European Commission Approves CABOMETYX™ (cabozantinib) Tablets for the Treatment of Advanced Renal Cell Carcinoma Following VEGF-Targeted Therapy

On September 14, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported that the European Commission (EC) has approved CABOMETYX (cabozantinib) tablets for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy (Press release, Exelixis, SEP 14, 2016, View Source [SID:SID1234515135]). CABOMETYX was granted accelerated assessment by the European Medicines Agency, and is the first therapy to demonstrate in a phase 3 trial for patients with advanced RCC, robust and clinically meaningful improvements in all three key efficacy parameters — overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). This approval allows for the marketing of CABOMETYX in all 28 member states of the European Union, Norway and Iceland.

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EC approval of CABOMETYX triggers a $60 million milestone payment to Exelixis under the licensing agreement with Ipsen for the commercialization and further development of CABOMETYX indications outside of the United States, Canada and Japan. The approval is based on the results of the large, randomized phase 3 METEOR trial.

"The marketing authorization of CABOMETYX by the European Commission to treat patients with advanced renal cell carcinoma reflects the strong efficacy results observed with cabozantinib in the phase 3 METEOR trial, and is an important milestone in our collaboration with Ipsen," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "This marketing authorization helps address an unmet medical need in Europe by providing patients with a new therapy that slows disease progression and prolongs overall survival. We look forward to further examining the use of CABOMETYX in earlier lines of therapy and in other difficult-to-treat cancers."

About CABOMETYX (cabozantinib)

CABOMETYX is the tablet formulation of cabozantinib. CABOMETYX targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, the U.S. FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.

On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

About the METEOR Phase 3 Pivotal Trial

METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior VEGFR TKI therapy. The primary endpoint was PFS in the first 375 patients randomized. Secondary endpoints included OS and objective response rate in all enrolled patients. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia. Patients were randomized 1:1 to receive 60 mg of CABOMETYX daily or 10 mg of everolimus daily and were stratified based on the number of prior VEGFR TKI therapies received and on MSKCC risk criteria. No cross-over was allowed between the study arms.

METEOR met its primary endpoint by significantly improving PFS. Compared with everolimus, CABOMETYX was associated with a 42 percent reduction in the rate of disease progression or death. Median PFS for CABOMETYX was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). CABOMETYX also significantly improved the objective response rate compared with everolimus, be it through investigator assessment (24% versus 4%, p<0.0001) or through central review (17% versus 3%, p < 0.0001). These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.1

CABOMETYX also demonstrated a statistically significant and clinically meaningful increase in OS in the METEOR trial. Compared with everolimus, CABOMETYX was associated with a 34 percent reduction in the rate of death. Median OS was 21.4 months for patients receiving CABOMETYX versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).

CABOMETYX benefit in OS was robust and consistent across all pre-specified subgroups. In particular, benefit was observed regardless of risk category, location and extent of tumor metastases, and tumor MET expression level. These results were presented on June 5, 2016 at the ASCO (Free ASCO Whitepaper) Annual Meeting and concurrently published in The Lancet Oncology.2

At the time of the analysis, the median duration of treatment in the trial was 8.3 months with CABOMETYX versus 4.4 months with everolimus. The most frequent adverse events regardless of causality were diarrhea, fatigue, decreased appetite and hypertension for CABOMETYX and fatigue, anemia, decreased appetite and cough for everolimus. Dose reductions occurred for 62 percent and 25 percent of patients, respectively. Discontinuation rate due to an adverse event not related to disease progression was 12 percent with CABOMETYX and 11 percent with everolimus.

About Advanced Renal Cell Carcinoma

Renal cell carcinoma (RCC) represents 2-3 percent of all cancers3, with the highest incidence occurring in Western countries. Generally, during the last two decades until recently, there has been an annual increase of about 2 percent in incidence both worldwide and in Europe, though in Denmark and Sweden a continuing decrease has been observed.4 In 2012, there were approximately 84,400 new cases of RCC and 34,700 kidney cancer related deaths within the European Union.5 In Europe, overall mortality rates for RCC have increased up until the early 1990s, with rates generally stabilizing or declining thereafter.6 There has been a decrease in mortality since the 1980s in Scandinavian countries and since the early 1990s in France, Germany, Austria, the Netherlands, and Italy. However, in some European countries (Croatia, Estonia, Greece, Ireland, Slovakia), mortality rates still show an upward trend with increasing rates. 6

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.7,8 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.9-12 MET and AXL may provide escape pathways that drive resistance to VEGFR inhibitors.8,9

U.S. Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-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. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-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: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. 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. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): 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: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see full Prescribing Information at View Source

Array BioPharma Announces Phase 3 BEACON CRC SPA Agreement with FDA

On September 14, 2016 Array BioPharma (Nasdaq: ARRY) reported that it has reached agreement with the U.S. Food and Drug Administration (FDA) regarding a Special Protocol Assessment (SPA) related to BEACON CRC, a global Phase 3 trial of encorafenib and Erbitux (cetuximab), with or without binimetinib, versus standard of care in patients with BRAF-mutant colorectal cancer (CRC) who have previously received first-or second-line systemic therapy (Press release, Array BioPharma, SEP 14, 2016, View Source [SID:SID1234515134]).

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"Colorectal cancer is the third most common cancer among men and women in the United States and BRAF-mutant CRC represents a high unmet medical need, as there are currently no targeted treatment options available for patients with this form of the disease," said Scott Kopetz, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center in Houston and BEACON CRC investigator. "The SPA agreement between Array and the FDA represents a welcome next step for the CRC community and, as a physician, I look forward to exploring these novel treatment combinations."

The SPA provides agreement that the design and planned analysis of BEACON CRC adequately address the objectives necessary to support a regulatory submission for the approval of the doublet regimen of encorafenib and Erbitux. The FDA also communicated that sharing evidence from the study that the triplet regimen (encorafenib, Erbitux and binimetinib) both met its primary endpoint (Overall Survival) as compared to the control arm, and demonstrated a clinically meaningful benefit as compared to the doublet regimen, would provide support for approval of the triplet regimen.

Trial Design

BEACON CRC is a randomized, open-label, global study evaluating the efficacy and safety of encorafenib and Erbitux, with or without binimetinib, in patients with BRAF-mutant metastatic CRC who have previously received first-or second-line systemic therapy. The study includes a safety lead-in with approximately 30 patients. With appropriate results from the lead-in, approximately 615 patients are expected to be randomized 1:1:1 to receive triplet therapy (encorafenib, Erbitux and binimetinib), doublet therapy (encorafenib and Erbitux) or the control arm (irinotecan-based therapy and Erbitux). The primary endpoint of the trial is OS of the triplet therapy compared to the control arm. Secondary endpoints address efficacy of the doublet therapy compared to the control arm, and the triplet therapy compared to the doublet therapy. Other secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response, safety and tolerability. Health related quality of life data will also be assessed.

Array is conducting BEACON CRC in partnership with Pierre Fabre and Merck KGaA, Darmstadt, Germany at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.

About BRAF-mutant Metastatic Colorectal Cancer
Colorectal cancer is the third most common cancer among men and women in the United States, with more than 134,000 new cases and nearly 50,000 deaths from the disease projected in 2016. In the United States, BRAF mutations occur in 8 to 15 percent of patients with colorectal cancer and represent a poor prognosis for these patients. Historical published PFS and OS results after first-line treatment range from 1.8 to 2.5 months and 4 to 6 months, respectively, and published response rates from various studies for EGFR-based therapy in this population range from 6 percent to 8 percent.

About Binimetinib & Encorafenib
MEK and BRAF 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, such as melanoma, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway.

Binimetinib and encorafenib are being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib and binimetinib in combination in patients with BRAF-mutant melanoma and the recently initiated BEACON CRC trial that will study encorafenib in combination with Erbitux, with or without binimetinib, in patients with BRAF V600E-mutant colorectal cancer. On September 1, 2016, Array announced that the FDA has accepted its New Drug Application (NDA) for binimetinib with a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2017. Array completed its NDA submission of binimetinib in late June 2016 based on findings from the pivotal Phase 3 NEMO trial in patients with NRAS-mutant melanoma.

About a Special Protocol Assessment
A Special Protocol Assessment (SPA) is a process by which sponsors ask the FDA to evaluate a protocol to determine whether it adequately addresses scientific and regulatory requirements for the purpose identified by the sponsor. A SPA agreement indicates concurrence with the adequacy and acceptability of specific critical elements of protocol design and analysis. To review the FDA’s complete SPA guidance, please click the following link:

View Source

10-K – Annual report [Section 13 and 15(d), not S-K Item 405]

Nabi Biopharmaceuticals 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, Nabi Biopharmaceuticals, SEP 13, 2016, View Source [SID1234515123]).

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Siamab Therapeutics Presents Promising Preclinical Data at 2016 AACR Ovarian Cancer Research Symposium

On September 13, 2016 Siamab Therapeutics, Inc., a biotechnology company developing novel cancer immunotherapies, reported new pre-clinical data that showed its novel ST1 antibody drug conjugates (ADCs) target chemoresistant ovarian cancer cells and demonstrate strong efficacy in ovarian cancer models (Press release, Siamab Therapeutics, SEP 13, 2016, View Source [SID:SID1234515130]). These data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s 11th Biennial Ovarian Cancer Research Symposium 2016 in Seattle, Wash., on Monday, Sept. 12, 2016.

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"The preclinical results are exciting and show the potential of our antibody approach to target chemoresistant tumors in ovarian cancer"

Siamab’s ST1 ADCs target the cancer associated antigen, sialyl-Tn (STn) with high specificity and affinity. STn is present on multiple solid tumors including ovarian, pancreatic, prostate and colon, while showing little normal tissue expression, and has been implicated in immune suppression, metastasis, and a cancer stem cell phenotype.

"The preclinical results are exciting and show the potential of our antibody approach to target chemoresistant tumors in ovarian cancer," said Jeff Behrens, president and chief executive officer of Siamab Therapeutics. "We have developed multiple anti-glycan antibodies and ADCs with unprecedented cancer specificity and efficacy in animal models. These findings hold promise for developing new cancer therapeutics for ovarian cancer patients with disease recurrence who have limited treatment options."

The preclinical data were presented in a poster titled "Targeting a chemoresistant ovarian cancer cell population via the carbohydrate antigen sialyl Tn." The findings showed that Siamab’s ST1 ADCs significantly reduce tumor volume in a sustained fashion in ovarian cancer models. In addition, Siamab’s ST1 target, STn, demarks a population of cells that display a cancer stem cell phenotype as demonstrated by colony- and sphere-forming assays. The findings also showed that following platinum- and taxane-based cytotoxic chemotherapy, STn+ cancer cells are significantly enriched, further supporting their cancer stem cell and chemoresistant phenotype.

Siamab collaborated with Bo Rueda, Ph.D., director of the Vincent Center for Reproductive Biology, in the Department of Obstetrics and Gynecology at Massachusetts General Hospital on this research, funded by a National Cancer Institute SBIR Phase I contract. The collaboration explored the potential of Siamab’s anti-glycan antibodies to target populations of chemoresistant cancer cells. This research also looked at the relationship between tumor associated carbohydrate antigens (TACAs) and chemoresistant cancer cells that demonstrate a cancer stem cell (CSC) phenotype.

"We know chemoresistant cancer cells play a central role in disease recurrence and are particularly challenging to target," said Dr. Rueda. "Siamab’s ADCs targeted STn positive cells, demarking a chemoresistant population, and were effective in shrinking ovarian tumors in animal models. I look forward to continuing to work closely with Siamab as they move this program toward clinical development."

Interim Results for the six months ended 30 June 2016

On September 2016 Oxford BioMedica plc (LSE: OXB), ("OXB" or "the Group") a leading gene and cell therapy group, reported interim results for the six months ended 30 June 2016 (Press release, Oxford BioMedica, SEP 13, 2016, View Source [SID:SID1234515125]).

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HIGHLIGHTS (including post-period end):

OPERATIONAL

State-of-the-art bioprocessing facilities
Capacity expansion of bioprocessing and laboratory facilities now complete and approved for GMP vector manufacture

Partnering activities continuing to build

Novartis contract progressing well, contributing to 184% growth in first half Group revenues – multiple confirmed purchase orders through to Q2 2017
Second CAR-T programme for undisclosed indication underway with Novartis
New IP licence and expanded collaboration agreement signed with Immune Design
R&D collaboration signed with Green Cross LabCell to identify and develop gene modified natural killer (NK) cell-based therapeutics

Good progress across product development programmes

OXB to capture value of clinical products via out-licensing or spin out approach
OXB-102 and OXB-202 will be ready to start Phase I/II studies within next 6-9 months, subject to successfully out-licensing or spinning out these products
OXB-302 pre-clinical studies expected to complete by end of 2016
SAR422459 (for Stargardt Disease), licensed to Sanofi, has entered Phase IIa development
Novartis still on course to file CTL019 BLA in early 2017, with approval expected mid-2017 due to Breakthrough Therapy designation

FINANCIAL

Revenue increased by 184% to £12.5 million (H1 2015: £4.4 million) due in large part to Novartis contract
R&D, bioprocessing and administrative costs of £16.1 million (H1 2015: £11.7 million)
Operating loss of £6.9 million (H1 2015: £8.3 million)
Capital expenditure £6.0 million (H1 2015: £4.6 million)
Cash of £11.9 million (31 December 2015: £9.4 million) which includes the $10 million (£7.6 million) ring-fenced under the Oberland loan agreement
Fundraising of £10.0 million net of expenses announced separately today. In February 2016, the Group also raised a net £7.5 million through a 5% placing

Commenting on today’s announcement, John Dawson, Chief Executive Officer at Oxford BioMedica, said: "With world-class facilities, expertise and a broad intellectual property position, Oxford BioMedica is a leading gene and cell therapy company. Our unrivalled expertise in the bioprocessing and production of lentiviral vector makes us an ideal partner for the increasing number of potential companies wishing to use this exciting technology in clinical studies and, in due course, commercial therapeutics.

"Oxford BioMedica’s wholly-owned priority product programmes have progressed well during the period. In order to advance the clinical assets as expeditiously as possible whilst still capturing value for shareholders, the Group has decided to employ an external funding approach, via spin outs or out-licensing partnerships. Based on this approach, the proceeds raised in today’s fundraising will enable us to build upon our strong position by furthering the development and enhancement of our proprietary lentiviral vector delivery platform technology as we look to maximise bioprocessing revenues."