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Mersana Therapeutics Focuses its Resources on Advancing XMT-1536, its First-in-Class ADC Candidate Targeting NaPi2b

Mersana Therapeutics, a clinical-stage biopharmaceutical company developing a pipeline of antibody-drug conjugates or ADCs designed to target cancers in areas of high unmet need, confirmed that, after a strategic evaluation, the company and its partner Takeda, will discontinue the development of XMT-1522, a  antibody-drug conjugate targeting HER2-expressing tumors, including patients with advanced HER2-positive breast and gastric cancer, as well as advanced breast cancer with low HER2 expression and non-small cell lung cancer (NSCLC).

XMT-1522 contains a proprietary HER2 antibody which is conjugated with Mersana’s Dolaflexin® platform – a Fleximer polymer linked with a novel, proprietary, auristatin payload. The investigational agent provides a drug load of approximately 12 molecules per antibody, specifically designed to improve potency while simultaneously increasing tolerability.

In a statement, the company confirmed that it will work with investigators to ensure that patients benefiting from XMT-1522 will continue to have access to the therapy as needed.

“On behalf of the Company and our partner Takeda we want to thank the patients and their families for their participation in the study, as well as the investigators and our team for their diligent work on the clinical development of XMT-1522. We are committed to leveraging our proprietary ADC platforms to generate a differentiated pipeline of ADCs,”  said Dirk Huebner, MD, Chief Medical Officer, Mersana Therapeutics.

XMT-1536
Following strategic evaluation, Mersana will focus its resources on the advancement of XMT-1536, a first-in-class ADC candidate targeting NaPi2b.

“While still in early clinical development, we are encouraged with the safety, tolerability, and activity of XMT-1536 as well as the pace at which the current study is advancing. For this reason, we have decided to focus our resources on advancing XMT-1536, our first-in-class ADC candidate targeting NaPi2b, a clinically validated ADC target broadly expressed in ovarian and NSCLC adenocarcinoma, for which there remains a significant unmet medical need,” explained Anna Protopapas, President and CEO, Mersana Therapeutics.

According to Protopapas, XMT-1536 has the potential to play a significant role in the treatment of these diseases. The shift in focus resulted in the discontinuation of the XMT-1522 development program.

“We have made the difficult decision to terminate the further development of XMT-1522 despite a favorable emerging profile of efficacy and tolerability due to the competitive environment for HER2-targeted therapies,” Protopapas added.

Dose escalation study
The data to date from the ongoing XMT-1536 dose escalation study indicate that the trial has reached clinically relevant dose levels but has not yet reached a maximum tolerated dose. The once-every-three-week regimen has been fully explored.  The once-every-four-week schedule is currently being evaluated.  The 20 mg/m2 dose cohort has been shown to be well tolerated and the 30 mg/m2 is currently being evaluated.

As of December 31, 2018, the dose escalation study of XMT-1536, in multiple tumor types, includes eight heavily pretreated and evaluable ovarian cancer patients treated at clinically relevant doses. These patients are unselected for NaPi2b expression and had 3 to 11 (median 6) prior regimens in the platinum resistant or refractory setting. Of these eight patients, two achieved a partial response and the remaining six achieved stable disease. The higher dose levels currently being evaluated, as well as additional patient enrollment, provide the opportunity to further define and optimize the profile of XMT-1536.

Corporate Goals
Mersana expects to select a dose for use in its Phase I expansion studies and to initiate enrollment of patients in the expansion cohorts in the first half of 2019. The expansion cohorts will focus on platinum-resistant ovarian cancer and NSCLC adenocarcinoma. Mersana also plans to utilize its proprietary and validated immunohistochemistry assay to retrospectively determine NaPi2b expression to determine whether a companion diagnostic would facilitate the clinical development of XMT-1536. Mersana also plans to report Phase I dose escalation data in the first half of 2019.

Pipeline Expansion
The Company expects to disclose its next clinical candidate in the second half of 2019 and is targeting the filing of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) in the first half of 2020.

Research and Discovery
Mersana continues to build a pipeline of promising ADCs across a variety of tumor types with significant unmet need, leveraging its three proprietary ADC platforms (Dolaflexin, Dolasynthen, and Alkymer).

Based on the strategic evaluation, Mersana will apply its expertise in ADCs to optimize and validate Immunosynthen, a new platform designed to allow systemic delivery of a potent immunostimulatory molecule to provide optimal efficacy and tolerability.

Collaboration
This week Mersana and Synaffix, a Dutch biotechnology company, confirmed that the two companies have entered into a license agreement in which Mersana gets access to Synaffix’s industry-leading site-specific GlycoConnect™ ADC technology.

“After evaluating several site-specific conjugation platforms, we have chosen Synaffix’s GlycoConnect™ technology for use in future ADC candidates,” Protopapas explained.

“We are excited about the potential of this technology as it is designed not to require additional antibody engineering or cell-line modifications, which would offer us the potential to create site-specific antibodies for use in our ADCs when required,” she concluded.


Last Editorial Review: January 4, 2019

Featured Image: Details of medical laboratory | microscope. Courtesy: © 2017 – 2019. Fotolia Used with permission.

Copyright © 2013 – 2019 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Interim Results from Ongoing Studies of Brentuximab Vedotin + Nivolumab in Frontline or Relapsed Hodgkin Lymphoma Presented at ISHL 2018

Multiple presentations evaluating brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda*) across a broad range of Hodgkin lymphoma (HL) settings were presented at the 11th International Symposium on Hodgkin Lymphoma (ISHL) taking place in Cologne, Germany, October 27-29, 2018.  This year’s presentations will highlighted Phase III and other clinical data from brentuximab vedotin and continue to build upon our research in CD30-positive lymphoma.

More than 1,100 delegates from over 70 countries participated in an intensive scientific discourse organized by the German Hodgkin Study Group (GHSG).

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.


After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma…


Trial evaluation
The data presented at the 11th International Symposium on Hodgkin Lymphoma included both encore and additional analyses from the Phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline Stage III or IV classical HL adult patients, which formed the basis of U.S. Food and Drug Administration (FDA) approval in this indication in March 2018.

Interim results will be presented from two ongoing clinical trials evaluating brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company), including in newly diagnosed older HL patients.

Finaly, five-year follow-up from the phase III AETHERA clinical trial were presented.

Antibody-drug Conjugate
Bentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor pathogenesis.  The agent uses a protease-cleavable linker system that is designed to be stable in the bloodstream but to release monomethyl auristatin E (MMAE), a microtubule disrupting agent, upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials. Brentuximab vedotin and nivolumab are not approved in combination for the treatment of HL.

Progresss
“After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma,” said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Development and Global Medical Affairs at Seattle Genetics.

“At ISHL, we [presented] additional analyses from the ECHELON-1 trial, which demonstrated that Brentuximab vedotin plus AVD improves upon a frontline standard of care regimen, ABVD, in advanced patients and resulted in the first change in advanced stage HL in over 40 years. In addition, three oral presentations will highlight brentuximab vedotin plus nivolumab combination data in frontline and relapsed/refractory HL and five-year data from the phase III AETHERA trial. We are pleased to share these results from our broad brentuximab vedotin clinical development program with the Hodgkin lymphoma community.”

“The presented data a continue to reinforce our dedication to advancing treatment for those affected by Hodgkin lymphoma,” said Jesús Gómez-Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda.

“[Overal,] the progress we have made in the development of brentuximab vedotin serves as a true testament to the leadership role we have established in the treatment of CD30-positive malignancies, which confirm the long-term benefits of brentuximab vedotin across treatment lines and support its role as an important targeted therapy for Hodgkin lymphoma,” he added.

Analyses
Data from four analyses of the phase III ECHELON-1 clinical trial were be presented at ISHL. Among the presentations are an oral and poster presentation included an analysis from the ECHELON-1 study (Abstract #0038) showing PFS data per investigator that is consistent with the previously reported modified PFS data per Independent Review Facility (IRF).

The ECHELON-1 abstracts included the following:

  • Frontline brentuximab vedotin plus chemotherapy exhibits superior modified progression-free survival vs chemotherapy alone in patients with stage III or IV Hodgkin lymphoma: Phase III ECHELON-1 study (Abstract #0038, oral presentation and poster on Monday, October 29 at 07:30-07:50 CEST)
  • Population pharmacokinetic modeling and exposure-response assessment of brentuximab vedotin efficacy and safety in patients with advanced classical Hodgkin lymphoma from the Phase III ECHELON-1 study (Abstract #0137, poster presentation)
  • Serum sCD30 and TARC do not correlate with PET-based response assessment in patients with stage III or IV classical Hodgkin lymphoma (cHL): phase III ECHELON-1 study of brentuximab vedotin plus chemotherapy vs. chemotherapy alone (Abstract #0159, poster presentation)
  • Brentuximab vedotin plus chemotherapy in high risk advanced-stage classical Hodgkin lymphoma (cHL) patients: Results of pre-specified sub-group analyses from the ECHELON-1 study (Abstract #0136, poster presentation)

Combination
Additional data presentations at 11th International Symposium on Hodgkin Lymphoma also included the results from a follow-up results from the Phase I/II study with brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin Lymphoma  (Abstract #0005, oral presentation on Monday, October 29 at 14:40-14:50 CEST)

Thi presentation included data from 62 patients with relapsed or refractory HL who received the combination regimen of brentuximab vedotin plus nivolumab after failure of frontline therapy. In this study patients were treated once every three weeks, with up to four cycles of combination therapy in the outpatient setting. After completion of the fourth cycle of treatment, patients were eligible to undergo an autologous stem cell transplant (ASCT). The median age of patients was 37 years. The majority of patients (95%) were refractory or had relapsed after receiving the standard of care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) or some variation of the standard of care (ABVE-PC, R-ABVD). Key findings were presented in an oral presentation by Alex Herrera, M.D., Assistant Professor at the City of Hope Medical Center, Duarte, California.

Herrera showed that of 61 response-evaluable patients, 49 patients (80%) had an objective response, including 37 patients (61%) with a complete response and 12 patients (20 percent) with a partial response.
Of the 61 response-evaluable patients, the estimated 21-month overall survival (OS) and PFS were 95 % and 82%, respectively.

The median follow-up time was 21.8 months and both median OS and PFS were not yet reached. Of 42 patients who underwent ASCT directly after treatment with brentuximab vedotin plus nivolumab, estimated PFS at 21-months was 97 percent and median PFS was not yet reached.

PFS was evaluated by response to treatment. The estimated PFS at 21-months for patients with a complete response was 97%, for patients with a partial response was 83% and patients with stable disease was 50 percent.

As previously reported, the most common adverse events (AEs) of any grade occurring prior to ASCT or subsequent salvage therapy in at least 20% of patients were nausea, infusion-related reaction (IRR), fatigue, pruritus, diarrhea, headache, vomiting, cough, pyrexia, dyspnea and nasal congestion.

Schematic: The AETHERA trial (NCT01100502) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial to evaluate the efficacy and safety of brentuximab vedotin (SGN-35) and best supportive care (BSC) compared to placebo and BSC in treatment of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT).

Combination in patients older than 60 years
Another presentation discussed the results from a phase II study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin Lymphoma aged ≥60 years (Abstract #0153, oral presentation on Monday, October 29 at 15:05-15:15 CEST).

Jonathan Friedberg, M.D., Director of the University of Rochester Medical Center, NY and presented the interim results from an ongoing Phase II clinical trial evaluating brentuximab vedotin in combination with nivolumab as frontline therapy for HL patients age 60 years or older. The reported results included data from 14 patients. The median age of patients was 71.5 years. The majority of patients (79%) had stage III/IV disease at the time of diagnosis.

Friedberg showed that of 11 response-evaluable patients with a median follow-up time of eight months, nine patients (82%) had an objective response, including six patients (55%) with a complete response and three patients (27%) with a partial response. In addition, two patients (18%) had stable disease which equates to all 11 patients (100%) experiencing disease control (complete response + partial response + stable disease) as a result of treatment with brentuximab vedotin in combination with nivolumab.

The most common Adverse Events of any grade occurring in at least 25% of patients were fatigue, diarrhea, constipation, nausea, arthralgia, chills, decreased appetite, pyrexia, IRR, aspartate aminotransferase increased and peripheral sensory neuropathy.

Grade 3 or higher adverse events occurred in seven patients (50%), and the most common were peripheral neuropathy and lipase increased (three patients each); nausea and alanine aminotransferase increased (two patients each).

Five patients (36%) had IRRs, with the majority of symptoms at Grade 1 and there were no Grade 3 or higher symptoms. Four patients (29%) were treated with corticosteroid and no patients discontinued treatment due to an IRR.

Consolidation after Autologous Stem-Cell Transplantation
Five-Year Progression-Free Survival Outcomes from a Pivotal Phase III Study of Consolidative Brentuximab Vedotin after Autologous Stem-Cell Transplantation (ASCT) in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression (AETHERA) (Abstract #0110, oral presentation on Monday, October 29 at 17:10-17:20 CEST)

The five-year follow-up efficacy and safety data from the Phase III AETHERA clinical trial designed to evaluate the potential of single-agent brentuximab vedotin to extend PFS post-ASCT in patients with classical HL who were at high risk of relapse or progression were presented by Craig Moskowitz, M.D., Physician in Chief, Sylvester Comprehensive Cancer Center, University of Miami.

Brentuximab vedotin was approved by the FDA in August 2015 for the treatment of adult patients with classical HL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

Moskowitz showed that the five-year PFS rate per investigator was 59% in the brentuximab vedotin arm compared to 41% in the placebo arm. Median PFS per investigator was not yet reached in the brentuximab vedotin arm versus 15.8 months in the placebo arm. The hazard ratio was 0.521 indicating a 48% reduction in the risk of progression or death with treatment of brentuximab vedotin compared to placebo.

Fewer patients in the brentuximab vedotin arm of the study received subsequent anti-cancer therapies versus the placebo arm (32% versus 54%, respectively). In addition, fewer patients in the brentuximab vedotin arm received allogeneic stem-cell transplants versus the placebo arm (17 patients versus 31 patients).

A PFS analysis evaluating subgroups included patients in the brentuximab vedotin arm with either two or more or three or more risk factors, showed patients with a greater number of risk factors for relapse post-ASCT appeared to have the greatest benefit from brentuximab vedotin consolidation therapy. In both subgroups evaluating either two or more or three or more risk factors, median PFS was not reached in the brentuximab vedotin arm and was 9.7 months and 6.3 months, respectively, in the placebo arm.
In the brentuximab vedotin arm, 112 patients (67%) reported peripheral neuropathy.

To date, 90% of these patients had resolution or improvement in symptoms, with 73% having complete resolution.


* Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

Last Editorial Review: November 3 , 2018

Featured Image: Adcetris/Takeda booth at ISHL 2018 . Courtesy: © 2010 – 2018 ISHL/Ralf Juergens. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Antibody-drug Conjugates: Technologies and Global Markets

Less than 3 decades old, antibody-drug conjugate or ADC-technology is a relatively new.  Due to many technological advances, recognition of appropriate target antigens, success in the development on novel monoclonal antibodies (mAbs) and increasing demand for biologics and biotherapeutics the market of targeted therapies, including ADCs, is rapidly increasing.

This week, ReportLinker, an award-winning market research organization published the latest industry data covering ADCs. According to the authors of the report, developed by BCC research, the global market for antibody drug conjugates was valued at $1.3 billion in 2016 and is expected to reach $4.2 billion by 2021, growing at a compound annual growth rate or CAGR of 25.5% from 2016 to 2021. [1]

In 2016, the market for ADCs in North American was valued at $588.6 million and should reach $2.0 billion by 2021, growing at a CAGR of 27.2% from 2016 to 2021. In Europe this market was valued $395.0 million in 2016 and is expected to reach $1.2 billion by 2021, growing at a CAGR of 24.1% from 2016 to 2021.

Currently approved ADCs
Advances in targeting antibodies, potent payloads and drug-linker technologies that facilitate improved ADC stability, potency and targeting efficiency have led to the development of two commercially viable ADCs. BCC Research’s goal in conducting this study is to provide an overview of the current and future characteristics of the global market for antibody drug conjugates.

The new report explores present and future strategies within the antibody-drug conjugates market, which includes, by type of payload (cytotoxic agent), by type of monoclonal antibodies and by type of linker. The inception of the market, and its demands and restraints are discussed in this report. Classification, comparisons and usage of ADC products are also presented in this report.

The authors analyzed the structure of the antibody-drug conjugate industry and broke down revenues by region, with sales estimated for the five-year period from 2016 through 2021. Applications of antibody drug conjugates and significant patents and their allotments in each category discussed.

Study background
Advancements in research have changed the way many diseases are treated. ADCs represent an innovative class of drugs that are mainly developed by conjugating already-developed or marketed small molecules and biologics. ADCs have shown great potential in cancer therapy. ADC products are becoming an important part of the biomedical industry and have the potential to replace conventional treatment options.

Research & Development spending, along with increasing competition, patent expires and new technologies are providing a new direction to the market. Advancements, new product launches and changing lifestyles are expected to influence the future growth of the market. This study looks at the majority of the systems affected by these factors.

Acquisition strategies and collaborations by companies are also covered in this report. This study also discusses the strength and weaknesses of each type company in light of the new technologies, growing competition and changing customer needs.

Scope
Antibody drug conjugates are mainly used to treat cancer and are safer and more effective than many other cancer therapies. This report focuses on the global market for antibody drug conjugate products and provides an updated review, including their basic design and application in various areas of the biomedical sciences.

The report covers three main areas of application, breast cancer, lymphoma and other cancers, including acute myeloid leukemia or AML. The scope of this study includes the current market for ADCs. The report also discusses regulatory aspects, current and developing technologies, market projections and market shares. An analysis of clinical trials, innovations and opportunities and the latest trends in ADC market are also discussed in the report.

Also included in the report is an analysis of relevant patents and profiles of companies, including Seattle Genetics, Takeda Pharmaceuticals and Genentech/Roche that lead the antibody-drug conjugate product market.

Sales data for the global and regional markets were corroborated for the present and forecasted values via statistical analysis, and sales are broken down geographically into North America, Europe, Asia- Pacific and the emerging markets. The application of ADCs in various types of cancer is discussed from both a commercial perspective and that of a research and development (R&D) perspective.

The report only covers antibody-drug conjugates in which an antibody is conjugated with small-molecule cytotoxins (payload) through a linker. Other forms of antibody conjugates such as radioisotopes conjugated with an antibody are beyond the scope of this report.

Information Sources
For this report, the authors surveyed many companies to obtain data for this study. This included manufacturers and end users of antibody-drug conjugate products. Data was also gathered from various industry sources.  The authors spoke with officials within the industry, consulted newsletters, company literature, product literature and a host of technical articles, journals, indexes and abstracts. Exhaustive database searches were conducted using key terminology. In addition, data were compiled from current financial, trade and government sources.

Methodology
Both primary and secondary research methodologies were used in preparing this study. The authors also conducted a comprehensive literature search, which included technical newsletters and journals, including ADC Review | Journal of Antibody-drug Conjugates, and many other sources and conducted interviews experts and key opinion leaders. Projections were based on estimates such as the current number of end users, potential end users, mergers and acquisitions, and market trends.

Highlights
Antibody-drug conjugates, representing the convergence of chemistry with biology, include an antibody linked with a cytotoxic drug called payload. They combine the extraordinary affinity and specificity of antibodies with the anticancer potential of payloads. Continuous efforts to improve the therapeutic potential of biologics and to develop novel efficacious drugs either by modification or derivatization led to the development of ADCs.

Over the last decades, ADCs have revolutionized the field of cancer treatment. Unlike conventional chemotherapeutics, which damage normal cells along with the cancer cells, ADCs target only cancer cells. Through the synergistic combination of monoclonal antibody with the cytotoxic drug, via a stable linker, an extremely efficacious class of anticancer drugs has been emerged. To date, three ADCs have gained entry into the market, of which only two remain. Gemtuzumab ozogamicin (Mylotarg®), marketed by Pfizer, became the first FDA approved ADC in 2000.

This drug was approved for the treatment of relapsed acute myeloid leukemia. In 2010, a decade after its approval, gemtuzumab ozogamicin was withdrawn from the market due to serious hepatotoxicity issues.

However, in late January 2017 Pfizer’s Biologics License Application (BLA) for gemtuzumab ozogamicin (Mylotarg®; previously known as CMA-676) was accepted for filing by the U.S. Food and Drug Administration (FDA). And a Marketing Authorization Application (MAA) for review by the European Medicines Agency (EMA) was validated in December 2016.[2]

The Biological License Application (BLA) was based on additional data from a Phase III study that evaluated the potential benefits of adding gemtuzumab ozogamicin to standard induction chemotherapy in the treatment of patients with acute myeloid leukemia aged 50–70 years old. The FDA’s decision on the application is expected sometime in September 2017.

Only brentuximab vedotin (Adcetris®; marketed by Seattle Genetics and Takeda Pharmaceutical) and ado-trastuzumab emtansine (Kadcyla®; marketed by Genentech/Roche), are commercially available. Brentuximab vedotin was approved in 2011 for relapsed Hodgkin lymphoma and relapsed anaplastic large-cell lymphoma, and ado-trastuzumab emtansine was approved in 2013 for human epidermal growth factor receptor 2 (HER2)-expressing breast cancer.

Technological advancements, the growing number of cancer patients and increasing demand for biologics for the treatment of chronic diseases are the prime factors that are driving the market for ADCs.

North America continues to lead the market for ADCs as it has the advanced technologies needed to develop ADCs. In addition, rising healthcare expenditures and huge government initiatives are also driving the North American market. Improving economic conditions, demand for better healthcare facilities, increasing health awareness, increasing incidence of chronic diseases and growing R&D activities will help the market for ADCs grow in Asia-Pacific.

The ADC industry involves a specialization business model, more specifically a technology licensing model. In specialization models, certain companies discover and license its ADC technology to pharmaceutical companies. The two main ADC technology companies in terms of sheer numbers of licensing deals to date are ImmunoGen and Seattle Genetics. ImmunoGen, with its maytansinoid-based targeted antibody payload (TAP-) technology, produced ado-trastuzumab emtansine with Genentech.

Brentuximab vedotin is developed by Seattle Genetics and includes the company’s ADC linker and cytotoxin expertise coupled with an antibody from Millennium Pharmaceuticals, now part of the Takeda Pharmaceutical.

Innovation in ADCs typically occur through the development of new cytotoxic agents as well as new linkers that are adequately stable and at the same time can be cleaved efficiently to deliver the cytotoxic drug. Thus, key future trends in the market for ADCs include the development of novel payloads, new linker chemistry and the site-specific conjugation technology. All these advancements are expected to lead to the development of more specialized, personalized and targeted ADCs.

The manufacturing of antibody-drug conjugates requires specific manufacturing facilities. In turn, this requires high capital investment and extensive specialized training of operators and both of these requirements indicates the trend towards the contract development and manufacturing of ADCs.

Product pipeline
The product pipeline is a key determinant of any industry’s future growth. And that is also the case with antibody-drug conjugates. The industry’s acceptance of ADC technology is evident from the continual increase in novel ADCs entering clinical trials during the past few years. During 2003-2007, 10 ADCs reached Phase I trials and this number increased to 30 during 2008-2012. About 24 novel ADCs entered Phase I trials during 2012- 2016.

A number of ADCs with promising preliminary data are in the clinical trial pipeline. Mirvetuximab soravtansine, also known as IMGN853, sacituzumab govitecan and vadastuximab talirine are in late stage phase III clinical development. These three ADCs are expected to reach the market during forecast period.

Inotuzumab ozogamicin, an anti-CD22 ADC being developed by Pfizer for the treatment of relapsed or refractory acute lymphoblastic leukemia, is expected to be approved by FDA at the end of 2017. It received priority review designation from the FDA in February 2017. Through the FDA’s priority review program, Pfizer is expected to receive the FDA’s decision on inotuzumab ozogamicin with breakthrough therapy designation within six months.

In October 2016 rovalpituzumab tesirine, also known as Rova-T, an antibody-drug conjugate being developed by AbbVie/Stemcentrx, was recognized at the 7th Annual World Antibody Drug Conjugate (ADC) Awards as the “Most Promising Clinical Candidate” for fighting cancer. The novel biomarker-specific ‘smart-bomb’ antibody-drug conjugate targets the delta-like protein 3 or DLL3 protein, expressed in more than 80% of small-cell lung cancers (SCLC) patient tumors, appears to be safe and shows efficacy in treating patients with advanced SCLC. The authors expect this investigational agent to also reach the market during the forecast period.

Market expectation
The market for ADCs was worth approximately $1.3 billion in 2016 with just two approved drugs, and its potential remains very large. Total revenues, representing product sales (collaboration and royalty revenues are not considered), are expected to be $4.2 billion worldwide by 2021 at a CAGR of 25.5% from 2016 through 2021.

These revenues reflect the estimated addition of other ADCs that are directed toward acute lymphocytic leukemia and ovarian cancer. Much of the market growth is expected to come from added indications for both the marketed ADCs. In addition, the expected approval of several other antibody-drug conjugates, such as Pfizer’s gemtuzumab ozogamicin and inotuzumab ozogamicin, during the forecast period will help the market for ADCs to grow significantly.

North America led the antibody drug conjugate market due to the presence of major pharmaceutical companies working on the development of antibody drug conjugate drugs there. Both the North American and European markets benefited from the fast track approval of ADCs. Expanded access to ADCs in Asia-Pacific and the emerging markets drove the market for ADCs in these geographies.

The two most common therapeutic areas for ADCs from 2014 to 2016 were lymphoma and breast cancer, with breast cancer representing 61.3% of ADC revenues in 2016. By 2021, with the approval of two novel ADCs to treat acute myeloid leukemia and ovarian cancer, breast cancer ADCs will represent a market share of 47.1%.


Last editorial review: July 20, 2017

Featured Image: Business background with graph, digits and pen, in greens and blues.. Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Positive Results from Phase III ECHELON-1 Trial Evaluating Brentuximab Vedotin in Frontline Advanced Hodgkin Lymphoma

ECHELON-1, a randomized, multicenter, phase III clinical trial evaluating brentiximab vedotin(Adcetris®) as part of a combination chemotherapy regimen in 1,334 patients with advanced Hodgkin Lymphoma, met primary endpoint, demonstrating a statistically significant improvement in modified progression-free survival (PFS) per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma versus control.[1]

This endpoint was chosen as it provides a clearer picture of the efficacy of frontline chemotherapy and eliminates the confounding impact of salvage and consolidation chemotherapies and radiotherapy. Secondary endpoints include overall survival, complete remission and safety.

The study, conducted in North America, Europe, South America, Australia, Asia and Africa, enrolled 1,334 patients who had a histologically-confirmed diagnosis of Stage III or IV classical Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

Based on these results, Seattle Genetics and Takeda plan to submit an abstract for presentation during the 2017 annual meeting of the American Society of Hematology, to be held in Atlanta, GA, December 9-12, 2017. The companies are also planning to submit these results to regulatory authorities for approval in their respective territories.

Diagram 1.o: The ECHELON 1 clinical trial (NCT01712490) is an open-label, randomized, 2-arm, multicenter, phase III study has the primary objective of comparing the modified progression-free survival (mPFS) obtained with brentuximab vedotin (Adcetris®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin],bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma(HL).
Brentiximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma.

The drug is currently not approved as a frontline therapy for Hodgkin lymphoma.

Patients in ECHELON-1 were randomized to receive either a combination of brentiximab vedotin + AVD (Adriamycin, vinblastine, dacarbazine) or ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care for frontline Hodgkin lymphoma.

Study results
The results of the ECHELON-1 trial demonstrated that combination treatment with brentiximab vedotin resulted in a statistically significant improvement in modified PFS versus the control arm as assessed by an Independent Review Facility (hazard ratio=0.770; p-value=0.035).

The two-year modified PFS rate for patients in the brentiximab vedotin arm was 82.1 percent compared to 77.2% in the control arm. Interim analysis of overall survival (OS), the key secondary endpoint, also trended in favor of the brentiximab vedotin + AVD arm.

Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Safety profile
The safety profile of brentiximab vedotin + AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen.

The researchers observed an increased incidence of febrile neutropenia and peripheral neuropathy in the brentiximab vedotin + AVD arm. Febrile neutropenia was reduced through the use of prophylactic growth factors in a subset of patients, and peripheral neuropathy was managed through dose modifications. The control arm had an increased rate and severity of pulmonary toxicity.

Positive results
“We are excited about the positive result which shows a statistically significant improvement in the primary endpoint of modified PFS,” said Dirk Huebner, MD., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “The results of this trial signify an important step forward in the development of brentiximab vedotin and have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”

“The outcome of the Phase III ECHELON-1 trial represents a significant milestone for the Hodgkin lymphoma community,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Seattle Genetics’ goal is to establish brentiximab vedotin as the foundation of care for CD30-expressing lymphomas, including Hodgkin lymphoma. Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin.”


Last editorial review: June 28, 2017

Featured Image: Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histocytes. Courtesy: © 2017. Fotolia. Used with permission. Photo: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. Courtesy: © 2017. Seattle Genetics. Used with permission.

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Takeda and Maverick Therapeutics Develop Novel Biologics Platform to Advance T-Cell Engagement Therapies

Maverick Therapeutics, a private start-up biotechnology company that had been solely financed by MPM Capital when it was spun out of its former parent, Harpoon Therapeutics, and Takeda Pharmaceutical Company Limited announced today that they have entered a collaboration to further develop Maverick’s T-cell engagement platform created specifically to improve the utility of T-cell redirection therapy for the treatment of cancer. As part of the agreement, Takeda invests U.S. $125 million.

Maverick’s  novel T-cell engagement format has the potential to eliminate the toxicity challenges inherent in the use of T-cell redirection therapy due to expression of the target antigen on normal tissue.  The company’s therapeutic antibodies are designed to be inactive upon administration but fully active in the tumor microenvironment.


Collaborations are critical to helping us advance our aspiration of curing cancer. Working together with Maverick will enable us to leverage a potentially groundbreaking biologics platform to support Takeda’s goal of developing innovative, targeted therapies to treat people with cancer.


Exclusive option-to-acquire
Takeda‘s U.S. $125 million of funding includes an upfront option, equity and research and development funding payments, and provides Takeda an exclusive option-to-acquire Maverick after five years for an undisclosed sum. Maverick was founded in 2016.

Jeanmarie Guenot
Photo 1.0: Jeanmarie Guenot, Ph.D., co-founder of Maverick Therapeutics

“We believe that this collaboration validates Maverick’s approach to T-cell engagement in the tumor microenvironment which we believe will allow us to address previously intractable oncology targets,” said Jeanmarie Guenot, Ph.D., Maverick’s co-founder (photo 1.0).

“Importantly, this strong collaboration should allow us to move rapidly to the clinic and address unmet needs in cancer immunotherapy,” Guenot explained.

“We see significant potential in Maverick to develop unique, small and customizable T-cell engagement therapeutics,” said Phil Rowlands, Interim Head, Oncology Therapeutic Area Unit, Takeda (photo 2.0)

“Collaborations are critical to helping us advance our aspiration of curing cancer. Working together with Maverick will enable us to leverage a potentially groundbreaking biologics platform to support Takeda’s goal of developing innovative, targeted therapies to treat people with cancer,” Rowlands added.

MPM’s BioVentures 2014 and the UBS Oncology Impact Fund, managed by MPM Capital, join Takeda in a $23 million Series B Financing as a key element of the financing package. Takeda will add a director to Maverick’s Board.

phil-rowlands
Photo 2.0: Phil Rowlands, Interim Head, Oncology Therapeutic Area Unit, Takeda.

Investment group
The management team of Maverick will be led by President and Chief Scientific Officer Hans-Peter Gerber, Ph.D. Before joining the Maverick team, Gerber where he was most recently Vice President and Chief Scientific Officer of Bioconjugates Discovery and Development at Pfizer’s Oncology Research Unit. Prior to this role, he held positions at Wyeth Discovery Research – subsequently acquired by Pfizer – and Seattle Genetics, where he was head of the Translational Biology Department and contributed to the development of therapeutic antibodies and antibody-drug conjugates.

Takeda signed agreements with Maverick Therapeutics through its wholly-owned subsidiary, Millennium Pharmaceuticals.

Collaboration with LegoChem
This week Takeda also signed a research agreement with South Korea-based LegoChem. This agreement gives Takeda access to the company’s firm’s proprietary antibody-drug conjugate technology ConjuAll™ for the evaluation of next-generation ADC candidates.

Under the terms of the agreement, the companies will focus on evaluating novel ADC candidates. Takeda will have an exclusive option to license global rights for the project results.

Yong Zu Kim, President & CEO of LegoChem Biosciences said, “We are delighted that Takeda has recognized the potential of our proprietary ADC technology to address unmet medical needs in the ADC field. Takeda is a desirable partner for LegoChem Biosciences as they have expertise and experience in the global commercialization of an antibody drug conjugate therapy.”

Jeiwook Chae, chief business development officer of LegoChem Biosciences, commented: “We strongly believe that our proprietary conjugation platform addresses significant unmet needs of current ADC technologies.”

LegoChem Biosciences focuses on the development of next-generation novel therapeutics utilizing its proprietary medicinal drug discovery technology LegoChemistry™ and ConjuAll™, a next-generation Antibody-drug conjugates development platform technology utilizing novel linker chemistry combined with site-specific enzymatic conjugation. Its platform provides solutions for site-specific conjugation, linker stability and efficient payload release which are three major unmet needs in ADC development.

Since its foundation in 2006, LegoChem Biosciences has focused on the research and development of ADC, antibiotics, anticoagulants and anticancer therapeutics based on proprietary platform technologies.

In October 2016, LegoChem Biosciences partnered with Nordic Nanovector to develop CD37-targeting ADCs for the treatment of leukemias.


Last Editorial Review: January 11, 2017

Featured Image: Business partners, partnership, handshake. Courtesy: © Fotolia. Used with permission.

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Patient Enrollment in Phase III ECHELON-2 Clinical Trial of Brentuximab Vedotin in Frontline Mature T-cell Lymphoma Completed

This week, Seattle Genetics and Takeda Pharmaceutical Co. confirmed that enrollment in the ECHELON-2 clinical trial, a global phase III randomized trial evaluating brentuximab vedotin (Adcetris®) as part of a frontline combination chemotherapy regimen in patients with previously untreated CD30-positive mature T-cell lymphoma (MTCL) has been completed.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphomas are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. The World Health Organization (WHO) identifies 22 subtypes of mature T- and NK-cell neoplasms, including systemic anaplastic large cell lymphoma (ALCL) which is an aggressive type of T-cell non-Hodgkin lymphoma that expresses CD30. Other mature T-cell lymphomas include peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma and adult T-cell lymphoma.


“… The Goal is… to establish brentuximab vedotin as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and MTCL through… a broad, late-stage clinical development program currently underway. The ECHELON-2 clinical trial represents our fourth phase III study to complete enrollment”


Antibody-drug Conjugate
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, which is expressed on several types of non-Hodgkin lymphoma, including subsets of MTCL, as well as Hodgkin lymphoma. The drug is currently not approved for the frontline treatment of MTCL.

The agent includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule disrupting agent, utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin is being evaluated broadly in more than 70 ongoing clinical trials, including two phase III studies, ECHELON-1 in frontline classical Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

The ECHELON-2 trial is a double-blind, placebo-controlled global phase III trial is investigating brentuximab vedotin plus CHP versus CHOP as frontline therapy in patients with CD30-positive MTCL. The primary endpoint is progression-free survival per independent review facility assessment using the Cheson 2007 Revised Response Criteria for Malignant Lymphoma. Secondary endpoints include overall survival, complete remission rate and safety.

Why important
The unmet need in T-cell lymphoma is quite significant. CD30-positive mature T-cell lymphoma (MTCL) is a generally aggressive form of non-Hodgkin lymphoma that is currently underserved by existing chemotherapy regimens. The goal of Seattle Genetics’ ECHELON clinical program is to redefine the frontline standard of care for mature T-cell lymphomas, so that brentuximab vedotin is hopefully part of the regimen called A plus CHP.

Brentuximab vedotin is proving to be an important addition to clinicians’ current arsenal of therapies. Since the approval of the agent in the U.S. five years ago, more than 30,000 lymphoma patients have been treated worldwide, with meaningful impacts on patient outcomes. The ECHELON-2 clinical trial is the company’s fourth phase III trial to complete enrollment.

The trial represents a key component of late-stage clinical development strategy to establish brentuximab vedotin as foundation of care for CD30-expressing lymphomas. Study results from the trial  are expected in late 2017 or early 2018.

Trial design
Patients in ECHELON-2 were randomized to receive a novel combination regimen consisting of brentuximab vedotin plus cyclophosphamide (C), doxorubicin (H) and prednisone (P), referred to as A+CHP, versus cyclophosphamide, doxorubicin, vincristine (O) and prednisone, referred to as CHOP, the recognized standard of care treatment regimen for frontline MTCL. The trial enrolled 452 patients. The ECHELON-2 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA) and the trial also received European Medicines Agency (EMA) scientific advice.

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Figure 1.0: ECHELON-2 (NCT01777152) is a Clinical Trial designed to establish brentuximab vedotin (Adcetris®) as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and mature T-cell lymphoma (MTCL), a generally aggressive form of non-Hodgkin lymphoma that is currently underserved by existing chemotherapy regimens.

Foundation of care
“Our goal is to establish brentuximab vedotin as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and MTCL through our broad, late-stage clinical development program currently underway. The ECHELON-2 clinical trial represents our fourth phase III study to complete enrollment,” noted Naomi Hunder, M.D., Vice President, Clinical Development at Seattle Genetics.

“We look forward to the results of the ECHELON-2 frontline MTCL study in the 2017 to 2018 timeframe and expect to refine the timeline in the future. The ultimate goal of this phase III trial is to improve outcomes for frontline patients with CD30-expressing MTCL and, if the trial results are positive, to submit data from this trial to regulatory agencies to expand the label for brentuximab vedotin use in the frontline setting,” Hunder added.

Changing the standard of care
“Mature T-cell lymphoma is a rare, aggressive type of cancer in which the standard of care chemotherapy regimen has not changed in decades,” explained Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

“Achieving target enrollment represents a key milestone for ECHELON-2 as we evaluate the efficacy and safety of brentuximab vedotin in newly diagnosed mature T-cell lymphoma patients, and to our ultimate goal of bringing important new therapies to patients with CD30-positive malignancies,” Huebner added.

American Society of Hematology
Data from a phase I trial evaluating brentuximab vedotin plus CHP in MTCL were previously presented at the American Society of Hematology (ASH) Annual Meetings in 2012 and 2015.  An analysis of these results demonstrated that 26 of 26 patients (100%) achieved an objective response (OR), including 23 (88%) with a complete remission (CR) and three patients (12%) with a partial remission (PR).

Long-term follow-up data estimated the three-year overall survival was 80% and three-year progression-free survival was 52%, with no patients receiving a consolidative stem cell transplant in first remission. Three-year overall survival and progression-free survival rates of less than 40% and 30%, respectively, have previously been reported for patients in this setting treated with CHOP [1][2] .

The most common adverse events of any grade occurring in more than 30% of patients in this phase I trial were peripheral sensory neuropathy, diarrhea, fatigue and hair loss. Additional four-year follow-up data from this trial will be presented in a poster presentation at the 2016 ASH Annual Meeting in December.


Featured Image: Researchers in Laboratory Courtesy: © Fotolia. Used with permission. Illustration:  ECHELON-2 (NCT01777152) is a Clinical Trial designed to establish brentuximab vedotin (Adcetris®) as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and mature T-cell lymphoma (MTCL), a generally aggressive form of non-Hodgkin lymphoma that is currently underserved by existing chemotherapy regimens. Courtesy: © Sunvalley Communication. Used with permission.

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ISHL 2016: Seattle Genetics Commits to Improving Hodgkin Lymphoma Treatment

In a pre-conference announcement before the start of 10th International Symposium on Hodgkin Lymphoma (ISHL) taking place at the Gürzenich in Cologne, Germany, October 22-25, 2016, Seattle Genetics confirmed that brentuximab vedotin (Adcetris®) will be highlighted in 21 data presentations.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system and is the most common type of blood cancer. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other lymphomas by the characteristic presence of CD30-positive Reed-Sternberg cells.

screen-shot-2016-10-20-at-12-45-43-pmAccording to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2016 and more than 1,100 will die from the disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

International Symposium on Hodgkin Lymphoma
Over the last decade, the ISHL10 symposium, this year hosted by the German Hodgkin Study Group (GHSG), has become the central forum for clinicians and scientists for a comprehensive exchange of up-to-date results and new treatment ideas, discussing the relevance of new findings for daily clinical practice in Hodgkin Lymphoma.

ISHL10 is expected to cover the most recent results in basic research, diagnostics and treatment of Hodgkin Lymphoma and related malignancies. In addition to the scientific program, a number of Satellite symposia and scientific workshops will complement the program.

Photo 1.0 Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.
Photo 1.0 Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

Brentuximab vedotin
The presentations discuss a number of studies evaluating brentuximab vedotin across a broad range of Hodgkin lymphoma disease settings. The data from these presentations sports the goal to establish brentuximab vedotin as the Foundation of Care for classical Hodgkin lymphoma.

Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma that plays a role in tumor pathogenesis.  The drug is being evaluated globally as the foundation of therapy for Hodgkin lymphoma in more than 45 ongoing corporate- and investigator-sponsored clinical trials.

“For more than a decade, we have been committed to improving treatment outcomes for classical Hodgkin lymphoma patients. We have made tremendous progress with Adcetris, which is now FDA-approved for two Hodgkin lymphoma indications in the U.S. and Europe and is being evaluated broadly across all lines of therapy and in many novel regimens,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“The data presented at ISHL10 continue to advance our goal of establishing Adcetris as the foundation of care for HL. With 21 abstracts accepted for presentation, we, along with our partner Takeda, are pleased to share new and updated data with the scientific community at ISHL to help move the field forward,” Drachman added.

“The data to be presented at this year’s ISHL are a proof point of the excellent progress we have made
in furthering the clinical program of brentuximab vedotin,” said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

“Through our robust ongoing clinical investigation program, we have continued to see benefit of brentuximab vedotin, particularly in patients with Hodgkin lymphoma or other CD30-positive malignancies who would typically face a poor prognosis. We remain committed to bringing this important therapy to all patients who might benefit from it,” Takeda’s Huebner added.

AETHERA trial
Data presented at ISHL10 include an update of the progression-free survival and safety from the phase III AETHERA trial approximately four years since the last patient was enrolled, demonstrating sustained progression-free survival benefit after extended observation. In addition, updates will be presented from trials evaluating brentuximab vedotin as both mono- and combination therapy in frontline Hodgkin lymphoma patients age 60 and older, and as second-line therapy for relapsed or refractory Hodgkin lymphoma. Lastly, preclinical data will be presented indicating additional potential mechanisms of action for brentuximab vedotin , including immunogenic cell death, supporting evaluation of combination therapy with immuno-oncology agents.

Brentuximab vedotin is currently not approved for the treatment of frontline or salvage Hodgkin lymphoma in patients eligible for autologous transplant, graft-versus-host disease (GVHD) or as a combination therapy for Hodgkin lymphoma.


Last Editorial Review: October 20, 2016

Featured Image: Cologne Cathedral and Hohenzollern Bridge, Cologne, Germany. Courtesy: © Fotolia/Elena Shchipkova. Used with permission. Photo 1.0 Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. Courtesy: © Seattle Genetics. Used with permission.

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Takeda and Crescendo Collaborate to Generate Tumor Targeting Drug-conjugates and Immuno-oncology Therapeutics

Crescendo Biologics, based in Cambridge, UK, the drug discovery and developer of Humabody®-based therapeutics, and Takeda Pharmaceutical Company announced a global, strategic, multi- target collaboration and license agreement for the discovery, development and commercialization of Humabody® -based therapeutics for cancer indications with a high unmet medical need.

Crescendo’s Humabody® therapeutics are based on its proprietary, robust and highly efficient fully human VH domain technology platform (VH domains are only just a quarter of the size of Fab fragments). The company’s technology platform is centred on a unique and proprietary Triple Knock Out (TKO) transgenic mouse technology – the gold standard in antibody therapeutics development – in which all three endogenous antibody loci (heavy chain, κ light chain and λ light chain) are functionally silenced. This technology combines the benefits of producing a huge diversity of fully human VH domains (Humabody VH) in a background completely devoid of mouse antibodies with in vivo maturation and optimizes the affinity and biophysical properties of resulting monovalent VH building blocks and any configured mono- and multispecific Humabody therapeutics derived from them.


“… this collaboration is critical to helping us achieve our aspiration of curing cancer… and develop the next generation, highly modular and targeted therapies…”


Compared with monoclonal antibodies, Humabodies have differentiated pharmacological properties, offering a unique combination of potential benefits that results from their small size (e.g. 36 kDa for a trispecific Humabody), cost-effective production and modular plug & play engineering options for generating novel bi- or multi-specific formats.  Among the unique features is that Humabodies can rapidly penetrate and accumulate in tissue/tumours while clearing quickly from circulation to minimise systemic toxicity.

The unique properties of  Crescendo’s Humabody therapeutics, makes it possible to put them together in a rapid and highly flexible way, including site specific and homogenous drug conjugation. This, in turn,  offers increased specificity and superior toxicology profiles leading to an improved Therapeutic index (enabled by a “high dose, hit hard and leave” approach).

Research
Earlier this year, during the 2nd Biologics and Biosimilars Congress in Berlin, Germany, Brian McGuinness PhD., MBA,  Crescendo’s Vice President of Discovery, presented data from a biosdistribution study confirming the rapid, homogeneous penetration and effective accumulation of Humabody constructs in a mouse xenograft tumour along with fast clearance of unbound material from systemic circulation. As a consequence, HDCs with highly potent payloads have the potential to generate a substantially superior therapeutic index to standard Antibody-drug Conjugates comprised of whole IgG.

Pipeline
Crescendo’s researchers have successfully demonstrated in vivo that Humabodies rapidly penetrate and accumulate within tumours resulting in a greatly increased tumour to blood ratio compared to IgGs. Based on these early results, Crescendo is building a pipeline of new differentiated medicines, including Humabody® Drug Conjugates, also known as HDCs, and multi-specific immuno-oncology (IO) modulators, through in-house development and strategic partnerships.

Agreement
Under the agreement with Takeda, Crescendo will use its proprietary transgenic platform and engineering expertise to discover and optimally configure Humabody® candidates (Humabody® Drug Conjugates and Immuno-Oncology modulators) against multiple targets selected by researchers at Takeda.

“We see significant potential in Crescendo and its innovative technology to develop unique, small and customizable Humabody®-based therapeutics,” said Andrew Plump M.D., Ph.D., Chief Medical and Scientific Officer, Takeda.

“Collaborations are critical to helping us achieve our aspiration of curing cancer. Working together with Crescendo will enable us to leverage its important technology to support Takeda’s goal of developing next generation, highly modular and targeted therapies to treat cancer,” Plump added.

Validation
“This collaboration with Takeda represents a significant step forward for Crescendo. It provides validation of our transgenic platform and our capabilities to rapidly assemble and configure small, differentiated Humabody®-based therapeutics, opening routes to novel biology,” noted Dr. Peter Pack, CEO, Crescendo Biologics.

“As a leading global pharmaceutical company, Takeda brings extraordinary expertise in the oncology area with significant capabilities in developing and delivering novel medicines to patients. This first major collaboration enables us to potentially broaden and accelerate innovative Humabody®-based product candidates,” he said.

Investment
Crescendo is eligible to receive up to $36 million, in a combination of an upfront payment, investment, research funding and preclinical milestones. Takeda will have the right to develop and commercialize Humabody®-based therapeutics resulting from the collaboration. Crescendo is also eligible to receive further clinical development, regulatory and sales-based milestone payments of up to $754 million. In addition, Crescendo will be eligible to receive royalties on Humabody®-based product sales by Takeda.


Last Editorial Review: October 10, 2016

Featured Image: ResearchersCourtesy: © Fotolia. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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INSIGHT-MM Study Designed to Advance Real-world Understanding of Multiple Myeloma

In late Augustus 2016 Takeda Oncology announced that the INSIGHT-MM, the company’s global non-interventional, observational multiple myeloma study, is now enrolling patients. The study aims to enroll 5,000 patients over three years with a goal of following each patient for a minimum of five years in an effort to track patterns in disease presentation, patient characteristics, treatment and outcomes and thereby enhance the understanding of real world experience of patients with multiple myeloma.

Multiple myeloma is a relatively rare form of cancer, with, according to the American Cancer Society, approximately 30,000 new cases in the United States, 39,000 new cases in the European Union and approximately 114,000 new cases globally per year.

Photo 1.0: Liviu Niculescu, Vice President, Global and U.S. Oncology Medical Affairs, Takeda Oncology.
Photo 1.0: Liviu Niculescu, Vice President, Global and U.S. Oncology Medical Affairs, Takeda Oncology.

The disease is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of monoclonal plasma cells, or myeloma cells, becomes cancerous and multiplies.

These malignant plasma cells have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain.

Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia.

Overall, the care of patients with multiple myeloma is complex. Generally, protocols emphasize that care should focus on treatment of the disease process and any associated complication.  Although several drug therapies as well as autologous stem cell transplantation, radiation, and, in certain cases, surgery are valuable in the treatment of patients with multiple myeloma, the disease remains incurable.

Much work is being done in the development of novel treatment options. But even with the recent introduction of new therapies, as well as novel therapeutic options in clinical trials, more work needs to be done to improve outcomes for patients across the globe.

Integrating patient insights
Scientists and researchers at Takeda have pioneered the practice of integrating patient insights into clinical trial protocols sponsored by the company. The INSIGHT-MM study gives the community of scientists, researchers, doctors and patients an opportunity to work together to better understand how clinical advances affect multiple myeloma patients in the real world. This approach has helped them develop medicines that truly make a difference for patients.

Understanding multiple myeloma
Earlier this month we spoke with Liviu Niculescu, Vice President, Global and U.S. Oncology Medical Affairs, Takeda Oncology.

Question: I noticed that there is not a direct link to a specific therapy. Is that correct or did I miss something here?

Answer: That is correct. This is a disease study, not a drug study. INSIGHT-MM is a global non-interventional, observational study. Participation in INSIGHT-MM will not determine or alter patients’ treatment; rather, patients will receive their usual therapy as determined by their healthcare provider during the course of their care. No study drug or medications will be provided, and no change will be required in the patients’ management (routine clinical care or treatments) as a result of this study.

Q: Other than observing patients and learning about disease progression, treatment etc., what is the rationale?

A: The only rationale is to advance the understanding of the disease and treatment patterns, so we can further advance the care for patients with this cancer. Currently, only a fraction of patients is enrolled in clinical trials (observational or interventional), so our data are limited. The treatment approaches to multiple myeloma are changing rapidly, with the introduction of new treatments that have demonstrated an impact on survival. Despite recent clinical advances in multiple myeloma treatment, many questions remain unanswered, and there is a need for real-world data on global patterns in disease presentation, patient characteristics, treatment and outcomes for patients with multiple myeloma.

Over the course of the INSIGHT-MM study, information will be recorded based on review of hospital or clinic records. Multiple myeloma management data and safety data will be obtained as part of routine office visits. Patients will complete health-related quality of life and patient self-reported outcomes surveys at inclusion and at predefined intervals throughout the study, and this information will be collected using a secure electronic data collection system (technical devices and/or paper survey forms will be provided for patients who cannot access the internet).

Q: How does Takeda benefit from this study, why is this important and how do (future) patients benefit from this?

A: The benefits of INSIGHT-MM for Takeda Oncology and the benefits for patients are the same – greater knowledge that may facilitate better outcomes. By gathering comprehensive real world data on this scale, we hope to identify best practices across the globe and gather important insights with the aim of advancing care for patients with multiple myeloma and help guide future clinical research direction. Patients who participate in INSIGHT-MM will have the opportunity to help increase global understanding of how multiple myeloma and its treatment affect people in the real world.

These learnings can in turn enhance our efforts to improve disease management for people living with multiple myeloma.

We designed the innovative INSIGHT-MM trial to be an open source of data – large enough to reveal differences and trends globally. We invite collaborations from other similar studies in order to increase the size of available databases and move us closer to a future when robust data on multiple myeloma enables us to change the face of the disease.

Participation and study locations
The INSIGHT-MM trial will be conducted on a global scale. The first 3 study sites of more than 150 anticipated global sites are at University of Arkansas for Medical Sciences, the University of California, San Diego; and the University of Cincinnati Cancer Institute.

Participation in INSIGHT-MM, a non-interventional study, will not determine or alter patients’ treatment; rather, patients will receive their usual therapy as determined by their healthcare provider during the course of their care.


Last Editorial Review: September 9, 2016

Photo: Liviu Niculescu, Vice President, Global and U.S. Oncology Medical Affairs, Takeda Oncology. Courtesy: © Takeda Oncology. Used with permission.

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Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin lymphoma: Study Details Five-year Survival and Durability Results

The final data of the brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda Oncology) monotherapy pivotal phase II clinical trial in relapsed or refractory (R/R) classical Hodgkin lymphoma were published in the July 18, 2016 edition of Blood, a peer reviewed journal published by the American Society of Hematology[1] The article, which summarizes the five-year, end-of-study results, highlights data showing that patients who attained a complete response achieved long-term disease control.

Brentuximab vedotin is an antibody-drug conjugate or ADC that targets CD30, a protein on the surface of some Hodgkin lymphoma cells and a key driver of classical Hodgkin lymphoma tumor pathogenesis. As an ADC, the drug delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, directly to CD30-expressing cells.

The drug, approved in 2011 for relapsed or treatment-resistant Hodgkin lymphoma, is commonly prescribed to patients whose disease has progressed after autologous stem cell transplant, a procedure that replenishes the bone marrow with the patient’s own healthy stem cells after therapy, and is being evaluated globally as the foundation of therapy for Hodgkin lymphoma in more than 45 ongoing corporate- and investigator-sponsored clinical trials.


… this is the first study to observe long-term success in patients who have exhausted all other treatment options…


Hodgkin lymphoma
Classical Hodgkin lymphoma, known to spread by the lymphatic system, is one of the most unique types of hematological malignancies known. In Hodgkin lymphoma, the surrounding environment plays an important role in influencing the behavior of the malignant cells. And unlike non-Hodgkin lymphoma, Hodgkin lymphoma spreads in a very predictable manner, and is not considered a systemic disease at diagnosis. [2]

An estimate by the American Cancer Society, suggests that there will be about 8,500 new cases (3,710 women and 4,790 men) of  Hodgkin lymphoma in the United States in 2016.  Based on the same estimate, about 1,120 patients are expected to die (480 women, 640 men) from this disease, which is characterized by the presence of CD30‑positive Reed-Sternberg cells.

While progress in treating Hodgkin lymphoma is often presented as one of the great accomplishments in all of cancer medicine, only about 70% of patients can really expect to be cured. For those patients cured with conventional chemotherapy, the disease can be managed, and sometimes becomes more indolent and chronic in nature.

Standard of care
The standard of care for patients with relapsed or refractory (R/R) Hodgkin lymphoma is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT).  Achieving and maintaining a complete remission (CR) prior to transplant is generally considered a major aspect resulting in a favorable progression-free and overall survival (OS) after transplant.

Approximately 50% of patients treated for relapsed or refractory Hodgkin lymphoma will experience relapse or progression after auto-SCT. This usually occurs within the first year, and represents a significant therapeutic challenge. [3] In this category of patients, treatment outcomes have, historically, been very poor, with median Overall Survival (OS) from time of relapse ranging from 10.5 to 27.6 months. [2][3]

“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said Robert Chen, M.D., City of Hope National Medical Center’s Department of Hematology & Hematopoietic Cell Transplantation in Duarte, California, and lead author of the study published in Blood.

“The median survival of the patients on brentuximab vedotin monotherapy in this pivotal Phase II trial exceeds these historic figures, and I am pleased to see the publication of the final data,” Chen further noted.

“For a patient population that typically only sees an overall survival of one to two years after relapse from autologous stem cell transplantation, the fact that we can report such durable results after five years is incredible,” Chen added

“Each day that these individuals continue to spend with their loved ones is a testament to the strides our community is making in understanding and beating treatment-resistant lymphomas,” he observed, referencing the 15 patients still in remission at the close of this longitudinal study.

Commitment to improvement
“For over a decade, we have demonstrated our commitment to improve treatment outcomes in Hodgkin lymphoma through numerous clinical trials evaluating novel therapeutic approaches. Today’s final publication of the [brentuximab vedotin] monotherapy pivotal study in Hodgkin lymphoma patients represents a significant milestone for the trial that supported approval in more than 60 countries globally and established current use as standard-of-care in the relapsed setting,” noted Jonathan Drachman, MD, Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

Foundation of care
“The long-term safety and efficacy data from the pivotal trial are supportive of our ongoing development of [brentuximab vedotin] for other classical Hodgkin lymphoma settings, including the frontline setting. Our broad clinical program is investigating [brentuximab vedotin] as a foundation of care for Hodgkin lymphoma and potentially other CD30-expressing malignancies,” Drachman further added.

“The positive final results from this trial of [brentuximab vedotion] demonstrated that of the patients who had a complete response, 38% achieved long-term disease control for the duration of the study,” said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

Patients’ median progression-free survival (PFS) on brentuximab vedotin was longer than the median PFS, increasing it by more than 3 months.

“In addition, the median overall survival of 40.5 months and progression-free survival of 9.3 months observed across the trial further establish the role of [brentuximab vedotin] in improving outcomes for patients with relapsed Hodgkin lymphoma,” Huber observed.

Table 1.0: NCT00848926 is a single-arm, open-label, multicenter, pivotal clinical trial designed to evaluate the efficacy and safety of brentuximab vedotin as a single agent in patients with relapsed or refractory (R/R) Hodgkin lymphoma.

Pivotal trial
The pivotal, single-arm trial, which supported the U.S. Food and Drug Administration’s (FDA) approval in 2011 of brentuximab vedotin for this indication, was conducted in 102 patients with relapsed or refractory classical Hodgkin lymphoma who had previously received an autologous stem cell transplant (ASCT) to assess the efficacy and safety of single-agent brentuximab vedotin. Enrolled patients had received a median of more than three prior chemotherapy regimens. [5]

After a five-year follow-up period, the final results from the pivotal trial showed a median overall survival and progression-free survival of 40.5 months (95% confidence interval [CI]: 28.7, 61.9) and 9.3 months (95% CI: 7.1, 12.2), respectively. The estimated five-year overall survival and progression-free survival rates were 41% and 22%.

Of the 102 patients treated, 34 patients (33%) had a complete remission, with the median response duration not reached. For patients who had a complete remission (CR), the estimated five-year overall survival rate was 64% (95% CI: 48, 80) and the estimated five-year progression-free survival rate was 52 percent (95% CI: 34, 69).

Thirteen of the 34 patients (38%) who achieved a complete remission (CR) continued to be followed and remained in remission for over five years at study closure. Of these patients, four underwent consolidative allogeneic stem cell transplants while in remission, and nine received no further therapy.

“It is critical to note that nine of patients [achieving a complete remission] have been in remission for over five years after receiving only brentuximab vedotin,” Chen noted.

“The fact that these patients are doing so well, even five years out, provides a new perspective for prognosis,” he pointed out.

Most common adverse events
The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia and diarrhea. Treatment emergent peripheral neuropathy, a common adverse event characterized by tingling in the extremities, reported among patients treated with brentuximab vedotin, was experienced by 56 patients (55%).  However, these toxicities were considered manageable. Eighty-eight percent of these patients in the study experienced improvement of their peripheral neuropathy symptoms, including 73% with complete resolution, Chen concluded.

Previously, primary results and 3-year follow-up of the data were reported earlier. [6][7][8]

While brentuximab vedotin is becoming standard care, this is the first study to observe long-term success in patients who have exhausted all other treatment options. The final data and end-of-study results of the pivotal trial demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with R/R Hodgkin lymphoma, particularly in patients who achieve Complete Response.[9]

These results suggests that the targeted therapy with brentuximab vedotin should be standard of care for patients with relapsed or treatment-resistant Hodgkin lymphoma.


Last Editorial Review: July 18, 2016

Featured Image: Oncology nurse talking to a patient. Courtesy: © 2016 Fotolia. Used with permission. Secondary Featured Image (Homepage): Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histiocytes. Courtesy: © 2016 Michael Bonert (Nephron). Licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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