir pénétré dans les cellules, la ribavirine est convertie en dérivés mono, di et triphosphate, qui inhiberaient la synthèse des acides nucléiques viraux. = analogue nucléosidique

57. Treatment and perspective
Before 2011 : Bitherapy
Ribavirine + Interferon alfa = SoC
Cure rate : 40-50% in genotype 1 people
Since 2011 : Two new treatments in the market Tritherapy
Soc + Telaprevir or Boceprevir
Cure rates : 66-79% in genotype 1 people
Needs of treatment
There is an unmet need for novel treatments that present improved outcomes in the form of :
Increased viral cure rates
Shorter treatment durations
Minimal side effects
Non specific agents
Directs actives agents

58. 58
Infectious Diseases
Hepatitis C Research TMC435

59. Medivir and his partner
180 million patients infected
Partnership :
Tibotec
MEDIVIR RIGHTS
The disease
5-20% develop a cirrhosis and 1-5% die for cirrhosis or liver cancer
patients 59
Medivir will receive royalties from TMC435 sales in the rest of the world 59

60. What’s TMC435 ? A protease inhibitor 60
Inhibition of the cleavage of viral polypeptides
NS3 encodes a heterodimer composed of a protease domain and a helicase domain
NS4A Cofactor : activate the NS3 and cleave the viral polypeptide
Recent Patents on Anti-Infective Drug Discovery, 2008, Vol. 3, No. 3

61. 61
New drugs hit the target, 9 J U N E | V O L | N A T U R E | S 5 61

62. Clinical trial

63. Clinical trial Phase III Phase IIb Pillar (C205) Quest 1 (C208)
Clinical development program in HCV genotype 1 infected patients
Phase IIb
Pillar (C205)
N = 386
Treatment naïve patients
Dragon (C215)
N = 92
Aspire (C206)
N = 462
Treatment experienced patients
Phase III
Quest 1 (C208)
N = 375
Treatment naïve patients
Quest 2 (C216)
Promise (C3007)
Infected relapsed patients
ENDURING 63

64. Results Pillar study – naïve patients - EOT : 94-97% vs 82%
TMC435+SoC vs SoC
24 weeks of treatment vs 48 weeks
Demonstrate a potent antiviral activity in each arms :
- EOT : 94-97% vs 82%
Response rate remains high after the EOT :
- SVR24 : 81-86%
Aspire study – experience patients
TMC435+SoC vs SoC
48 weeks of treatment
Excellent SVR24 response rate in all subgroups
TMC435
PR48
N=199
Placebo
N=66
Relapser
85%
37%
Partial responder
75% 9%
Null responder
51%
19%

65. A competitive landscape65
A competitive landscape
VictrelisTM – Boceprevir
Authorized on July 2011 in UE
Authorized on May 2011 in USA
IncivekTM – Telaprevir
Authorized on September in UE Authorized on May 2011 in USA

66. TMC435 Boceprevir Telaprevir 66 Status In development Phase 3
Fast tract designation
Authorized in USA and EU
Indications
Chronic hepatitis C - genotype 1 infection
1st intention
2nd intention
Dosage
1 pill (150mg),
one time a day
Food doesn’t interfere
four pills (800mg), three times a day
With food
2 pills (750mg), three times a day
With fat food
Treatment duration
24 to 48 weeks
38 weeks to 48 weeks
EOT= End Of Treatment
Sides effects telaprevir = 1/10 des patients 66

67. TMC435 Boceprevir Telaprevir 67 Sides effects Fatigue, Headache
Anemia, Fatigue, Nausea, Headache, Dysgeusia
Anemia, Nausea, Diarrhea, Vomiting, protalgia, pruritus hemorrhoids, and rash
Effectiveness
1st intention
SVR24 = %
SVR24 = 63-66%
SVR24 = %
2nd intention
R SVR24= 85%
PR SVR24= 75%
NR SVR24= 51%
R SVR24 = 75%
PR SVR24 = 52%
R SVR24 = 86%
PR SVR24 = 59%
NR SVR24 = 32%
EOT= End Of Treatment
Sides effects telaprevir = 1/10 des patients 67

68. Better efficacity
Better safety
1 pill a day
No food
Better compliance

69. Evolution in Hepatitis C treatment69
Evolution in Hepatitis C treatment
DAA combination
IFNa and Rbv free
therapy
IFNa free
therapy
2016
2013
Quadra therapy
2011
Triple therapy
Bi therapy 69

70. TMC435 and other treatment
35 studies on TMC435
Non inferiority study
TMC435 vs Telaprevir
Association study - IFNa /Rbv free study:
Collaboration with Pharmasset
TMC435 + PSI – (nucleotide polymerase inhibitor)
Collaboration with BMS
TMC435 + Daclatasvir (NS5A replication complex inhibitor)

71. 71
Infectious Diseases
Hepatitis C Research Polymerase inhibitor

72. 2 product in preclinical research72
1 product in
Phase 1b : TMC649128
2 product in preclinical research
New drugs hit the target, 9 J U N E | V O L | N A T U R E | S 5 72

73. 73
Infectious Diseases
Herpes Virus Valomaciclovir

74. Herpes Virus: Valomaciclovir
Licensee = Epiphany Bioscience
Target: Herpes Virus DNA Polymerase
Mechanism of Action:
Nucleoside analogue
Polymerase Inhibitor
Prodrug of H2G
Disease :
Varicella Zoster Virus (shingles)
Epstein Barr Virus (Mononucleosis )
H2G= potent and selective inhibitor of herpes virus replication
Nucleoside analogue, its triphosphate derivative is a competitive inhibitor of herpes virus DNApolymerase
Zap: present during the initial disease outbreak. During this period of dermal eruptions, pain is common and may persist after the resolution of lesions. ZAP is a major contributor to morbidity in zoster.
PHN: persistent pain that is present long after the lesions have resolved. The pain can persist for months and sometimes years. The pain associated with PHN does not respond well to traditional analgesic treatment and remains a  major unmet need in shingles.
Results:
Shingles: ph 2b study safety and efficacy of once-daily dosed Valomaciclovir compared to an active comparator dosed three-times successfully completed
Mononucleosis: ph 2a study successfully  completed

75. Conclusion

76. SWOT STRENGTH WEAKNESS THREATS OPPORTUNITIES Strong competition
Class expertise in polymerase and protease drug targets 
Strong partnership
Marketing of XerclearTM within a short time around the world
Net profit is positive in 2011
Presence in the Nordic Market
Acquisition of Biophausia
R&D : main operation. Highly risky process, most of the CDs never reached market registration
Very slow development of some projects
Dependency in partnerships
THREATS
OPPORTUNITIES
High competitive pipeline (niched products)
Ph III results for TMC435 (future best in class)
Associations of TMC435 with others DAA
Extension to non-infection diseases with Cathepsin inhibitors
BioPhausia develops and sells prescription medicines in the Nordic region.
We offer the healthcare system and general public cost-effective and well-proven medicines. This is achieved through running a business-driven organization with a focus on constantly seeking new opportunities and developing current and new products.
By identifying business opportunities and developing mature or niched products, BioPhausia can offer cost-effective medicines without needing to carry out research or production. 
Maris Hartmanis, CEO of Medivir commented, "Few companies of our size have experienced the launch of a product, developed in-house, that is now being introduced in Europe and has also been available in the US since last spring. This strengthens Medivir in our efforts to develop new drugs and is yet another step toward our goal of becoming profitable."
Strong competition
Xerclear ® /Zovirax® cream
TMC435 / Telaprevir
TMC435/ Boceprevir

77. Do you have any questions?

78. Cathepsin K inhibitor : MIV 711
Target = Cathepsin K:
a lysosomal cysteine protease
involved in bone remodeling and resorption
expressed predominantly in osteoclasts
Catabolize: elastin, collagen and gelatin  break down bone and cartilage
Disease and Market:
Osteoporosis, osteoarthritis, metastatic bone disease
Estimated combined global market opportunity in excess of USD 12 billions

79. MIV 711: beneficials effects in osteoarthritis and osteoporosis
Mechanism of action:
reduced bone resoption and cartilage breakdown
Maintained bone formation in contrast to other anti-resorptives
First results:
Urinary biomarkers for bone and cartilage resorption reduced by 86% and 80% respectively (p< 0,001)
MIV 711 in preclinical development aiming for start of phase 1 clinical trials in H1 2012

80. Cathepsin S inhibitor:
Target: Cathepsin S
Lysosomal cystein protease
is secreted from spinal microglial cells
induces nociception by cleaving fractalkine from the surface of sensory neurons.
Free fractalkine subsequently activates microglial cells, contributing to the maintenance of neuropathic pain
Disease and Market:
25 million patients worldwide suffers from neuropathic pain
Global market: USD 2, 3 billions for neuropathic pain, and RA is estimated to USD 7 billions.

81. Cathepsin S inhibitor:
Mechanism of Action :
Inhibition of cathepsin S prevents inflammatory dammage to the sensory system in the spinal cord, by bloking fractalkine activation
Cathepsin S inhibitors program:
Highly potent compounds with high selectivity and good pharmacokinetic characteristics have been identified.
Medivir-developed Cathepsin S inhibitor compounds have been evaluated in preclinical models of neuropathic pain and rheumatoid arthritis with positive outcomes

82. Dengue fever: NS3 protease inhibitor
Target: Dengue virus NS3 protease,essential for viral replication
Medical need and market opportunity:
Up to 50 millions infections occur annualy in over 100 endemic countries ( death/year)
40% of world population are now at risk
Project:
Early research phase
Collaboration with Janssen Pharmaceutica

83. Others development Hepatitis C Lagaciclovir valactate
Polymerase inhibitor
Phase I
Effective against multiR HBV that become resistant to the other pharmaceuticals products
Partners: Daewoong
HIV
HIV PI
Preclinical optimization
Potent antiviral effect against wild type and multiresistant virus
Partners : Tibotec and J§J
MIV410
Preclinical development
Potent NRTI with a new inhibition mechanism
Partners : Presidio