On November 15, 2017 EUSA Pharma and AVEO Oncology (NASDAQ:AVEO) reported the first commercial launch of FOTIVDA (tivozanib) with the initiation of product sales in Germany (Press release, AVEO, NOV 15, 2017, View Source;p=RssLanding&cat=news&id=2317048 [SID1234522076]). In the European Union, Norway and Iceland, tivozanib is indicated for the first line treatment of adult patients with advanced renal cell carcinoma (aRCC) and for adult patients who are vascular endothelial growth factor receptor (VEGFR) and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for aRCC.i Tivozanib is an oral, once-daily, potent and highly-selective vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI). EUSA Pharma is the licensee for tivozanib in Europe, North and South Africa, Latin America and Australasia.

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Lee Morley, EUSA Pharma’s Chief Executive Officer said, "We are delighted that we have been able to grant access to FOTIVDA for patients in one of Europe’s key markets so soon after our regulatory approval. We look forward to working with physicians in Germany to ensure the profile and benefits of FOTIVDA are known and understood. We will of course continue to work with health authorities across all European markets to ensure early access to FOTIVDA as a therapeutic option in the ongoing fight against aRCC."

"The first-ever commercial launch of FOTIVDA is a tremendous accomplishment for AVEO, our partner EUSA Pharma, and, most importantly, patients with aRCC who now have access to a new and differentiated therapeutic option," said Michael Bailey, president and chief executive officer of AVEO. "Over the course of its development, FOTIVDA’s efficacy and tolerability profile among VEGF TKIs has been recognized by investigators as an important potential option for their patients, making this long-anticipated milestone a gratifying achievement. We continue to leverage this profile as we work towards exploring the full extent of FOTIVDA’s use in the emerging aRCC market. We also look forward to continuing to expand its availability in Europe, through our partner, EUSA, and potentially in North America, where we plan to file for FDA approval pending the results of our pivotal study, TIVO-3."

FOTIVDA was approved by the European Commission in August 2017. Approval was primarily based on data from a global, open-label, randomized, multi-center Phase 3 trial (TIVO-1)i,ii which evaluated the efficacy and tolerability of tivozanib compared to a currently available comparator VEGFR-TKI treatment (sorafenib) in 517 patients with advanced RCC. Patients treated with tivozanib experienced superior PFS (11.9 vs. 9.1 months in the overall population [HR, 0.797; 95% CI, 0.639 to 0.993; P =.042] and 12.7 vs. 9.1 months in treatment naïve patients [HR, 0.756; 95% CI, 0.580 to 0.985; P =.037]) versus sorafenib.ii There was also an improved side effect profile with tivozanib, with only 14% (versus 43% with sorafenib) requiring a dose reduction due to adverse events (AEs). In addition, fewer people on tivozanib experienced burdensome side effects, such as diarrhea (23% vs 33%) and hand-foot syndrome (14% vs 54%).ii

About RCC in Europe

RCC is the most common form of kidney cancer,iii which accounts for an estimated 49,000 deaths in Europe each year.iv It is expected to be one of the fastest increasing cancers over the next ten years.v Tyrosine Kinase Inhibitor (TKI) vascular endothelial growth factor (VEGF) inhibitors are the standard of care treatment for advanced RCC in Europe, however, patients on current treatments can often experience significant side effects.ii,vi

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma in the European Union plus Norway and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.i,ii Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.

Istari Oncology’s second technology platform consists of a series of ADCs for a variety of oncology targets (Company Web Page, Istari Oncology, NOV 15, 2017, View Source [SID1234522093]). These select, highly specific, monoclonal antibodies are presently conjugated with PE-38 toxin to maximize the killing effect.
We believe our platform overcomes some of the challenges associated with other ADCs because it is based on genetic linkage, which provides more stability than chemical linkers, making it is easier to manufacture. The FDA granted our ADC conjugate, D2C7-IT, Orphan Drug designation in 2016.
Beyond the various PE-38 toxins, our technology could be linked with other therapeutic agents for different targets. Toxins used in construction of immunotoxins are typically derived from bacteria, fungi, and plants. These agents and linkers potentially provide another platform for additional pipeline therapeutics. Possible tumor targets include solid, nonlymphoid tumors.

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On November 15, 2017 Arvinas LLC, a private biotechnology company creating a new class of drugs based on protein degradation, reported it has expanded its ongoing license agreement with Genentech, a member of the Roche Group, for the development of new therapeutics using Arvinas’ novel PROTAC technology (Press release, Arvinas, NOV 15, 2017, View Source [SID1234558785]). The multi-year strategic license agreement, initiated in October 2015, will encompass additional disease targets and expand the collaboration.

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Under the revised terms of the agreement, Arvinas is eligible to receive development and commercialization milestone payments in excess of $650 million based on achievement of certain predetermined milestones. In addition, Arvinas is eligible to receive tiered-royalties on sales of products resulting from the license agreement. Full financial terms have not been disclosed.

"Genentech’s decision to expand our original agreement to include additional disease targets shows the promise seen in our first two years together and further supports our targeted protein degradation platform as a novel drug modality to treat a broad array of diseases," said John Houston, Ph.D., President and Chief Executive Officer of Arvinas. "This expansion also supports our initial decision to work with Genentech in 2015 and we look forward to this growing collaboration."

The PROTAC Platform offers potential improvements over traditional small molecule inhibitors using the ubiquitin and proteasome system within a cell to degrade disease causing proteins. By removing target proteins directly rather than inhibiting them, PROTACs can provide multiple advantages over small molecule inhibitors, which can require high systemic exposure to achieve sufficient inhibition, often resulting in toxic side effects and eventual drug resistance.

On November 15, 2017 Moderna Therapeutics, a clinical stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, reported that it has started dosing patients in a Phase 1 study of mRNA-4157, an mRNA-based personalized cancer vaccine (Press release, Moderna Therapeutics, NOV 15, 2017, View Source [SID1234522100]). The Phase 1 open-label, dose escalation, multicenter study in the United States (KEYNOTE-603) will assess the safety, tolerability and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy, marketed by Merck (known as MSD outside the U.S. and Canada) in subjects with unresectable solid tumors.

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The first-in-human dosing of mRNA-4157 marks a key milestone in the strategic collaboration between Moderna and Merck to advance the novel mRNA-based personalized cancer vaccine in combination with KEYTRUDA for the treatment of multiple types of cancer.

"When we combine the potential for robust T-cell response stimulated by our mRNA vaccine, which encodes for 20 patient-specific mutations, with Merck’s checkpoint inhibitor, Keytruda, we have a unique opportunity to make a transformative difference for patients with cancer," said Tal Zaks, M.D., Ph.D., Chief Medical Officer at Moderna. "Having now successfully designed, manufactured and dosed a completely customized personalized cancer vaccine, we look forward to progressing the Phase 1 clinical study and gathering important human data on mRNA-4157 in the months ahead."

KEYNOTE-603 is expected to enroll up to 90 patients across multiple clinical study sites in the United States. Part A of the study will assess the safety, tolerability and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors (in the adjuvant setting). Part B of the study will evaluate mRNA-4157 in combination with KEYTRUDA in subjects with unresectable solid tumors. The ClinicalTrials.gov Identifier for the mRNA-4157 study is: NCT03313778. A link to the ClinicalTrials.gov listing for the study can be found here.

"Our goal in this important collaboration is to deliver personalized vaccines to patients suffering from malignant disease, with the hope that this stimulus will generate a tumor-specific immune response in the presence of Keytruda, our approved immune-stimulatory cancer therapy," said Roger M. Perlmutter, M.D., Ph.D., President, Merck Research Laboratories. "This trial leverages advances in genomics, advanced data analytics, and immunology to permit the generation of personalized cancer vaccines, a potentially transformative approach to cancer treatment. We are hopeful that this collaboration with Moderna, now entering clinical trials, will yield tangible benefits for cancer patients."

"Checkpoint inhibitors and other immuno-oncology therapies are continuing to revolutionize how we treat cancer. However, despite the strong and durable responses we see in some patients, many other patients’ disease continues to progress," said Howard A. "Skip" Burris III, MD, President, Clinical Operations & Chief Medical Officer at Sarah Cannon, and a Principal Investigator of the mRNA-4157 Phase 1 study. "An individualized medicine designed to help each patient’s immune system better recognize cancer as foreign and attack it would be a critical addition to oncologists’ treatment arsenal, potentially helping many more patients respond more effectively to treatment."

About mRNA-4157

Moderna is creating an individualized, mRNA-based personalized cancer vaccine to deliver one medicine for one patient at a time. Through next-generation sequencing, Moderna identifies mutations found on a patient’s cancer cells, called neoepitopes. Neoepitopes can help the immune system distinguish cancer cells from normal cells. Using algorithms developed by its in-house bioinformatics team, Moderna predicts 20 neoepitopes present on the patient’s cancer that should elicit the strongest immune response, based on unique characteristics of the patient’s immune system and particular mutations. Moderna then creates a vaccine that encodes for each of these mutations and loads them onto a single mRNA molecule.

Once injected into the patient, the vaccine should direct the patient’s cells to express the selected neoepitopes. In turn, this may help the patient’s immune system better recognize cancer cells as foreign and destroy them. Leveraging its rapid cycle time, small-batch manufacturing technique and digital infrastructure, Moderna plans to manufacture and supply each individually manufactured personalized cancer vaccine to patients within weeks.

mRNA-4157 also has the potential to enhance clinical outcomes associated with checkpoint inhibitor therapies. In 2016, Moderna and Merck formed a collaboration to develop mRNA-4157 in combination with Merck’s anti-PD-1 therapy, KEYTRUDA.

About the Moderna and Merck Collaboration to Advance mRNA-4157

Under the terms of the agreement announced in June 2016, Merck made an upfront cash payment to Moderna of $200 million, which Moderna is using 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-4157 in combination with KEYTRUDA. Moderna is also utilizing the upfront payment to fund a portion of the ongoing build-out of its GMP mRNA clinical manufacturing facility in Norwood, Mass., for the purposes 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 mRNA-4157. Moderna will have the right to elect to co-promote mRNA-4157 in the U.S. The agreement entails exclusivity around combinations with KEYTRUDA. Moderna and Merck will each have the ability to combine mRNA-4157 with other immuno-oncology (non-PD-1) agents.

On November 15, 2017 Invitae Corporation (NYSE: NVTA), one of the fastest growing genetic information companies, reported it has completed its acquisition of CombiMatrix, which specializes in providing genetic information for prenatal diagnosis, miscarriage analysis and diagnosis of pediatric developmental disorders, establishing Invitae as a new leader in family and reproductive genetic health services (Press release, CombiMatrix, NOV 15, 2017, View Source [SID1234522094]).

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Invitae’s (NVTA) mission is to bring comprehensive genetic information into mainstream medical practice to improve the quality of healthcare for billions of people. www.invitae.com (PRNewsFoto/Invitae Corporation)

"With the addition of CombiMatrix to Invitae, we have completed our entry into prenatal and perinatal genetics, currently the second-largest category of genetic testing services. Our integrated offering will build on the expertise and technologies developed by CombiMatrix to offer customers the most comprehensive offering from a single provider in the category," said Sean George, chief executive officer of Invitae. "Invitae’s platform now delivers comprehensive genetic information services that support the use of genetics in mainstream medical care throughout all stages of life."

CombiMatrix leverages cytogenomic and cytogenetic technologies such as single nucleotide polymorphism chromosomal microarray analysis and next generation sequencing, supported by long-standing expertise in technically challenging sample types, to provide in-depth answers for patients and clinicians addressing complex reproductive health questions.

"Access to actionable genetic information is essential for monitoring pregnancies, particularly for women going through IVF or facing recurrent miscarriages," said Robert Nussbaum, MD, chief medical officer of Invitae. "Our integrated platform and world-class expertise can provide genetic information that helps women and their clinicians with some of the most important decisions of their lives today, even as we continue to advance the understanding of the role genetics plays in having healthy pregnancies."

In connection with the closing, Invitae issued approximately $21.2 million in shares of its common stock to former CombiMatrix securityholders, or approximately 2.7 million shares. Together with the approximately 1.7 million shares of Invitae common stock underlying CombiMatrix Series F warrants assumed in the Merger, the transaction has a total enterprise value of approximately $34.9 million.

The acquisition of CombiMatrix complements Invitae’s recent acquisition of another reproductive genetics company, Good Start Genetics, to establish a category-leading menu with the breadth and depth needed to provide comprehensive support for women, their partners and clinicians to use genetic information when considering their reproductive health options, from carrier screening to preimplantation genetic screening and diagnosis to newborn diagnostics.

Transaction Details

At the closing of the Merger, Invitae issued shares of its common stock to (i) CombiMatrix’s common stockholders, at an exchange ratio of 0.8692 of a share of Invitae common stock (the "Merger Exchange Ratio") for each share of CombiMatrix common stock outstanding immediately prior to the Merger, (ii) CombiMatrix’s Series F preferred stockholders, at the Merger Exchange Ratio for each share of CombiMatrix common stock underlying Series F preferred stock outstanding immediately prior to the Merger, (iii) holders of outstanding and unexercised in-the-money CombiMatrix stock options, which were fully accelerated to the extent of any applicable vesting period and converted into the right to receive a number of shares of Invitae common stock adjusted for the Merger Exchange Ratio and reduced by the aggregate exercise price, and (iv) holders of outstanding and unsettled CombiMatrix restricted stock units ("RSUs"), which were fully accelerated to the extent of any applicable vesting period and converted into the right to receive a number of shares of Invitae common stock adjusted for the Merger Exchange Ratio. No fractional shares were issued in connection with the Merger and Invitae will pay cash in lieu of any such fractional shares. The Merger Exchange Ratio was determined through arm’s-length negotiations between Invitae and CombiMatrix.

In addition, at the closing of the Merger, (a) all outstanding and unexercised out-of-the money CombiMatrix stock options were cancelled and terminated without the right to receive any consideration, (b) all CombiMatrix Series D Warrants and Series F Warrants outstanding and unexercised immediately prior to the closing of the Merger were assumed by Invitae and converted into warrants to purchase the number of shares of Invitae common stock determined by multiplying the number of shares of CombiMatrix common stock subject to such warrants by the Merger Exchange Ratio, and with the exercise price adjusted by dividing the per share exercise price of the CombiMatrix common stock subject to such warrants by the Merger Exchange Ratio, and (c) certain entitlements under CombiMatrix’s executive compensation transaction bonus plan (the "Transaction Bonus Plan") were paid in shares of Invitae common stock or RSUs to be settled in shares of Invitae common stock. All outstanding and unexercised CombiMatrix Series A, Series B, Series C, Series E, and PIPE warrants were repurchased by CombiMatrix prior to closing pursuant to that certain CombiMatrix Common Stock Purchase Warrants Repurchase Agreement dated July 11, 2016.

Invitae’s previously announced offer to exchange each outstanding Series F warrant (the "CombiMatrix Series F warrants") to acquire one share of common stock of CombiMatrix for 0.3056 of a share of Invitae common stock (the "Exchange Offer") expired at 12:00 midnight (one minute after 11:59 p.m.), New York City time, on November 13, 2017. Because the minimum tender condition of 90% was not achieved in the Exchange Offer, Invitae did not accept any of the CombiMatrix Series F warrants that were tendered in the Exchange Offer prior to its expiration. Accordingly, any CombiMatrix Series F warrants that were tendered will be promptly returned to the holder by the exchange agent.

Invitae issued an aggregate of 2,726,324 shares of its common stock and 214,976 RSUs in connection with the Merger (including shares and RSUs issued pursuant to the Transaction Bonus Plan). Immediately after the Merger, (i) there were approximately 52.9 million shares of Invitae common outstanding, (ii) the former CombiMatrix securityholders and executives owned approximately 8.6% of the fully-diluted common stock of the combined company, and (iii) Invitae securityholders, whose shares of Invitae capital stock remain outstanding after the Merger, owned approximately 91.4% of the fully-diluted common stock of the combined company.

Upon completion of the Merger, CombiMatrix became a wholly owned subsidiary of Invitae. As a result, the CombiMatrix common stock and Series F warrants will cease trading on the Nasdaq Capital Market and will be delisted.

About Invitae’s Family and Reproductive Health Genetic Services

Invitae’s reproductive genetics products, which include CombiPGS, CombiPGD and CombiSNP from CombiMatrix and Good Start Genetics’ GeneVu, EmbryVu and VeriYou, provide affordable and accessible genetic information to help people have healthy families. Good Start Genetics became part of Invitae in August 2017.