On November 5, 2018 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development of novel products for serious rare and ultra-rare genetic diseases, reported its financial results and corporate update for the quarter ended September 30, 2018 (Press release, Ultragenyx Pharmaceutical, NOV 5, 2018, View Source [SID1234530762]).

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"We’re encouraged by the growing demand for Crysvita from both children and adults with XLH in the United States, and we are making significant progress reaching doctors and helping them get patients on commercially available therapy in this early launch phase," said Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and President of Ultragenyx. "Next year, we expect to file for potential approval of our third therapy, UX007 in fatty acid oxidation disorders, and we continue to advance our two gene therapy clinical programs with additional data expected around the end of this year and in 2019."

Financial Results

For the third quarter of 2018, Ultragenyx reported a net loss of $87.3 million, or $1.74 per share, basic and diluted, compared with a net loss for the third quarter of 2017 of $79.2 million, or $1.87 per share, basic and diluted. For the nine months ended September 30, 2018, net loss was $109.8 million, or $2.22 per share, basic and diluted, compared with a net loss for the same period in 2017 of $220.4 million, or $5.22 per share, basic and diluted. The loss from the first nine months was reduced by the sale of the Mepsevii (vestronidase alfa) priority review voucher (PRV) in January 2018 for net proceeds of $130.0 million and a $40.3 million gain from Ultragenyx’s portion of the sales of the PRV received with the Crysvita (burosumab) approval. The net loss for the first nine months of 2018 reflected cash used in operations of $234.7 million compared to $172.0 million for the same period in 2017.

Net Revenues

For the third quarter of 2018, Ultragenyx reported $11.8 million in total revenue. For Crysvita, Ultragenyx recognized $5.4 million in profit sharing and royalty revenue from its collaboration and license agreement with Kyowa Hakko Kirin. This includes $4.4 million in collaboration revenue in the U.S. profit share territory and $1.0 million in royalty revenue in the European territory. Net product sales for Crysvita in other regions were nominal. Mepsevii product revenue for the third quarter of 2018 was $2.1 million, and UX007 named patient revenue was $0.4 million. Ultragenyx recognized $3.6 million in revenue from its research agreement with Bayer.

Operating Expenses

Total operating expenses for the third quarter of 2018 were $101.4 million compared with $83.9 million for the same period in 2017, including non-cash stock-based compensation of $20.7 million and $17.2 million in the third quarter of 2018 and 2017, respectively. Total operating expenses for the nine months ended September 30, 2018, were $316.3 million compared with $232.3 million for the same period in 2017, including non-cash stock-based compensation of $59.0 million and $48.5 million in the first nine months of 2018 and 2017, respectively. The increase in total operating expenses is due to the increase in commercial, development, and general and administrative costs as the company commercializes, grows and advances its pipeline.

Cash, Cash Equivalents and Investments

Cash, cash equivalents and investments were $503.1 million as of September 30, 2018.

Recent Updates

Crysvita in X-Linked Hypophosphatemia (XLH)

Ultragenyx submitted regulatory filings in Canada, Brazil and Colombia. We anticipate regulatory decisions in these markets over the course of 2019. Reimbursed named patient treatment has already begun in Argentina in response to physician requests for multiple patients.
Crysvita in Tumor-Induced Osteomalacia (TIO)

Positive longer-term 48-week and 72-week data from the Phase 2 study of Crysvita in adults with TIO were presented at the American Society for Bone and Mineral Research (ASBMR) 2018 Annual Meeting in Montreal. In adults with TIO, Crysvita was associated with increases in serum phosphorus and serum 1,25 dihydroxy vitamin D levels; improvements in osteomalacia, mobility and vitality; and reductions in fatigue. Adverse events (AE) generally reflected the patients’ underlying diseases, and there were no serious treatment-related AEs during the study. Discussions with the U.S. Food and Drug Administration (FDA) regarding the regulatory pathway are ongoing.
Mepsevii in Mucopolysaccharidosis VII (MPS VII)

The European Commission (EC) approved the Marketing Authorization Application (MAA) for Mepsevii under exceptional circumstances for the treatment of non-neurological manifestations of MPS VII. Mepsevii is now approved for use in all 28 EU countries as well as in Iceland, Liechtenstein and Norway, and has launched in Germany.
Brazil’s National Health Surveillance Agency approved Mepsevii for the treatment of MPS VII for patients of all ages. Additional regulatory decisions for patients in Columbia and Chile are anticipated over the course of 2019.
UX007 in Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) and Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)

The FDA accepted Ultragenyx’s proposal to submit a New Drug Application (NDA) for UX007 for the treatment of LC-FAOD based on currently available data. Further details will be forthcoming following a pre-NDA meeting, which is scheduled to take place by the end of 2018. Additionally, discussions are progressing with the European Medicines Agency regarding a potential conditional marketing authorization in Europe.

In October 2018, Ultragenyx announced that the Phase 3 study evaluating UX007 in patients with Glut1 DS did not achieve its primary endpoint compared to placebo. The safety profile observed in this study was consistent with what has been previously reported with UX007. Ultragenyx plans to discontinue further Glut1 DS clinical development for UX007, and expects no impact on plans for the LC-FAOD indication.
DTX301 Gene Therapy in Ornithine Transcarbamylase (OTC) Deficiency

Positive topline data from the first two dose cohorts of the Phase 1/2 study demonstrate normalization of ureagenesis in two patients and further support proof-of-concept. The first responder (Cohort 1) showed a further increased level of ureagenesis at 52 weeks and has been clinically stable for more than eight months after discontinuing alternate pathway medications and also after liberalizing a protein-restricted diet near the 52 week time point. The second responder (Cohort 2) achieved normalization of ureagenesis at 24 weeks, and has been clinically stable for more than one month after also discontinuing all alternate pathway medications. The remaining four patients in Cohorts 1 and 2 continue to demonstrate no clinically meaningful change in rate of ureagenesis. All patients have remained clinically and metabolically stable, with only modest rises in ALT well treated by a reactive, tapering steroid regimen. The first patient in cohort 3 has been dosed. Data from higher dose Cohort 3 are expected in mid-2019.
DTX401 Gene Therapy in Glycogen Storage Disease Type Ia (GSDIa)

All three patients in the lowest-dose Cohort 1 of the Phase 1/2 study have been dosed. Data from this cohort are expected around the end of 2018.
CDKL5 Deficiency Disorder (CDD)

Ultragenyx exercised its option with REGENXBIO Inc. to develop a gene therapy to treat patients with CDD using REGENXBIO’s adeno-associated virus (AAV) vectors, including AAV9. CDD is a severe and debilitating neurological disorder that shares many features of Rett Syndrome. It was commonly identified as an atypical Rett Syndrome until improved genetic testing led to more accurate diagnosis and an increasing prevalence of diagnosed CDD-affected patients.
Corporate

Ultragenyx appointed a Chief Operating Officer, Wladimir (Vlad) Hogenhuis, M.D., on September 28, 2018. In this newly created role, Dr. Hogenhuis oversees the Global Commercial, Business Development, and Manufacturing organizations.
Conference Call and Webcast Information

Ultragenyx will host a conference call today, Monday, November 5, 2018, at 2 p.m. PT/ 5 p.m. ET to discuss third quarter 2018 financial results and provide a corporate update. The live and replayed webcast of the call will be available through the company’s website at View Source To participate in the live call by phone, dial (855) 797-6910 (USA) or (262) 912-6260 (international) and enter the passcode 1290627. The replay of the call will be available for one year.

On November 5, 2018 BioXcel Therapeutics, Inc. ("BTI" or "Company") (BTAI), reported that the U.S. Food and Drug Administration ("FDA"), has accepted its Investigational New Drug ("IND") application for its lead immuno-oncology candidate, BXCL701 (Press release, BioXcel Therapeutics, NOV 5, 2018, View Source [SID1234530886]). BTI plans to evaluate BXCL701 in combination with pembrolizumab (Keytruda) as a potential therapy for treatment-emergent neuroendocrine prostate cancer ("tNEPC"), with the trial expected to initiate in the fourth quarter of 2018. BTI is a clinical stage biopharmaceutical development company that utilizes novel artificial intelligence approaches to identify the next wave of medicines across neuroscience and immuno-oncology.

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Dr. Vincent J. O’Neill, Senior Vice President and Chief Medical Officer of BTI, commented, "FDA approval of this IND is a significant milestone for our BXCL701 program, as we are now able to commence the Phase 1b/2 combination study in tNEPC patients. We believe that the combination of BXCL701 and pembrolizumab has the potential to meaningfully improve the lives of patients with this highly aggressive, rare form of prostate cancer, and to succeed where current checkpoint inhibitor monotherapies have demonstrated limited clinical benefit. We have an obligation to tNEPC patients to find a viable treatment and look forward to evaluating the combination in this trial."

Dr. Vimal Mehta, Chief Executive Officer of BTI added, "The FDA approval of this IND and initiation of this trial provides an important validation of our AI-powered approach to drug development, which enables us to develop therapeutic candidates more quickly, at a lower cost and with a higher probability of success than with traditional drug development approaches."

The Phase 1b/2 study is expected to enroll up to 40 subjects at multiple trial sites. The goal of this single arm, Simon 2-stage open label study is to examine the safety, pharmacokinetics and anti-tumor activity of the combination of BXCL701 and pembrolizumab in tNEPC patients with the efficacy endpoint of objective response rate. Data readouts are expected throughout 2019.

About BXCL701

BXCL701 is an orally-available systemic innate-immune activator with dual mechanisms of action. It has demonstrated single agent activity in melanoma, with an established

safety profile from 700 healthy subjects and cancer patients. Designed to stimulate both the innate and acquired immune systems, BXCL701 works by inhibiting dipeptidyl peptidase (DPP) 8/9 and blocking immune evasion by targeting Fibroblast Activation Protein (FAP). Preclinical combination data evaluating BXCL701, a checkpoint inhibitor and other immuno-oncology agents has demonstrated encouraging anti-tumor activity in multiple tumor types and formation of functional immunological memory. BXCL701’s primary mechanism of action has recently been highlighted in multiple peer reviewed journals, providing an important validation of the scientific rationale behind BXCL701.

About Treatment-emergent neuroendocrine prostate cancer (tNEPC)

tNEPC is a rare hormone-refractory manifestation of prostate cancer occurring secondary to treatment with androgen deprivation therapies such as Zytiga (Johnson & Johnson) and Xtandi (Pfizer). This form of highly aggressive tumor, with no current treatment, is observed in approximately 20-30% of patients treated with androgen inhibitors and has a median survival time of less than one year. Single agent checkpoint inhibitor therapy produces very low response rates in hormone refractory prostate cancer, creating a major unmet medical need for tNEPC patients.

On November 5, 2018 Crescendo Biologics Ltd (Crescendo), the drug developer of novel, targeted T-cell enhancing therapeutics, reported that Takeda Pharmaceutical Company Limited (Takeda), has exercised an option under its existing, multi-target collaboration and license agreement (Press release, Crescendo Biologics, NOV 5, 2018, View Source [SID1234530725]). Takeda has taken an exclusive licence to Humabodies directed to one of its oncology targets.

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This licence option exercise comes substantially earlier than planned and marks the highly successful delivery and further pre-clinical evaluation by Takeda of Humabody leads meeting its stringent criteria.
Dr Peter Pack, CEO of Crescendo, commented:

"The team at Crescendo has made great progress on our Humabody programmes, working closely with the Takeda team. To date, we have met all the technical milestones on time or earlier than planned, which is proof of our excellent collaboration. We are delighted that the option to license has been taken by Takeda ahead of schedule and look forward to further future successes."

Chris Arendt, Head, Oncology Drug Discovery Unit & Immunology Unit, Takeda, commented:
"At Takeda, we continue to research diverse modalities to bring transformative treatments to patients with cancer. Our decision to exercise the licence was based on the quality of the Humabody leads and the potential we see to develop improved and differentiated immuno-oncology therapies."

Takeda’s option is part of the existing multi-target collaboration and licence agreement announced in October 2016 where Takeda received the right to develop and commercialise Humabody-based therapeutics resulting from the collaboration. Under the agreement, Crescendo is eligible to receive clinical development, regulatory and sales-based milestone payments of up to $754 million plus royalties on Humabody-based product sales by Takeda.

On November 5, 2018 AVEO Oncology (NASDAQ: AVEO) reported positive topline results from the primary analysis of the TIVO-3 trial, the Company’s Phase 3 randomized, controlled, multi-center, open-label study to compare tivozanib (FOTIVDA) to sorafenib in 351 subjects with highly refractory advanced or metastatic renal cell carcinoma (RCC) (Press release, AVEO, NOV 5, 2018, View Source [SID1234530742]).

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The trial met its primary endpoint of demonstrating a statistically significant benefit in progression-free survival (PFS). Tivozanib demonstrated a 44% improvement in median PFS and 26% reduction in risk of progression or death (Hazard Ratio [HR]=0.74, p=0.02). Median PFS was 5.6 months for tivozanib compared to 3.9 months for sorafenib. The TIVO-3 trial enrolled patients with RCC who have failed at least two prior regimens. Among these, approximately 26% of patients received checkpoint inhibitor therapy in earlier lines of treatment. Tivozanib PFS was longer than sorafenib both in patients who received prior checkpoint inhibitor therapy and those who did not.

The analysis of the secondary endpoint of overall survival (OS) was not mature at the time of the final PFS analysis, with only 46% of potential OS events having been reported. At the time of the preliminary OS analysis, no statistically significant difference in OS was observed (HR=1.06, p=0.69). The final survival analysis per protocol is planned for August 2019, two years following the last patient enrolled. Detailed results of the trial will also be submitted for presentation at an upcoming major medical meeting. The secondary endpoint of overall response rate for patients receiving tivozanib was 18% compared to 8% for patients receiving sorafenib (p=0.02).

Tivozanib was generally well-tolerated, with grade 3 or higher adverse events consistent with those observed in previous tivozanib trials. Infrequent but severe adverse events reported in greater number in the tivozanib arm were thrombotic events similar to those observed in previous tivozanib studies. The most common adverse event in patients receiving tivozanib was hypertension, an adverse event known to reflect effective VEGF pathway inhibition.2

Based on results from the TIVO-3 trial, together with the previously completed Phase 3 TIVO-1 trial of tivozanib in the first line treatment of RCC, the Company’s goal is to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in approximately six months.

"Tivozanib’s therapeutic profile is distinct among VEGF TKIs as a treatment for RCC, with the TIVO-3 trial demonstrating a significant PFS benefit and a favorable tolerability profile," said Brian Rini, MD, Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Director, Cleveland Clinic Genitourinary Cancer Program, and principal investigator of the TIVO-3 trial. "In the advanced disease setting, these outcomes are particularly meaningful, providing the first large, pivotal dataset that shows sequencing of treatment following earlier TKI and immunotherapy treatment. This profile suggests an important place for tivozanib in the evolving treatment paradigm for RCC and, taken together with early combination data, the need to study tivozanib further in combination with immunotherapies."

"Our determination to fight for tivozanib in 2015, when AVEO faced an important strategic crossroads, came from our belief that it could have a meaningful impact not just on how a disease was treated, but also what the patient experiences through that treatment. Today’s outcome is the culmination of that multi-year effort, and a first step in our goal to improve both outcomes and patient experience," said Michael Bailey, president and chief executive officer of AVEO. "We owe our deepest gratitude to the healthcare professionals, many of whom long believed in the potential of tivozanib, and to the patients and their families for participating in our pivotal studies."

Conference Call and Webcast

In connection with this announcement, AVEO will host a conference call and slide webcast today, November 5, 2018 at 5:00 pm Eastern Time. The call can be accessed by dialing (844) 882-7841 (U.S. and Canada) or (574) 990-9828 (international). The passcode for the conference call is 7078805. To access the live audio webcast, or the subsequent archived recording, please visit the Investors section of the AVEO website at www.aveooncology.com. The webcast will be recorded and available for replay on AVEO’s website for two weeks.

About TIVO-3

The TIVO-3 trial was designed to enroll patients with RCC who have failed at least two prior regimens, including VEGFR-TKI therapy. Eligible patients may also have received checkpoint inhibitor therapy in earlier lines of treatment. Patients are randomized 1:1 to receive either tivozanib or sorafenib, with no crossover between arms. The primary endpoint of the study is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and safety and tolerability. TIVO-3, together with the previously completed TIVO-1 trial of tivozanib in the first line treatment of RCC, is designed to support a regulatory submission of tivozanib in the U.S. as a treatment for RCC in multiple lines of therapy. TIVO-3 patients were exclusively enrolled in North America, Western Europe, and Central Europe.

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 (RCC) 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.3,4 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models, enabling potentially enhanced activity when used in combination with immune modulating therapy.5 Tivozanib has been investigated in several tumors types, including renal cell, hepatocellular, colorectal and breast cancers.

On November 5, 2018 FLX Bio, Inc., a clinical-stage, biopharmaceutical company focused on the development of oral small-molecule drugs that target drivers of cancer and other immune-related disorders, reported that it has established a clinical trial collaboration agreement with Merck (known as MSD outside the U.S. and Canada) to conduct a Phase 1/2 study evaluating the safety and efficacy of the combination of KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy , and FLX Bio’s investigational oral small molecule CCR4 inhibitor, FLX475, in patients with multiple types of cancer (Press release, FLX Bio, NOV 5, 2018, View Source [SID1234530726]).

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The open-label, dose-escalation and cohort expansion Phase 1/2 study is enrolling patients with multiple types of cancer at leading cancer centers across the United States, Australia and Asia. In addition to evaluating the safety and tolerability of FLX475 as a monotherapy and in combination with pembrolizumab, the study will evaluate changes in the tumor microenvironment and the antitumor activity of both monotherapy and combination therapy. For more information please visit clinicaltrials.gov identifier NCT03674567.

"We are extremely pleased to collaborate with Merck, an established leader in the field of cancer immunotherapy," said Brian Wong, M.D., Ph.D., CEO of FLX Bio. "KEYTRUDA is an anti-PD1 immunotherapy that has demonstrated efficacy in a range of cancers. FLX475 targets a novel mechanism to selectively inhibit the recruitment of regulatory T cells (Treg) into the tumor, where Treg potentially suppress the anti-tumor immune response; thus FLX475 has the potential to deepen and broaden the efficacy of KEYTRUDA when combined. We are excited to collaborate with the Merck team to evaluate the efficacy of a combination of FLX475 and KEYTRUDA which we believe could substantially improve patient outcomes."

Keytruda is a registered trademark of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

About FLX475
FLX475 is a best-in-class oral, small molecule antagonist of CCR4 which selectively blocks suppressive regulatory T cells in tumor tissue and promotes a durable anti-tumor immune response. FLX Bio has completed a study of FLX475 in healthy volunteers, demonstrating that the compound is safe with excellent pharmacokinetic and pharmacodynamic properties. In preclinical studies, FLX475 inhibited tumor growth and increased tumor regression as a single agent. In addition, FLX475 enhanced the anti-tumor effects of various checkpoint inhibitors as well as immune agonist antibodies. FLX475 also has the potential to enhance cell-based immunotherapies such as CAR-T and cancer vaccines. In contrast to depleting antibody approaches, FLX475 selectively blocks the recruitment of regulatory T cells to the tumor site and does not deplete cells beneficial to an anti-tumor response or regulatory T cells in healthy tissue.