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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

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U.S. FDA Lifts Partial Clinical Hold for Mersana’s XMT-1522

The United States Food and Drug Administration (FDA) has lifted the partial clinical hold on the Phase I study of XMT-1522, a Dolaflexin® Antibody-drug Conjugate (ADC) targeting HER2-expressing tumors being developed by Mersana Therapeutics.

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.

Lower levels of HER2-expression
XMT-1522 has the potential to extend HER2-targeted therapy beyond the current HER2-positive populations into patients with lower levels of HER2 expression. The Phase I protocol will evaluate XMT-1522 in 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). More information on the ongoing Phase 1 clinical trial can be found at clinicaltrials.gov.

Changes to the protocol
Mersana and the FDA reached alignment on changes to the protocol. These changes include increased monitoring as well as the exclusion of patients with advanced hepatic impairment. Although XMT-1536, another investigational agent being developed by Mersana,was not subject to a clinical hold, the company decided to implement similar modifications to the XMT-1536 protocol.

XMT-1536 is Mersana’s highly potent immunoconjugate targeting the sodium-dependent phosphate transport protein (NaPi2b) comprised of an average of 10-15 DolaLock™ payload molecules conjugated to XMT-1535, a proprietary humanized anti-NaPi2b antibody, via the Dolaflexin ADC platform.

In addition to the changes in the protocol, alternative dosing regimens will be evaluated for both clinical trials.

The XMT-1522 trial will begin with a once-every-four-week dose regimen. This dosing regimen has already been implemented in the XMT-1536 trial at previously explored dose levels in order to enable a comparison of relevant doses and their impact on the safety, efficacy and PK profile of the drug candidate. The company may evaluate additional regimens as well. Data on XMT-1536 is expected in the first half of 2019.

“We are excited to resume enrollment on the XMT-1522 trial and to work with investigators to explore the full potential of both promising drug candidates in the solid tumor setting,” said Anna Protopapas, Chief Executive Officer of Mersana.


Last Editorial Review: September 17, 2018

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XMT-1522 Trial in Progress Data Presented at ASCO

Data from a trials in progress abstract presented during the 2017 annual meeting of the American Society of Clinical Oncology (ASCO) confirmed the continued advancement of Mersana Therapeutics Phase I clinical trial of XMT-1522.

Mersana is a clinical-stage biotechnology company focused on discovering and developing a pipeline of antibody-drug conjugates or ADCs based on the company’s proprietary Dolaflexin® platform with DolaLock payload technology.

XMT-1522 is an antibody-drug conjugate or ADC consisting of a novel human IgG1 anti-HER2 monoclonal antibody conjugated to a proprietary auristatin-based cytotoxic payload.

An average of 12 auristatin-based cytotoxic payload molecules are, via a biodegradable polymer, conjugated to each antibody .

In October, 2016, U.S. Food and Drug Administration (FDA) cleared Mersana’s Investigational New Drug (IND) application to begin Phase I clinical trials for XMT-1522, which is the company’s first pipeline product, and could define a new class of HER2-targeted therapies.

Clinical trial
The Phase Ib trial is an open label, multi-center study of XMT-1522 administered as an intravenous infusion once every three weeks.

The dose escalation part of the study is designed to help establish the maximum tolerated dose or recommended Phase II dose for in patients with advanced breast cancer and either a HER2 immunohistochemistry (IHC) score of at least 1+ using a validated IHC assay or with evidence of HER2 amplification.

Patients with HER2 positive (by IHC or amplification) gastric cancer or nonsmall cell lung cancer may also be eligible for participation in the dose escalation part of the trial. Upon completion of dose escalation, the cohort expansion segment of the study is designed to consist of four parallel cohorts of different patients groups to confirm the maximum tolerated dose or the recommended Phase II dose and estimate the objective response in each of the patient populations.

Photo 1.0: Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer, Mersana Therapeutics.

“The clinical experience with XMT-1522 to date has been consistent with the promising preclinical data,” noted Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer, Mersana Therapeutics.

“We look forward to providing interim Phase I results for XMT-1522 at a scientific conference later in 2017 as well as beginning clinical trials in Q1 2018 with XMT-1536, our second Dolaflexin ADC.”

“We anticipate that the Phase I data for these two assets will establish the potential of the Dolaflexin ADC platform to generate products that bring meaningful clinical benefit to patients,” Bergstrom cocluded.


Last editorial review: June 5, 2017

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Preclinical Data on XMT-1522 Supports Efficacy and Tolerability

During the 108th Annual Meeting of the American Association for Cancer Research (AACR), held April 1 to 5, 2017, in Washington, D.C, Mersana Therapeutics, a clinical-stage biotechnology company focused on discovering and developing a pipeline of antibody drug conjugates (ADCs) based on its proprietary Fleximer® technology, presented data that highlighted the company’s emerging antibody drug
conjugate (ADC) XMT-1522.

XMT-1522 consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxy-propylamide, AF-HPA). An average DAR of 12 AF-HPA molecules is achieved via a biodegradable polymer conjugation platform.

XMT-1267
In two poster presentations scientists from Mersana confirmed that the small molecule Auristatin F – HPA (XMT-1267), which has the capacity for bystander effect, is a primary ADC drug release product.

They found that XMT-1267 is further metabolized in the tumor to form Auristatin F (XMT-1521), the most abundant XMT-1267 metabolite.

XMT-1521, which is negatively charged and not freely cell permeable, is observed in the tumor at significant levels two weeks post-administration of XMT-1522, supporting a trapping effect of this active metabolite.

XMT-1522
XMT-1522 is Mersana’s lead ADC compound, and is being developed for the treatment of patients with HER2-positive cancers, as well as for patients with HER2-expressing tumors not meeting the current diagnostic definition of HER2-positive.

The second poster presentation, presented in a session on Monday, April 3, demonstrated in pre-clinical models that XMT-1522 and its active release product, XMT-1267, can lead to immunogenic cell death. The potential for XMT-1522 to have monotherapy activity in HER2-expressing NSCLC, as well as a rationale for combinations of XMT-1522 and immunomodulatory therapies in NSCLC, was also reported.[2]

Overall, the data presented at AACR included results from the combination of XMT-1522 + the checkpoint inhibitor pembrolizumab tested in a patient-derived HER2-expressing PDX models in a mouse with a humanized immune system. In these trial expression of huPD-L1 in the tumor was confırmed by FACS and immunohistochemistry (IHC). Lymphocyte sub-populations were quantifıed in whole blood and in tumor by FACS and IHC. XMT-1522 treatment alone induced tumor growth delay after 3 weekly doses of 1 mg/kg. Pembrolizumab as a single agent administered every 5 days for 6 doses (q5dx6) at a dose of 2.5 mg/kg led to less tumor growth delay than XMT-1522 treatment. The combination of these two treatment regimens resulted in a better response than either of the two monotherapies. These data provide a rationale for XMT-1522 to be tested clinically as a single agent in HER2-expressing NSCLC, as well as a rationale for combination of XMT-1522 and immunomodulatory therapies in NSCLC.[2]

“The pre-clinical support for the potential benefit to patients of XMT-1522 continues to strengthen and we are excited to have initiated clinical development for the program,” noted Anna Protopapas, President and Chief Executive Officer of Mersana.

Progress
“The presentations at AACR highlighted the progress we have made with our lead antibody drug conjugate, XMT-1522, as an ADC-based therapy, but also in the important field of immuno-oncology, where the data suggests the compound’s potential as a monotherapy in HER2-expressing non-small-cell lung cancer (NSCLC), as well as in combination with immunomodulatory therapies in NSCLC,” Protopapas added

“Our presentation in immuno-oncology strongly suggests that XMT-1522 and its active release molecule, XMT-1267, lead to immunogenic cell death, and can significantly enhance the effect of immuno-oncology agents such as checkpoint inhibitors,“ said Timothy B. Lowinger, Ph.D., Chief Scientific Officer of Mersana
Therapeutics.

“The second presentation demonstrates Mersana’s deeper understanding of XMT-1522’s drug metabolism and pharmacokinetic (DMPK) properties, which support the potential of Mersana’s Dolaflexin ADC platform to provide a greater therapeutic index by simultaneously improving efficacy, via greater payload
delivery, and tolerability due to the unique pharmacology designed into our novel auristatin payload.”


Last Editorial Review: April 2, 2017

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AACR 2017: New Preclinical Data to be Presented on Mersana’s XMT-1522

Mersana Therapeutics earlier today announced that it will present data on its lead preclinical immunoconjugate, XMT-1522, at the American Association of Cancer Research (AACR) Annual Meeting 2017 in Washington, D.C.

The two poster presentations will highlight results from ongoing non-clinical studies where XMT-1522, an antibody drug conjugates or ADCs based on the company’s Fleximer® platform technology, was evaluated as a potential combination partner with immunomodulatory cancer therapies and it was also characterized for its pharmacokinetics, metabolism and biodistribution in tumor-bearing mice. The drug is being co-developed with Takeda Pharmaceutical Company.

AACR Logo_Newsroom
AACR Logo_Newsroom

XMT-1522 incorporates a novel, proprietary HER2 antibody, which is conjugated with Mersana’s Dolaflexin platform which includes the company’s most advanced Fleximer antibody-drug conjugates technology platform and a high dose of the proprietary auristatin payload, a derivative of the dolastatin family of cytotoxic agents.

The investigational compound provides a drug load of approximately 12-15 molecules per antibody, specifically designed to improve potency while simultaneously increasing tolerability. XMT-1522 has the potential to extend HER2-targeted therapy beyond the current “HER2-positive” populations into patients with lower levels of HER2 expression.

Investigational New Drug application
In October 2016 the U.S. Food and Drug Administration (FDA) cleared the Mersana’s Investigational New Drug (IND) application to begin Phase I clinical trials for XMT-1522.

“XMT-1522 represents a promising therapeutic approach for cancer patients with significant unmet medical needs and we are pleased to be in a position to move this therapy into clinical development,” noted  Donald A. Bergstrom, M.D. Ph.D., Chief Medical Officer, Mersana Therapeutics in October 2016, during the announcement of the clearance of the IND application. “We have designed a robust Phase I program that will allow us to better understand the potential of XMT-1522 to address the needs of several patient groups who currently have limited options.

The accepted abstracts are listed below and are now available online on the AACR 2017 conference website.

Abstract Title Autors Data & Location and Session Description
# 6879 Combination of anti-HER2 ADC XMT-1522 and checkpoint inhibitor pembrolizumab for treatment of NSCLC in preclinical models Bodyak N, Protopopova M, Zhang Q, Yurkovetskiy A, Yin M, Qin L, Poling LL, Mosher R,  Bergstrom DA, Lowinger TB Monday Apr 3, 2017 1:00 PM – 5:00 PM

Convention Center, Halls A-C, Poster Section 26 (poster board 29).

Immune Response to Hematopoietic Tumors: New Developments in Tumor Immunology

# 6716 Non-clinical pharmacokinetics of XMT-1522, a HER2 targeting auristatin-based antibody drug conjugate. Bergstrom DA, Bodyak N,  Yurkovetskiy A, DeVit M, Yin M, Poling LL, Thomas JD, Gumerov D, Xiao D, Ter-Ovanesyan E, Bu C, Qin L, Uttard A, Johnson A, Lowinger TB Sunday Apr 2, 2017 1:00 PM – 5:00 PM

Convention Center, Halls A-C, Poster Section 26 (Poster board 29).

Experimental and Molecular Therapeutics


Last Editorial Review: March 3, 2017
Last Editorial Update: March 6, 2017

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U.S. FDA Accepts Investigational New Drug Application for Mersana’s Lead Antibody-Drug Conjugate XMT-1522

The U.S. Food and Drug Administration (FDA) cleared Mersana Therapeutics’ Investigational New Drug (IND) application to begin Phase I clinical trials for its lead investigational antibody-drug conjugate drug candidate XMT-1522. The investigational compound is Mersana’s first pipeline product, and defines a new class of HER2-targeted therapies. The investigational drug is based on Mersana’s Fleximer® technology.

The drug is being co-developed with Takeda Pharmaceutical.   Under the terms of the agreement Mersana will, based on the FDA clearance of this IND, receive a $20 million milestone payment.

Earlier this year, in February, Takeda, through its wholly owned subsidiary Millennium Pharmaceuticals,, entered into a strategic partnership with Mersana to co-develop XMT-1522. The execution of the Phase I trial will be managed by Mersana. The company will also retain full commercial rights in the United States and Canada while Takeda will have rights in rest of world.

Current ADC Development
Industry-wide there are 60 antibody-drug conjugates in clinical development. Today 40 of these investigational compounds are in phase I trials, 16 in phase II and 4 phase III. Currently, there are two licensed ADCs on the market. In 2015 17 novel ADCs entered the clinic while an additional 7 have entered clinical trials in 2016. Many of the ADCs in phase I trials are not identifying a target disease, but are broadly recruiting for solid tumors. With more than 10 ADCs, breast and lung cancer are common diseases for ADCs. Of the 30 different targets for solid tumors 11 target breast cancer and 9 lung cancer.

296_mersanabw_demaniophotography
Photo 1.0: Donald A. Bergstrom, M.D. Ph.D., Chief Medical Officer, Mersana Therapeutics.

A promising approach
“XMT-1522 represents a promising therapeutic approach for cancer patients with significant unmet medical needs and we are pleased to be in a position to move this therapy into clinical development.” said Donald A. Bergstrom, M.D. Ph.D., Chief Medical Officer, Mersana Therapeutics.

“We have designed a robust phase I program that will allow us to better understand the potential of XMT-1522 to address the needs of several patient groups who currently have limited options,” Bergstrom added.

Breast and Gastric cancers
XMT-1522 is an anti-HER2 antibody-drug conjugate. The investigational drug incorporates HT-19, a novel, proprietary anti-HER2 antibody optimized for cytotoxic payload delivery. The antibody is conjugated with Mersana’s Dolaflexin platform which includes its Fleximer biodegradable hydrophilic polymer technology and proprietary auristatin payload.

XMT-1522 provides a drug load or drug-to antibody ratio (DAR) of approximately 12 molecules per antibody, specifically designed to improve potency while simultaneously increasing tolerability. XMT-1522 has the potential to extend HER2-targeted therapy beyond the current HER2-positive populations into patients with lower levels of HER2 expression.

Illustration 1.0: Mersana Therapeutics’ Fleximer® technology platform represents a revolutionary development in immunoconjugate technology. It allows researchers to overcome many of the limitations of currently available technologies used in the development of antibody-drug conjugate (ADC). Using proprietary Fleximer polymer and linker chemistries, researchers an Mersana custom design a drug-conjugate with a unique combination of properties aimed specifically at attacking a particular type of cancer. By engineering a drug conjugate with industry-leading payloads of anti-cancer agents and precisely controlling when, where and how those agents are released, these novel ADC therapies have the potential to more effectively treat broader populations of cancer patients while minimizing undesired side effects. 

In this illustration: Green = mAb; Blue = Fleximer polymer; Red = Auristatin F-HPA payload

Early and pre-clinical results
Early and pre-clinical data presented during the 2015 annual meeting of the American Society for Cancer Research (AACR) and the 2015 San Antonio Breast Cancer Symposium (SABCS) has shown nanomolar potency in cultured tumor cells with HER2 receptor densities as low as 10,000 per cell.  This data also shows that XMT-1522 is typically 1-3 logs more potent than ado-trastuzumab emtansine, also known as T-DM1 (Kadcyla®; Genentech/Roche), an antibody-drug conjugate consisting of the antibody trastuzumab linked to the cytotoxic agent emtansine, also called DM1, a thiol-containing maytansinoid.

Researchers at Mersana have further shown that XMT-1522 is active across a panel of 25 tumor cell lines [1] and in a range of models representing HER2+ disease where current  HER2-targeted therapies, including ado-trastuzumab emtansine, are not active. XMT-1522 is also active in models representing HR+ and HR- HER2 IHC 1+ and 2+ disease. [2][3][Note]

In mouse xenograft studies XMT-1522 has excellent pharmacokinetic properties and achieves complete tumor regressions at well- tolerated doses. In one high HER2-expressing model of gastric cancer (800,000 HER2 receptors/cell), complete regressions was achieved with a single 1 mg/kg dose of XMT-1522. To achieve comparable activity with ado-trastuzumab emtansine, a dose of 10 mg/kg is required. [1]

One of the unique features of XMT-1522 is that it is non-competitive with existing therapies  – trastuzumab or pertuzumab (Perjeta®; Genentech/Roche) – for HER2 binding. A triple combination of XMT-1522 + trastuzumab + pertuzumab in the same mouse xenograft model mentioned above, resulted in tumor regressions where the same doses of XMT-1522 alone or the trastuzumab/pertuzumab doublet result in tumor stasis.[1]

In a low HER2-expressing breast cancer model (79,000 HER2/cell) and gastric cancer  model (22,000 HER2/cell) models, complete regressions was achieved with single 1 mg/kg or 0.67 mg/kg doses of XMT-1522, respectively while ado-trastuzumab emtansine is inactive at doses ≥10 mg/kg.[1]

In non-human primates XMT-1522 demonstrated good stability of the drug-conjugate in plasma with t1/2 ~5 days (comparable to antibody t1/2) and minimal exposure to free payload.[1]

One of the interesting findings in early and pre-clinical studies is that despite the high potency of XMT-1522 in low HER2 tumor models, researchers did not observe XMT-1522-related toxicity in critical HER2-expressing tissues including heart and lung. The preclinical data further support testing XMT-1522 as a single agent in tumors with low HER2 expression where current HER2- directed therapies are not indicated. Finally, the combination of XMT-1522 with trastuzumab and/or pertuzumab achieves efficient cytotoxic payload delivery while retaining the potential for full inhibition of HER2 signaling, which may be necessary to improve on current regimens in HER2-driven tumors.[1]

Phase I protocol
The Phase I protocol will evaluate XMT-1522 in patients with advanced HER2-positive breast and gastric cancer, as well as advanced breast cancer with low HER2 expression and HER2-expressing non-small cell lung cancer.

Partnership
“Our partnership with Mersana exemplifies our approach of uniting Takeda’s experience in bringing novel oncology therapies to market with promising drug discovery technology like Mersana’s Fleximer to help drive science forward for patients with unmet medical needs,” noted Phil Rowlands, Interim Head, Oncology Therapeutic Area Unit, Takeda.

In addition to developing novel antibody-drug conjugates with select pharmaceutical partners, including Takeda, Mersana is also developing its own portfolio of next-generation Fleximer-ADCs with superior properties not found with current ADC technologies to address unmet needs and improve patient outcomes in multiple oncology indications.


[Note]: IHC or or Immunohistochemistry is a staining process performed on fresh or frozen breast cancer tissue removed during biopsy. It is used to show whether or not the cancer cells have HER2 receptors and/or hormone receptors on their surface. This information plays a critical role in treatment planning.

Last Editorial Review: October 24, 2016

Featured Image: Pipette and laboratory test tubes. Courtesy: © Fotolia. Used with permission. Photo 1.0 Donald A. Bergstrom, M.D. Ph.D., Chief Medical Officer, Mersana Therapeutics. Courtesy: © Mersana Therapeutics/Demanio Photography. Used with permission. Illustration 1.o: Fleximer® platform technology. Courtesy: © Mersana Therapeutics.

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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Best ADC Platform Technology Awarded to Mersana Therapeutics

This week, during the 7th World ADC Conference in San Diengo, Mersana Therapeutics, a biotechnology company focused on discovering and developing a pipeline of antibody-drug conjugates or ADCs based on its proprietary Dolaflexin® technology, received “Best ADC Platform Technology” award for its Dolaflexin platform.

Now in their third year, the World ADC Awards are designed to showcase excellence within antibody drug conjugate research. The awards reward the innovation, leadership, and devotion shown by the best companies, teams, and individuals in the industry. Across eight categories the the organizers of the event recognize the extraordinary endeavours, teamwork and commercial acumen that has propelled the field to the forefront of cancer research today.

Mersana was also selected as a runner-up in the “New Drug Developer” category.


“Receiving this award underscores the scientific innovation of Mersana’s Discovery team and potential of …[the] Dolaflexin platform…”


The 7th World ADC’s “Best ADC Platform Technology” award acknowledges the best linker or payload platform technology and is selected for the system’s novelty and originality as well as scientific and commercial validation of the platform.  In addition, the “New Drug Developer” class, recognizes an emerging company involved in the (early) development of antibody-drug conjugates that it has made significant progress within its preclinical pipeline with at least one pipeline drug.

Dolaflexin Platform
Dolaflexin, Mersana’s lead platform technology, is based on the company’s Fleximer polymer backbone and a proprietary aurastatin payload. Fleximer allows for significantly higher DAR (Drug to Antibody Ratio) or payload per antibody (>15) than other ADC approaches resulting in higher efficacy. Furthermore, Fleximer-based immunoconjugate molecules have been shown to have superior efficacy, including with targets previously considered not amenable to antibody-drug conjugate approaches.

The proprietary auristatin payload is designed to be highly potent when released in the tumor cell but to subsequently be metabolized into less potent agent hence resulting in improved tolerability. In early and pre-clinical studies Dolaflexin based ADCs have been shown to be highly efficacious while maintaining a wider therapeutic index than traditional ADCs approaches.

“Receiving this award underscores the scientific innovation of Mersana’s Discovery team and potential of our Dolaflexin platform,” noted Anna Protopapas, President and Chief Executive Officer of Mersana.

“We are grateful to the Conference for this recognition and will continue to commit ourselves to developing novel cancer treatments to address ongoing patient needs,” she added.

Pipeline
Using the company’s Dolaflexin technology platform, Mersana has rapidly developed a burgeoning oncology pipeline that includes two compounds that are advancing towards clinical studies. XMT-1522, Mersana’s first pipeline product, defines a new class of HER2-targeted therapies.

The investigational drug is an anti-HER2 ADC that incorporates HT-19, a novel, human anti-HER2 antibody optimized for cytotoxic payload delivery.[1]  In addition HT-19 was selected to be non-competitive for HER2 binding with existing therapies – trastuzumab or pertuzumab, to allow the potential of combination therapies.

XMT-1522 is armed with about 15 auristatin molecules per antibody, making it highly potent in tumor models that express relatively low amounts of the HER2 protein. XMT-1522 has the potential to extend HER2-targeted therapy beyond the current HER2+ population into patients with lower levels of HER2 expression.

The second pipeline product, XMT-1536, is a highly potent anti-sodium-dependent phosphate transport protein 2B (anti-NaPi2b) immunoconjugate comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody. Earlier this year during the 2016 annual meeting of the American Association for Cancer Research (AACR), data were presented that demonstrated significant anti-cancer activity in non-small cell lung cancer (NSCLC) and ovarian cancer tumor models.[2]

investigational compound known as XMT-1536 may help patients with NaPi2b-expressing tumors. Preclinical data with this immunoconjugate product demonstrated significant anticancer activity in NSCLC and ovarian cancer tumor models. Based on the data presented during the annual meeting of the AACR , Mersana advanced XMT-1536 into IND-enabling studies for the treatment of patients with NaPi2b-expressing tumors.


Last Editorial Review: October 13, 2016

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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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Mersana and Takeda Expand Partnership to Advance Development of Fleximer® based Antibody-Drug Conjugates

Mersana Therapeutics and Takeda Pharmaceutical Company Limited announced that they have entered a new, expanded, strategic partnership.  Under the terms of the agreement,  Takeda obtains the rights to Mersana’s lead product candidate, XMT-1522, outside the United States and Canada. XMT-1522 has the potential to address significant unmet needs and improve patient outcomes in multiple oncology indications.

The new agreement between the companies, signed in January, also expands an existing collaboration to provide Takeda with additional access to Mersana’s Fleximer® antibody-drug conjugate or ADC platform technology and grants Mersana an option, at the end of Phase I, to co-develop and co-commercialize one of these programs in the United States. In addition, the companies will co-develop new payloads for use with ADCs.

HER2-expressing tumors
XMT-1522 is a novel, investigational, Fleximer-based antibody-drug conjugate targeting HER2-expressing tumors, including breast, gastric and non-small cell lung cancers. The Fleximer immunoconjugate technology carries approximately 15 proprietary auristatin payload molecules. Preclinical data suggest that XMT-1522 may have anti-tumor activity in patients with HER2 low-expressing cancers as well as in patients with HER2 high-expressing cancers that do not respond to currently available HER2-targeting therapies. Mersana anticipates filing an Investigational New Drug application or IND for XMT-1522 with the U.S. Food and Drug Administration (FDA) in mid-2016.

“We believe XMT-1522 has the potential to make a dramatic difference for HER2 low-expressing patients who currently have limited treatment options, and are confident that our Fleximer-based technology can address significant patient needs not currently met by other ADC platform technologies,” said Anna Protopapas, President and Chief Executive Officer, Mersana. “Takeda’s knowledge of oncology and commitment to ADCs as a key therapeutic approach make the company the best partner for us to progress our transformative platform and advance XMT-1522 into the clinic.”

During a poster session at the 2015 San Antonio Breast Cancer Symposium (SABCS), being held December 8-12, 2015 in San Antonio, Texas, scientists confirmed positive preclinical data for XMT-1522. According to Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer of Mersana, the drug candidate demonstrated significant anti-cancer activity in both HER2-positive and HER2 low-expressing tumor models refractory to currently available therapies.“These results demonstrate XMT-1522’s potential to expand the population of breast cancer patients for whom HER2-targeted therapy is appropriate, from the 20% currently diagnosed with HER2-positive breast cancer to the full range of patients with HER2 expression,” Bergstrom added.[1]

Development and commercialization
Takeda and Mersana will co-develop XMT-1522, and Mersana will lead execution of the Phase I trial. The company will also retain full commercial rights in the United States and Canada while Takeda will have rights in rest of world. Beyond development and commercialization of XMT-1522, the expanded partnership also grants Takeda access to additional targets within Mersana’s Fleximer-based ADC platform, with Mersana retaining the right to select one program at the end of Phase 1 for co-development and co-commercialization in the United States. Takeda and Mersana will also work together, leveraging Takeda’s proprietary small molecule libraries, to identify and develop novel payloads that both parties will be able to use in new ADC therapies.

“This is our third collaboration with Mersana in less than two years. We see great potential for Mersana’s Fleximer technology, combined with our oncology expertise and resources, to extend the benefits of targeted therapy with ADCs to underserved cancer patient populations,” noted Andrew Plump M.D., Ph.D., Chief Medical and Scientific Officer, Takeda. “We, along with the global oncology community, have made great strides in our fight against cancer, and we know that achieving our aspiration to cure cancer relies on great partnerships and innovation. We look forward to progressing these collaborations and, together, advancing the science of cancer care.”

Upfront payment
Takeda signed agreements with Mersana through its wholly owned subsidiary, Millennium Pharmaceuticals, under which, Mersana will receive an upfront payment of US$40 million and an additional payment of $20 million upon clearance of the IND for XMT-1522 by the FDA. Subject to the success of the XMT-1522 and ADC programs, Mersana is eligible to receive milestone payments of more than $750 million combined, as well as royalties. Takeda will also invest up to $20 million in equity in future rounds of Mersana financing.

Other collaborations
To advancing the company’s own pipeline, Mersana is accelerating the development of novel, Felximer-based, antibody-drug conjugate therapies through strategic collaborations with leading pharmaceutical and biotech companies.  In addition to the latest, expanded, agreement with Takeda, Mersana collaborates with Merck KGaA, and Asana BioSciences.


Last Editorial Review: February 3, 2016

Featured Image: Microscope/Medical Research. Courtesy: © Fotalia. 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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Mersana and Recepta Sign Agreement for Novel Antibody

Cambridge based Mersana Therapeutics and Recepta Biopharma, a clinical stage Brazilian biotechnology company, have entered into an exclusive license agreement in which Mersana will use its Fleximer® technology, a proprietary, biodegradable, hydrophilic polymer, to develop and commercialize an immunoconjugate with the undisclosed cancer antibody licensed from Recepta.

Researchers have shown that Fleximer-based immunoconjugate molecules offer superior efficacy, including with targets previously considered not amenable to antibody-drug conjugate approaches.

Unique approach
Mersana’s approach can dramatically improve drug solubility and pharmacokinetics, reduce immunogenicity and optimize drug load.

Furthermore, the Fleximer polymer, which serves as the backbone for the company’s drug conjugates, is uniquely biodegradable, well tolerated with a favorable safety profile and has been clinically validated. 

One of the unique features is that the size of the backbone can, based on the type and quantity of therapeutic payloads, as well as the nature of the targeting protein being attached, be customized to the required circumstances. 

Another feature is that Mersana’s scientists can determine which and how many linkers to use to attach the payload to the Fleximer backbone.  Using a diverse array of linker chemistries allows them to arm drug conjugates with significantly higher loads of anti-cancer agents than conventional antibody-drug conjugate technologies, as well as to potentially arm a single immunoconjugate with a combination of payloads. These custom-designed linkers allow scientists to control the rate, mechanism and localization of drug release, potentially increasing efficacy and minimizing off-target side effects.

Linker technology
Using a chemically distinct linker from those used to attach the therapeutic payload, scientists at Mersana can attach an antibody, or alternative targeting moiety such as an antibody fragment, to the backbone. What makes the Fleximer backbone unique, is the ability to attach a variety of targeting agents, allowing scientists  to choose the one that will most effectively reach, bind to and penetrate the tumor cell, while sparing healthy cells. By using separate linker chemistries to attach the targeting agent and drug payload, scientists are further able to choose the best linkers for each required task.

Overcoming limitations
The Fleximer platform developed by Mersana represents a next generation approach in the development of antibody-drug conjugates, allowing their scientists to overcome many of the limitations of current ADC-technologies.  Based on the unique technology as well as the linker chemistries, scientists at the company can custom design an antibody-drug conjugate with a significant higher drug-to antibody ratios (DAR; 20+ versus 3-4 with traditional technologies), with a unique combination of properties, resulting in higher efficacy in head-to-head studies aimed specifically at attacking a particular type of cancer. 

Agreement
Under the terms of the agreement, Recepta will provide Mersana exclusive rights to its novel monoclonal antibody to an undisclosed target, and Mersana, in turn, will leverage Fleximer to develop an immunoconjugate against the target. Financial terms of the agreement include an upfront payment and subsequent payments to Recepta, which together could total $86 million plus royalties if certain development, regulatory and commercial milestones are achieved. Mersana will conduct and fund clinical development and regulatory activities. Recepta will have rights to commercialize in Brazil, while Mersana will have rights to commercialize in the rest of the world. Mersana will be eligible to receive royalties from Recepta on sales in Brazil.

Pioneering R&D
“This licensing deal with Mersana follows pioneering R&D conducted by Recepta with this specific antibody, which was discovered by Ludwig Cancer Research, our partner and a global nonprofit research organization. It will enable the development of a novel immunoconjugate that has the potential to improve patient outcomes in oncology,” noted José Fernando Perez, PhD, Chief Executive Officer of Recepta.

“We are excited to develop a Fleximer-based immunoconjugate with this antibody to address unmet needs in cancer,” explained Anna Protopapas, President and Chief Executive Officer of Mersana. “This will expand our pipeline of oncology therapies that address the limitations of currently available antibody-drug conjugates and complement our objective to pursue one IND each year, starting with XMT-1522, our first product candidate with the potential to address significant unmet needs and improve patient outcomes in multiple oncology indications, later this year.”

XMT-1522 is an anti-HER2 antibody-drug conjugate using a novel, human anti-HER2 antibody optimized for cytotoxic payload delivery. Each antibody is conjugated to ~15 proprietary auristatin molecules using Mersana’s Fleximer technology.[1]


Last editorial review: July 14, 2015

Feature Image: Test tubes closeup – medical glassware. Photo courtesey: ©Fotolia 2015.

Copyright © 2015 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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XMT-1522 Demonstrates Potent Activity in Low HER2-Expressing Tumor Models

Preclinical data for XMT-1522, a novel HER2-targeting therapy based on Mersana Therapeutics’ Dolaflexin platform, the company’s most advanced Fleximer® proprietary immunoconjugate technology, demonstrates significant anti-cancer activity in low HER2-expressing tumor models refractory to currently available therapies, as well as HER2-amplified tumor models in combination with trastuzumab-based therapies.

These data were presented in a late-breaking poster during the annual meeting of the American Association for Cancer Research (AACR) which was held April 18 – 22, 2015 in Philadelphia, PA.

XMT-1522 is a novel HER2-targeting therapy that carries an average of 15 proprietary auristatin payload molecules. The conjugate, optimized for payload delivery, utilizes a novel HER2-targeted antibody, which binds to a different epitope than existing anti-HER2 antibodies.

Fleximer technology
The investigational drug has the potential to address significant unmet needs and improve patient outcomes in multiple oncology indications. Fleximer-based immunoconjugate molecules, including XMT-1522, have shown to have superior efficacy, including with specific targets previously considered not to be amenable to antibody-drug conjugate approaches.

The Mersana’s Fleximer polymer, which serves as the backbone for the drug conjugates being developed by the company, dramatically improves drug solubility and pharmacokinetics as well as reduce immunogenicity and optimize drug load.

Linker chemistry
Researchers at Mersana also use a diverse array of linker chemistries to arm their drug conjugates with significantly higher loads of anti-cancer agents than conventional ADC technologies can do, as well as to potentially arm a single immunoconjugate with a combination of payloads. The custom-designed linkers allow researchers to control the rate, mechanism and localization of drug release, which can, potentially, increasing the efficacy and minimizing off-target adverse events and side effects.

Using a chemically distinct linker from the linkers used to attach the therapeutic payload, researchers can then attach an antibody, or alternative targeting moiety such as an antibody fragment, to the Fleximer backbone.  This approach makes it possible to attach a variety of targeting therapeutic agents to the Fleximer backbone which allows researchers to choose a specific agent that will most effectively reach, bind to and penetrate the targeted tumor cell.  By using separate linker chemistries to attach the targeting agent and drug payload, Mersana’s researchers can choose the best linkers for each of the task.

More patients benefitting from HER2-targeted therapies
“Current HER2-targeted therapies are effective in treating HER2-positive cancers, but only address roughly 20% of patients with breast or gastric cancer,” explained Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer of Mersana. “Our preclinical data suggest that XMT-1522 has the potential to greatly expand the number of patients who may benefit from HER2-targeted therapies, because the compound provides efficient drug delivery in cancers where there are as few as 10,000 HER2 receptors, where other therapies are inactive,” he continued.

Combination therapies
One of the unique characteristics of XMT-1522 is that it is highly potent in tumor models that express relatively low amounts of the HER2. In a model representing HER2 1+ gastric cancer, XMT-1522 achieved complete, durable tumor regressions where ado-trastuzumab emtansine (T-DM1; Kadcyla ®/Genentech/Roche), an antibody drug conjugate approved to treat HER2-positive metastatic breast cancer, is inactive at a 15-fold higher dose. XMT-1522 has the potential to extend HER2-targeted therapy beyond the current “HER2-positive” population into patients with lower levels of HER2 expression.  More specific, a single doses of 1 mg/kg or 0.67 mg/kg of XMT-1522 showed complete regression in low HER2-expressing breast and gastric cancer models, where ado-trastuzumab emtansine was inactive at doses of 10 mg/kg and above.

In HER2-driven tumor models, XMT-1522 showed synergistic efficacy in combination with widely used anti-HER2 therapies trastuzumab and pertuzumab. XMT-1522 demonstrated an excellent pharmacokinetic profile and was well tolerated in non-human primates at therapeutic doses.

Significant advantage
“XMT-1522, our lead clinical immunoconjugate candidate, exemplifies the significant advantages of Mersana’s Fleximer platform. It’s the first in a portfolio of targeted therapies we are working on to address unmet needs in cancer,” Anna Protopapas, President and Chief Executive Officer of Mersana, noted.

The company confirmed that an investigational new drug (IND) application is to be anticipated in the fourth quarter of 2015.


Last editorial review: May 29, 2015

Photo: The 2015 AACR/American Association for Cancer Research Annual Meeting – Julie K. Schwarz speaks during the AMC: Career Conversations – In Transition: From Student to Leader at the American Association for Cancer Research Annual Meeting on, Monday April 20, 2015. More than 18,000 physicians, researchers, health care professionals, cancer survivors and patient advocates are expected to attend the meeting at the Pennsylvania Convention Center. The Annual Meeting highlights the latest findings in all major areas of cancer research from basic through clinical and epidemiological studies. Photo courtesy: AACR/Todd Buchanan.

Copyright © 2015 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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