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Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?

Curator & Reporter: Stephen J. Williams, Ph.D.

Take aways:

  • RNA based vaccines are a cost-effective method of developing and manufacturing a personalized cancer vaccine strategy; traditional vaccine methodology has not been met with much success as a cancer therapeutic
  • Most of the older RNA vaccine technology depended on isolated dendritic cells or T cell populations and ex-vivo treatment with RNA vaccine, HOWEVER, Moderna has developed a technology that circumvents the need for ex-vivo vaccination
  • There are multiple companies involved in this new RNA strategy (Moderna, Caperna {now Moderna}, CureVac, Biontech)

From BusinessWire at http://www.businesswire.com/news/home/20160629005446/en/Merck-Moderna-Announce-Strategic-Collaboration-Advance-mRNA-Based

Merck and Moderna Announce Strategic Collaboration to Advance Novel mRNA-Based Personalized Cancer Vaccines with KEYTRUDA®(pembrolizumab) for the Treatment of Multiple Types of Cancer

Collaboration Combines Merck’s Leadership in Immuno-Oncology with Moderna’s Pioneering mRNA Vaccine Technology and Rapid Cycle Time, Small-Batch GMP Manufacturing Capabilities

KENILWORTH, N.J. & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, and Moderna Therapeutics today announced a strategic collaboration and license agreement to develop and commercialize novel messenger RNA (mRNA)-based personalized cancer vaccines. The collaboration will combine Merck’s established leadership in immuno-oncology with Moderna’s pioneering mRNA vaccine technology and GMP manufacturing capabilities to advance individually tailored cancer vaccines for patients across a spectrum of cancers.

“Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients”

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Moderna and Merck will develop personalized cancer vaccines that utilize Moderna’s mRNA vaccine technology to encode a patient’s specific neoantigens, unique mutations present in that specific patient’s tumor. When injected into a patient, the vaccine will be designed to elicit a specific immune response that will recognize and destroy cancer cells. The companies believe that the mRNA-based personalized cancer vaccines’ ability to specifically activate an individual patient’s immune system has the potential to be synergistic with checkpoint inhibitor therapies, including Merck’s anti-PD-1 therapy, KEYTRUDA® (pembrolizumab). In addition, Moderna has developed a rapid cycle time, small-batch manufacturing technique that will uniquely allow the company to supply vaccines tailored to individual patients within weeks.

Under the terms of the agreement, Merck will make an upfront cash payment to Moderna of $200 million, which Moderna will use to lead all research and development efforts through proof of concept. The development program will entail multiple studies in several types of cancer and include the evaluation of mRNA-based personalized cancer vaccines in combination with Merck’s KEYTRUDA® (pembrolizumab). Moderna will also utilize the upfront payment to fund a portion of the build-out of a GMP manufacturing facility in suburban Boston for the purpose of personalized cancer vaccine manufacturing.

Following human proof of concept studies, Merck has the right to elect to make an additional undisclosed payment to Moderna. If exercised, the two companies will then equally share cost and profits under a worldwide collaboration for the development of personalized cancer vaccines. Moderna will have the right to elect to co-promote the personalized cancer vaccines in the U.S. The agreement entails exclusivity around combinations with KEYTRUDA. Moderna and Merck will each have the ability to combine mRNA-based personalized cancer vaccines with other (non-PD-1) agents.

Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients,” said Dr. Roger Perlmutter, President, Merck Research Laboratories. “While the area of personalized cancer vaccine research has faced challenges in the past, there have been many recent advances, and we believe that working with Moderna to combine an immuno-oncology approach, using KEYTRUDA, with mRNA-based personalized cancer vaccines may have the potential to transform the treatment of cancer.”

“Our team has made significant progress since beginning our work in personalized cancer vaccines just last year. Through this collaboration with Merck, we are now well-positioned to accelerate research and development with a goal of entering the clinic in 2017, as well as to apply our unique GMP manufacturing capabilities to support the rapid production of these highly individualized vaccines,” said Stéphane Bancel, chief executive officer of Moderna. “We value our continued collaboration with Merck, and we look forward to working together to harness the potential of personalized cancer vaccines and immuno-oncology to bring a new treatment paradigm to patients.”

Merck and Moderna have an existing collaboration and license agreement focused on the discovery and development of mRNA-based infectious disease vaccines and passive immunity treatments. Moderna is also advancing its own pipeline of infectious disease vaccine candidates and currently has two phase 1 studies underway in Europe and the U.S.

About Moderna Therapeutics

Moderna is a clinical stage pioneer of messenger RNA Therapeutics™, an entirely new in vivo drug technology that produces human proteins, antibodies and entirely novel protein constructs inside patient cells, which are in turn secreted or active intracellularly. This breakthrough platform addresses currently undruggable targets and offers a potentially superior alternative to existing drug modalities for a wide range of diseases and conditions. Moderna is developing and plans to commercialize its innovative mRNA drugs through its own ventures and its strategic relationships with established pharmaceutical and biotech companies. Its current ventures are:

  • Onkaido, focused on oncology,
  • Valera, focused on infectious diseases,
  • Elpidera, focused on rare diseases, and
  • Caperna, focused on personalized cancer vaccines.

Cambridge-based Moderna is privately held and currently has strategic agreements with AstraZeneca, Alexion Pharmaceuticals and Merck. To learn more, visit www.modernatx.com.

From the Moderna Therapeutics Website

Our mRNA Platform

At Moderna, we are pioneering the development of a new class of drugs made of messenger RNA (mRNA). This novel drug platform builds on the discovery that modified mRNA can direct the body’s cellular machinery to produce nearly any protein of interest, from native proteins to antibodies and other entirely novel protein constructs that can have therapeutic activity inside and outside of cells.

Our efforts are helping Moderna and the industry to flatten the mRNA learning curve across the full breadth of competencies needed to drive the platform forward, including chemistry, mRNA biology, formulation, process development, automation and high-throughput production, quality, and Good Manufacturing Practice (GMP) manufacturing.

Drug Modalities

Building from our mRNA core expression platform, we have created a new scale of drug discovery and development that enables a series of new drug modalities. Each modality represents a distinct approach to using the mRNA platform to encode proteins that achieve a therapeutic benefit, enabling us to develop numerous drug candidates across a wide array of therapeutic areas.

Vaccines

Vaccines are substances that teach the immune system to rapidly recognize and destroy invading pathogens such as bacteria or viruses, preparing the body’s adaptive immunity for future exposure to the pathogen. Historically, vaccines have introduced immune-activating markers from pathogens into the body. Conversely, Moderna is developing mRNA-based vaccines that enable the body to produce and present immunogenic proteins to the immune system.

Moderna is also developing mRNA-based personalized cancer vaccines to prime the immune system to recognize cancer cells and mount a strong, tailored response to each individual patient’s cancer. Moderna’s technology allows for a rapid turn-around time in production of these unique mRNA vaccines.

Intracellular/Transmembrane

Many diseases are caused by defects in proteins that function inside cells. Existing methods of protein-based therapy do not allow for proteins to reach the intracellular space, and as such are unable to replace the defective, disease-causing proteins within cells. Moderna’s platform allows for the development of mRNA therapies that can stimulate production of intracellular proteins as well as transmembrane proteins. This could potentially lead to a novel approach to treating a vast array of rare genetic and other diseases caused by intracellular protein defects.

Intratumoral

Many targets for the treatment of cancer have been identified but their therapeutic potential has been limited by either the inability to access these targets, or by systemic toxicities. Moderna’s platform allows for localized expression of therapeutic proteins within the tumor microenvironment.

Secreted antibodies

Antibodies are secreted proteins that bind to and inhibit specific targets. Moderna’s platform has the potential to stimulate the body’s own cells to produce specific antibodies that can bind to cellular targets.

Secreted proteins

Proteins are large, complex molecules that have many critical functions both inside and outside of cells. Moderna’s platform stimulates cells to produce and secrete proteins that can have a therapeutic benefit through systemic exposure.

Moderna is comprised of four smaller companies, the following three are involved in their personalized immunotherapy and cancer vaccine strategy

Caperna LLC

Caperna

Caperna LLC is the fourth Moderna venture company — formed, funded and wholly-owned by Moderna — and focused exclusively on the advancement of personalized cancer vaccines.

Caperna will apply Moderna’s mRNA vaccine technology to the field of cancer vaccines, building on advances in recent years in cancer immunotherapy. Utilizing Moderna’s demonstrated engineering and process capability to synthesize over 1,000 unique novel mRNA’s per month in Moderna’s, automated, in-house productions systems. This provides the basis for a vision of rapid turnaround times that will allow Caperna’s personalized cancer vaccine, customized after tumor biopsy and sequencing to code for specific neoantigens in patients’ tumors, to be used to treat patients with aggressive tumors and high unmet need (rather than those with less aggressive tumors which can’t wait for prolonged turnaround times). Caperna will develop its personalized cancer vaccines in combination with checkpoint inhibitors that unleash the immune system and other cancer immunotherapies.

Corporate Facts

  • President: Tal Zaks, M.D., Ph.D.
  • Head of Research: Nicholas Valiante, Ph.D.
  • Head of Operations: Ted Ashburn, M.D., Ph.D.
  • Headquarters: 500 Technology Square, Cambridge, Mass.
  • Phone: 617-714-6500
  • Website: Caperna.com

 

Onkaido

Onkaido

Onkaido Therapeutics is the first Moderna venture company – formed, funded and wholly-owned by Moderna. Onkaido is focused exclusively on developing mRNA-based oncology treatments for currently undruggable targets or as a superior alternative to existing drug modalities. Onkaido is leveraging all of the tools and modalities developed at Moderna, with plans to rapidly turn mRNA science into truly novel cancer therapies that can make a real difference for patients.

Onkaido is currently focused on three therapeutic areas of oncology drug discovery and development: immuno-oncology, hepatocellular carcinoma (liver cancer) and myeloid malignancies – with programs investigating multiple targets and therapies simultaneously. Onkaido scientists are also exploring the power of mRNA technology in precision cancer pharmacology – researching areas such as tumor biology, targeting and gene silencing, driving the science toward the delivery of truly personalized cancer treatment.

Corporate Facts

  • President: Stephen Kelsey, M.D.
  • Headquarters: 500 Technology Square, Cambridge, Mass.
  • Phone: 617-714-6500
  • Website: Onkaido.com

 

Valera

Valera

Valera LLC is the second Moderna venture company — formed, funded and wholly-owned by Moderna — and focused exclusively on the advancement of vaccines and therapeutics for the prevention and treatment of viral, bacterial and parasitic infectious diseases.

The vaccines work of Valera builds on a body of preclinical research at Moderna showing the ability of modified mRNA to express viral antigens in vivo and to induce robust immune responses. Valera’s therapeutic passive immunity programs will expand on Moderna’s research using mRNA to express antibodies that bind to viral and other targets. The robust data from these programs across a range of preclinical infectious disease models, together with the inherent, rapid turn-around time in creating novel mRNA constructs, provide Valera with a potentially powerful and versatile new platform for the creation of a broad array of vaccines and passive immunity therapies.

Corporate Facts

  • President: Michael Watson, MB ChB, MRCP, AFPM
  • Chief Scientific OfficerGiuseppe Ciaramella, Ph.D.
  • Interim Chief Medical OfficerTal Zaks, M.D., Ph.D.
  • Headquarters: 500 Technology Square, Cambridge, Mass.
  • Phone: 617-714-6500
  • Website: Valeratx.com

And from http://endpts.com/neoantigens-beckon-merck-into-a-200m-cancer-collaboration-with-moderna/

Neoantigens beckon Merck into a $200M cancer collaboration with Moderna


Now that Galena has added fresh evidence that first-gen cancer vaccines make for a poor R&D program, Merck is betting $200 million upfront that the next-gen neoantigen approach to personalized cancer vaccines can succeed where all else has failed.

Merck is tying up with the mRNA specialists at Cambridge, MA-based Moderna, which has inked a long lineup of marquee partnerships. The big idea here is that each person’s cancer cells present unique “neoantigens” that can be used to tailor a cancer vaccine for each patient.

That’s a radical idea that has gained considerable steam in recent months, with Gritstone and Neon Therapeutics — paired now with Bristol-Myers on Opdivo — rounding up significant venture cash. Biotech billionaire Patrick Soon-Shiong has also jumped into the game, including it in its growing slate of cancer R&D work in a group of startups.

Moderna says it has already set up a manufacturing system that can be used to create these personalized vaccines in a matter of weeks. And Merck will use the partnership to advance new combination therapies that include its checkpoint inhibitor Keytruda.

The way the deal works, Moderna notes in its statement, is that Merck can step up after it sees some evidence in humans that the tech is working as planned. After human proof-of-concept, if Merck wants to opt in they can pay a significant milestone and then both companies can share the cost on Phase III and commercializations, profiting equally.Moderna CEO Stéphane Bancel says they can jump into the clinic next year.

The deal marks another rare pact by Merck R&D chief Roger Perlmutter, who’s been carefully focused on making Keytruda a foundation franchise that can sustain the company for years to come. While Merck has been a couple of steps behind Bristol-Myers in gaining market share, Perlmutter’s not settling for a second place finish.

“Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients,” said Perlmutter, president, Merck Research Laboratories. “While the area of personalized cancer vaccine research has faced challenges in the past, there have been many recent advances, and we believe that working with Moderna to combine an immuno-oncology approach, using KEYTRUDA, with mRNA-based personalized cancer vaccines may have the potential to transform the treatment of cancer.”

From FierceBiotech on failure of Galena’s breast cancer vaccine trial

Galena plummets into microcap territory on Phase III breast cancer vaccine trial halt

Immunother Cancer. 2015; 3: 26.
Published online 2015 Jun 16. doi:  10.1186/s40425-015-0068-y
PMCID: PMC4468959

Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study

Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
CureVac GmbH, Paul-Ehrlich-Str. 15, Tuebingen, 72076 Germany
Charité University Hospital Berlin, Berlin, Germany
University Hospital Freiburg, Freiburg, Germany
Universitäty Hospital Essen, Essen, Germany
San Raffaele Scientific Institute, Milan, Italy
University Hospital of the Johannes-Gutenberg-University Mainz, Mainz, Germany
Ortenau Klinikum Offenburg-Gengenbach, Offenburg, Germany
University Hospital Göttingen, Göttingen/University Hospital Mannheim, Mannheim, Germany
University Hospital Schleswig-Holstein Campus Luebeck, Luebeck, Germany
Rippin-Consulting, Solingen, Germany
University Hospital Tuebingen, Tuebingen, Germany
Hubert Kübler, ed.nehcneum-ut.zrl@relbeuK.H.
corresponding authorCorresponding author.
#Contributed equally.

Abstract

Background

CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer.

Methods

44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3–6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17.

Results

The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a].

Conclusions

The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic.

The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach.

SOURCE

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468959/

Other articles in the Open Access Journal on Cancer Vaccines Include:

Cancer Vaccines: Targeting Cancer Genes for Immunotherapy – A Conference by Keystone Symposia on Molecular and Cellular Biology

AACR2016 – Cancer immunotherapy

Aduro Biotech Phase II Pancreatic Cancer Trial CRS-207 plus cancer vaccine GVAX Fails

Cases in Biotech Entrepreneurship: Selective Start Ups in 2016

at #JPM16 – Moderna Therapeutics turns away an extra $200 million: with AstraZeneca (collaboration) & with Merck ($100 million investment)

 

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