Mithra Pharmaceuticals: MITHRA REPORTS 2016 ANNUAL

Mithra reports 2016 annual results

• Significant operational progress across our transformational E4 (Estetrol) programs and our complex therapeutic solutions positions Mithra for long-term international growth
• Mithra is accelerating investment and business development activities for its highly promising E4-based pipeline, including the 5 ^th generation oral contraceptive Estelle ® and next generation menopause therapy Donesta ®
• Phase III Estelle ® oral contraceptive studies initiated in Europe and US

Liège, Belgium, 2 March 2017 - Mithra Pharmaceuticals (Euronext Brussels: MITRA), a company focused on women's health, today announces its results for the year ended 31 December 2016, prepared in accordance with IFRS.

KEY HIGHLIGHTS

• Operational & Corporate Highlights (including post-period end)
  • Phase III Estelle® oral contraceptive studies, E4Freedom , initiated in EU and US
  • Partnership agreement signed with Fuji Pharma to commercialize Estelle® in Japan and ASEAN
  • Phase II study of Donesta® for menopause, E4Relief , initiated in Europe in May 2016; following discussions with regulators and North American and EU advisory boards, Phase II protocols amended to provide robust platform for pivotal studies with top line results now expected in Q1 2018
  • Vaginal contraceptive Myring on track for EU and US regulatory submission in Q2 2017
  • Marketing Authorizations received in 12 European countries for hormone therapy (HT) product Tibelia®, with 8 licensing and supply agreements secured during the period
  • Mithra Contract Development and Manufacturing Organization (CDMO) opened in Flémalle, Belgium, to drive innovation, development and product supply
  • Key Board appointments: Marc Coucke appointed Chairman of the Board of Directors; Koen Hoffman, Freya Loncin, and Prof. Jean-Michel Foidart appointed to the Board of Directors; Christiane Malcorps appointed to the Board of Mithra's CDMO  
• Financial Highlights
  • Revenues increased almost 10% to EUR 22.5 million from EUR 20.4 million, mainly due to the deal with Fuji Pharma to commercialize Estelle® in Japan (EUR 5.5 million). Revenues for the generic business were EUR 1.7 million lower than in 2015 due to pricing pressures. However, Mithra reconfirmed its leadership position in the contraceptive market in Belgium.  
  • R&D expenditure rose to EUR 34.3 million from EUR 9.5 million, reflecting targeted investment in the Phase III Estelle® and Phase II Donesta® programs.
  • Cash at December 31 2016 was EUR 45.7 million (EUR 96.8 million in 2015), reflecting strategic investment in the advanced clinical pipeline.

Commenting on the 2016 results, François Fornieri, CEO Mithra Pharmaceuticals, said : "During 2016 we made substantial progress on the key programs that we believe will deliver Mithra's long-term international growth as a transformational leader in women's health. This includes investment in the international Phase III trials of our innovative 5 ^th generation oral contraceptive, Estelle ®, now underway in Europe and North America, which is designed to overcome the safety and convenience concerns of current oral contraceptives and offer women greater choice. We have also taken steps to ensure that the Phase II study of Donesta ®, our novel candidate for hot flushes in menopause, provides the strongest possible platform for the planned Phase III program and partnering discussions. We also continued to move ahead with our innovative research, development and manufacturing platform in Li è ge, which will provide the necessary infrastructure to develop and manufacture our own products as well as those of our partners. The recent deal with Mayne for Myring as well as the agreement with Fuji Pharma for Donesta® that we announced yesterday clearly underlines Mithra's attractiveness for collaborations as well as the confidence of international partners in the expertise of Mithra's CDMO.

We look forward to building on this progress in the year ahead as we move closer to commercializing Estelle® and to selecting a suitable partner to further develop Donesta®. We also anticipate filing for marketing approval for our vaginal contraceptive, Myring, in both Europe and the US in Q2 2017."

OPERATIONAL OVERVIEW

Clinical Developments

Clinical Development in Contraception: Estelle®

• Mithra is currently in Phase III studies in the US & Canada as well as in Europe & Russia for its lead compound, Estelle®, a combined oral contraceptive (COC) developed using 15mg of E4 and 3mg of DRSP.
• The Phase III studies are open-label single arm trials to assess the safety and efficacy of Estelle® in approximately 1,550 participants in Europe and 2,000 participants in the US and Canada over a period of 12 months.
• In April 2016 Mithra announced top-line food effect study results for Estelle®, a mandatory first step before commencing the Phase III trial. In July 2016, the start of the Phase III clinical trial of Estelle® was approved by regulators in the US and Canada.
• The first subjects in the European study, which is taking place in Sweden, Poland, Norway, Belgium, Finland, Germany, Hungary, Czech Republic and Russia, were screened in June 2016, and in September 2016, patient enrollment started for the US study.
• Post period-end, Mithra announced in February 2017 that it completed recruitment into the European arm of its Phase III study, with 1,709 subjects screened, of which at least 1,550 are expected to qualify for enrollment into the study.
• The Phase III Estelle® studies are expected to report top line results between Q3 2018 and early 2019.
• Topline results of the Phase I study evaluating the effect of single, multiple and supratherapeutic oral doses of E4/DRSP combinations (up to 5 times the therapeutic dose) on safety, tolerability and pharmacokinetic (PK) parameters show a good tolerability of all combinations and complete PK data. This study also included a QT assessment, the results of which are currently under evaluation.

Clinical Development in Menopause: Donesta®

• Donesta®, the Company's next-generation hormone therapy (HT) with oral administration of E4, entered into a Phase II dose-ranging study in Europe in May 2016. In total, the study will recruit 225 patients in Czech Republic, Poland, Belgium, the Netherlands and the UK, for a treatment period of 12 weeks.
• The main objective of the Phase II clinical trial is to identify the minimum dose required to effectively treat vasomotor menopausal symptoms (VMS), or hot flushes. In total five doses will be tested in this blinded study, including placebo.
• Following discussions with regulatory agencies as well as recommendations from its international clinical advisory boards, the Company has decided to expand the protocol for the study and amend patient exclusion criteria. Regulatory approval of the new protocol is expected towards the end of Q1 2017, with completion of the study now expected in Q1 2018. Topline results of the Phase II study should be available late Q1 2018.
• The amended study protocols are expected to generate significant additional safety and efficacy data and provide a much stronger platform for the Phase III program. In particular, the protocol includes specific steps related to endometrial safety to rule out endometrial hyperplasia and subject exclusion criteria based on lipid levels. Importantly, in addition to assessing the effect of E4 on reduction of hot flashes, the protocol will evaluate a series of important parameters, including vulvo-vaginal atrophy improvement (VVA), bone metrics and patient satisfaction. It will also provide a detailed understanding of key safety issues including the E4 coagulation profile and lipid and glucose metabolism.
• In September 2016, Mithra contracted another CRO, Synteract HCR Inc., with specific expertise in women's' health, to support patient recruitment and site management for the Phase II study. The change of CRO is expected to further speed up recruitment, thanks to the addition of new sites and new motivational tools for investigators.
• Post period-end, Mithra's scientific advisory boards in both Europe and North America provided further support for the amended Phase II study protocol and for further development and commercialization of Donesta®. Moreover, data show that the EUR 6 billion HT market is fast-growing, positioning Mithra well for partnering discussions following the Phase II Donesta® study. IMS Health data show a CAGR of 10.3% for the global menopause market over 2012-2016, and should exceed the EUR 12.4 billion for the years ahead according to Datamonitor.
• In order to maximize the global potential of Donesta® and spread development cost and risks, the Board has decided to seek development partners as early as Phase III.

Clinical Development of Myring:

• In March 2016, Mithra announced the completion of the formulation development for Myring, the Company's combined hormonal contraceptive vaginal ring.
• In December 2016 and January 2017, Mithra announced the results of two bioequivalence studies, which demonstrated that its combined hormonal contraceptive vaginal ring, Myring, is bioequivalent to the branded European and US version of NuvaRing®.
• Mithra intends to file for marketing approval for Myring in both Europe and the United States in Q2 2017.
• Production of the first technical and clinical batches by Mithra's external contract manufacturing organization (CMO) started in October 2016. Following completion of initial technical batches, Mithra transferred manufacturing to its CDMO.
• In September 2016, Mithra submitted an application for the manufacturing authorization of the production facility for Myring to the Federal Agency for Medicines and Health Products in Belgium (AFMPS). AFMPS's GMP ^[1] audit took place post-period, in February 2017, and Mithra expects to announce a further update regarding GMP's findings in Q2 2017.   
• Receipt of GMP approval will enable Mithra to ship its first commercial batch of Myring into the EU.

Clinical Development of Zoreline ®

• In March 2016, Mithra announced that the PD study results for the 3-month implant showed that more than 8 patients did not respond to the current formulation. The PK study is currently drawing to a close and the full clinical study report is expected in Q2 2017.
• For the 1-month implant, the PK study is currently ongoing, and the clinical study report is expected in H2 2017.
• Mithra remains committed to finding a partner to co-develop and commercialize Zoreline®, in line with the Company's strategy to partner with leaders in women's health for its different product candidates.

E4 (Estetrol): Patents & Publications update

• Mithra obtained further patents to protect E4's synthesis process in additional territories such as Europe, Mexico, Hong Kong and Chile. This optimization of the E4 synthesis will significantly drive down costs, while having a positive effect on the environment.
• The Company has also filed patent applications for sublingual forms of E4-based products and formulations. The patents on these formulations could offer a protection period running until 2036. In parallel, Mithra has initiated development of its sublingual form of E4-based products following a collaboration with Pharmavize in April 2016.
• In May 2016, Mithra published an article in Contraception based on the results of the E4 FIESTA Phase II study of its E4-based product candidate Estelle®. This study showed that of the four treatment modalities investigated, the 15 mg of E4/DRSP combination has the most favourable bleeding pattern and cycle control and is the preferred combination for further Phase III clinical development. ^[2]
• Contraception also published a scientific paper in September 2016 highlighting the reduced hemostatic effects of the E4/DRSP combination, namely the Estelle® product candidate developed by Mithra, in a comparative study with another combined oral contraceptive. The published results suggest a low procoagulant effect of the E4/DRSP combination, which will be clinically verified for low antithrombotic side effects. ^[3]
• Post period-end, the US Patent and Trademark Office (USPTO) issued a Notice of Allowance for US Application Serial Number 14/238,310, a patent which covers the use of E4 as an emergency contraceptive. The patent specifically covers E4 as a potential new emergency contraception option when used alone. This new method differs from currently approved emergency contraceptives, which includes progestin only pills and combined estrogen-progestin pills.

Mithra CDMO

• In September 2016, Mithra announced the official opening of its CDMO. Construction of Phase I of the project has been completed and will provide production capabilities for polymeric forms, implants and sterile injectables. Mithra CDMO is currently producing the first validation batches of Myring. As mentioned above, Mithra's CDMO could receive GMP approval in Q2 2017, which would allow the company to ship its first commercial batch of Myring in the EU in 2017.
• The second and final phase of construction is underway and on track to be completed in Q4 2018 within the allocated budget (EUR 25.8 million). This Phase II is dedicated to tablet manufacturing, and is supported by the Walloon region by a non-refundable investment grant.

Business development

• In August 2016, Mithra signed a 20-year exclusive license and supply agreement for Estelle® with Fuji Pharma, the Japanese leader in women's health with a market leading position in sales of contraception and dysmenorrhea products. Under the terms of the agreement, Mithra will, depending on the progress of the development, receive up to EUR 26 million, including EUR 10 million upfront. In addition, the agreement includes an exclusive supply obligation for the duration of the agreement, which in the future could provide Mithra's CDMO with a steady flow of production work for E4-based products, and a source of revenue over the period of the agreement. The total value of this agreement is anticipated to be between EUR250 and EUR600 million.
• In November 2016, Mithra signed an LOI with Zhejiang Xianju Pharmaceutical related to E4 in China. Discussions between both parties continue.
• In December 2016, Mithra announced that it obtained Marketing Authorizations (MA) for the commercialization of its product Tibelia®, a synthetic steroid (tibolone) for use in hormone therapy in the UK, Belgium, Holland, Luxembourg, Spain, Portugal, Germany, Hungary, Poland, Norway, Sweden and Finland. In January 2017, Mithra obtained MAs for Greece and Italy. A French authorization is pending.
• Mithra also signed 8 License and Supply Agreements for Tibelia® in a number of territories in and outside of Europe, which amounts to a double digit deal size. In 2017, Mithra expects to sign additional agreements in other territories, and the product will be launched in Sweden, Finland and Italy in the course of 2017. Post period, a second order came in for the UK.
• Trends analysis points to Tibelia®'s potential to offer a shelf-life of 36 months compared to 24 months for competitor products based on improved formulation stability. An evaluation of the 36-month shelf live is planned for H2 2017.
• Post period, Mithra announced a deal with Mayne Pharma (ASX: MYX) for the exclusive license for its vaginal contraception ring, Myring. Mayne Pharma is the second-largest supplier of oral contraceptives in the US market, and the agreement covers commercialization in the United States. As part of the agreement, Mayne Pharma will pay EUR2.4m upon signature and milestones of at least EUR10.0m following approval by the US FDA. Currently, the US market for biocompatible contraceptive rings is worth USD 780m ^[4] , which represents approximately 30% of the total global market by volume and over 75% by value, making this a key territory for the commercialization of Myring.
• Importantly, Mithra will produce Myring at its CDMO, and as part of Mayne Pharma's long-term exclusive sourcing commitment, Mithra is considering the expansion of its production capacity for Myring.
• Post period, Mithra announced that it signed a binding term sheet with Fuji Pharma, the Japanese leader in Women's Health, to commercialize Donesta® in Japan and ASEAN ^[5] . See separate press release of March 1 2017 for more information.

              CORPORATE

• In August 2016, a number of changes were announced to the Board of Directors of Mithra Pharmaceuticals. Herjan Coelingh Bennink, Barbara De Saedeleer, Marc Foidart, Jean Sequaris were replaced by the following Board Members:
  • Mithra Pharmaceuticals announced the appointment of Marc Coucke as chairman of the Board of Directors.
  • In addition, Koen Hoffman, CEO of Value Square and former CEO of KBC Securities, was appointed an independent director of the Company and became chairman of Mithra's Audit Committee.
  • Freya Loncin, General Counsel Alychlo, was appointed new non-executive director.
  • Professor Jean-Michel Foidart, co-founder of Mithra and current co-chairman of its Scientific Committee, was appointed Executive director.
  • Christiane Malcorps, Global Head of Facility Excellence & Country Manager Belgium at Solvay, was appointed as member of the Board of Mithra's CDMO.
• In February 2016, Francois Fornieri, CEO of Mithra, was named AstraZeneca Business Development Executive of the Year 2015 for leading three transformational deals throughout 2015, making Mithra a leading player in women's health.
• In March 2016, Mithra launched Gyn&Co, a website focused on identifying the needs of women. The aim is to keep a finger at the pulse of the questions and concerns amongst women, and to ensure that Mithra remains at the forefront of developing innovative therapeutics in women's health.
• In October 2016, Mithra was named finalist at the Essenscia Innovation Awards 2016 , a highly regarded industrial innovation award in Belgium, for its E4 development programme
• Post period, In February 2017, Mithra announced the appointment of Christophe Maréchal as Chief Financial Officer. Before joining Mithra, Mr. Maréchal was Director, Group Treasury and Credit Risk Manager, at Hamon Group (Euronext Brussels: HAMO), an engineering and contracting company. He has more than 20 years of financial experience in the international industrial, telecommunications, manufacturing and banking industries, including M&A, operational and financial strategy, and tactical initiatives to drive long term business growth.
• Post period, in February 2017 the appointment of Michaël Dillen as Chief Legal Officer was also announced. Mr. Dillen has 10 years of experience in various legal positions, predominantly focused on the healthcare sector. Michaël started his career as a lawyer, where he developed a legal practice focused on corporate and commercial advisory towards private and institutional clients in the life sciences industry. Before joining Mithra in 2017 as Chief Legal Officer he worked for Terumo, a Japanese listed medical devices company. Here, he acted as senior counsel responsible for covering legal services in the EMEA region.

Financial Results PROFIT AND LOSS ACCOUNTS

BALANCE SHEET

CASH FLOW

• PROFIT AND LOSS  
  • Mithra's revenues increased almost 10% from EUR 20.4 million to EUR 22.5 million. The main reason for the increase in revenues was the deal with Japanese market leader Fuji Pharma for EUR 5.5 million (as a reminder, the 2015 results included the Zoreline® deal for EUR 1.8 million). With regard to the generic business, Mithra gained market share and volume, but due to pricing pressure in the contraceptive market, revenues for this segment were EUR 17 million, EUR 1.8 million lower than in 2015.
  • Gross margin for 2016 increased by EUR 3.2 million from EUR 10.2 million to EUR 13.4 million. The increase of 31% is due to the deal with Fuji Pharma (EUR 5.5 million) while in 2015 the gross margin included the Zoreline® deal with GSP for an amount of EUR 1.8 million.
  • R&D investments have risen from EUR 9.5 million to EUR 34.3 million, which amounts to an increase of EUR 24.8 million. This is mainly due to development expenses related to the Phase III of Estelle® and the Phase II of Donesta®, as well as API investments in E4 (EUR 21.4 million in 2016). Investments in Myring, Zoreline® and Tibolone® accounted for EUR 7.6 million. The remainder of the R&D costs relate to payroll and consultancy expenses, and more specifically to start-up expenses at the level of the CDMO.
  • G&A expenses are well controlled and have been lowered by EUR 2.1 million from EUR 10.3 million in 2015 to EUR 8.2 million in 2016. The difference is mainly attributable to the exceptional and one-time listing costs in 2015.
  • Selling expenses have gone up in 2016 due to investments in the subsidiaries in Germany, Brazil and France. However, in the course of 2016, the Company decided to put the subsidiaries on hold and to seek external distribution partners in these countries. As a result, the selling structure decreased by the end of 2016, and expenses for these territories came to EUR 3.3 million as at 31 December 2016.
  • The financial loss for 2016 amounts to EUR 4.6 million which was mostly driven by changes in fair value on existing earn outs, mainly for Estelle®.
  • The loss of the period before taxes amounts to EUR 40.6 million. This is an increase of EUR 26 million compared to 2015, driven by R&D expenses in 2016.
  • The tax result of the year shows a profit of EUR 5.5 million. This is a deferred tax asset to be offset against future taxable income. Taking this tax profit into consideration, the net loss for 2016 was EUR 35.1 million.  
• BALANCE SHEET
  • As of 31 December 2016, the balance sheets shows a total of EUR 114.8 million in non-current assets, the largest part of which are other intangible assets (EUR 79.1 million). These intangible assets are the result of the acquired assets and represent the fair value of the assets, aside from Donesta® which was acquired at purchase cost of EUR 8 million. The fair value mainly relates to Estelle® for an amount of EUR 30.6 million and to Zoreline® for an amount of EUR 24.4 million.
  • In the noncurrent assets we note a considerable increase in tangible fixed assets (EUR 16.9 million at the end of 2016 vs. EUR 3.57 million in 2015). The increase relates to the investments at the level of the CDMO where Mithra is preparing the production of Myring.
  • Current assets at the end of 2016 represent a value of EUR 57.8 million, the bulk of which is the company's cash position of EUR 45.7 million on 31 December 2016.
  • The equity position at the end of the year has decreased from EUR 127.4 million in 2015 to EUR 93.0 million in 2016. The decrease is primarily related to the loss booked in 2016.
  • Non-current liabilities increased to EUR 51.9 million at the end of 2016, compared to EUR 43.6 million in 2015, primarily due to the financing obtained for the CDMO facility as well as an increase of the fair value of the earn out for Estetra. Other loans of EUR 32.5 million represent the fair value debt towards the former owners of Estelle® for EUR 22.4 million and the former owners of Zoreline® for EUR 6 million.
  • The reduction in current liabilities to EUR 27.7 million (from EUR 34.5 million in 2015) is primarily attributable to the reimbursement of the short term financing, compensated for by an increased deferred revenue position related to the Fuji deal. (Note that this relates to the conditional part of the Fuji deal, which is currently not yet recognized as revenue.)  
• CASH FLOW
  • Full year cash flow amounted to EUR -51 million, which is composed of:
    • Operating cash flow : EUR -24.7 million. The negative EBIT of EUR -35.9 million and the withholding taxes on the Fuji deal of EUR 1 million are partly offset by an increase in trade payables (+ EUR 7.2 million) and deferred revenues of the Fuji deal (+ EUR 4.5 million)
    • Investing cash flows : EUR -23.1 Million. The cash flows for the business combinations refer to the payment of EUR 8.5 million to GSP during H2 2016. Investments in tangible assets are predominately related to capex for the CDMO (EUR 13.2 million) while investments in intangible assets mainly include the products bought as part of the GSP deal.
    • Financing cash flows : EUR -1.8 million. Reimbursement of financing mainly include the reimbursement of a short term bridge financing of EUR 16.9 million as well as the normal reimbursements on existing financing facilities. Proceeds from financing primarily refer to the CDMO financing.

              Outlook

Building on the progress in 2016, Mithra is looking forward to further preparing the commercialization of its lead contraceptive product candidate Estelle®, working to select a suitable partner for the Phase III Donesta® study, and filing for marketing approval of its vaginal contraceptive, Myring, in both Europe and the US in Q2 2017. The company believes that these developments, along with its innovative research, development and manufacturing facility in Liège, will further strengthen its position as a leading international player in women's health.

In 2017, Mithra will further accelerate its business development efforts, as it plans to partner its E4-based programs for territories including Europe and the US. The Company is currently identifying potential partners, and discussions are expected to ramp up in 2017. The partnering strategy for Donesta® will reduce upfront expenditure while maximizing product opportunities by working with well-established partners on Phase III, regulatory approvals and commercialization

The significant investment in the development of its advanced pipeline, especially the E4-based products, is expected to continue in 2017. Mithra is confident that it can accelerate its partnership discussions in view of the significant potential of its programs to transform options for women in the large and fast-growing segments of safe contraceptives and HT solutions.

For more information, please contact: Press Julie Dessart Chief Communication Officer +32 4 349 28 22 / +32 475 86 41 75 press@mithra.com

Investor Relations François Fornieri, CEO +32 4 349 28 22

Sofie Van Gijsel Investor Relations Officer +32 485 19 14 15 investorrelations@mithra.com

Consilium Strategic Communications Jonathan Birt, Sue Stuart, Hendrik Thys +44 2 037 095 700 mithra@consilium-comms.com

About Mithra Mithra Pharmaceuticals SA, founded in 1999 as a spin-off of the University of Liège by Mr. François Fornieri and Prof. Dr. Jean-Michel Foidart, is a Euronext listed pharmaceutical company (MITRA) focused on Women's Health. Mithra's mission is to improve every stage of women's life with innovative and accessible pharmaceutical solutions. As such the Company aims to become a worldwide leader in women's health by developing, manufacturing and commercializing proprietary, innovative and differentiated drugs and complex therapeutic solutions in four therapeutic fields of women's health: fertility and contraception, menopause and osteoporosis, gynecological infections and female cancers. Mithra has an approximate headcount of 141 staff members and is headquartered in Liège, Belgium. Further information can be found at: www.mithra.com

Important information The contents of this announcement include statements that are, or may be deemed to be, "forward-looking statements". These forward-looking statements can be identified by the use of forward-looking terminology, including the words "believes", "estimates," "anticipates", "expects", "intends", "may", "will", "plans", "continue", "ongoing", "potential", "predict", "project", "target", "seek" or "should", and include statements the Company makes concerning the intended results of its strategy. By their nature, forward-looking statements involve risks and uncertainties and readers are cautioned that any such forward-looking statements are not guarantees of future performance. The Company's actual results may differ materially from those predicted by the forward-looking statements. The Company undertakes no obligation to publicly update or revise forward-looking statements, except as may be required by law.

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^[1] Good Manufacturing Practices

^[2] Apter D, Zimmerman Y, Beekman L, et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception 2016; 94 : 366-73.

^[3] Kluft C, Zimmerman Y, Mawet M, et al. Reduced haemostatic effects with drospirenone-based oral contraceptives containing estetrol versus ethinyl estradiol. Contraception 2016; 95 : 140-147

^[4] As determined by Mayne Pharma, based on IMS Health for the 12 months ending 31 December 2016.

^[5] Association of Southeast Asian Nations : Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Phillipines, Singapore, Thailand and Vietnam