On June 6, 2016 Castle Biosciences, Inc., a provider of molecular diagnostics to improve cancer treatment decisions, reported the results from a study evaluating the performance of its gene expression profile (GEP) test, DecisionDx-Melanoma, in 334 new melanoma patients (Press release, Castle Biosciences, JUN 6, 2016, View Source [SID:1234513096]). The data confirmed the positive results from two previously published multicenter clinical validation studies demonstrating the test’s ability to identify patients’ risk of melanoma recurrence in the 5 years following diagnosis. The data were presented in a poster session at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL. A second, independent, prospective study of DecisionDx-Melanoma was also presented further confirming the results of the three prior multicenter studies.

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Expanded Multicenter Performance Study

In a study titled "Performance of a 31-Gene Expression Profile in a Previously Unreported Cohort of 334 Cutaneous Melanoma Patients" (Abstract # 9581), 334 cutaneous melanoma tumors from 12 centers in the U.S. were analyzed using the DecisionDx-Melanoma test. Tumors were classified as either low-risk Class 1 or high-risk Class 2. The test’s prognostic results were compared to actual clinical outcomes over a 5-year period, as well as traditional methods for disease staging and prognosis including sentinel lymph node (SLN) biopsy, ulceration, Breslow thickness and mitotic rate. Study endpoints included recurrence-free survival (RFS), defined as time to either a regional or distant metastatic event; distant metastasis-free survival (DMFS), defined as time to any metastatic event beyond the regional node; and melanoma-specific survival (MSS), defined as time from diagnosis to death documented as specifically resulting from melanoma. A summary of the results is below:

RFS DMFS MSS
5-year rate # of events 5-year rate # of events 5-year rate # of events
Class 1 (n=181) 86% 29 91% 19 98% 5
Class 2 (n=153) 51% 69 60% 54 75% 31
The study also highlighted the GEP test’s ability to predict which patients are not likely to recur (Negative Predictive Value, or NPV) when used by itself, and in combination with other standard prognostic techniques such as SLN biopsy. While both the DecisionDx-Melanoma test and SLN biopsy were shown to have strong sensitivity to detect patients at risk of metastasis, a combination of the two was the most effective. Results include:

MSS SLN Status GEP Class SLN + GEP
Sensitivity 67% (49-81%) 86% (71-95%) 94% (81-99%)
Specificity 72% (66-77%) 59% (53-65%) 48% (42-54%)
PPV 22% (15-31%) 20% (14-28%) 18% (13-24%)
NPV 95% (91-97%) 97 (94-99%) 99% (95-100%)
95% confidence interval shown in parentheses

Study authors also combined previously studied populations, reviewing the total of 514 patient cases from validation and performance studies of the GEP test to date. Results from the Stage I/II and Stage III patients are shown below:

MSS Stage I/II (n=356) Stage III (n=158)
Sensitivity 80% (52-96%) 87% (70-96%)
Specificity 65% (60-70%) 32% (24-41%)
PPV 9% (5-15%) 24% (16-33%)
NPV 99% (96-100%) 91% (79-98%)
95% confidence interval shown in parentheses

"These study results confirm the prognostic accuracy of this GEP test, demonstrating its ability to provide prognostic information that is independent of and additive to conventional staging," commented Jonathan S. Zager, MD, FACS, lead study author and Professor of Surgery in the Cutaneous Oncology and Sarcoma Departments at the Moffitt Cancer Center. "For melanoma-specific survival, combining this GEP test with SLN status improves sensitivity to 94% and Negative Predictive Value to 99% over SLN status or the GEP test alone – providing support for low-risk management/surveillance plans for Class 1 patients. For Class 2 patients, increased surveillance per guidelines for high-risk patients appears to be warranted."

"We are extremely pleased with the continued strong performance of our GEP test," commented Federico A. Monzon, M.D., FCAP, Chief Medical Officer of Castle Biosciences. "The test, when used with standard melanoma staging tools, provides the most accurate prognostic information from which to plan follow-up care. In addition to improving patient care, the GEP test offers the opportunity to improve clinical trial design to advance adjuvant treatment in patients who have a Class 2, high-risk test result."

Second, Independent, Prospective Study Also Presented

Also at the meeting, a study titled "Prospective Validation of Gene Expression Profiling in Primary Cutaneous Melanoma" (Abstract #9565), was presented by Eddy C. Hsueh, M.D., Professor and Director, Division of Surgical Oncology, St. Louis University Hospital. This study evaluated 159 prospectively enrolled melanoma patients undergoing SLN biopsy and successful testing with the DecisionDx-Melanoma GEP test. The data show that GEP classification is significantly associated with early recurrence in patients diagnosed with melanoma. With a median follow-up time of 18 months, the study found a Negative Predictive Value of 98% for disease-free survival. To date, all Stage III patients with a Class 1 result are recurrence free. The DecisionDx-Melanoma test correctly identified 16 of 18 patients who had recurrence events as high-risk (Class 2). Overall the high-risk Class 2 group had a 38% recurrence rate. Patients who were both high-risk Class 2 and Stage III had a 77% recurrence rate compared to 43% with Stage III status alone.

"An important milestone in test development is demonstrated consistency in prospective studies," added Derek Maetzold, President and CEO of Castle Biosciences. "This prospective study represents the second such DecisionDx-Melanoma study presented in the last six weeks, and provides further independent confirmation for the consistent results seen in Castle Biosciences’ sponsored multicenter studies."

About Melanoma
Cutaneous melanoma is diagnosed in approximately 76,000 people in the U.S. each year, according to the American Cancer Society. Seventy-five percent are diagnosed as Stage I or II, meaning there is no evidence of the melanoma spreading beyond the primary tumor. It is not the most prevalent form of skin cancer, but it is the most aggressive. Unlike other more common skin malignancies such as basal cell and squamous cell carcinomas, melanoma often spreads to other parts of the body, either via the lymphatic or blood system, resulting in cancers of distant organs including the brain or lungs. So, while it represents just 4% of skin cancers, melanoma accounts for about 80% of skin cancer-related deaths.

On June 06, 2016 Atara Biotherapeutics, Inc. (Nasdaq:ATRA), a biopharmaceutical company focused on developing meaningful therapies for patients with severe and life threatening diseases that have been underserved by scientific innovation, reported that its collaborating investigators at Memorial Sloan Kettering Cancer Center (MSK) reported clinical results for Atara’s allogeneic Epstein-Barr Virus Cytotoxic T-Lymphocyte (EBV-CTL) product candidate (Press release, Atara Biotherapeutics, JUN 6, 2016, View Source [SID:1234513088]). Data were presented from an on-going Phase 2 clinical trial, which enrolled a heterogeneous group of EBV associated malignancies including NPC and post-transplant lymphoproliferative disorders, at an oral presentation at the ASCO (Free ASCO Whitepaper) 2016 Annual Meeting. This data included safety and efficacy of EBV-CTL in the treatment of 14 patients with recurrent metastatic nasopharyngeal carcinoma (NPC). EBV-associated NPC accounts for approximately 6,000 cases annually in the US and EU combined and approximately 80,000 cases worldwide. Historical median survival rates range from five to eleven months for patients with metastatic disease.

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Dr. Susan Prockop, M.D., and colleagues reported the following data:

A 21% objective response rate in NPC patients, including one complete response, and two partial responses.
11 of the 14 NPC patients were alive with median 18-month follow-up.
EBV-CTLs expanded after administration to immunocompetent NPC patients without concomitant lymphodepleting chemotherapy.
Of the 126 patients enrolled across all indications, there were two grade 4 and seven grade 3 possibly related serious adverse events.
"We are pleased that this study has demonstrated the potential therapeutic benefit of an allogeneic therapy for patients with solid tumors," commented Chris Haqq M.D., Ph.D., Chief Medical Officer of Atara Bio. "We look forward to developing this product candidate as both a single agent and in combination with other therapies in NPC and other indications. In addition, we will be commencing our two upcoming pivotal trials in patients with rituximab refractory EBV Post-Transplant Lymphoproliferative Disorder (EBV-PTLD) after solid organ transplant (SOT) and hematopoietic stem cell transplant (HCT) later this year."

About EBV-CTL

T-cells are a critical component of the body’s immune system and can be harnessed to counteract viral infections and some cancers. By focusing the T-cells on specific proteins involved in cancers and infections, the power of the immune system can be employed to combat these diseases. Atara Bio’s EBV-CTL utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens. The resulting activated T cells are then expanded, characterized, and stored for future therapeutic use in an appropriate partially human leukocyte antigen, or HLA, matched patient, providing an "off-the-shelf", allogeneic, cellular therapeutic option for patients. EBV-CTLs are designed to find cancer cells expressing EBV and kill them. Phase 2 clinical results from trials conducted at MSK have been reported in multiple peer-reviewed forums. Atara Bio plans to commence two pivotal clinical trials of EBV-CTL for rituximab-refractory EBV Post-Transplant Lymphoproliferative Disorder (EBV-PTLD) following hematopoietic cell transplant (HCT), as well as solid organ transplant (SOT), towards the end of 2016.

On June 6, 2016 Threshold Pharmaceuticals, Inc. (NASDAQ:THLD) reported multiple presentations on clinical trials on its hypoxia-activated prodrugs, evofosfamide and tarloxotinib at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 3 through 7, 2016 in Chicago, Ill (Press release, Threshold Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513086]).

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Today, Threshold presented additional data from its analysis of the randomized, double-blind Phase 3 MAESTRO clinical trial of evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma conducted by Merck KGaA. A meaningful improvement in overall survival was reported for the subgroup of 123 Asian patients enrolled at Japanese and South Korean sites in which the risk of death was reduced by 48 percent for patients on the treatment arm compared to patients on the control arm with an associated stratified hazard ratio of 0.52 (95% CI: 0.32 – 0.85). The patients from Asia also had significant improvements in PFS, objective response rates, and reductions in the pancreatic cancer biomarker, CA19-9 (abstract 4007). As previously reported in January 2016, the primary efficacy endpoint of this study of overall survival narrowly missed statistical significance based on specified intent-to-treat analysis while showing improvements in secondary efficacy endpoints of progression-free survival (PFS) and response.

On June 4, 2016, the following posters were displayed:

Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide and Pemetrexed in Second Line Advanced Non-Squamous Non-Small Cell Lung Cancer. Csoszi et al. (abstract 9075).

As reported in January 2016, the study was stopped early based on a futility analysis of overall survival conducted by the study Data and Safety Monitoring Board (DSMB). The study enrolled 265 patients of a planned 440 patients. The response rate with evofosfamide plus pemetrexed was 18.0 percent and significantly higher compared to 8.1 percent with placebo plus pemetrexed. The median PFS with evofosfamide plus pemetrexed was 4.5 months (95% CI: 4.0 to 6.4 months) and significantly higher compared to 2.9 (95% CI: 2.6 to 4.1) months with placebo plus pemetrexed. Hematologic toxicity was greater in the evofosfamide plus pemetrexed arm, while non-hematologic toxicity was similar across treatment arms. No new safety signals were identified.

Evofosfamide combined with gemcitabine/nab-paclitaxel in patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma (PAC): results of a phase I trial. Borad et al. (abstract 4114).

Nineteen patients were treated for a median of 6 cycles. The maximum tolerated dose of evofosfamide was established at 340 mg/m2 in combination with 800 mg/m2 gemcitabine and 100 mg/m2 nab-paclitaxel. No new safety signals were identified with myelosuppression being the primary dose limiting toxicity. The best response rate was 53 percent and the confirmed response rate was 37 percent.

Two additional trials-in-progress posters were also displayed:

A Phase 2 Study of Tarloxotinib Bromide (TRLX) in Patients with Recurrant or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) or Skin (SCCS).
Rischin et al. (abstract TPS6105)

A Phase 2 Study (NCT02454842) of Tarloxotinib Bromide (TH-4000) in Patients with EGFR Mutant, T790M-Negative, Advanced NSCLC Progressing on an EGFR TKI.
Liu et al. (abstract TPS9100)

Copies of the posters may be obtained from Threshold’s website, www.thresholdpharm.com, under Scientific Publications.

About Evofosfamide
Evofosfamide (previously known as TH-302) is an investigational hypoxia-activated prodrug of a bis-alkylating agent that is preferentially activated under severe hypoxic tumor conditions, a feature of many solid tumors. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood vessel supply. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic. On December 6, 2015, the Company announced the outcomes of two Phase 3 studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide stating that neither study met its primary endpoint.

About Tarloxotinib Bromide
Tarloxotinib bromide (the proposed International Nonproprietary Name, previously known as TH-4000), or "tarloxotinib", is a prodrug designed to selectively release a covalent (irreversible) EGFR tyrosine kinase inhibitor under severe hypoxia, a feature of many solid tumors. Accordingly, tarloxotinib has the potential to effectively shut down aberrant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the systemic side effects associated with currently available EGFR tyrosine kinase inhibitors. Tarloxotinib is currently being evaluated in two Phase 2 proof-of-concept trials: one for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR tyrosine kinase inhibitor, and the other for patients with recurrent or metastatic squamous cell carcinomas of the head and neck or skin. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.

On June 6, 2016 Stemline Therapeutics, Inc. (Nasdaq:STML) reported that Ivan Bergstein, M.D., Stemline’s CEO, will present at the Jefferies 2016 Healthcare Conference on Wednesday, June 8, 2016 at 10:00 AM ET (Press release, Stemline Therapeutics, JUN 6, 2016, View Source [SID:1234513078]). During the presentation, Dr. Bergstein will discuss the SL-401 Phase 2 blastic plasmacytoid dendritic cell neoplasm (BPDCN) data presented on June 4th at the 2016 ASCO (Free ASCO Whitepaper) conference. He will also review next steps for the SL-401 program as well as provide updates on the company’s overall pipeline. A live webcast of the presentation can be viewed on the company’s website at www.stemline.com.

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On June 6, 2016 Merck KGaA, Darmstadt, Germany, and Pfizer (NYSE: PFE) reported results from the first pivotal, international, multicenter, open-label, Phase II study of avelumab*, which showed a 31.8% objective response rate (ORR) (28 of 88 patients; 95.9% CI: 21.9–43.1%†), in the pre-planned primary analysis of the study, and a manageable safety profile in patients with metastatic Merkel cell carcinoma (MCC) who were treated with avelumab in second or subsequent lines of therapy (Press release, Pfizer, JUN 6, 2016, View Source [SID:1234513077]). Tumor responses were rapid, with 78.6% of patients (22 of 28) responding within 7 weeks of starting treatment, and durable, with 82.1% of patients (23 of 28) still responding at the time of analysis. No unexpected safety signals were reported. These data will be reported today during an oral presentation at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

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"To see a tumor response in almost a third of patients in this trial, and for the majority to keep responding after six months, represents a potential breakthrough for this challenging disease," said lead investigator Howard L. Kaufman, M.D., FACS, Rutgers Cancer Institute of New Jersey, USA. "Currently, the only treatment option available for advanced stages of this aggressive type of skin cancer is chemotherapy, where the response rates are not adequate or durable."

Metastatic MCC has a poor prognosis with less than 20% of patients surviving longer than five years.1 Although chemotherapy is considered a second-line treatment option for metastatic MCC, it is not a standard of care. Current guidelines recommend that these patients participate in clinical trials.2

"This is an important milestone for us as this is the largest data set of any anti-PD-L1 or anti-PD-1 reported to date in this patient population," said Luciano Rossetti, Executive Vice President, Global Head of Research & Development in the biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "The clinically meaningful tumor response rate for avelumab in metastatic Merkel cell carcinoma where chemotherapy has failed, reinforces our belief in the promise of this molecule, particularly considering the high unmet need in this disease."

In the trial, eight patients (9.1%) achieved complete responses and 20 patients (22.7%) achieved partial responses. The median duration of response has not been reached (95% CI: 8.3 months – not estimable; range, 2.8–17.5+ months). Tumor responses were seen in patients regardless of the status of certain biomarkers (PD-L1 and Merkel cell polyomavirus). The progression-free survival (PFS) rate at 6 months was 40% (95% CI: 29–50%, estimated by the Kaplan-Meier method). Early data also showed an overall survival (OS) rate at 6 months of 69% (95% CI: 58–78%) and a median OS of 11.3 months (7.5–14.0 months); however, these OS data are still maturing since minimum follow-up was 6 months for inclusion in this analysis. Treatment-related adverse events (AEs) occurred in 62 patients (70.5%); the most common were fatigue (23.9%) and infusion-related reactions (17.0%), all of which were Grade 1 or 2. Grade 3 treatment-related AEs were reported in four patients (4.5%). There were no Grade 4 treatment-related AEs or deaths.

"This has been an exciting ASCO (Free ASCO Whitepaper) for the strategic collaboration between the two companies, between the MCC data and the other encouraging responses observed across a broad range of tumors," said Chris Boshoff, M.D., PhD., Vice President and Head of Early Development, Translational and Immuno-Oncology at Pfizer Oncology. "The clinical benefits for avelumab as a monotherapy in notably hard-to-treat cancers may be amplified even further when combined with other therapies."

Avelumab has received multiple regulatory designations in MCC from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), including Orphan Drug (FDA and EMA), Fast Track and Breakthrough status (FDA). There are plans to submit marketing applications for avelumab to regulatory authorities based on these data.

About JAVELIN Merkel 200

JAVELIN Merkel 200 is an international, multicenter, open-label, Phase II study of avelumab conducted in 88 patients with metastatic MCC. Patients in this study were generally elderly (median age was 72.5 years, range 33–88 years) and pre-treated, with at least one line of chemotherapy (one [59.1%], two [29.5%] or three or more [11.4%] previous treatments). Patients received avelumab 10 mg/kg intravenously once every two weeks. The protocol-defined analysis set for efficacy and safety consisted of all patients who received at least one dose of study treatment. The cut-off date for the planned primary analysis was 6 months after start of study treatment of the last patient. The primary endpoint of the study was confirmed best overall response according to RECIST v1.1 and assessed by an independent review committee. Secondary endpoints were duration of response, PFS, OS, response status by RECIST at 6 and 12 months, safety and tolerability, pharmacokinetics, and immunogenicity of avelumab.

*Avelumab is the proposed nonproprietary name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.

†Multiplicity adjustment accounting for interim analysis to achieve overall 95% confidence level.

References

Lemos B, Storer B, Iyer J, et al. Pathologic Nodal Evaluation Improves Prognostic Accuracy in Merkel Cell Carcinoma: Analysis of 5,823 Cases as the Basis of the First Consensus Staging System for this Cancer. Journal of the American Academy of Dermatology. 2010;63:751-761.
NCCN Merkel Cell Carcinoma Guidelines Version I. 2016. Available from: www.nccn.org/professionals/physician_gls/PDF/mcc.pdf (link is external). Accessed April 2016.
About Avelumab

Avelumab (also known as MSB0010718C) is an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US

Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US, enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an investigational anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance Pfizer’s PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab as a monotherapy, as well as in combination regimens, and is striving to find new ways to treat cancer.

About Merck KGaA, Darmstadt, Germany

All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group Website. In case you are a resident of the USA or Canada please go to www.emdgroup.com/subscribe (link is external) to register again for your online subscription of this service as our newly introduced geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

Merck KGaA, Darmstadt, Germany, is a leading science and technology company in healthcare, life science and performance materials. Around 50,000 employees work to further develop technologies that improve and enhance life – from biopharmaceutical therapies to treat cancer or multiple sclerosis, cutting-edge systems for scientific research and production, to liquid crystals for smartphones and LCD televisions. In 2015, Merck KGaA, Darmstadt, Germany, generated sales of € 12.85 billion in 66 countries.

Founded in 1668, Merck KGaA, Darmstadt, Germany, is the world’s oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck KGaA, Darmstadt, Germany operates as EMD Serono, MilliporeSigma and EMD Performance Materials in the United States and Canada.