Author: [email protected]

BioInvent Interim Report 1 January – 30 June 2015

On July 22, 2015 BioInvent reported its Interim Report 1 January – 30 June 2015 (Press release, BioInvent, JUL 22, 2015, View Source [SID:1234506579]).

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BioInvent’s transformation into a clinical company continues at a fast pace.

Second quarter 2015,
April – June
Net sales for April – June 2015 amounted to SEK 3.7 (32) million.
Earnings after tax for April – June 2015: SEK -25 (3.7) million.
Earnings after tax per share for April – June 2015 before and after dilution:-0.19 (0.04) SEK.
Cash flow from current operations and investment activities for April – June 2015: SEK -31 (-25) million.

Half year results 2015,
January – June
Net sales for January – June 2015 amounted to SEK 4.3 (34) million.
Earnings after tax for January – June 2015: SEK -47 (-15) million.
Earnings after tax for January – June 2015 before and after dilution: SEK -0.39 (-0.17).
Liquid funds as of 30 June 2015: SEK 63 (74) million. Cash flow from current operations and investment activities for January – June 2015: SEK -51 (-48) million.

Important events in the second quarter and after the reporting period

Research results published in April in the respected science journal Cancer Cell showed that BioInvent’s drug candidate BI-1206 has the potential to inhibit resistance to antibody drugs for the treatment of cancer. The article also described groundbreaking findings that resistance to many types of antibody drugs can be overcome by preventing cancer cells from ‘hiding’ from immune cells.
In the second quarter BioInvent raised SEK 77.7 million through an oversubscribed rights issue. Management and key personnel subscribed for new shares corresponding to a total of 2.8 per cent of the shares offered in the rights issue.

In June BioInvent and University of Southampton entered into a research collaboration to develop new immune therapy treatments for cancer by targeting regulatory T cells (T regs).

In June BioInvent announced that its partnership with a leading U.S. biotechnology company had advanced to next phase. The collaboration aims to discover novel therapeutic antibodies to be incorporated into the company’s CAR-T programs. The first of up to three targets covered by the agreement has now been identified and the work to develop appropriate antibodies will be initiated.

BioInvent announced in July that the upcoming phase I/IIa study of TB-403 will be expanded to include children with Ewing’s sarcoma and neuroblastoma in a dose escalation phase of the trial, in addition to the already announced indication medulloblastoma. Further it was announced that late stage negotiations are on-going with a leading clinical network in the US to conduct the trial. The study is planned to commence in Q4 2015.

Comments from the CEO
"The transformation of BioInvent into a company with an internationally competitive clinical portfolio is continuing at a fast pace. In the second quarter of the year we strengthened our financial position through an oversubscribed new issue.

Important progress was made with the publication of BI-1206 research in Cancer Cell, one of the highest ranked science journals in the world, the announcement of a new research partnership with world-leading researchers at the University of Southampton and the high level of activity in our new partnership with a leading US biotech company in the CAR-T area.

The foundations have been laid to create significant financial value. Within the next 12 months three of our projects will be in active clinical trials. This will place BioInvent at the leading edge of immuno-oncology, the most exciting area in drug development. We have a broad portfolio of development projects, we have the expertise to prioritise the most interesting development pathways from a commercial perspective and we have the resources to generate the data necessary to secure lucrative agreements.

Transforming BioInvent has involved a lot of work and there are undoubtedly some big challenges ahead, but I note that we are now in exactly the right place at exactly the right time," says Michael Oredsson, CEO of BioInvent.

Project overview

BioInvent is developing a clinical oncology portfolio with a focus on strategic value creation, retained
market rights and a balanced risk.

Transforming BioInvent has involved a lot of work and there are undoubtedly some big challenges ahead, but I note that we are now in exactly the right place at exactly the right time," says Michael Oredsson, CEO of BioInvent.

Multiple myeloma (BI-505)
Background

In the western world, an average of 5.6 new cases of multiple myeloma per 100,000 people are registered every year, which is equivalent to around 60,000 new cases a year. Multiple myeloma is an incurable cancer for which there are no good drugs to prevent the relapses that affect all patients after treatment with cytotoxic drugs or after a stem cell transplant. Expression of an adhesion protein, ICAM-1 (also called CD54), is elevated in myeloma cells, which makes it a suitable target for a drug candidate. The BI-505 drug candidate is a human antibody that specifically binds to the ICAM-1. BI- 505 affects tumours in two ways – by inducing cell death of myeloma cells and by engaging the Project Primary Indication Discovery Preclinic Phase I Phase II Collaboration BI-505 Multiple Myeloma University of Pennsylvania BI-1206 CLL, NHL Cancer Research UK, Univ. of Southampton TB-403 Medulloblastoma ThromboGenics Preclinical pipeline (based on F.I.R.S.T.TM and n-CoDeR)1) T-reg Oncology University of Southampton Tumor Macrophage Oncology Cancer Research Technology AML Hematologic cancer Internal development 1) The preclinical CLL project has been removed from the list of preclinical projects as this part is included in the development project BI-1206. Development pipeline 3 patient’s immune cells, known as macrophages, to attack myeloma cells. Macrophages are abundant in the bone marrow of myeloma patients, where they are thought to contribute to disease progression and development of resistance to currently available drugs. BI-505 has the ability to get macrophages to attack myeloma cells and has, in several relevant animal models, proved to be more effective at killing tumours than existing drugs. The good safety profile and the effectiveness of the substance against cancer cells that do not bind to tumours, even where these are expressed in low quantities, makes BI-505 especially suitable in preventing multiple myeloma relapses.

Project status
The initial results from the phase I study of BI-505 on patients in advanced stages of multiple myeloma showed that the substance has a good safety profile. In the dosage groups to which extended therapy was offered, 24 percent of these severely ill patients demonstrated stable disease for at least two months, which indicates a positive effect of BI-505, and is in parity with Phase I data for Elotuzumab, currently in phase III clinical development for multiple myeloma. Results from the phase I study were presented in an international conference on multiple myeloma in Kyoto, Japan, and were published in the scientific journal, Clinical Cancer Research, in February 2015. New preclinical data was also presented on the same occasion showing significantly enhanced anti-tumour activity compared with monotherapy when combining the registered drugs Velcade or Revlimid with BI- 505.

The scientific journal, Cancer Cell, presented data showing preclinical proof-of-concept for both BI-505 and for BioInvent’s function-based F.I.R.S.T. platform. The article presents data showing the potent effect of BI-505 in several preclinical multiple myeloma models.

In April 2013 a phase II study in patients with asymptomatic smoldering myeloma was initiated. The study has now been prematurely terminated due to a strategic review of the commercial potential of BI-505 in light of the preclinical and clinical data package. BI-505 will be repositioned to target residual disease in combination with treatments designed to lower tumour burden in conjunction with and after stem-cell transplantation in patients with myeloma. Asymptomatic multiple myeloma is currently not treated with drugs because the side effects are not acceptable in symptom free patients. This indication therefore has very limited commercial potential and the development path is expected to be relatively complicated.

Instead, a clinical study in collaboration with Penn Medicine will be initiated to investigate the potential of BI-505 to deepen the response after autologous stem cell transplantation in combination with low dose Revlimid . BioInvent has also identified an opportunity to develop BI-505 in other orphan indications, and is evaluating parallel clinical development of these at a significantly lower cost and in a shorter timeframe compared with the multiple myeloma indication.

BI-505 has received Orphan Drug Designation for the multiple myeloma indication by both the U.S. Federal Drug Administration (FDA) and European Medicines Agency (EMA).

Non-Hodgkin lymphoma and cronic lymphatic leukemia (BI-1206)
Background

Non-Hodgkin lymphoma (NHL) is an umbrella term for a group of cancers that develop in the body’s lymphatic system. Since lymphatic tissue is present throughout the body, lymphoma can start anywhere. High-grade lymphoma is treated with radiation and/or cytostatic drugs and in many cases with rituximab (Rituxan , Mabthera , Roche). Low-grade lymphoma has a better prognosis and treatment is often only initiated once a patient has disease symptoms.

Chronic lymphatic leukaemia (CLL) is an incurable lymphoma that most commonly affects older men. The disease progression is often slow and patients are normally treated with cytostatic drugs, often in combination with monoclonal antibodies.
In Europe and North America, around 157,000 people every year are diagnosed with NHL and around 35,000 with CLL.

BioInvent’s drug candidate BI-1206 is a fully human antibody aimed at CD32b, an immunosuppressive protein that is overexpressed in patients with lymphoma, especially in patients who respond poorly to currently available drugs like the anti CD20 treatment rituximab. It is well known that CD32b is involved in the development of resistance to current state-of-the-art treatments for NHL and CLL – rituximab. In models for different cancers, CD32b has also been shown to be involved in the development of resistance to treatment with other antibodies. BI-1206 therefore has a very interesting mechanism with the potential for use in both NHL and CLL, as well as other cancer indications. As BI- 1206 blocks the immunosuppressant effect of CD32b, the immune system can be stimulated, which can strengthen the therapeutic effect of both rituximab as well as other antibody-based drugs. Combination therapy with BI-1206 and rituximab in clinically relevant animal models with tumour cells 4 from patients with NHL has demonstrated significantly improved antitumour effects compared to monotherapy with rituximab. A series of studies have shown that as many as half of the cancer patients who responded to an initial rituximab treatment proved to be resistant to the drug at relapse, which indicates a significant medical need for improved therapies for these patients. Combination therapy therefore has the potential to significantly improve the treatment of patients with this disease.

BI-1206 has also shown a strong ability to kill lymphoma cells in preclinical models using tumour cells taken directly from patients. The results indicate that BI-1206 may have the potential to be used as a monotherapy.

Project status

In January 2015 BioInvent entered into an agreement with Cancer Research UK (CRUK),
Cancer Research Technology (CRT) and Leukaemia & Lymphoma Research (LLR) on implementation of a phase I/II study with BI-1206 in patients with CLL and NHL. The first study in patients will be financed and executed by CRUK, CRT and LLR. BioInvent has the opportunity to utilise an exclusive licence for the study data in return for low milestone payments and royalties paid to Cancer Research Technology.

The plan is for this open phase I study to include 50–60 patients who will be treated either only with BI-1206 or BI-1206 in combination with rituximab. Patients with CLL with be recruited first, but smaller groups of patients with other types of NHL, such as mantle cell lymphoma, follicular lymphoma and diffuse large B cell lymphoma, may also be included in the study. The study is expected to start in the second half of 2015.

In April 2015 the prestigious scientific journal Cancer Cell published data showing that BI-1206 has anti-tumour activity and can overcome resistance to antibody treatment in clinically relevant animal models. It is these data that forms the basis for the planned clinical study of BI-1206 in combination with rituximab.

Alongside this clinical study, preclinical studies will continue, principally focused on proving the combination effects of BI-1206 and CD38 antibodies within multiple myeloma. CD38 antibodies constitute a new, very promising class of drug where market approval is pending in the multiple myeloma indication. Despite proven good effects in clinical studies, the data indicates that patients develop resistance to these new drugs as well, which shows that there is a medical need to complement this class of drugs to optimise the treatment of patients. In addition, research regarding CD32b expression in subpopulations within NHL will be done, with the potential to identify the optimal population for treatment with BI-1206.

Medulloblastoma (TB-403)
Background

Medulloblastoma, neuroblastoma and Ewing’s sarcoma are life-threatening, debilitating cancer diseases that exclusively affect children and adolescents. Both diseases are rare and are diagnosed in just over ten individuals per million and year. Preclinical data from medulloblastoma animal models using the monoclonal antibody TB-403 indicates the potential for better clinical results for these patients than with available therapies. The antibody will therefore be evaluated in a clinical study for this indication.

The TB-403 drug project is conducted in cooperation with Oncurious, a subsidiary of the Belgian biopharma company ThromboGenics. BioInvent is paying half of the development costs and has the right to 40 percent of all future revenue from the project.

Project status

A new clinical study with TB-403 in children with medulloblastoma will start in the fourth quarter of 2015. In the dose escalation part of the study, children suffering from neuroblastoma and Ewing’s sarcoma will also be recruited. Preclinical studies evaluating the effect of the antibody in models for neuroblastoma are ongoing. The antibody TB-403 has demonstrated an excellent safety profile in previous clinical trials in patients with liver cancer and glioblastoma. The decision to launch a new clinical trial and further preclinical evaluations is based on new knowledge about the antibody’s mechanism of action, which is described in an article published by Jain et al in the respected journal Cell.

The relatively high development risk of the project is being weighed against the favourable safety profile that TB-403 has demonstrated in earlier trials, the project’s low development costs, and the possibility of using a faster development process than is normally the case.

Preclinical projects

BioInvent’s preclinical research is aimed at expanding the Company’s portfolio of drug candidates. Since 2012 the Company has focused its own research resources entirely on cancer. Over the past decade the Company has accumulated a significant body of experience of relevant disease models within cancer biology and tumour immunology. The basis of the preclinical research are the models used to identify the most effective and potent antibody candidates. These models make it possible to simultaneously conduct an extensive study of the safety and tolerability of the antibody, based on the biology of the disease and the mechanism of action of the antibody.

BioInvent’s research is aimed at developing antibodies with the ability to kill tumour cells through apoptosis (programmed cell death) or by activating the body’s own immune system. With the help of the F.I.R.S.T. platform, the Company is actively seeking new drug candidates for the treatment of different cancers. BioInvent collaborates with leading Swedish and international academic groups to gain access to new therapeutic concepts for the treatment of both serious haematological and solid cancers, which can serve as a basis for the development of new projects. One example is a partnership with Professor Martin Glennie and Professor Mark Cragg and their team at the University of Southampton with whom BioInvent is conducting several parallel collaborative immuno-oncology projects.

Licensing agreements and research collaborations with external partners
The Company has entered into several licensing agreements and, in some cases, research collaborations with a number of external partners including Bayer Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Servier and Xoma. The structure and terms of these agreements and partnerships vary, but they all have in common that BioInvent receives licence fees, research financing, milestone payments and royalties on the sale of commercial products. Of these external drug development programmes, four projects are currently in phase I and five are in the preclinical phase. It should be noted that one preclinical project is added during the quarter.

Revenues and result
April-June
Net sales for the April-June period amounted to SEK 3.7 million (32). Revenues for the period are derived from partners developing therapeutic antibodies from the n-CoDeR antibody library. BioInvent received in the second quarter of 2014 revenue from sales of the Company’s rights to the drug development candidate ADC-1013 to Alligator Bioscience AB.

The Company’s total costs for the April-June period amounted to SEK 29 million (29). Operating costs are divided between external costs of SEK 19 million (18), personnel costs of SEK 10 million (10) and depreciation of SEK 0.4 million (0.5). Research and development costs for April-June amounted to SEK 21 million (20).

Earnings after tax for April-June amounted to SEK -25 million (3.7). The net financial items, April-June, amounted to SEK 0.0 million (0.3). Earnings per share before and after dilution, April-June, amounted to SEK -0.19 (0.04).

January-June
Net sales for the January-June period amounted to SEK 4.3 million (34). Revenues for the period are derived from partners developing therapeutic antibodies from the n-CoDeR antibody library. BioInvent received in the second quarter of 2014 revenue from sales of the Company’s rights to the drug development candidate ADC-1013 to Alligator Bioscience AB.

The Company’s total costs for the January-June period amounted to SEK 52 million (51). Operating costs are divided between external costs of SEK 32 million (31), personnel costs of SEK 19 million (19) and depreciation of SEK 0.8 million (1.0). Research and development costs for the January-June period amounted to SEK 36 million (34).

Earnings after tax for the January-June period amounted to SEK -47 million (-15). The net financial items amounted to SEK 0.1 million (0.4). Earnings per share before and after dilution amounted to SEK -0.39 (-0.17).

Financial position and cash flow
As of 30 June 2015, the Group’s liquid funds amounted to SEK 63 million (74). The cash flow from current operations and investment activities for the January-June period amounted to SEK -51 million (-48).

The annual general meeting in April 2015 approved the Board of Directors’ resolutions in March 2015 to carry out a new share issue with pre-emptive rights for shareholders of SEK 77.7 before issue costs. The new share issue was completed in May 2015. The subscription price for the new share issues was set to SEK 1.55 per share. The rights issue was oversubscribed. After the share issue the share capital consists of 162,918,961 shares.
The shareholders’ equity amounted to SEK 73 million (91) at the end of the period. The Company’s share capital at the end of the period was SEK 13 million. The equity/assets ratio at the end of the period was 80 (76) per cent. Shareholders’ equity per share amounted to SEK 0.45 (0.81). The Group had no interest-bearing liabilities.

Investments Investments in tangible fixed assets amounted to SEK 0.2 million (-). No investments were made in intangible assets during the period (-).

Parent company
All operations of the Group are conducted by the Parent Company. The Group’s and the Parent Company’s financial statements coincide in every material way.

Organisation
As of 30 June 2015, BioInvent had 39 (36) employees. 33 (30) of these work in research and development.

Employee Incentive Programme
Employee Incentive Programme 2011/2015
The 2011 Annual General Meeting voted in favour of complementing the already established Employee Incentive Programme 2008/2012 aimed at newly employed senior executives and key individuals not participating in Employee Incentive Programme 2008/2012. The number of employee options was within the framework of the number of options still not exercised in Employee Incentive Programme 2008/2012, including previous supplementary programmes.

Each employee option entitles the holder to acquire 1.163 new shares in BioInvent for a subscription price of SEK 26.13 up to 1 December 2015. Subscription price and number of shares that each employee option entitles to are converted pursuant to rights issues carried out. Under the programme 48,105 employee options have been allotted.

Employee Incentive Programme 2013/2017
The 2013 Annual General Meeting voted in favour of establishing a new, long-term employee incentive programme involving the allotment of a maximum of 900,000 employee options free of charge to all Group employees.

The employees will receive options based on their performance in the 2013, 2014 or 2015 financial years and allotment will take place in connection with the publication of the year-end financial statement for the subsequent year. Each employee option will entitle the holder to acquire 1.157 new share in BioInvent for a subscription price of SEK 3.04 during the period from the date of publication of the Company’s year-end financial statement for the 2016 financial year up to and including 1 December 2017. Subscription price and number of shares that each employee option entitles to are converted pursuant to rights issues carried out. Allotment of 100,747 employee options took place in February 2014 and 74,516 employee options took place in February 2015.

To guarantee BioInvent’s commitment and cover the costs associated with Employee Incentive programme 2013/2017, the 2013 Annual General Meeting resolved to issue a maximum of 1,182,780 warrants to BioInvent Finans AB.
If fully exercised, Employee Incentive Programme 2011/2015 and Employee Incentive Programme 2013/2017 will represent a dilution equivalent to around 1.1 percent of the shares in the Company.

Risk factors
The Company’s operations are associated with risks related to factors such as pharmaceutical development, clinical trials and product responsibility, commercialisation and partners, competition and fast technological development, biotechnology and patent risk, compensation for pharmaceutical sales, qualified personnel and key individuals, additional financing requirements, currency risk and interest risk. The aforementioned risks summarize the factors of significance for BioInvent and thus an investment in the BioInvent share.
No significant changes to the risks and uncertainty factors occurred during the period. For a more detailed description of risk factors, see section "Risks and Risk Management", page 29, in the company’s annual report 2014.

Accounting principles
This interim report was prepared in accordance with IAS 34, Interim Financial Reporting, and applicable sections of the Swedish Annual Accounts Act. The accounting principles applied here are the same as those applied in the preparation of the most recent annual report. Changes in IFRS standards entered into force in 2015 has had no material impact on the financial statements. The financial statements of the Parent company coincide in every material way with the consolidated financial statements.

Genmab Announces Submission of Supplemental Biologics License Application to FDA for Ofatumumab as Maintenance Therapy for Relapsed CLL

On July 22, 2015 Genmab A/S (OMX: GEN) reported that a supplemental Biologics License Application (sBLA) has been submitted to the U.S. Food and Drug Administration (FDA) for the use of ofatumumab (Arzerra) as maintenance therapy of patients with relapsed chronic lymphocytic leukemia (CLL) (Press release, Genmab, JUL 22, 2015, View Source [SID:1234506592]). The application was submitted by Novartis under our ofatumumab collaboration.

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The application is based on interim results from a Phase III study, PROLONG (OMB112517) which evaluated ofatumumab maintenance therapy versus no further treatment in patients with a complete or partial response after second or third line treatment for CLL. Results from this trial were presented at the 2014 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"The submission of the application to expand the label to use ofatumumab as a maintenance therapy for patients with relapsed CLL in the U.S. follows closely behind the marketing application for this indication in Europe. We are looking forward to the response from both the U.S. and European regulatory authorities, and hope that ofatumumab will soon become available for maintenance therapy of patients with relapsed CLL," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About CLL
CLL, the most commonly diagnosed adult leukemia in Western countries, accounts for approximately 1 in 4 cases of leukemia1,2. Most CLL patients experience disease progression despite initial response to therapy and may require additional treatment3.

About Ofatumumab (Arzerra)
Ofatumumab is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL who are refractory after prior treatment with fludarabine and alemtuzumab.
Arzerra is not approved anywhere in the world as maintenance therapy for relapsed chronic lymphocytic leukemia.

Please see full Prescribing Information, including Boxed WARNING for Arzerra (ofatumumab).

Arzerra is marketed under a co-development and collaboration agreement between Genmab and Novartis, as successor in interest to GSK.

ABLYNX SIGNIFICANTLY EXPANDS ITS IMMUNO-ONCOLOGY COLLABORATION WITH MERCK & CO., INC.

On July 22, 2015 Ablynx [Euronext Brussels: ABLX; OTC: ABYLY] reported an expansion of its immuno-oncology collaboration with a subsidiary of Merck & Co., Inc. ("Merck") [known as MSD outside the United States and Canada], to address an increased number of immune checkpoint modulator targets (Press release, Ablynx, JUL 22, 2015, View Source [SID:1234506584]).

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The original collaboration announced in February 2014 focused on the discovery and development of five pre-defined Nanobody candidates (including multi-specific Nanobody combinations) directed towards immune checkpoint modulator targets for evaluation as immunotherapies for cancer.

As part of this expansion of the 2014 agreement, Ablynx will be responsible for the discovery and development of up to 12 additional Nanobody programmes against individual protein targets and target combinations (mono-specific and multi-specific Nanobodies) through to the in vivo pre-clinical proof-ofconcept stage, after which Merck will have the option to advance specified lead candidates.

Under the terms of this four year expansion, Ablynx will receive a €13 million upfront payment comprising exclusivity fees and FTE payments as well as further research funding over the term of the collaboration. In addition, Ablynx will be eligible to receive additional exclusivity fees, depending on the number of programmes for which Merck decides to exercise its licensing option, plus development, regulatory and commercial milestone payments of up to €340 million per programme, as well as tiered royalties on annual net sales upon commercialisation of any Nanobody products. Merck will be responsible for clinical development, manufacturing and commercialisation of any products resulting from the collaboration.

Commenting on the announcement, Dr Edwin Moses, CEO of Ablynx, said: "This significant expansion of our collaboration with Merck after less than 18 months underlines the promise offered by our Nanobody platform in the discovery of unique new therapeutic agents. The speed and flexibility of the platform and its ability to develop multi-specific candidates against target combinations is a very powerful characteristic of the Nanobody technology. We are pleased that Merck, one of the leaders in this emerging field, has expanded its collaboration with us and we look forward to continuing our collaboration in the development of these innovative immuno-oncology drug candidates which could potentially transform the treatment of many cancers."

"Immuno-oncology remains a key area of focus for Merck," said Dr Joseph Miletich, Senior Vice President Discovery Research and Development, Merck Research Laboratories. "The expansion of this ongoing collaboration with Ablynx allows us to increase our ability to evaluate the potential of more immune checkpoint targets for the treatment of cancer."

About the immuno-oncology collaboration between Ablynx and Merck & Co., Inc.

In February 2014, Ablynx entered into a research collaboration and licensing agreement with a subsidiary of Merck & Co., Inc. This exclusive collaboration and licensing agreement is focused on the discovery and development of several predefined Nanobody candidates (including bi- and tri-specifics) directed toward so-called immune checkpoint modulators.
Under the terms of the original agreement, Ablynx received an upfront payment of €20 million and is entitled to up to €10.7 million in research funding during the initial three year research term of the collaboration. In addition, Ablynx is eligible to receive development, regulatory and commercial milestone payments on achieved sales thresholds for a number of products with ultimate potential to accrue as much as €1.7 billion plus tiered royalties. Merck will be responsible for the development, manufacturing and commercialisation of any products resulting from the collaboration.
Merck and Ablynx have a separate collaboration in the field of ion channel drug development, announced in October 2012, with a €6.5 million upfront payment, €2 million research funding and up to €448 million in research, regulatory and commercial milestone payments associated with the progress of multiple candidates as well as tiered royalties on any products derived from the collaboration.

European Commission Approves Merck’s Anti-PD-1 Therapy, KEYTRUDA® (pembrolizumab), for Both First-line and Previously-treated Patients with Advanced Melanoma

On July 22, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the European Commission has approved KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of advanced (unresectable or metastatic) melanoma in adults (Press release, Merck & Co, JUL 22, 2015, View Source [SID:1234506583]).

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The European Commission approval of KEYTRUDA is based on data from three clinical studies conducted in more than 1,500 first-line and previously-treated patients with advanced melanoma. KEYTRUDA received European Commission regulatory approval based on Phase 3 data which showed it is the first and only anti-PD-1 therapy to provide a statistically superior survival benefit as a monotherapy compared to ipilimumab, the current standard of care for advanced melanoma. Today’s approval allows marketing of KEYTRUDA in all 28 EU member states at the approved dose of 2 mg/kg every three weeks.

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"Today’s European approval supports our goal of accelerating immuno-oncology research for the benefit of patients around the world," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "We believe that the broad data set supporting this approval helps illustrate the significant potential of KEYTRUDA to treat advanced melanoma, a devastating disease."

"Merck has long-believed that innovation and access must go hand-in-hand, which is why we work to bring forward new innovations, and ensure access to those innovations," said Deepak Khanna, senior vice president and regional president, Europe, MSD Oncology. "Merck is committed to working collaboratively with governments and other stakeholders to ensure that KEYTRUDA will be made available to advanced melanoma patients in Europe as rapidly as possible."

About KEYNOTE-001, 002 and 006

The European Commission’s approval is based on data from three studies — KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006. These studies evaluated the efficacy and safety of KEYTRUDA in advanced melanoma patients – across treatment lines, prognostic factors, tumor characteristics, and BRAF mutational status – and established 2 mg/kg every three weeks as the approved dose.

KEYNOTE-001, the largest Phase 1b study to date of an anti-PD-1 antibody, is a single arm, open label study of KEYTRUDA (2 mg/kg every three weeks or 10 mg/kg every two or three weeks) that included patients with advanced melanoma who were previously-treated with ipilimumab (and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor) and patients who were ipilimumab-naïve. In two cohorts of advanced melanoma patients comparing doses of KEYTRUDA, of the 140 patients receiving the approved 2 mg/kg every three week dose, the overall response rate (ORR) (primary endpoint) for KEYTRUDA was 33 percent in ipilimumab-naïve patients (95% CI, 21, 48) (n=51) and 25 percent in patients previously-treated with ipilimumab (95% CI, 16, 35) (n=89). The secondary endpoints were overall survival (OS), progression-free survival (PFS), and duration of response per RECIST v1.1. Results were similar across dosing schedules.

KEYNOTE-002 is a Phase 2, multi-center, randomized study of KEYTRUDA (2 mg/kg every three weeks or 10 mg/kg every three weeks) compared to investigator-choice chemotherapy in 540 patients with advanced melanoma who were previously-treated with ipilimumab and, if BRAF V600 mutation positive, a BRAF or MEK inhibitor. The primary endpoints were PFS and OS. Both KEYTRUDA doses evaluated were superior compared to chemotherapy for PFS at both six-months and nine-months, with PFS rates of 34 and 24 percent, respectively, for the 2 mg/kg dose (95% CI, 0.57 [0.45, 0.73]) (n=180) and 38 and 29 percent for the 10 mg/kg dose (95% CI, 0.50 [0.39, 0.64]) (n=181), compared to 16 and 8 percent for investigator-choice chemotherapy (n=179). OS data were not mature at the time of the analysis. The secondary endpoints were ORR and duration of response per RECIST v1.1.

KEYNOTE-006 is a Phase 3, multi-center, randomized, study of KEYTRUDA (10 mg/kg every two or three weeks) compared to ipilimumab in 834 patients with advanced melanoma. In the planned interim analysis of the co-primary endpoints, KEYTRUDA demonstrated superior PFS and OS compared to ipilimumab. The estimated 6-month and 9-month PFS rates for KEYTRUDA were 47 and 40 percent, respectively, for the 2-week group (95% CI, 0.58 [0.46, 0.72], p<0.00001) (n=279) and 46 and 42 percent for the 3-week group (95% CI, 0.58 [0.47, 0.72], p<0.00001) (n=277), compared to 27 and 16 percent for ipilimumab (n=278). One-year OS for KEYTRUDA was 74 percent (2-week group) (95% CI, 0.63 [0.47, 0.83], p = 0.00052) and 68 percent (3-week group) (95% CI, 0.69 [0.52, 0.90], p = 0.00358), compared to 58 percent for ipilimumab. The risk of death was reduced by 31 percent for patients treated with KEYTRUDA in the 3-week group (hazard ratio 0.69) and 37 percent in the 2-week group (hazard ratio 0.63). The secondary endpoints were ORR and duration of response per RECIST v1.1.

The safety analysis supporting the European approval of KEYTRUDA was based on 1,012 advanced melanoma patients across three doses (2 mg/kg every three weeks or 10 mg/kg every two or three weeks) in studies KEYNOTE-001 and KEYNOTE-002 combined. The most common adverse reactions (>10%) with KEYTRUDA were diarrhea (15%), nausea (12%), pruritus (25%), rash (25%), arthralgia (13%) and fatigue (33%). The majority of adverse reactions reported were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades. In Europe, approximately 100,000 new cases were estimated to be diagnosed in 2012, which is almost half of the global incidence of melanoma. The five-year survival rates for advanced or metastatic melanoma (Stage IV) are estimated to be 15 to 20 percent in the United States and 5 to 22 percent in Europe.

About KEYTRUDA

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

With the European Commission decision, KEYTRUDA is now approved in more than 35 countries for the treatment of advanced melanoma. Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

U.S. Indication for KEYTRUDA (pembrolizumab)

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

AstraZeneca Provides Update On Selumetinib In Uveal Melanoma

On July 22, 2015 AstraZeneca reported that the Phase 3 SUMIT study of selumetinib in combination with dacarbazine for the treatment of patients with metastatic uveal melanoma did not meet its primary endpoint of progression free survival (Press release, Array BioPharma, JUL 22, 2015, View Source [SID:1234506580]).

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This combination therapy showed an adverse event profile generally consistent with current knowledge of the safety profiles of dacarbazine and selumetinib. A full evaluation of the data is ongoing.

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Selumetinib is a MEK inhibitor in late-stage development, with a primary Phase 3 program in second-line KRAS-mutant advanced non-small cell lung cancer in combination with docetaxel. Selumetinib is also being investigated in a Phase 3 study in differentiated thyroid cancer and in a Phase 2 registration study in patients with neurofibromatosis Type 1.

Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca said: "Selumetinib is supported by a strong development program with different scientific rationale in multiple tumor types as both monotherapy and in alternative combinations. The findings from SUMIT have no impact on the other studies and we look forward to presenting the data in due course."

About Selumetinib and Uveal Melanoma
Selumetinib is an oral small molecule MEK inhibitor invented by Array BioPharma (NASDAQ: ARRY) and licensed to AstraZeneca in 2003. AstraZeneca is responsible for development and commercialization of selumetinib. Selumetinib inhibits the MEK enzyme in the RAS/RAF/MEK/ERK pathway in cancer cells to prevent the tumor from growing.

The Selumetinib in Uveal Melanoma Investigator Trial (SUMIT) is a randomized, double-blind, placebo controlled trial being carried out in 45 centers, across 11 countries.

Uveal melanoma is an orphan disease in which cancer cells grow in the tissues of the eye. It is the most common primary intraocular malignancy in adults and comprises 5% of all melanomas. There are currently no effective treatments for advanced uveal melanoma and in April 2015, selumetinib was granted Orphan Drug Designation by the US Food and Drug Administration in recognition of the need for new, safe and effective therapies for the disease.

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