On March 13, 2018 Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a clinical-stage biotechnology company that designs and develops innovative human enzyme therapeutics for patients with rare genetic diseases and cancer, today reported new repeat dose data from its Phase 1/2 open-label trial of pegzilarginase (AEB1102) in patients with Arginase 1 Deficiency (Press release, Aeglea BioTherapeutics, MAR 13, 2018, View Source [SID1234524967]). The Company also reported financial results for the fourth quarter and year ended December 31, 2017.

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"We have seen encouraging results after repeated doses of pegzilarginase in patients with Arginase 1 Deficiency," said Anthony G. Quinn, M.B Ch.B, Ph.D., interim chief executive officer of Aeglea. "Along with marked and sustained reductions in plasma arginine levels, we are seeing consistent reductions in the levels of other guanidino compounds beyond what appears to be achieved through current approaches to disease management. This is important given the potential contribution of guanidino compounds to the progressive hyperargininemia-related neurological abnormalities seen in this patient population. In addition to our developing understanding of the effects of lowering arginine levels in patients with Arginase 1 Deficiency, we have a good understanding of the safety profile in a larger population that includes patients from our cancer trials. We look forward to sharing additional updates on Arginase 1 Deficiency at the ACMG Annual Clinical Genetics Meeting in April 2018 and in the third quarter of 2018. These updates will include clinical insights from the two adult patients in the long-term extension study."

"Repeated doses of pegzilarginase lowered and maintained plasma arginine and guanidino compound metabolites beyond what was achievable with current standard of care, which consists of a protein-restricted diet and ammonia scavengers," said George Diaz, M.D., Ph.D, professor and chief, Division of Medical Genetics, Icahn School of Medicine at Mount Sinai, and co-author on the abstract. "Given that some patients benefit from the reductions in plasma arginine achieved with dietary protein restriction, it will be important to learn whether longer term reductions in plasma arginine with pegzilarginase beyond that achieved with diet translates into clinical benefit."

Clinical Updates

Arginase 1 Deficiency:

Aeglea presented repeat dose data from the Phase 1/2 clinical trial of pegzilarginase for two adult patients and single ascending dose data for one pediatric patient with Arginase 1 Deficiency at the 2018 Society for Inherited Metabolic Disorders (SIMD) Annual Meeting on March 12, 2018.

Sustained lowering of plasma arginine was achieved with repeated weekly IV dose of 0.04 mg/kg of pegzilarginase.

Arginine-derived metabolites elevated at baseline were rapidly decreased and reductions maintained with repeat doses of pegzilarginase.

Pegzilarginase was well tolerated with the exception of a single infusion-associated reaction in one pediatric patient who had anti-drug antibodies (ADA) and blunting of the expected reduction in plasma arginine after the second dose. The patient transitioned to the repeat dose part of the trial and received three further infusions. Although dosing was well tolerated with premedication and slower infusion rates, the patient withdrew consent due to the burden of balancing school and the clinical trial.

No marked or sustained increase in ADA titers were seen in the two adult Arginase 1 Deficiency patients or in the 48 cancer patients tested after dosing with pegzilarginase. Baseline ADA at low titer was detected in one of two adult Arginase 1 Deficiency patients and four of 48 cancer patients. There was no apparent effect of the presence of the ADA on arginine reduction or safety profile.

The effects of repeat dosing of pegzilarginase provides an opportunity to evaluate the clinical benefits of sustained reduction of plasma arginine beyond what can be achieved with standard of care therapy.

The Company expects to report pediatric and adult repeat dose data in patients with Arginase 1 Deficiency in the third quarter of 2018.
Cancer:

The first uveal and cutaneous melanoma patients were dosed with pegzilarginase in Aeglea’s open-label Phase 1 cohort expansions, with the intent to confirm the safety profile and Phase 2 dose and identify further signals of clinical activity.

The Company expects to report Phase 1 cohort expansion topline data, including safety and clinical activity, in the fourth quarter of 2018.
Upcoming Events

Aeglea will present a corporate update at the 17th Annual Needham Healthcare Conference on March 27, 2018 in New York.

Aeglea will present a poster with additional data on Arginase 1 Deficiency patients at the 2018 ACMG Annual Clinical Genetics Meeting on April 12, 2018 in Charlotte, North Carolina that will include additional clinical insights on baseline standardized assessments of neuromotor function and on short-term treatment with repeat doses of pegzilarginase.

Fourth Quarter and Full Year Financial Results

As of December 31, 2017, Aeglea had available cash, cash equivalents and marketable securities of $50.3 million. Based on Aeglea’s current operating plan, management believes it has sufficient capital resources to fund anticipated operations through the third quarter of 2019.

Aeglea recognized grant revenues of $1.5 million in the fourth quarter of 2017, compared with $1.2 million in the fourth quarter of 2016. The grant revenues were the result of a $19.8 million research grant received from the Cancer Prevention and Research Institute of Texas (CPRIT). The revenue increase was primarily due to higher qualifying expenditures associated with the clinical trials for pegzilarginase in cancer patients in the fourth quarter of 2017 compared with the fourth quarter of 2016.

Grant revenues of $5.2 million were recognized in the year ended December 31, 2017, compared with $4.6 million in the year ended December 31, 2016. The increase was primarily due to higher qualifying expenditures associated with the clinical trials for pegzilarginase in cancer patients in 2017 compared with 2016.

Research and development expenses totaled $5.8 million for the fourth quarter of 2017, compared with $4.7 million for the fourth quarter of 2016. The increase was primarily due to expanded clinical activity for Aeglea’s lead product candidate, pegzilarginase, as Aeglea initiated three solid tumor single-agent cohort expansions and a Phase 1/2 combination trial in patients with small cell lung cancer.

Research and development expenses totaled $22.8 million for the year ended December 31, 2017, compared with $18.1 million for the year ended December 31, 2016. The increase was primarily associated with expanded manufacturing, regulatory, research, and clinical development capabilities, as Aeglea completed its Phase 1 dose escalation trial in patients with advanced solid tumors. Additionally, the Company initiated enrollment in three solid tumor single-agent cohort expansions and a Phase 1/2 combination trial in patients with small cell lung cancer.

General and administrative expenses totaled $2.3 million for the fourth quarter of 2017, compared with $2.0 million in the fourth quarter of 2016. This increase was primarily due to higher employee compensation costs.

General and administrative expenses totaled $10.1 million for the year ended December 31, 2017, compared with $8.4 million for the year ended December 31, 2016. This increase was primarily due to higher employee compensation, consulting, and facility costs.

Net loss totaled $6.5 million and $5.5 million for the fourth quarter of 2017 and 2016, respectively. Net loss totaled $27.2 million and $21.7 million for the years ended December 31, 2017 and 2016, respectively.

Conference Call & Webcast Details

Aeglea will hold a conference call on Tuesday, March 13, 2018 at 8:00 a.m. ET. To access the live conference call via phone, please dial (877) 709-8155 (toll free) within the United States, or +1 (201) 689-8881 internationally. A replay of the call will be available through March 20, 2018 by dialing (877) 660-6853 within the United States or +1 (201) 612-7415 internationally. The conference ID is 13677425.

To access the live and archived webcast of the presentation, please visit the Presentations & Events section of the Aeglea BioTherapeutics investor relations website. Please connect to the website at least 15 minutes prior to the presentation to allow for any software download that may be necessary.

On 13 March, 2018 Boehringer Ingelheim and Vanderbilt University reported the expansion of their successful existing collaboration to develop novel anti-cancer compounds (Press release, Boehringer Ingelheim, MAR 13, 2018, View Source [SID1234524727]).

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The expanded research partnership will focus on the discovery and development of new chemical therapeutics targeting the pro-survival protein MCL1 as a potential therapy against MCL1 dependent cancers. This is the third collaboration between Boehringer Ingelheim and Vanderbilt University to pursue discoveries made in the laboratory of Stephen W. Fesik, Ph.D., at Vanderbilt University School of Medicine.

"Boehringer Ingelheim and Vanderbilt University have the expertise and are jointly focused on discovering breakthrough medicines against the cancer causing proteins KRAS, SOS and now, MCL1," said Darryl McConnell, Ph.D., Vice President and Research Site Head, Boehringer Ingelheim, Austria. "Together, we are committed to driving scientific research and development forward to help patients win the fight against cancer."

"MCL1 is one of the top ten overexpressed genes in human cancer where it plays a role as a survival factor," said Lawrence J. Marnett, Ph.D., Dean of Basic Sciences in the Vanderbilt University School of Medicine.

"It is a great target for therapy but candidate drugs need to disrupt high affinity protein-protein interactions, which is very challenging," Marnett said. "The Fesik laboratory has made impressive strides in developing such compounds and it is exciting to see them advanced toward clinical development through the partnership with Boehringer Ingelheim."

MCL1, when overexpressed, can prevent cancer cells from undergoing programmed cell death (also known as apoptosis). This necessitates the discovery of a molecule that binds extremely tightly and selectively to MCL1 in order to sufficiently induce on-target, mechanism-based cancer cell death.

"Boehringer Ingelheim has an outstanding oncology drug discovery infrastructure that brings various research and development groups together to tackle challenging cancer targets," said Fesik, Professor of Biochemistry, Pharmacology, and Chemistry at Vanderbilt. "In combination with our multidisciplinary team of structural biologists, medicinal chemists and cell biologists, we will work to search for anti-cancer compounds that inhibit MCL1 in order to tackle this complex area of unmet medical need."

Boehringer Ingelheim is steadfast in its partnership with Vanderbilt University and is deeply committed to delivering breakthrough, first-in-class treatments to help cancer patients everywhere, despite the challenges that may present themselves. This agreement between Boehringer Ingelheim and Vanderbilt University includes undisclosed upfront and milestone payments, with the ambition of delivering a new cancer drug to market as quickly as possible.

About Boehringer Ingelheim in Oncology
Cancer takes. Takes away loved ones, time and untapped potential. At Boehringer Ingelheim we are providing new hope for patients by taking cancer on. We are collaborating with the oncology community to deliver scientific breakthroughs to transform the lives of patients. Our primary focus is in lung and gastrointestinal cancers, with the goal of delivering breakthrough, first-in-class treatments that can help win the fight against cancer. Our commitment to innovation has resulted in pioneering treatments for lung cancer and we are advancing a unique pipeline of cancer cell directed agents, immune oncology therapies and intelligent combination approaches to help combat many cancers.

On March 13, 2018 Actinium Pharmaceuticals reported that the Medical College of Wisconsin received clearance from the U.S. Food and Drug Administration (FDA) for the previously announced Investigational New Drug (IND) application for the Phase 1 trial of Actimab-A in combination with CLAG-M for relapsed or refractory Acute Myeloid Leukemia (AML) patients (Press release, Actinium Pharmaceuticals, MAR 13, 2018, View Source [SID1234524720]). This investigator initiated trial will be conducted at the Medical College of Wisconsin and led by principal investigator Dr. Sameem Abedin in collaboration with Dr. Ehab Atallah. This trial will enroll up to 18 patients and will assess safety as well as efficacy, which will be based on response rates, percentage of patients receiving a bone marrow transplant and overall survival. Actimab-A is an antibody radio-conjugate (ARC) that combines the anti-CD33 antibody lintuzumab with the radioisotope actinium-225. CLAG-M is a salvage chemotherapy regimen consisting of cladribine, cytarabine, filgrastim and mitoxantrone that has become the standard of care at many institutions across the U.S. in AML patients with relapse.

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Dr. Mark Berger, Actinium’s Chief Medical Officer said, "The use of our actinium-225 – anti-CD33 ARC in combination with cytotoxic therapies such as CLAG-M has the potential to improve outcomes for a significant number of patients. We believe our ARC approach, which has shown to be potent while having minimal extramedullary toxicities in over 100 patients to date, has the potential to be synergistic with cytotoxic chemotherapy agents. CLAG-M has shown compelling results in patients with relapsed or refractory disease and we believe that the combination with our ARC can improve response rates, transplant rates and overall survival for patients. We are excited to begin enrolling patients on this trial and look forward to working with Dr. Abedin, Dr. Atallah and their colleagues at the Medical College of Wisconsin on this important Phase 1 study."

This Phase 1 combination trial is the fourth clinical trial from Actinium’s CD33 program. The Company’s other CD33 program trials include its Phase 2 trial Actimab-A trial for patients newly diagnosed with AML who are over the age of 60 and unfit for intense chemotherapy and the Phase 1 Actimab-M trial for patients with refractory multiple myeloma. A Phase 2 trial is planned for patients with high-risk myelodysplastic syndrome with a p53 genetic mutation for myeloablation prior to a bone marrow transplant.

Sandesh Seth, Actinium’s Chairman and CEO said, "We see the use of our ARC’s in combination with chemotherapy as an exciting development opportunity that has the potential to bring benefits to a significant number patients. We believe that this will be the first of many combinations given the potency of our ARC approach together with its minimal extramedullary toxicities and its unique mechanism of action. Together these attributes make our ARC a versatile therapy that we believe can bring benefits to patients as a monotherapy, in combination and for myeloablation prior to a bone marrow transplant."

About Actimab-A

Actimab-A is Actinium’s lead drug candidate from its CD33 program and is an antibody radio-conjugate (ARC) that is comprised of the CD33 targeting antibody lintuzumab and actinium-225, an alpha-emitting radioisotope. This ARC is currently being studied in the Phase 2 Actimab-A is clinical trial in patients that are newly diagnosed with AML who are over the age of 60 that are ineligible for intense chemotherapy, also known as unfit patients. Actimab-A has been granted Orphan Drug Designation for newly diagnosed AML in patients 60 and above by the U.S. Food and Drug Administration and the European Medicines Agency. The Company is also conducting the Phase 1 Actimab-M trial, an investigator initiated trial for patients with refractory multiple myeloma. Also, Actinium plans to begin the Phase 2 Actimab-MDS trial for patients with high-risk myelodysplastic syndrome (MDS) that have a p53 genetic mutation myeloablation prior to a bone marrow transplant. Actimab-A is a second-generation therapy from the Company’s CD33 Program, which was developed at Memorial Sloan Kettering Cancer Center and has now been studied in over 100 patients in four clinical trials.

On March 13, 2018 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has accepted a new supplemental Biologics License Application (sBLA) and granted Priority Review for KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy (Press release, Merck & Co, MAR 13, 2018, View Source [SID1234524713]). The application is seeking approval for KEYTRUDA as a treatment for patients with advanced cervical cancer with disease progression on or after chemotherapy. This is the first filing acceptance and Priority Review granted for an anti-PD-1 therapy in cervical cancer and the 14th regulatory submission accepted by the FDA for KEYTRUDA. The FDA has set a PDUFA, or target action, date of June 28, 2018.

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"Advanced cervical cancer is an illness with a poor prognosis and a high unmet medical need. We look forward to working with the FDA on the review of this application to help bring KEYTRUDA to previously-treated patients with advanced cervical cancer," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories.

The application, which is seeking accelerated approval for this new indication, is based in part on data from the phase 2 KEYNOTE-158 trial. KEYNOTE-158 is an ongoing global, open-label, non-randomized, multi-cohort, multi-center study evaluating KEYTRUDA in patients with multiple types of advanced solid tumors – including cervical cancer – that have progressed on standard of care therapy.

Merck is executing an extensive clinical development program in a broad range of cancers that affect women. To date, the program includes numerous studies evaluating KEYTRUDA (pembrolizumab) as monotherapy or in combination with other anti-cancer treatments across various types of breast and gynecological cancers.

About Cervical Cancer

Cervical cancer forms in the cells lining the cervix, or the lower part of the uterus. In 2017, approximately 12,820 cases of cervical cancer were diagnosed in the U.S. The five-year survival rate of women with stage IV disease is an estimated 15-16 percent. Any woman can develop cervical cancer, but it is more commonly diagnosed in women between the ages of 35 and 44. While screenings and vaccinations have resulted in declining cervical cancer rates, the disease continues to affect women in the U.S. and throughout the world.

On March 12, 2018 Eleven Biotherapeutics, Inc. (NASDAQ: EBIO), a late-stage clinical company advancing next-generation antibody-drug conjugate (ADC) therapies for the treatment of cancer, reported that the company has completed enrollment in the VISTA Phase 3 registration trial of Vicinium in patients with non-muscle invasive bladder cancer (NMIBC) who have been previously treated with bacillus Calmette-Guérin (BCG) (Press release, Eleven Biotherapeutics, MAR 13, 2018, View Source [SID1234524701]). Bladder cancer is the sixth most common cancer in the United States and approximately 80 percent of bladder cancer patients are diagnosed with NMIBC. Vicinium is a fusion protein, designed to be a next-generation ADC, which specifically targets the epithelial cell adhesion molecule (EpCAM) antigens on the surface of bladder cancer cells to deliver a potent cytotoxin to those cells.
"Bladder cancer is one of the most prevalent cancers in the United States, yet there has been limited development of new therapeutic options for patients in more than 30 years," commented Donald Lamm, M.D., University of Arizona professor, director of BCG oncology and an investigator in the VISTA trial. "Today’s standard-of-care for NMIBC provides initial responses in many patients; however, after BCG is no longer effective, there are no meaningful FDA-approved options except surgical removal of the bladder in high-risk patients. I am encouraged by the data demonstrated with Vicinium in prior trials and its potential to offer my patients an alternative to radical cystectomy."

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"We believe Vicinium is the most advanced candidate in development for NMIBC and has the potential to be an effective and tolerable treatment for patients who have been previously treated with BCG," said Stephen Hurly, president and chief executive officer of Eleven Biotherapeutics. "The complete response rate and favorable safety seen in our Phase 2 trial were encouraging, and based on learnings from that trial, we modified the dosing regimen to potentially further enhance responses in the VISTA trial. With Phase 3 recruitment complete, we are on-track to report topline, three-month data in mid-2018, and look forward to further assessing Vicinium’s potential in treating patients with this devastating cancer."

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. Patients in the

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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. For more information, please visit www.mybladdercancer.com.

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. 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.

About Non-Muscle Invasive Bladder Cancer
Bladder cancer is the sixth most commonly diagnosed cancer in the United States, and approximately 80 percent of patients have non-muscle invasive bladder cancer (NMIBC). In NMIBC, cancer cells are in the lining of the bladder or have grown into the lumen of the bladder, but have not spread into muscle or other tissue. NMIBC primarily affects men and is associated with carcinogen exposure. Initial treatment includes surgical resection; however, there is a high rate of recurrence and more than 60 percent of all patients diagnosed with NMIBC will receive bacillus Calmette-Guérin (BCG) immunotherapy. While BCG is effective in many patients, challenges with tolerability have been observed and many patients will experience recurrence of disease. If BCG is not effective or a patient can longer receive BCG, the recommended option for treatment is radical cystectomy, the complete removal of the bladder.