On March 22, 2018 Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX) reported that Evotec and Apeiron Biologics have entered into a research collaboration with the objective of developing immunomodulatory lead compounds for the treatment of cancer (Press release, Evotec, MAR 22, 2018, View Source;announcements/press-releases/p/evotec-and-apeiron-biologics-announce-collaboration-on-cancer-immunotherapy-5107 [SID1234525396]). Apeiron Biologics will contribute in vitro and in vivo pharmacology expertise to this collaboration while Evotec will be responsible for medicinal chemistry as well as chemical proteomics. The collaboration is based on the successful outcome of a phenotypic high throughput screen previously commissioned by Apeiron Biologics to Evotec.

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Dr Mario Polywka, Chief Operating Officer of Evotec, commented: ‘We look forward to continue working with Apeiron on this important project. The collaboration highlights the strength of Evotec’s phenotypic screening capabilities to identify novel mechanisms and hits in important therapeutic areas.’

Dr Hans Loibner, Chief Executive Officer of Apeiron Biologics, added: ‘We were excited about the outcome of the primary screen and look forward to refining the hit compounds in this collaboration applying our immunological know-how. There is no doubt that immunomodulatory compounds like these carry huge therapeutic and commercial potential.’

No financial details are disclosed.

ABOUT APEIRON Biologics AG
Apeiron is a mostly privately financed biotech company in Vienna that develops immunological/biological therapies against cancer. Its portfolio consists of five clinical projects (lead in phase III) as well as some preclinical approaches. The most advanced project APN311 is an antibody to treat the pediatric cancer neuroblastoma. The immunocytokine hu14.18-IL2 (APN301) is being developed clinically in neuroblastoma as well as in melanoma. Moreover, recombinant human superoxide dismutase is in clinical development, notably in a topical liposomal formulation (APN201) as a potent anti-inflammatory tissue-protective biologic. Two complementary approaches are pursued (APN401, APN411) that stimulate immune cells in a novel way to treat cancer more effectively. The recombinant human Angiotensin Converting Enzyme 2 (GSK2586881, previously APN01) was licensed out to GlaxoSmithKline in early 2010 and is currently investigated in a phase II trial in patients suffering from acute lung injury. Apeiron started operations in 2006 and has 23 employees as of today.

FORWARD LOOKING STATEMENTS – Information set forth in this press release contains forward-looking statements, which involve a number of risks and uncertainties. The forward-looking statements contained herein represent the judgement of Evotec as of the date of this report. Such forward-looking statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.

On March 22, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported that detailed results of its pivotal Phase 3 COLUMBUS trial for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma were published in The Lancet Oncology (Press release, Array BioPharma, MAR 22, 2018, View Source;p=RssLanding&cat=news&id=2339334 [SID1234524945]). In the analysis of the primary endpoint, the median progression-free survival (mPFS) for patients treated with the combination of encorafenib, 450 mg daily, plus binimetinib, 45 mg twice daily (COMBO450) was 14.9 months versus 7.3 months for patients treated with vemurafenib, 960 mg twice daily [hazard ratio (HR) 0.54, 95% CI 0.41–0.71; p<0.0001].

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The manuscript entitled "Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial," was published online on March 21, 2018. Array previously announced top line results from this study in September 2016.

"A median progression-free survival of nearly 15 months with the combination of encorafenib and binimetinib is clinically meaningful for patients with advanced BRAF-mutant metastatic melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "Further, a median overall survival of 33.6 months, compared to 16.9 months with vemurafenib monotherapy (HR of 0.61, 95% CI 0.47-0.79, p<0.001), a secondary endpoint not included in this publication, was recently announced. This further supplements the published data and shows that the combination of encorafenib and binimetinib may become a promising new therapy for patients with advanced BRAF-mutant metastatic melanoma."

As previously reported, the combination of encorafenib and binimetinib was generally well-tolerated. The median duration of treatment was 51.2 weeks (27.1-79.7) for encorafenib and 50.6 weeks (26.1-79.7) for binimetinib. The median dose intensity was 100% (93-100) of planned doses of encorafenib and 99.6% (80-100) of planned doses of binimetinib. The most common Grade 3/4 adverse events (AEs) seen in more than 5% of patients were increased gamma-glutamyltransferase (GGT) 9% (18/192 patients), increased creatine phosphokinase 7% (13), and hypertension 6% (11) in the encorafenib plus binimetinib group.

The U.S. Food and Drug Administration (FDA) is currently reviewing the New Drug Applications to support use of the combination of encorafenib and binimetinib for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the European Medicines Agency (EMA), as well as the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA), are reviewing the Marketing Authorization Applications for encorafenib and binimetinib.

An update from the COLUMBUS trial will be presented at an upcoming medical congress.

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [1, 2] There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma. [1, 3, 4]

About COLUMBUS
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive COMBO450, encorafenib, 300 mg daily (ENCO 300), or vemurafenib, 960 mg twice daily alone. The dose of encorafenib in the combination arm is 50% higher than the single agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was an mPFS comparison of the COMBO450 arm versus vemurafenib. mPFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the mPFS of COMBO450 arm to that of ENCO300 and a comparison of overall survival (OS) in patients treated in the COMBO450 arm to that of vemurafenib alone. Results from Part 1 of the COLUMBUS trial previously presented at the 2016 Society for Melanoma Research Annual Congress, showed that COMBO450 more than doubled mPFS in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib [HR 0.54, (95% CI 0.41-0.71, p<0.0001)]. In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months [HR 0.75, (95% CI 0.56-1.00, p=0.051)].
In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg plus binimetinib 45 mg twice daily (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.
As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the protocol specified analysis of OS is descriptive.

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial.

Array BioPharma has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

On March 22, 2018 AbbVie (NYSE:ABBV), a global research and development-based biopharmaceutical company, reported that after consulting with the U.S. Food and Drug Administration (FDA), it will not seek accelerated approval for Rova-T in third-line relapsed/refractory (R/R) small cell lung cancer (SCLC) based on magnitude of effect across multiple parameters in this single-arm study (Press release, AbbVie, MAR 22, 2018, View Source [SID1234525398]).

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"We continue to believe Rova-T has potential for patients with small cell lung cancer and other DLL3-expressing cancers," said Mike Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "Although the results from the study were not what we hoped for, we look forward to receiving data from the ongoing Phase 3 studies in the first- and second-line settings and remain committed to developing Rova-T for the treatment of patients with small cell lung cancer."
Summary of Investigator Assessed Best Overall Response Rate, Independent Review Committee (IRC) Assessed Objective Response Rate, Duration of Response and Overall Survival in Third-Line SCLC Patients with High DLL3 Expression (N = 177)*

*Data represent 74 percent of the TRINITY study population with high DLL3 expression
a Best overall response is defined as a subject with a response of complete response (CR) or partial response (PR) at any time prior to receiving any subsequent anticancer therapy.
b Objective response is defined as a subject with a response of complete response (CR) or partial response (PR) prior to receiving any subsequent anticancer therapy, with confirmation of CR or PR at least 4 weeks (28 days) from the initial determination per RECIST v1.1.
­­c Based on Kaplan-Meier estimate.

In the study, the most common treatment-emergent adverse events were fatigue (38 percent), photosensitivity reaction (36 percent), pleural effusion (32 percent), edema peripheral (31 percent), decreased appetite (30 percent), nausea (26 percent), dyspnea (25 percent), thrombocytopenia (25 percent), constipation (22 percent), vomiting (17 percent), anemia (17 percent), hypoalbuminemia (16 percent), and cough (16 percent). Grade three and higher severe toxicities ≥ 5 percent were thrombocytopenia (11 percent), photosensitivity reaction (7 percent) and pleural effusion (5 percent)
.
About the Phase 2 TRINITY Study
TRINITY is a multicenter, open-label, single-arm, Phase 2 study of Rova-T in DLL3-expressing small cell lung cancer (SCLC) patients with relapsed/refractory (R/R) disease after receiving at least two previous regimens, including at least one platinum-based regimen. The primary objective was to investigate the efficacy of Rova-T as third-line and later treatment for R/R DLL3-expressing SCLC. Secondary objectives included assessment of safety and tolerability, pharmacokinetics, RECIST-assessed progression-free survival, duration of response and clinical benefit rate.

About Rovalpituzumab Tesirine (Rova-T)
Rova-T is an investigational antibody-drug conjugate targeting the cancer-stem cell-associated delta-like protein 3 (DLL3)[1], which is expressed in more than 80 percent of small cell lung cancer (SCLC) patient tumors, where it is prevalent on tumor cells, including cancer stem cells, but not present in healthy tissue.[2] Rova-T combines a targeted antibody that delivers a cytotoxic agent directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells. Rova-T is under investigation as a third-line treatment in SCLC.[2] The expression of DLL3 suggests Rova-T may be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme and some prostate, pancreatic and colorectal cancers.[2]
Rova-T is an investigational compound and its efficacy and safety have not been established by the FDA or any other health authority.

On March 22, 2018 CBT Pharmaceuticals (CBT), a U.S. and China-based innovative biopharmaceutical company committed to becoming a leader in the discovery and development of oncology combination therapies, reported a strategic licensing agreement with Crown Bioscience, Inc (Press release, CBT Pharmaceuticals, MAR 22, 2018, View Source [SID1234525458]). The agreement gives CBT exclusive world-wide development and commercialization rights to a novel, recombinant, human monoclonal antibody which targets a differentiated epitope on the cytotoxic T-lymphocyte antigen-4 (CTLA-4) molecule. Binding of this antibody to CTLA-4 blocks the interaction of CTLA-4 with its ligands CD80/CD86 thus allowing the cytotoxic T cells to function actively.

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Under the terms of this global licensing agreement, CBT gains access to a third checkpoint inhibitor to complement the existing immuno-oncology pipeline of PD-1 and PD-L1 inhibitors. CrownBio is eligible to receive potential future development, regulatory and sales-based milestones payments over $47 M, as well as royalties on net sales. Once the recommended Phase 1 monotherapy portion of the Phase 1/2 trial is completed, combination with other complementary therapies in CBT’s immuno-oncology and targeted therapy portfolios will be initiated.

"This acquisition from Crown Bio is another building block in our strategy to develop a portfolio of programs in combination with our pipeline of immuno-oncology and targeted therapies that we believe will lead to a meaningful durable clinical benefit and impact on cancer survival in variety of malignancies and in larger proportion of cancer patients," said Sanjeev Redkar, PhD, Chief Executive Officer and President of CBT. "The CTLA-4 asset fits well with our ongoing clinical studies and we hope to advance an additional three single agent and two combination clinical trials are expected to enter the clinic by the end of 2018." Tillman Pearce, MD, Interim Chief Medical Officer, added "The CTLA-4 asset demonstrated stronger binding and its performance in nonclinical models compares quite favorably to the marketed CTLA-4 which may allow for differentiation in the clinic."

Dr. Jean Pierre Wery, CEO of Crown Bio stated, "Crown Bio enables biopharmaceutical clients and partners the scientific platform to advance drugs to market to improve treatment options to patients. This includes strategic licensing of proprietary antibodies. We are pleased to support CBT’s innovati

Caladrius Biosciences has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission (Filing, 10-K, Caladrius Biosciences, 2018, MAR 22, 2018, View Source [SID1234524943]).

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