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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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Preclinical Data Supports the Development of XMT-1536 in a Broad Population of Patients with Ovarian Cancer

Update data from preclinical studies with XMT-1536, an antibody-drug conjugates or ADC being developed by Mersana Therapeutics targeting NaPi2b, were presented in a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications, held  October 26 – 30, 2017 in the Pennsylvania Convention Center in Philadelphia, Pennsylvania.  was given by Rebecca Mosher, M.D., Executive Director, Translational Medicine, Mersana Therapeutics.[1]

The data confirms that XMT-1536 may offer positive results for patients with ovarian cancer, which ranks, according to the American Cancer Society, fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. A woman’s risk of getting ovarian cancer during her lifetime is about 1 in 75. Overall, a woman’s lifetime chance of dying from ovarian cancer is about 1 in 100.

The American Cancer Society estimates that in the United States in 2017 about 22,440 women will receive a new diagnosis of ovarian cancer. About 14,080 women will die from ovarian cancer.

This means that ovarian cancer represents a major unmet medical need.

Anti-sodium-dependent phosphate transport protein
XMT-1536 is a highly potent anti-sodium-dependent phosphate transport protein (NaPi2b; SLC34A2) immunoconjugate 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. NaPi2b is an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer. XMT-1536 is scheduled to begin Phase I clinical trials in early 2018.


…the data … support … NaPi2b [as an] outstanding target for ADC development … and the Dolaflexin ADC platform allows us to fully exploit the advantages of this … target…


Outstanding target
“The data presented at AACR-NCI-EORTC further support that NaPi2b is an outstanding target for ADC development and that the Dolaflexin ADC platform allows us to fully exploit the advantages of this interesting target,” said Donald Bergstrom, M.D., Ph.D, Chief Medical Officer, Mersana Therapeutics.

“These results in ovarian cancer models are consistent with data we’ve previously presented on the broad activity of XMT-1536 in preclinical models of non-squamous non-small cell lung cancer (NSCLC). We look forward to initiating Phase I testing of XMT-1536 in patients with ovarian cancer, non-squamous NSCLC and other NaPi2b-expressing tumors by early 2018,” he added.

The study revealed that XMT-1536 induced at least a 50% median reduction in tumor volume relative to baseline in 10/19 (53%) primary patient-derived ovarian cancer xenograft models, that were selected for testing without prior knowledge of NaPi2b expression status. The activity of XMT-1536 was comparable in models derived from tumors from treatment-naïve patients as well as models that came from patients with heavily pre-treated tumors.

Target expression
When NaPi2b target expression was evaluated using a proprietary immunohistochemistry (IHC) assay discovered at Mersana in conjunction with XMT-1536, there was an association between NaPi2b IHC H-score and tumor volume change after XMT-1536 treatment. Among tumors with an H-score ≥70, 10/12 (83%) of models achieved 50% or greater reduction in tumor volume after XMT-1536 treatment, vs. 0/7 (0%) models with an H-score ‹70. Applying the same IHC assay to primary human ovarian tumors, 12/20 (60%) tested tumors had an H-score ≥70, indicating the majority of human ovarian tumors express levels of NaPi2b associated with deep regressions in response to XMT-1536 in pre-clinical models.

“We are extremely pleased with the results of this research and the progress the program has made to date,” said Rebecca Mosher, M.D., Executive Director, Translational Medicine, Mersana Therapeutics.

“The data described in the presentation suggest that XMT-1536 could be broadly active in ovarian cancer, and that we may have a diagnostic tool that could further enrich the patient population to enhance clinical benefit,” she further noted.


Last Editorial Review: October 30, 2017

Featured Image: Laboratory glass. Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 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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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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Mersana’s XMT-1536 Demonstrates Anti-tumor Activity in Lung Cancer Patient-Derived Xenograft Studies

Encouraging data from preclinical studies presented at the 2016 IASLC 17th World Conference on Lung Cancer, in Vienna, Austria, suggests that Mersana Therapeutics‘ immunoconjugate XMT-1536 induces durable complete tumor regressions in patient-derived xenograft models of non-small cell lung cancer (NSCLC). Results demonstrating outstanding pharmacokinetics and tolerability in non-human primates was also presented.[1]


…Based on these data, we plan to move rapidly into studies in patients that will help us develop new therapeutic options to treat this devastating disease…


Non-small cell lung cancer is the most common type of lung cancer. About 85% of lung cancers are non-small cell lung cancers. Squamous cell carcinoma, adenocarcinoma, and large cell carcinoma are all subtypes of non-small cell lung cancer. Both small cell and non-small cell lung cancer combined are, according to American Cancer Society, the second most common cancers in both men and women. In men, prostate cancer is more common, while in women breast cancer is more common. About 14% of all new cancers are lung cancers. [2]

The American Cancer Society’s estimates that there will be about 224,390 new cases of lung cancer in the United States in 2016 (117,920 in men and 106,470 in women) and that about 158,080 deaths people will die of the disease (85,920 in men and 72,160 in women). [2]

Lung cancer mainly occurs in older people, on average 2 out of 3 people diagnosed with lung cancer are 65 or older while less than 2% are younger than 45. Statistically, each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. [2]

Early results
“We are encouraged by these early results that demonstrate XMT-1536’s potential in treating patients who have limited treatment options for their lung cancer,” noted Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer of Mersana.

“The data we presented at the conference suggest that XMT-1536 can induce complete and durable regressions in patient-derived lung cancer models. Based on these data, we plan to move rapidly into studies in patients that will help us develop new therapeutic options to treat this devastating disease.”

The study confirms that NaPi2b is expressed at high levels in a majority of non-squamous non-small cell lung cancers (NSCLC), suggesting it may be an attractive therapeutic target for antibody-drug development in this disease.

Highly potent immunoconjugate
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, via the Dolaflexin™ antibody-drug conjugate (ADC) platform. Dolaflexin is one of Mersana’s proprietary multivalent hydrophilic polymer (Fleximer®) immunoconjugate platforms.

Mersana’s technology platforms allows for significantly higher drug loads, providing greater efficacy while simultaneously increasing tolerability. The anti-tumor activity of XMT-1536 was evaluated in eight patient-derived xenograft models of NSCLC adenocarcinoma representing a spectrum of oncogenic driver mutations prevalent in NSCLC, including tumors without oncogenic drivers.

Trial design
The standard dose of XMT-1536 used across models was 3 mg/kg administered intravenously once weekly for 3 weeks (last dose on Day 14). Experiments ran until tumor growth past a pre-specified endpoint or Day 60. At the 3 mg/kg dose, XMT-1536 was active in 7/8 models: complete tumor regression in 4 models, partial tumor regression in 1 model, and significant tumor growth inhibition in 2 models. In 4 of the 5 models where XMT-1536 induced tumor regression, regressions were durable, with a majority of the animals maintaining partial or complete regression at Day 60.

Non-human primates
XMT-1536 was also evaluated for tolerability in a cynomolgus monkey study, in which there was no body weight loss, no clinical observations attributable to XMT-1536, and limited clinical pathology findings, including no evidence of neutropenia. Target organ toxicity was minimal to mild and generally reversible. Exposure to XMT-1536 indicated good conjugate stability, low exposure to free drug payload in plasma (<1 ng/mL), and supported the 3 mg/kg dose level in mouse studies as a potentially clinically-relevant dose.


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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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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

Featured Image: 7th World ADC, San Diego, CA Courtesy: © Sunvalley Communication, LLC. 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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XMT-1536 Demonstrates Anti-Cancer Activity in Patients with NaPi2b-expressing Tumors

Preclinical data for Mersana Therapeutics‘ new immunoconjugate product candidate, XMT-1536, demonstrated significant anti-cancer activity in non-small cell lung cancer (NSCLC) and ovarian cancer tumor models.

The data presented during a poster session at annual meeting of the American Association for Cancer Research (AACR) being held April 16 – 20 in New Orleans, LA, shows that XMT-1536 is a highly potent anti-sodium-dependent phosphate transport protein 2B (anti-NaPi2b) immunoconjugate or antibody-drug conjugate (ADC) comprised of an average of 15 monomethyl auristatin E (MMAE) molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via Mersana’s Dolaflexin™ ADC- platform. Dolaflexin is one of Mersana’s proprietary Fleximer® immunoconjugate platforms.

IND-enabling studies
We are encouraged by the durable regressions XMT-1536 achieved in non-small cell lung cancer and ovarian cancer tumor models, as well as the excellent tolerability and pharmacokinetics in non-human primate exploratory toxicology studies,” noted Donald A. Bergstrom, MD, PhD, Chief Medical Officer of Mersana.

“Based on these data, we are advancing XMT-1536 into IND-enabling studies for the treatment of patients with NaPi2b-expressing tumors,” Bergstrom continued.

NaPi2b expression
The study evaluated XMT-1536 in non-squamous NSCLC and non-mucinous ovarian cancer tumor models, indications in which NaPi2b is highly expressed. XMT-1536 demonstrated significant efficacy in all four patient-derived xenograft models representative of the target patient populations. In three patient-derived models of NSCLC, including KRAS-mutant NSCLC, XMT-1536 induced tumor regressions after three weekly doses of 3 mg/kg.

In an ovarian cancer xenograft model, XMT-1536 induced partial tumor regressions after a single dose of 3 mg/kg, and complete tumor regressions after a single dose of 5 mg/kg or three weekly doses of 3 mg/kg. XMT-1536 was well-tolerated with no evidence of bone marrow toxicity in non-human primates at up to seven times the dose associated with tumor regression in the mouse xenograft models.

“XMT-1536 further validates the ability of Mersana’s Fleximer platform to generate targeted therapies that have the potential to address unmet needs and improve outcomes for patients with cancer. While there have been recent advancements in the treatment of non-small cell lung cancer and ovarian cancer, there remains tremendous need to address the significant proportion of patients who do not derive full benefit from currently available treatments,” Anna Protopapas, President and Chief Executive Officer of Mersana, explained.

“We look forward to the continued development of this second product candidate in our growing pipeline of Fleximer-based immunoconjugate therapies, as we prepare to enter the clinic with XMT-1522 this year,” she continued.

XMT-1536 has the potential to address significant unmet needs and improve patient outcomes in multiple oncology indications. The Fleximer-based immunoconjugate molecules have been shown to have superior efficacy, including with targets previously considered not amenable to antibody-drug conjugate approaches.


Last Editorial Review: April 18, 2016

Featured Image: Inside the Ernest N. Morial Convention Center in New Orleans, LA.  Courtesy: © Sunvalley Communication/Evan Wendt. Used with permission. Logo: © AACR/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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