On November 15, 2018 SELLAS Life Sciences Group, Inc. (Nasdaq:SLS) ("SELLAS" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of novel cancer immunotherapies for a broad range of cancer indications, reported financial results for the quarter ended September 30, 2018 (Press release, Sellas Life Sciences, NOV 15, 2018, View Source [SID1234531355]).

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"Throughout the third quarter and in recent weeks, we made significant progress advancing our clinical development programs while also improving the Company’s financial standing. We strengthened our cash position with an equity offering in July and the recent settlement with JGB removed all outstanding debt while bringing an additional $6.6 million into the Company. Our Phase 1/2 galinpepimut-S (GPS) basket study in collaboration with Merck is progressing well and we are also further preparing for our registrational Phase 3 GPS trial in acute myeloid leukemia (AML) which we look forward to commencing in early 2019," said Angelos Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS. "We also continue to be excited about our nelipepimut-S (NPS, Neuvax) program in triple negative breast cancer (TNBC) patients as we review additional correlative data from the positive Phase 2b study. We have submitted a robust regulatory briefing to the FDA for review and hope to agree on the most optimal development program for NPS in TNBC in December while we continue our discussions with potential partners."

Third Quarter 2018 and Recent Business Highlights

Clinical Pipeline
During the third quarter, several clinical sites were activated in the planned Phase 1/2 open label five-arm basket type trial of galinpepimut-S (GPS) administered in combination with Merck & Co.’s PD-1 inhibitor, pembrolizumab (Keytruda), with patients currently being screened.
In October and November 2018, the Company reported on final data for nelipepimut-S (NPS, Neuvax). In October 2018, the independent Data Safety Monitoring Board concluded that the final positive data (median follow-up of more than 26 months) from the Phase 2b study of trastuzumab (Herceptin) +/- NPS in HER2 1+/2+ breast cancer patients confirmed the previously disclosed interim positive data (median follow-up of less than 19 months) in triple negative breast cancer (TNBC) patients. This positive final data was presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Annual Meeting. The final Phase 2b study data revealed a clinically meaningful and statistically significant difference in favor of the active arm, NPS plus trastuzumab (vs. trastuzumab alone), in TNBC patients at 26 months with a p-value of 0.013 and a 75.2% relative risk reduction of relapse or death and showed no imbalances in safety between the active arm and the control arm. In November 2018, SELLAS announced additional data from a preplanned secondary efficacy analysis of the Phase 2b study data showing consistent clinical effect across HLA allele subgroups in TNBC patients, including the HLA-A24+ subgroup which is highly prevalent in the Asian population. This additional efficacy analysis showed a clinically meaningful and statistically significant benefit in the HLA-A24+ subgroup with a p-value of 0.003 and a 90.6% relative risk reduction of relapse or death in favor of the active arm, NPS plus trastuzumab. The Company is continuing to advance potential partnering discussions for NeuVax.

Regulatory
A meeting with the U.S. Food and Drug Administration (FDA) to discuss the most optimal regulatory pathway for further development of NPS in TNBC patients is scheduled to take place in December 2018.
In September 2018, SELLAS announced that the Committee for Orphan Medicinal Products of the European Medicines Agency approved orphan medicinal product designation for GPS for the treatment of multiple myeloma (MM).
In July 2018, SELLAS announced that the FDA granted Fast Track designation to GPS for the treatment of MM.

Corporate
In October 2018, the U.S. District Court for the Southern District of New York entered an order granting in full the Company’s motion to dismiss the complaint brought by JGB (Cayman) Newton, Ltd. (JGB) in connection with a senior secured debenture entered into by SELLAS’ predecessor while allowing SELLAS’ substantive counterclaims against JGB to remain. In November 2018, the Company announced that it had reached a settlement with JGB regarding the counterclaims. The Company received approximately $6.6 million in the settlement and the debenture and all related agreements, liens and security interests were terminated.
In July 2018, SELLAS completed an underwritten public offering of common stock and pre-funded warrants, together with accompanying common stock warrants, for aggregate net proceeds of approximately $21.6 million, after deducting underwriting discounts, commissions and offering expenses.
As of September 30, 2018, unrestricted cash and cash equivalents were $10.0 million compared to $2.3 million as of December 31, 2017.
Third Quarter 2018 Financial Results

For accounting purposes, SELLAS Life Sciences Group Ltd., a private Bermuda exempted company (SELLAS Ltd.), is considered to have acquired the Company (which was formerly known as Galena Biopharma, Inc. (Galena) in the business combination between SELLAS Ltd. and Galena (the Merger); therefore, upon the Merger, the financial statements of Galena became those of SELLAS Ltd. and the results reported are those of SELLAS Ltd. reflecting the acquisition of Galena as of December 29, 2017.

Cash Position: As of September 30, 2018, unrestricted cash and cash equivalents totaled $10.0 million which does not include a $6.6 million payment received by the Company that was related to the settlement of litigation with JGB in November 2018. Unrestricted cash and cash equivalents as of December 31, 2017 totaled $2.3 million.

Net cash used in operating activities was $25.9 million for the nine months ended September 30, 2018, which includes $4.3 million used to reduce payables related to the Merger. During the third quarter SELLAS received a total of $21.6 million in net proceeds, after deducting fees and expenses, from an underwritten public offering of common stock and pre-funded warrants, together with accompanying common stock warrants that was completed in July.

R&D Expenses: Research and development expenses were $1.7 million for the third quarter of 2018, as compared to $1.1 million for the third quarter of 2017. The increase was primarily due to the initiation of the Phase 1/2 clinical trial for GPS in combination with Keytruda and ongoing costs incurred during the third quarter related to the Phase 2b trial for NPS in combination with trastuzumab in breast cancer, as well as increased licensing fees resulting from our expanded clinical portfolio as a result of the Merger. This increase was partially offset by a reduction in stock-based compensation during the third quarter of 2018. Research and development expenses for the nine months ended September 30, 2018 were $5.1 million and were $5.1 million for the same period in 2017.

G&A Expense: General and administrative expenses were $1.3 million for the third quarter of 2018, as compared to $3.2 million for the third quarter of 2017. The decrease in the current period was primarily due to a reduction in stock-based compensation and the accounting treatment for costs related to litigation and other legal matters associated with the settlement of the JGB litigation and resulting reimbursement of legal fees. This decrease was partially offset by an increase in personnel related expenses, insurance and other expenses. General and administrative expenses for the first nine months of 2018 were $10.1 million, as compared to $9.4 million for the nine months ended September 30, 2017. The increase was primarily related to costs associated with outside services, accounting and audit expenses, insurance and public company costs, partially offset by a reduction in stock-based compensation and a decrease in financing and advisory fees associated with the Merger.

Net Loss: Net loss attributable to common stockholders was $9.4 million for the third quarter of 2018, or a basic and diluted loss per share attributable to common stockholders of $0.53, as compared to a net loss attributable to common stockholders of $4.5 million for the third quarter of 2017, or a basic and diluted loss per share attributable to common stockholders of $2.27. The increase in net loss was driven primarily by non-cash charges related to equity issuances during 2018.

Conference Call and Webcast Information

SELLAS will host a conference call and live audio webcast today at 8:00 a.m. ET to discuss these financial results and provide a business update. To participate in the conference call, please dial (866) 416-7995 (domestic) or (409) 217-8225 (international) and refer to conference ID 7038536. A live webcast of the call can be accessed under "Events & Presentations" in the Investors section of the Company’s website at www.sellaslifesciences.com. An archived webcast recording will be available on the SELLAS website beginning approximately two hours after the call.

On November 15, 2018 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company focused on the development of oncology drug candidates, all of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center, reported it has filed a request with the US Food and Drug Administration (FDA) for a Pre-Investigational New Drug (IND) Meeting to seek FDA’s guidance and concurrence that the WP1732 development plan will meet requirements for an Initial IND filing and initiation of a proposed Phase 1 clinical trial (Press release, Moleculin, NOV 15, 2018, View Source [SID1234531354]).

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"Independent animal model testing has now confirmed high uptake and retention of WP1732 in the pancreas," commented Walter Klemp, Moleculin’s Chairman and CEO. "Taken together with the previous observations of consistent activity against pancreatic cancer in in vitro and in vivo tumor models, this could make WP1732 ideally suited as a new therapy for treating pancreatic cancer. Our request for a Pre-IND Meeting with the FDA represents another important milestone in our effort to begin clinical trials with this promising new drug candidate."

On November 15, 2018 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported updated data for the registration-enabling NAVIGATOR clinical trial of avapritinib, a potent and highly selective KIT and PDGFRA inhibitor in development for patients with advanced gastrointestinal tumors (GIST) (Press release, Blueprint Medicines, NOV 15, 2018, View Source [SID1234531353]). The data showed that avapritinib was highly active across all lines of therapy for patients with PDGFRα D842V-driven GIST and in second-, third- and fourth-line for other GIST patients. In addition, avapritinib was well-tolerated with most adverse events (AEs) reported by investigators as Grade 1 or 2. These results will be presented today in an oral presentation at the Connective Tissue Oncology Society 2018 Annual Meeting in Rome, Italy.

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The updated data from the ongoing Phase 1 NAVIGATOR trial support Blueprint Medicines’ plans to submit a New Drug Application (NDA) in the first half of 2019 to the U.S. Food and Drug Administration (FDA) for the treatment of PDGFRA Exon 18 mutant GIST, which primarily includes patients with the D842V mutation, and fourth-line GIST. There are currently no approved or effective therapies in these patient populations. In patients with PDGFRα D842V-driven GIST, avapritinib demonstrated an objective response rate (ORR) of 84 percent and a 12-month duration of response (DoR) of 76 percent. In heavily pre-treated patients with fourth-line or later GIST, avapritinib demonstrated an ORR of 20 percent, tumor reductions in 60 percent of patients and a median DoR of 7.3 months. ORR and DoR per central radiographic review will be the primary endpoints for the NDA submission, consistent with regulatory precedent for accelerated approvals based on single-arm oncology studies. In addition, avapritinib demonstrated an ORR of 26 percent in regorafenib-naïve third- and fourth-line GIST and an ORR of 25 percent in second-line GIST. Patients with PDGFRα D842V-driven GIST were excluded from both of these populations.

"With an increased understanding of molecular drivers of GIST over the last decade, it is encouraging to see an investigational drug, like avapritinib, bring a precision therapy approach to GIST," said Michael Heinrich, M.D., Professor of Medicine at Oregon Health & Science University and an investigator on the NAVIGATOR trial. "Avapritinib has the potential to be a significant therapeutic advance in GIST, a rare cancer with high medical needs across lines of treatment. In particular, the updated data demonstrate the broad clinical impact of avapritinib for patients with PDGFRα D842V-driven GIST and fourth-line GIST, where there are currently no effective therapies. In addition, the data strongly support clinical development of avapritinib in early lines, including second- and third-line treatment."

"These data highlight the potential of avapritinib, a potent and highly selective inhibitor of KIT and PDGFRA mutant kinases, to be a cornerstone precision therapy in GIST," said Andy Boral, M.D., Ph.D., Chief Medical Officer of Blueprint Medicines. "The results validate Blueprint Medicines’ approach to designing precision therapies that specifically target genetic drivers of disease, with the goals of delivering transformative benefit to patients and enabling rapid progress toward registration. Avapritinib’s highly potent anti-tumor activity in PDGFRα D842V-driven GIST, combined with differentiated activity across treatment lines in KIT-driven GIST, reflect its promise as a potentially foundational treatment option across multiple GIST populations. We are committed to advancing a comprehensive and scientifically driven clinical development program with the goal of improving the lives of GIST patients."

Data Highlights from the Ongoing Phase 1 NAVIGATOR Clinical Trial

As of the data cutoff date of October 15, 2018, 231 patients were treated with avapritinib in the dose escalation and expansion portions of the Phase 1 clinical trial at eight dose levels, ranging from 30 mg once daily (QD) to 600 mg QD. This population consisted of 167 patients with KIT-driven GIST, 56 patients with PDGFRα D842V-driven GIST and eight patients with other PDGFRA mutations. Patients in the expansion portion of the clinical trial were treated at the recommended Phase 2 dose of 300 mg QD.

Safety Data

As of the data cutoff date, avapritinib was well-tolerated, and most AEs reported by investigators were Grade 1 or 2. Across all doses, 20 patients (8.7 percent) discontinued treatment with avapritinib due to treatment-related AEs.

Across all grades, the most common treatment-emergent AEs (regardless of relationship to avapritinib) reported by investigators (≥20 percent) included nausea (61 percent), fatigue (55 percent), anemia (46 percent), periorbital edema (40 percent), diarrhea (39 percent), vomiting (38 percent), decreased appetite (35 percent), peripheral edema (33 percent), increased lacrimation (31 percent), memory impairment (26 percent), constipation (23 percent), face edema (23 percent), hair color changes (21 percent) and dizziness (20 percent).

Investigator-reported Grade 3 or 4 treatment-related AEs (≥2 percent) included anemia, fatigue, hypophosphatemia, increased bilirubin, decreased white blood count/neutropenia and diarrhea.

Clinical Activity Data

As of the data cutoff date, the following patients were evaluable for response assessments: 56 patients with PDGFRα D842V-driven GIST, 109 patients with fourth-line or later GIST, 23 patients with third- or fourth-line GIST who did not receive prior regorafenib (which is comparable to the VOYAGER trial population) and do not harbor the PDGFRα D842V mutation, and 20 patients with second-line GIST who do not harbor the PDGFRα D842V mutation. Patients were evaluable if they had at least one centrally reviewed radiographic scan, and data are based on modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1 criteria) for GIST.

Across multiple lines of therapy, avapritinib demonstrated important clinical activity in patients with PDGFRA- and KIT-driven GIST.

GIST Population

Evaluable
Patients

ORR

Clinical Benefit Rate
at Four Months
(≥Two Scans)

Median DoR

Median PFS

Central Review
(Investigator Review)

PDGFRα D842Va

56

84%f

96%

Not estimable;
76% at 12 months

Not reached

Fourth-line or laterb,c

109

20%g

40%

7.3 months

3.7 months
(5.4 months)

Regorafenib-naïve third-
or fourth-lineb,d

23

26%

70%

10.2 months

8.6 months
(10.2 months)

Second-lined,e

20

25%h

NRi

NRi

NRi

Notes: (a) Treated at all doses; (b) Treated at doses of 300 or 400 mg QD; (c) Included patients with the PDGFRα D842V mutation, whose proportion was consistent with the known mutational prevalence in this GIST population; (d) Did not include patients with the PDGFRα D842V mutation, whose proportion was greater than the known mutational prevalence in this GIST population; (e) Treated at doses up to and including 300 or 400 mg QD; (f) Four PR pending confirmation; (g) One PR pending confirmation; (h) Three PR pending confirmation; (i) NR, not reported, as data are too early to estimate.

Additional Data Support Clinical Development Strategy in Earlier Lines of Therapy

Third- and Fourth-Line GIST

Preliminary data showed robust clinical activity in regorafenib-naïve third- and fourth-line GIST patients lacking the PDGFRα D842V mutation. As of the data cutoff date, the ORR was 26 percent, tumor reductions were demonstrated in 78 percent of patients, and the median PFS was 8.6 months per central radiographic review and 10.2 months per investigator review. In contrast, historical data showed a 5 percent ORR and a median PFS of 4.8 months for regorafenib, the current standard-of-care treatment in third-line GIST.

In regorafenib-naive patients with PDGFRα D842V-driven third- or fourth-line GIST, the ORR was 80 percent (eight out of 10 evaluable patients, with one response pending confirmation). Blueprint Medicines’ ongoing Phase 3 VOYAGER trial of avapritinib versus regorafenib in third- or fourth-line GIST permits enrollment of patients with both KIT- and PDGFRA-driven GIST, including patients with the PDGFRα D842V mutation. Blueprint Medicines anticipates completing enrollment of the VOYAGER trial in the second half of 2019.

Second-Line GIST

Preliminary data showed a 25 percent ORR in second-line GIST, excluding patients with the PDGFRα D842V mutation. In patients with second-line PDGFRα D842V-driven GIST, the ORR was 94 percent (15 out of 16 evaluable patients, with two responses pending confirmation).

In addition, analyses of circulating tumor DNA (ctDNA) from the NAVIGATOR trial across all lines showed increased activity for avapritinib in patients without the secondary KIT V654A or T670I mutations, which are estimated to occur in about 20 to 25 percent of GIST patients following treatment with imatinib (second-line or later). Independently published data for sunitinib, the current standard of care therapy for second-line GIST, have shown activity against these mutations.

Based on the totality of data, Blueprint Medicines believes a precision medicine approach has the potential to optimize patient outcomes in second-line GIST. The company plans to initiate the registration-enabling Phase 3 COMPASS-2L clinical trial in the second half of 2019 using a ctDNA-guided patient selection strategy. The planned trial will select patients with PDGFRA- and KIT-driven second-line GIST who do not have the KIT V654A or T670I mutations, and randomize them to receive avapritinib or sunitinib with an anticipated primary endpoint of PFS.

Conference Call Information

Blueprint Medicines will host a live conference call and webcast on November 15, 2018 at 7:30 a.m. ET to review the updated data for avapritinib in GIST. The conference call may be accessed by dialing (855) 728-4793 (domestic) or (503) 343-6666 (international) and referring to conference ID 3479587. A live webcast of the conference call will be available under "Events and Presentations" in the Investors section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the conference call and will be available for 30 days following the call.

About the Avapritinib Clinical Development Program in GIST

Blueprint Medicines is pursuing a broad clinical development program for avapritinib across all lines of GIST. Avapritinib is currently being evaluated in two ongoing registration-enabling clinical trials for GIST: the Phase 1 NAVIGATOR trial and the Phase 3 VOYAGER trial.

The NAVIGATOR trial is designed to evaluate the safety and tolerability of avapritinib in patients with advanced GIST. The trial consists of two parts, a dose escalation portion and an expansion portion. The dose escalation portion is complete, and trial objectives include assessing response, pharmacokinetics and pharmacodynamic measures. Response assessments use blinded, central radiology review. The expansion cohorts of the trial are designed to enroll a total of approximately 200 patients at multiple sites in the United States, United Kingdom and European Union.

The VOYAGER trial is a global, open-label, randomized, Phase 3 trial designed to evaluate the safety and efficacy of avapritinib versus regorafenib in patients with third- or fourth-line advanced GIST. The trial is designed to enroll approximately 460 patients randomized 1:1 to receive either avapritinib or regorafenib at multiple sites in the United States, United Kingdom, European Union, Australia and Asia.

In the second half of 2019, Blueprint Medicines plans to initiate COMPASS-2L, a global, randomized, Phase 3 precision medicine trial. The trial will evaluate the safety and efficacy of avapritinib versus sunitinib in patients with second-line advanced GIST and pre-specified disease genotypes.

Patients and physicians interested in the Phase 3 VOYAGER trial can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. For more information about the VOYAGER trial, please visit www.voyagertrial.com. Additional details are available on www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03465722).

About GIST

GIST is a sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction.

Most GIST cases are caused by a spectrum of clinically relevant mutations that force the KIT or PDGFRA protein kinases into an increasingly active state. Because currently available therapies only bind to the inactive protein conformations, certain primary and secondary mutations typically lead to treatment resistance and disease progression.

Treatment options for KIT-driven GIST patients whose disease progresses or develops resistance are currently limited. There are no effective treatment options for patients with PDGFRA-driven GIST, and progression often occurs in as little as three months with available therapies. In advanced GIST, clinical benefits from existing treatments can vary by mutation type. Early testing is critical to help guide therapy that effectively treats the underlying driver of disease and is recommended in expert guidelines.

About Avapritinib

Avapritinib is a potent and selective oral inhibitor of KIT and PDGFRA mutant kinases. It is a type 1 inhibitor designed to target the active kinase conformation; all oncogenic kinases signal via this conformation. Avapritinib has demonstrated broad inhibition of KIT and PDGFRA mutations associated with GIST, and the most potent activity against activation loop mutations, which currently approved therapies do not inhibit. In contrast with existing multi-kinase inhibitors, avapritinib has shown marked selectivity for KIT and PDGFRA over other kinases. In addition, avapritinib is uniquely designed to bind and inhibit the KIT D816V mutation, the primary driver of disease in up to 95 percent of systemic mastocytosis (SM) patients. Preclinical studies have shown avapritinib potently inhibited KIT D816V at sub-nanomolar potencies with minimal off-target activity.

Blueprint Medicines is initially developing avapritinib, an investigational medicine, for the treatment of advanced GIST, advanced SM, and indolent and smoldering SM. The FDA has granted avapritinib two Breakthrough Therapy Designations, one for the treatment of PDGFRα D842V-driven GIST and one for advanced SM.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of avapritinib and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for avapritinib in the rest of the world.

On November 15, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that Center for Drug Evaluation of China’s National Medical Product Administration (NMPA, formerly known as CFDA) has granted priority review status to the New Drug Applications (NDAs) for the company’s investigational BTK inhibitor zanubrutinib in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) and for its investigational anti-PD-1 antibody tislelizumab in patients with R/R classical Hodgkin’s lymphoma (cHL) (Press release, BeiGene, NOV 15, 2018, View Source;p=irol-newsArticle&ID=2377287 [SID1234531352]).

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"We’re excited that the NDAs for both zanubrutinib and tislelizumab are receiving priority review by the NMPA," commented Wendy Yan, Senior Vice President, Global Head of Regulatory Affairs at BeiGene. "We look forward to working closely with the NMPA and CDE in the coming months and hope to bring more treatment options to cancer patients."

Zanubrutinib and tislelizumab were both discovered in BeiGene’s research facilities in Beijing, China. Zanubrutinib is being developed globally by BeiGene as a monotherapy and in combination with other therapies to treat various hematologic malignancies. The NDAs for zanubrutinib as a potential treatment for patients with R/R MCL and for patients with R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) were accepted by the NMPA in August and October 2018, respectively. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid and hematologic cancers. The NDA for tislelizumab as a potential treatment for patients with R/R cHL was accepted by the NMPA in August 2018.

Priority review and approval was established in China to facilitate drug registration management and accelerate the development of new drugs with clinical value under the guidance of Opinions on the Reform of the Review & Approval System for Drugs and Medical Devices issued by the State Council in August 2015, and Opinions on Encouraging Pharmaceutical Innovation via Priority Review & Approval issued by CFDA in December 2017. According to these guidelines, the regulatory authority will prioritize the review process and evaluation resources for applications under priority review should expect prioritized review and inspection resource and reduced review and approval timelines.

About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib was discovered in BeiGene’s research facilities in Beijing, China, and is being developed globally by BeiGene as a monotherapy and in combination with other therapies to treat various hematologic malignancies.

About Tislelizumab
Tislelizumab (BGB-A317) is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. Discovered by BeiGene scientists in Beijing, tislelizumab is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. Tislelizumab has demonstrated high affinity and specificity for PD-1 in pre-clinical studies. It is potentially differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells, based on preclinical data. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumor cancers outside of Asia (except Japan).

On November 15, 2018 Exelixis, Inc. (Nasdaq: EXEL) reported that its partner Ipsen received approval from the European Commission (EC) for CABOMETYX (cabozantinib) tablets as a monotherapy for hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib (Press release, Exelixis, NOV 15, 2018, View Source;p=irol-newsArticle&ID=2377258 [SID1234531351]). This approval allows for the marketing of CABOMETYX in this indication in all 28 member states of the European Union, Norway and Iceland.

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"The approval of CABOMETYX in the Europe Union is a very important milestone for our partner Ipsen and marks significant progress for people living with liver cancer, which is the second-leading cause of cancer death worldwide," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "This patient community is in dire need of new options to treat this aggressive disease, and we are excited to work with Ipsen to make this treatment available to patients in the European Union and other countries worldwide."

Under the terms of the Collaboration Agreement with Ipsen, Exelixis will receive a milestone payment of $40 million for the approval of the second-line treatment of HCC. This milestone will be paid by Ipsen within the next 70 days.

"Today’s European Commission approval of CABOMETYX provides a much-needed new option for HCC patients. Until now, physicians in Europe had only one approved therapy for the second-line treatment of this aggressive and difficult-to-treat cancer. We are proud to offer CABOMETYX as an innovative treatment that has been shown to extend survival in previously treated patients with HCC," said Harout Semerjian, Chief Commercial Officer of Ipsen. "This new indication reinforces Ipsen’s commitment to improving patients’ lives through the expansion of the clinical benefit of CABOMETYX in the treatment of solid tumors."

The EC approval is based on results from the CELESTIAL trial of CABOMETYX in patients with advanced HCC who received prior sorafenib. In this phase 3 pivotal trial, CABOMETYX demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. CABOMETYX is also approved in the European Union for the treatment of advanced renal cell carcinoma (RCC) in adults who have received prior VEGF-targeted therapy and for previously untreated intermediate- or poor-risk advanced RCC.

On May 29, 2018, Exelixis announced that the U.S. Food and Drug Administration (FDA) accepted for filing the supplemental New Drug Application (sNDA) for CABOMETYX for previously treated advanced HCC and assigned a Prescription Drug User Fee Act action date of January 14, 2019. An sNDA is an application to the FDA that, if approved, will allow a drug sponsor to make changes to a previously approved product label, including modifications to the indication.

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial. The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

In October 2017, Exelixis announced that the independent data monitoring committee for the CELESTIAL study recommended that the trial be stopped for efficacy following review at the second planned interim analysis, with cabozantinib providing a statistically significant and clinically meaningful improvement in OS compared with placebo in patients with previously treated advanced HCC. The data, originally presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Gastrointestinal Cancers Symposium (ASCO-GI) in January 2018, were published in The New England Journal of Medicine in July 2018.1

About HCC

Liver cancer is the second-leading cause of cancer death worldwide, accounting for more than 700,000 deaths and 800,000 new cases each year.2 In the U.S., the incidence of liver cancer has more than tripled since 1980.3 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2018.3 HCC is the fastest-rising cause of cancer-related death in U.S.4 Without treatment, patients with advanced HCC usually survive less than 6 months.5

About the Exelixis and Ipsen Collaboration

In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. Under the terms of the Collaboration Agreement with Ipsen, Exelixis is entitled to receive a tiered royalty of 22 percent to 26 percent of annual net sales.

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in: the European Union, Norway, Iceland, Australia, Switzerland, South Korea, Canada, Brazil and Taiwan for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union for previously untreated intermediate- or poor-risk advanced RCC; in Canada for adult patients with advanced RCC who have received prior VEGF targeted therapy; and in the European Union, Norway and Iceland for HCC in adults who have previously been treated with sorafenib. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment