On April 3, 2018 H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of next-generation cancer medicines using its data science and precision chemistry product engine, reported the publication of a comprehensive genomic landscape analysis illuminating the breadth, frequency and potential disease-driving significance of somatic mutations in RNA splicing factor genes in human cancers (Press release, H3 Biomedicine, APR 3, 2018, View Source [SID1234525375]). The findings demonstrate that splicing factor mutations, which lead to RNA splicing dysregulation, are highly prevalent in many hematologic and solid tumor cancers, suggestive of their role as a hallmark of tumor formation and growth and, thus, opportunities for therapeutic intervention. RNA splicing is the biological process by which pre-cursor messenger RNA (pre-mRNA) is edited into a mature messenger RNA (mRNA). Splicing factors carry out the editing process which is catalyzed by the core spliceosome complex. H3 Biomedicine scientists’ research and findings were published in the most recent online version of Cell Reports. (Seiler M. et al, "Somatic mutational landscape of splicing factor genes and their functional consequences across 33 cancer types"). This manuscript is part of The Cancer Genome Atlas (TCGA) Program, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI).

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"In recent years, somatic mutations in core splicing factors have been described in certain hematologic malignancies but the breadth of splicing factor mutations has been largely underappreciated. The findings published today give us for the first time a comprehensive understanding of just how common splicing factor mutations are across many types of cancer and of the role they may play in promoting tumor formation and progression," said Markus Warmuth, M.D., President and Chief Executive Officer of H3 Biomedicine Inc. "This knowledge further validates the therapeutic approach of modulating spliceosome dysregulation to control tumor formation and growth, one of our core focus areas at H3 Biomedicine as evidenced by H3B-8800, our small molecule modulator of the SF3b complex, which is currently being evaluated in a Phase 1 clinical trial for patients with hematologic cancers and splicing factor mutations. In addition, the research findings open up an expansive, actionable trove of spliceosome targets that could be explored with novel therapeutic strategies."

Using whole exome and RNA sequencing data in TCGA, H3 data scientists analyzed over 10,000 patient samples across 33 tumor types to identify somatic mutations in RNA splicing factors. The analysis of over 400 splicing factor genes identified 119 genes as having putative driver mutations, including over-representation, recurrent loss-of-function or recurrent hotspot (oncogene-like) mutations.

Mutations in splicing factor genes were found in all 33 tumor
types with the frequency of mutations in multiple splicing factor genes as high as 60% in patient samples of the same tumor types, representing a much larger occurrence than previously reported. In addition, H3 scientists, as exemplified in case studies of five genes, showed that mutations in splicing factor genes led to dysregulated or altered splicing in mutated cells.
"This research and analysis exemplifies our differentiated drug discovery approach. We have the computational power and know-how to mine vast amounts of genomic data and reveal critical insights that we in turn utilize to develop and investigate highly targeted, precision approaches to cancer," said Lihua Yu, Ph.D., Chief Data Science Officer of H3 Biomedicine Inc. "We’re particularly proud of this work because, beyond informing our own drug discovery efforts, it will help advance the entire field’s understanding of the role dysregulated RNA splicing plays in cancer."
H3 Biomedicine is advancing novel cancer therapies that target core splicing factor mutations. A Phase 1 trial is underway in patients with hematologic malignancies for the company’s first spliceosome pathway-targeting cancer therapeutic, H3B-8800, a potent, selective and orally bioavailable small molecule modulator of wild-type and mutant SF3b complex, a splicing factor gene. The study is evaluating the safety and preliminary efficacy of H3B-8800 in patients with myelodysplastic syndromes, acute myeloid leukemia, and chronic myelomonocytic leukemia who carry mutations in splicing factor genes. Preclinical data demonstrate that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in a range of spliceosome-mutant cancer models.

Splicing modulation is one of several research focus areas of H3 Biomedicine. H3 Biomedicine has two additional investigational therapies in Phase 1 clinical trials, including:

H3B-6545, an oral, first-in-class ESR1 covalent antagonist targeting wild-type and mutant estrogen receptor α in endocrine-therapy resistant metastatic breast cancer patients; and

H3B-6527, an oral, potent and highly selective small molecule covalent inhibitor of FGFR4 for treatment of hepatocellular carcinoma (HCC) patients with overexpression of FGF19.

On April 3, 2018 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic CAR T-cells (UCART), and Allogene Therapeutics, Inc. (Allogene), a biotechnology company focused on the rapid advancement of allogeneic CAR T therapies targeting blood cancers and solid tumors, reported that Allogene intends to assume from Pfizer the global strategic collaboration to develop "off-the-shelf" CAR T immunotherapies for oncology (Press release, Cellectis, APR 3, 2018, View Source [SID1234525157]). This agreement was initially formed with Cellectis in June 2014.

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Earlier today, Allogene and Pfizer announced that the two companies have entered into an asset contribution agreement for Pfizer’s allogeneic CAR T-cell therapy portfolio, which includes 16 preclinical assets and UCART19. Subject to certain closing conditions, Allogene will assume the strategic collaboration and license agreement with Cellectis, with exclusive rights to develop and commercialize previously defined allogeneic UCART programs directed at select targets. Cellectis will remain eligible to receive clinical and commercial milestone payments of up to $2.8 billion, or $185 million per target for 15 targets and tiered royalties in the high single digits on net sales of any products that are commercialized by Allogene under the agreement. This new alliance, with Allogene’s dedicated team, is expected to lead to a strong acceleration of CAR T therapies.

Allogene, co-founded and led by former executives of Kite Pharma, is well-positioned to catalyze the next revolution in cell therapy with its leaders’ unrivaled experience in the clinical development of autologous CAR T therapy. Arie Belldegrun M.D., FACS, Founder and former Chairman, President and Chief Executive Officer of Kite, will serve as Executive Chairman of Allogene, and David Chang, M.D., Ph.D., former Executive Vice President, Research and Development and Chief Medical Officer of Kite, will serve as President and Chief Executive Officer of Allogene.

Cellectis’ CAR T platform provides a proprietary, allogeneic approach that uses engineered T-cells from a healthy donor for use in multiple patients. This is distinct from autologous approaches that use a patient’s own T-cells to target tumor cells.

"Allogeneic represents the next transformative step in medicine, as it will potentially allow patients all over the world to quickly receive these potentially life-saving therapies in the most efficient and cost-effective way possible. The last four years of partnership with Pfizer have been very rewarding and productive. Pfizer was among the early adopters of the allogeneic approach, seeing that gene-edited CART programs are the future of immunotherapy to treat cancer. We sincerely thank everyone involved in this collaboration, from the top management to the scientists, for their foresight and their belief in our common portfolio," said Dr. André Choulika, Ph.D., Cellectis’ Chairman & Chief Executive Officer. "We strongly believe Allogene, together with Cellectis, will from the best possible team to continue this collaboration. Our expertise in allogeneic CART and gene-editing combined with the leadership of Drs. Arie Belldegrun and David Chang and their exemplary track record and execution in cell therapy paves the way for the future in off-the-shelf products enhanced by gene editing."

"We have built mutual trust and respect over the years in the CAR T industry and this collaboration will be the starting point for a long-term partnership," said David Chang, M.D., Ph.D., President and Chief Executive Officer of Allogene. "Our mission at Allogene is to catalyze the next revolution in cancer treatment through the development of allogeneic CAR T therapies directed at blood cancers as well as solid tumors. We believe this collaboration fuels our mission and we look forward to partnering with Cellectis to accelerate the development of allogeneic cell therapies."

On April 3, 2018 Eleven Biotherapeutics, Inc. (NASDAQ: EBIO), a late-stage clinical company developing next-generation antibody-drug conjugate (ADC) therapies for the treatment of cancer, reported that preliminary efficacy and safety data from its ongoing Phase 3 VISTA trial of Vicinium in patients with non-muscle invasive bladder cancer (NMIBC) who have been previously treated with bacillus Calmette-Guérin (BCG) have been selected for presentation during a plenary session currently scheduled for Monday, May 21, 2018 at 11:00 a.m. PT at the American Urological Association Annual Meeting taking place in San Francisco (Press release, Eleven Biotherapeutics, APR 3, 2018, View Source [SID1234525376]). Vicinium is a fusion protein, designed to be a next-generation ADC, that targets the epithelial cell adhesion molecule (EpCAM) antigens on the surface of bladder cancer cells to deliver a potent cytotoxin into those cells.

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Data, as reported in the abstract published online today, are from a subgroup of the first 75 evaluable carcinoma in situ patients. Within these patients, preliminary findings show that greater than 95 percent expressed EpCAM on the surface of tumor cells, the target of Vicinium. Efficacy data as measured by complete response rates at three-months will be reported during the plenary session. Vicinium has been well-tolerated. Treatment-related adverse events (AEs) were reported in 46 percent of patients, the majority of which were Grade 1 or 2. The most common of these were dysuria (12%), UTI or pollakiuria (10%) and hematuria (7%), which are often associated with catheter-delivered treatments into the bladder and bladder cancer itself. As of the December 2017 data cut off, three treatment-related serious AEs were reported, including renal failure (CTCAE Grade 5) with cholestatic hepatitis (Grade 4) in one patient and acute kidney injury (Grade 3) in a second patient who recovered.

In March 2018, recruitment was completed in the VISTA trial, a single-arm registration study designed in accordance with U.S. Food and Drug Administration’s final guidance for developing treatments for BCG-unresponsive NMIBC.
"When treatment with today’s standard of care, BCG, is no longer an option, the next treatment option is typically removal of the patient’s bladder, a challenging, life-altering procedure that many patients elect not to undergo," said Stephen Hurly, president and chief executive officer of Eleven Biotherapeutics. "Vicinium has demonstrated that it is a well-tolerated and active agent in patients with BCG unresponsive NMIBC in studies to-date. We are excited to be presenting the first preliminary data from our Phase 3 VISTA trial of Vicinium for patients with NMIBC at this year’s AUA meeting. During our plenary presentation, we will share initial efficacy findings and data supporting the favorable safety we have observed so far with Vicinium. We believe Vicinium holds tremendous potential as a treatment for bladder cancer, and we look forward to sharing these and additional data later in the year."
The company plans to host a conference call in conjunction with the data presentation, with details to follow.
About the VISTA Clinical Trial
The VISTA trial is an open-label, multicenter, single-arm Phase 3 clinical trial evaluating the efficacy and tolerability of Vicinium in patients with high-risk non-muscle invasive bladder cancer (NMIBC) that is carcinoma in situ (CIS, cancer found on the inner lining of the bladder that has not spread into muscle or other tissue) or papillary (cancer that has grown from the bladder lining out into the bladder but has not spread into muscle or other tissue), who have been previously treated with bacillus Calmette-Guérin (BCG). The primary endpoint of the trial is the complete response rate in patients with CIS with or without papillary disease and durability of that response. Patients in the study receive locally administered Vicinium twice a week for six weeks, followed by once-weekly treatment for another six weeks, then treatment every other week for up to two years. Topline data assessing responses and durability of responses at three-months on treatment are expected in mid-2018, with 12-month data anticipated in mid-2019.

About Vicinium
Vicinium, Eleven Biotherapeutics’ lead product candidate, is a next-generation antibody-drug conjugate developed using the company’s proprietary Targeted Protein Therapeutics platform. Vicinium is comprised of a recombinant fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens on the surface of tumor cells to deliver a potent protein payload, Pseudomonas Exotoxin A (ETA). Vicinium is constructed with a stable, genetically engineered linker to ensure the payload remains attached until it is internalized by the cancer cell, which is believed to decrease the risk of toxicity to healthy tissues, thereby improving its safety. In prior clinical studies conducted by Eleven Biotherapeutics, EpCAM has been shown to be overexpressed in non-muscle invasive bladder cancer (NMIBC) cells with minimal to no EpCAM expression observed on normal bladder cells. Eleven Biotherapeutics is currently conducting the Phase 3 VISTA trial, designed to support the registration of Vicinium for the treatment of NMIBC in patients who have previously received two courses of bacillus Calmette-Guérin (BCG) and whose disease is now BCG-unresponsive. Topline, three-month data from the trial are expected in mid-2018. Additionally, Eleven Biotherapeutics believes that Vicinium’s cancer cell-killing properties promote an anti-tumor immune response that may potentially combine well with immuno-oncology drugs, such as checkpoint inhibitors. The activity of Vicinium in BCG-unresponsive NMIBC is also being explored at the US National Cancer Institute in combination with AstraZeneca’s immune checkpoint inhibitor durvalumab.

On April 3, 2018 Pfizer Inc. (NYSE:PFE) and Allogene Therapeutics, Inc. (Allogene) reported that the two companies have entered into an asset contribution agreement for Pfizer’s portfolio of assets related to allogeneic chimeric antigen receptor T cell (CAR T) therapy, an investigational immune cell therapy approach to treating cancer (Press release, Pfizer, APR 3, 2018, https://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_allogene_therapeutics_enter_into_asset_contribution_agreement_for_pfizer_s_allogeneic_car_t_immuno_oncology_portfolio [SID1234525452]).

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Pfizer Inc. (NYSE:PFE) and Allogene Therapeutics, Inc. (Allogene) reported that the two companies have entered into an asset contribution agreement for Pfizer’s portfolio of assets related to allogeneic chimeric antigen receptor T cell (CAR T) therapy, an investigational immune cell therapy approach to treating cancer.

Pfizer views this agreement as an attractive opportunity to support the continued development of allogeneic CAR T therapy in a highly focused and skilled manner. Pfizer will continue to participate financially in the development of the CAR T portfolio through a 25 percent ownership stake in Allogene. Separately, Pfizer continues to have an 8 percent ownership stake in Cellectis through an equity agreement entered into in 2014. Allogene, a Two River portfolio company, was formed with Series A financing of $300 million from an investment consortium that includes TPG, Vida Ventures, BellCo Capital, the University of California Office of the Chief Investment Officer and Pfizer, among others. TPG, Vida Ventures, BellCo Capital and Pfizer will be represented on the Allogene Board of Directors. Closing is expected in the second quarter of 2018, subject to closing conditions.

"The allogeneic CAR T platform represents a potentially transformative approach to treating cancer, and we are very excited about what the future may hold for this area of research," said Robert Abraham, Senior Vice President and Group Head, Oncology Research & Development, Pfizer. "We believe that under the strong scientific, clinical development and regulatory expertise of Allogene’s leadership team, the portfolio of CAR T assets contributed by Pfizer will be well-positioned to rapidly advance into potential innovative new therapies, and ultimately to reach patients in need more quickly."

"While there is important work underway across the industry for next-generation autologous cell therapy, Allogene hopes to bring about the next revolution in the field with the successful development of allogeneic cell therapy and the potential for greater and faster patient access," said Belldegrun. "Under the direction of David Chang, an extraordinary scientist, physician and life sciences business executive with over 30 years of unprecedented experience in developing cancer treatments, Allogene is poised to potentially lead the development of one of the most exciting opportunities in our industry today."

"Last year, Kite’s anti-CD19 CAR T therapy became the first autologous CAR T treatment to be approved by the U.S. Food and Drug Administration for adult patients with aggressive non-Hodgkin lymphoma. Many believed the idea was rooted in science fiction, but science fiction became a reality," said Chang. "We believe that this partnership among leaders in the field – visionaries, industry forerunners, venture capitalists and researchers – has the potential to accelerate the development of allogeneic T cell therapy, making it a reality and forever changing how cancer is treated."

"Investing in innovation and R&D has long been a hallmark of who we are as investors, and for many years, we’ve been partnering with dynamic companies that are driving meaningful change in healthcare," said Todd Sisitsky, Managing Partner, TPG Capital. "We believe CAR T is one of the most exciting spaces within the pharmaceutical landscape today, and we are thrilled to partner with a best-in-class management team and industry leaders to invest in this potentially groundbreaking opportunity."

"As a pioneer of the allogeneic approach and expert in gene editing, the Cellectis team is excited by this agreement and eager to continue this groundbreaking work with Allogene’s experienced team, striving to accelerate the development of the portfolio and to continue along the path of making these treatments available to patients as soon as possible," said Dr. André Choulika, Cellectis CEO.

"I believe that the recognized expertise of the Allogene team in the field of CAR T will be of benefit to the development of UCART19, for which Servier is the sponsor of two clinical studies," commented Olivier Laureau, President of Servier Group. "The development of off-the-shelf allogeneic CAR T therapy in the field of oncology initiates a revolution that could potentially expand access of such innovative treatment to a larger number of oncologists and their patients."

Centerview Partners is acting as financial advisor to Pfizer, with Ropes & Gray LLP acting as its legal advisor. Cooley LLP is serving as legal counsel to Allogene, Vida Venture and TPG. Gibson Dunn & Crutcher LLP are also serving as legal counsel to TPG.

Allogeneic CAR T Cell Therapies

Allogeneic CAR T cell therapies have the potential to become the next advancement in one of the most powerful anti-cancer agents, eliminating the need to create personalized therapy from a patient’s own cells. These therapies are developed from cells of healthy donors and stored for "off-the-shelf" use in patients, simplifying manufacturing process and reducing waiting time for patients.

Allogene will receive from Pfizer the rights to 16 preclinical CAR T assets licensed from Cellectis and Servier and one clinical asset licensed from Servier, UCART19, an allogeneic CAR T therapy that is being developed for treatment of CD19-expressing hematological malignancies. In partnership with Servier, UCART19 is initially being developed in acute lymphoblastic leukemia (ALL) and is currently in Phase I. UCART19 utilizes TALEN gene editing technology pioneered and owned by Cellectis.

Allogene and Servier intend to initiate Phase 2 studies in 2019. Under the terms of the original development agreement, Allogene will have exclusive rights to develop and commercialize UCART19 in the United States, while Servier will retain exclusive rights for all other countries.

Pfizer’s Commitment to Immuno-Oncology

Immuno-Oncology (IO) is a key area of focus within Pfizer’s broad oncology portfolio, with research and development efforts spanning diverse modalities and mechanisms of action that tap into key immune system functions, harnessing the natural ability of the immune system to fight cancer. We believe that the future of IO lies in novel, biologically rational combinations based on unique tumor characteristics. We believe that Pfizer Oncology’s pipeline is in a strong position to help advance the next wave of IO science by developing new targeted therapies and IO combinations – areas in which Pfizer has a robust and proven legacy. We know that great science comes through collaboration, and we actively team up with strategic partners in IO who we believe will strengthen our portfolio and help speed innovative treatments to benefit more patients.

About Allogene Therapeutics

Allogene Therapeutics is a biotechnology company with a mission to catalyze the next revolution in cancer treatment through the development of allogeneic chimeric antigen receptor T-cell (CAR T) therapy directed at blood cancers and solid tumors. Founded and led by former Kite Pharma executives who bring unrivaled clinical development acumen in cell therapy, Allogene is well-positioned to further the potential of allogeneic cell therapy for patients.

Allogeneic CAR T therapies are engineered from cells of healthy donors and stored for "off-the-shelf" use in patients. This approach eliminates the need to create personalized therapy from a patient’s own cells, simplifies manufacturing, and reduces the time patients must wait for CAR T treatment. The Allogene portfolio includes 16 pre-clinical T cell therapy assets and UCART19, an allogeneic CAR T therapy currently in Phase 1 development for the treatment of acute lymphoblastic leukemia (ALL). Through its notable partnerships, Allogene leverages pioneering technology platforms, including TALEN gene editing technology, to progress its portfolio of immuno-oncology therapies. Allogene, with headquarters in San Francisco, California, is a Two River portfolio company formed with one of the largest Series A financings in biotechnology from an investment consortium that includes TPG, Vida Ventures, BellCo Capital, the University of California Office of the Chief Investment Officer and Pfizer, among others. For more information, please visit www.allogene.com, follow @AllogeneTx on Twitter and LinkedIn.

On April 3, 2018 Diffusion Pharmaceuticals Inc. (Nasdaq:DFFN) ("Diffusion" or "the Company"), a clinical-stage biotechnology company focused on extending the life expectancy of cancer patients using the novel small molecule trans sodium crocetinate (TSC) in conjunction with standard radiation and chemotherapy, reported 2017 financial results and provides a business update. Diffusion’s lead clinical trial program, the INvestigation of TSC Against Cancerous Tumors (INTACT) trial, is a Phase 3 study expected to enroll a total of 236 patients, with half in the treatment arm and half in the control arm (Press release, Diffusion Pharmaceuticals, APR 3, 2018, View Source [SID1234525158]). The design of INTACT is based on an almost four-fold increase in overall survival at two years demonstrated in inoperable GBM patients in the preceding Phase 2 study.

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"We began opening clinical sites for the INTACT trial in December as planned, and started enrolling and dosing patients in January while continuing to open more clinical sites," said David Kalergis, Chairman and Chief Executive Officer of Diffusion Pharmaceuticals. "We believe that the INTACT trial can provide a promising new treatment option for the thousands of patients who each year are newly diagnosed with inoperable GBM brain cancer and who, because of their poor prognosis, may be excluded from other clinical trials."

In January 2018 the Company conducted a public offering, raising gross proceeds of approximately $12.0 million from the sale of common stock and warrants. In conjunction with this capital raise, all the Company’s preferred stock was converted into common stock, eliminating the obligation for future dividend payments and certain restrictive provisions contained therein.

In January 2018 the Company, along with researchers from the University of California Los Angeles (UCLA) and the University of Virginia (UVA), presented an abstract at the International Stroke Conference in Los Angeles describing a Phase 2 trial design to test TSC for use in acute stroke. The planned Phase 2, randomized, double-blind, placebo-controlled trial calls for the administration of TSC by specially-trained Emergency Medical Technicians to ambulance-transported patients within two hours of the onset of a suspected acute stroke, potentially overcoming the current severe timing obstacle in the treatment of stroke patients. The trial, which has been named the Pre-Hospital Ambulance Stroke Trial – TSC (PHAST-T) is expected to commence in late 2018, subject to funding.

The Company further expanded its intellectual property portfolio in 2017, with the allowance of key patents that increased coverage of the therapeutic use of TSC and related compounds. The new areas include congestive heart failure, chronic renal failure, acute lung injury, chronic obstructive pulmonary disease and respiratory distress syndrome. Additional claims were also allowed relating to the treatment of a number of cancer types including brain and pancreatic, using TSC along with chemotherapy and radiation therapy.

Financial Results for the Year Ended December 31, 2017

We had cash and cash equivalents of $8.9 million as of December 31, 2017. Subsequent to the close of the year, on January 22, 2018 we closed an underwritten public offering of stock and warrants, raising approximately $12.0 million in gross proceeds.

We recognized $5.1 million in research and development expenses during 2017, compared with $7.3 million during 2016. This decrease was primarily attributable to a decrease of $1.3 million related to animal toxicology studies, a decrease of $0.9 million of pancreatic expenses, a decrease of $0.6 million related to stock-based compensation expense and a decrease of $0.3 million in manufacturing-related expenses. We also recognized a $1.0 million impairment charge upon our abandonment of future development efforts related to our RES-440 IPR&D asset in 2016. These decreases were offset by increases in GBM trial expenses of $1.6 million as we prepared for the Phase 3 clinical trial for TSC and increases in salaries and wages expenses of $0.2 million as a result of an increase in headcount. We currently expect our research and development expenses to increase significantly in future periods due to costs associated with our Phase 3 clinical trial for TSC, the Phase 2 trial for pre-hospital stroke therapy and overall efforts to advance the research and development of our technologies and product candidates.

General and administrative expenses were $6.2 million during 2017, compared with $11.1 million during 2016. The decrease was primarily due to a decrease of $3.2 million in professional fees incurred in 2016 in connection with preparations to operate as a public company and a $2.5 million decrease in non-cash litigation settlement fees, offset by increases in salary and wages and stock-based compensation expense of $0.4 million and $0.4 million, respectively, due to our increase in headcount.

In connection with the private placement of our Series A convertible preferred stock and common stock warrants in March 2017, we determined the warrants to be classified as liabilities and subject to remeasurement at each reporting period. As such, during 2017 we recorded a $22.1 million non-cash gain for the change in fair value of our common stock warrant liabilities, which was primarily attributable to the decrease in the market price for our common stock. We also recognized $10.2 million in excess fair value of the common stock warrants over the gross proceeds from our private placement and $2.9 million in placement agent commissions and other offering costs.