On June 12, 2017 Mateon Therapeutics, Inc. (OTCQX:MATN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported an update regarding the current status of all clinical trials of its investigational drugs (Press release, Mateon Therapeutics, JUN 12, 2017, View Source [SID1234519489]).

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Company-sponsored studies:
FOCUS for platinum-resistant ovarian cancer
FOCUS is a phase 2/3 study in patients with platinum-resistant ovarian cancer, evaluating whether the addition of CA4P to the current standard-of-care (bevacizumab plus chemotherapy) improves progression-free survival. As of June 9, 2017, FOCUS has enrolled 57 patients in the United States, Germany and Belgium, with enrollment on-going at 37 sites. The second interim analysis, which will occur after the first 40 patients have been treated for at least two months or withdrawn from the study, remains on track to be completed in August 2017. Based on the number of patients enrolled and projected enrollment trends, the company expects the third interim analysis, representing 60 patients, to be completed in late September 2017.

OX1222 for acute myeloid leukemia
OX1222 is a dose-ascending phase 1b/2 clinical trial evaluating OXi4503 in combination with cytarabine in patients with recurrent/relapsed acute myeloid leukemia (AML). Mateon recently completed enrollment and treatment for the fourth cohort of 7.81 mg/m2 of OXi4503, and no dose limiting toxicities or significant safety issues were identified among the three patients. One patient treated in the fourth cohort experienced a significant AML blast reduction, with blast counts going from 89% upon enrollment to 7% following the first cycle of treatment. However, the patient subsequently experienced an unrelated adverse event and withdrew from the study approximately two weeks after the last dose of OXi4503 in the second cycle of treatment, prior to an additional blast measurement and accordingly did not meet the criteria for a complete remission. Three complete remissions were observed in the first three cohorts (19% overall in the clinical trial to date), each of which occurred after two cycles of treatment, and two complete remissions remain on-going at 12+ and 3+ months. Enrollment is on-going in the fifth cohort of 9.76 mg/m2 of OXi4503.

Investigator-sponsored studies:
PAZOFOS for recurrent ovarian cancer
The PAZOFOS study is a phase 1b/2 investigator-sponsored study being conducted in the U.K., evaluating the combination of CA4P and the TKI-inhibitor pazopanib for patients with advanced recurrent ovarian cancer. To date, the study has enrolled and treated 20 patients with CA4P and pazopanib in the phase 1b and phase 2 portions of the trial. The study sponsor, The Christie NHS Trust, has temporarily suspended enrollment in the trial in order to collect and review additional information on two recent serious adverse events – one patient in the study experienced hypertension and myocardial ischemia, and a second patient experienced chest pain. In both cases, the events were of short duration and the clinical symptoms resolved.

The label for pazopanib, which is not approved for the treatment of ovarian cancer in the U.S., contains warnings for cardiac dysfunction, arterial thrombotic events and hypertension. CA4P has been observed in most patients to cause an acute and transient increase in blood pressure following administration.

Following review of the data available for the patients in PAZOFOS, the company does not believe any changes or adjustments to Mateon’s FOCUS study are warranted. FOCUS has restrictive enrollment criteria for patients with pre-existing cardiovascular risk factors and specific algorithms for treatment of patients that experience blood pressure increases.

Neuroendocrine tumors
The Markey Cancer Center at the University of Kentucky recently began a phase 1 study evaluating the combination of CA4P and everolimus for the treatment of neuroendocrine tumors. In the first part of the study, patients are being treated with two different dosing regimens of CA4P in combination with everolimus to evaluate the safety of the drug combination and establish appropriate CA4P dosing levels.

"We are pleased that studies in both our core programs, the FOCUS study of CA4P for platinum-resistant ovarian cancer and Study OX1222 of OXi4503 for AML, are enrolling well and showing a good safety profile, as well as initial indications of efficacy," stated William D. Schwieterman, M.D., President and Chief Executive Officer of Mateon. "We are looking forward to data read outs from each of these studies later this summer."

"The investigator-sponsored PAZOFOS study, which uses CA4P with a different combination of drugs for recurrent ovarian cancer, also holds significant potential for patients and we’re hopeful that enrollment will resume soon," Dr. Schwieterman added.

On June 12, 2017 Acceleron Pharma Inc. (NASDAQ:XLRN), a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of innovative therapeutics to treat serious and rare diseases, reported that the DART Phase 2 study of dalantercept plus axitinib did not achieve its primary endpoint in advanced renal cell carcinoma (RCC) (Press release, Acceleron Pharma, JUN 12, 2017, View Source [SID1234519496]). The primary efficacy endpoint of the study was to demonstrate a statistically significant increase in progression-free survival (PFS) for treatment of dalantercept plus axitinib versus placebo plus axitinib in advanced RCC patients.

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"We designed a robust Phase 2 study to evaluate the efficacy of dalantercept in combination with anti-VEGF therapy in advanced renal cell carcinoma patients whose disease has progressed on prior anti-VEGF therapy. We are disappointed by the results given the need for new agents that improve outcomes for patients with advanced RCC. We would like to thank the patients, caregivers, investigators, and our team who made the DART study possible," said Habib Dable, President and Chief Executive Officer of Acceleron. "Based on the lack of efficacy, we are discontinuing the development of dalantercept. We remain focused on the development of luspatercept across multiple Phase 3 and Phase 2 studies and ACE-083 across two neuromuscular diseases, and will continue to pursue additional candidates in areas of high unmet medical need."

The DART study enrolled 131 patients with advanced RCC. The efficacy data are based on the All-Treated Set (ATS) which is defined as all randomized patients who received any study drug (n=119) as of the database cutoff. In the ATS, 58 patients were randomized to dalantercept plus axitinib and 61 patients were randomized to placebo plus axitinib.

The median PFS for dalantercept plus axitinib was 6.8 months versus 5.6 months for placebo plus axitinib. Dalantercept plus axitinib did not decrease the rate of disease progression or death (HR 1.11, two-sided 95% CI [0.71, 1.73], one-sided p-value 0.67). The key secondary endpoint for the study was PFS for patients who received two or more prior systemic anti-cancer therapies. In this analysis, the median PFS for dalantercept plus axitinib was 8.1 months versus 7.0 months for placebo plus axitinib (HR 0.78, two-sided 95% CI [0.33, 1.87], one-sided p-value 0.29). The confirmed objective response rate (ORR) for dalantercept plus axitinib was 19% versus 25% for placebo plus axitinib (p-value 0.43, Cochran-Mantel-Haenszel test).

The safety data are based on the 119 ATS patients. The frequency of Grade 3 or higher adverse events (AEs) regardless of causality were similar overall in the dalantercept plus axitinib (59%) and the placebo plus axitinib (64%) study arms. The frequency of serious AEs of any grade regardless of causality were also similar in the dalantercept plus axitinib (29%) and the placebo plus axitinib (26%) study arms. The AEs associated with dalantercept were consistent with those previously observed.

About the DART Phase 2 Study

The Phase 2 DART clinical trial is a two-part study in patients with advanced renal cell carcinoma. Part 1 is a dose-escalation study of dalantercept plus axitinib to evaluate the safety and tolerability of the combination in patients whose disease has progressed following one to three lines of prior therapy. Part 2 is a randomized, double-blind study of 130 patients with advanced renal cell carcinoma who have progressed following treatment with a VEGF receptor tyrosine kinase inhibitor. Patients may have also received prior mTOR therapy and/or immunotherapy. For additional information on this clinical trial, please visit www.clinicaltrials.gov, identifier NCT01727336.

About Dalantercept

Dalantercept is an investigational protein therapeutic that inhibits angiogenesis by preventing BMP9, a protein in the transforming growth factor-beta (TGF-beta) superfamily, from interacting with activin receptor-like kinase 1 (ALK1), a cell-surface receptor found on proliferating vascular endothelial cells. Dalantercept inhibits ALK1 signaling, which is required for the development of mature, functional vasculature.

On June 12 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported an update on two combination studies of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in the blood cancer multiple myeloma (Press release, Merck & Co, JUN 12, 2017, View Source [SID1234519544]). Merck has accepted the external Data Monitoring Committee recommendation to pause new enrollment on KEYNOTE-183 and KEYNOTE-185, two studies exploring KEYTRUDA treatment in combination with other therapies in multiple myeloma. The pause is to allow for additional information to be collected to better understand more reports of death in the KEYTRUDA groups. Patients currently enrolled in these two studies will continue to receive treatment. Other studies of KEYTRUDA continue unchanged.

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KEYNOTE-183 is a Phase 3 study comparing pomalidomide and low-dose dexamethasone with KEYTRUDA to pomalidomide and low-dose dexamethasone alone in patients with refractory or relapsed and refractory multiple myeloma (rrMM) who have undergone at least 2 lines of prior treatment. KEYNOTE-185 is a Phase 3 study comparing lenalidomide and low-dose dexamethasone with KEYTRUDA to lenalidomide and low-dose dexamethasone alone in patients with newly diagnosed and treatment-naïve multiple myeloma who are ineligible for autologous stem cell transplant (Auto-SCT).

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA (pembrolizumab), as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) cancer or mismatch repair deficient (dMMR):

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The safety and effectiveness of KEYTRUDA (pembrolizumab) in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 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.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. 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.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. 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 replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA (pembrolizumab) for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. 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.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. 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 to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA (pembrolizumab) can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can 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.

KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

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 and for 4 months after the final dose.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 500 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

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On December 12, 2017 Selexis SA and TeneoBio, Inc. reported that they have entered into a service agreement to advance the development of a new class of biologics, Human Heavy-Chain Antibodies (UniAbs) targeting cancer (Press release, Selexis , DEC 12, 2017, View Source [SID1234533030]). Under the agreement, TeneoBio will leverage Selexis’ proprietary SUREtechnology Platform to develop and optimize the cellular expression of multi-specific UniAbs that were discovered using TeneoBio’s proprietary sequence-based TeneoSeek discovery engine and UniRat Human Heavy-Chain Antibody Platform.

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"TeneoBio is developing a new class of multispecific biologics for treatments of multiple myeloma, lymphoma and prostate cancer," said Yemi Onakunle, PhD, vice president, business development and licensing with Selexis. "We believe in the power of the Selexis SUREtechnology Platform to help TeneoBio to rapidly and predictably achieve the high antibody expression levels and cell line stability that are needed for the cost-effective production of their unique multi-specific antibody candidates."

Selexis’ SUREtechnology platform facilitates the rapid, stable, and cost-effective production of virtually any recombinant protein, including those that are difficult to express in other systems. It also provides seamless integration of the biologics and vaccine development continuum, spanning discovery to commercialization.

Omid Vafa, chief business officer at TeneoBio, Inc., added, "This is the first of several TeneoBio bi- and multi-specific UniAb candidates that leverages our unique T-cell redirection platform to target liquid and solid tumors. We are excited to work with Selexis, a pioneer in bioproduction that offers the right balance of speed, technology, and flexibility to generate cell lines for our lead program."

Belén Garijo CEO Healthcare Luciano Rossetti Global Head of Research & Development, Biopharma Rehan Verjee Chief Marketing and Strategy Officer, Healthcare June 12, 2017 Biopharma R&D pipeline Update Complete portfolio supporting leadership in a potentially disruptive class DNA damage response (DDR) Genomic instability: a hallmark of late stage cancers 1 • DNA damage response (DDR) keeps genetic information intact • In many cancers DDR pathways are defected, leading to greater dependency on remaining functional DDR pathways • Preferentially inhibiting remaining DDR pathways can result in cancer cell death ("synthetic lethality") 26 1 Sources : O’Connor, Molecular Cell, 2015 | Benjamin et al., Current Drug Targets, 2010, 11, 1336-1340 2 "A multicenter phase I trial of the DNA-dependent protein kinase (DNA-PK) inhibitor M3814 in patients with solid tumors", Mark van Bussel, ASCO (Free ASCO Whitepaper) 2017 Acronyms: ATM: ataxia-telangiectasia mutated |ATR: ataxia telangiectasia and Rad3 | DNA-PK: DNA-dependent protein kinase | Amplifying cytotoxic effects of conventional and novel cancer treatments potentially bears combination potential 1. Inhibitor portfolio targets all three leading pathways of double stranded breaks – enabling unique synergies 2. ASCO (Free ASCO Whitepaper) 2017: leading DNA-PK-I (M3814) found safe and tolerable in a phase I study, with limited single-agent activity (20 % of patients with stable disease for at least 18 weeks) 2 3 Lead Optimization Pre-clinical Phase I Phase II Phase III 28 DNA-PK-i ATR-i ATM-i VX-970 VX-803 VX-984 M-3814 M-3541 Clinical program targets all three DDR pathways, in mono-and combination Acronyms: ATM: ataxia-telangiectasia mutated |ATR : ataxia telangiectasia and Rad3 | DNA-PK: DNA-dependent protein kinase | CT : Chemotherapy | RT: Radiotherapy | Note : timelines are event-driven and may change Phase IB expansion cohorts ongoing in combination with CT (TNBC, NSCLC, SCLC) Phase I dose escalation ongoing for mono-and combination therapy (with CT) Phase I dose escalation ongoing in combination with CT (licensed-in) Two Phase Ib /II proof-of-concept studies in combination with CT and RT ongoing Expected to enter clinic in 2017 DNA damage response (DDR) 3 29 DNA damage response (DDR) Broad combination potential across multiple mechanisms Combination with CT ATR DNA-PK ATM Combination with DDR Combination with ADC Combination with IO Monotherapy Combination with RT At least 50% of all cancer patients receive some type of RADIATION therapy (NCI 2016) At least 70% of all cancer patients receive some type of CHEMOTHERAPY (NCI 2016) Significant share of patients to be treated with CHECKPOINT INHIBITORS 4 3 30 Early stage strengthened – enabling late stage optionality across all TAs 1 Pipeline Immuno-Oncology Immunology Phase I Phase II Phase III Oncology New in pipeline Moved to next phase Maintained position BTK inhibitor RA sprifermin Osteoarthritis Avelumab RCC 1L 1 Tepotinib HCC Avelumab NSCLC 2L 2 Avelumab Gastric 1L MN 1 Avelumab Urothelial 1L MN 1 Avelumab Ovarian plat. res./ref Avelumab Ovarian 1L (Chemo) 1 BTK inhibitor SLE tepotinib NSCLC Avelumab Gastric 3L 3 Avelumab LA SCCHN Atacicept SLE Avelumab NSCLC 1L 1 Biosimilars Adalimumab biosimilar Chr. plaque Psoriasis R Registered (US) Abituzumab SSc-ILD Externalized p70S6K & Akt-i Solid tumors DNA-PK-i Solid tumors BRAF-I (Beigene) Solid tumors BTK inhibitor Hem. malignancies Avelumab Solid tumors Avelumab Hem. malignancies anti-PD-L1/TGF-b trap Solid tumors Avelumab MCC 1L Anti-IL-17 A/F Psoriasis Avelumab 5 Merkel cell (EU) R BTK inhibitor MS DNA-PK-I (VX-984) Solid tumors ATR-i 7 (VX-970) Solid tumors ATR-I (VX-803) Solid tumors Filing Cladribine Tablets RMS (EU) ATX-MS-1467 MS Avelumab + NHS IL 12 Solid tumors Avelumab+41BB/OX40 Solid tumors Avelumab comb.** DLBCL Terminated 2 Atacicept IgA Nephropathy Avelumab (mono/combo) Various ISTs 1 Since R&D Update call on June 20, 2016 | 2 Either terminated (ATX, BRAF-i) or divested (Biosimilars) | Acronyms: SLE = systemic lupus erythematosus, RRMS = relapse remitting multiple sclerosis, NSCLC = non-small cell lung cancer, HCC = hepatocellular carcinoma, STS = soft-tissue carcinoma, MCC = Merkel cell ca rcinoma, RA = rheumatoid arthritis, SCCHN = squamous cell cancer of the head and neck, SSC-ILD: Systemic sclerosis with interstitial lung disease | DLBCL: Diffuse Large B-cell Lymphoma

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