On December 21, 2015 Boehringer Ingelheim reported that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for its novel, 3rd-generation, epidermal growth factor receptor (EGFR) mutation-specific tyrosine kinase inhibitor (TKI), BI 1482694* (HM61713**) (Press release, Boehringer Ingelheim, DEC 21, 2015, View Source [SID:1234508613]). The BTD is based on results1 from the Phase I/II HM-EMSI-101 clinical trial which were presented at the ESMO (Free ESMO Whitepaper) Asia 2015 Congress in Singapore. BTDs have been established by the FDA to facilitate and expedite the development and review of promising drugs for serious or life-threatening conditions.
The HM-EMSI-101 clinical trial investigated BI 1482694 in patients with advanced and pre-treated EGFR mutation-positive non-small cell lung cancer (NSCLC). Based on these positive data, a New Drug Application for HM61713 / BI 1482694 has recently been submitted to the Korean Ministry of Food and Drug Safety by Hanmi Pharmaceutical Co. Ltd, with whom Boehringer Ingelheim has an exclusive license and collaboration agreement for the development and global commercialisation rights (except South Korea, China and Hong Kong) of BI 1482694.
Results from the Phase I/II clinical trial of BI 1482694 presented at the ESMO (Free ESMO Whitepaper) Asia 2015 Congress in Singapore, showcase the tumour activity and favourable safety profile of BI 1482694 at the recommended Phase II dose of 800mg once daily, previously presented at this year’s American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.2 In patients with T790M-positive NSCLC who had previously been treated with an EGFR TKI:1
Objective responses (ORs) by independent assessment were observed in 62% patients, including 32 patients (46%) whose tumour response had been confirmed by the time of data cut-off
Disease control rate was 91% by independent assessment.
At the time of data cut off, median duration of response had not yet been reached and will be reported at a later date.
The most common treatment-related adverse events (AEs) included (total/grade 3) diarrhoea (55%/0%), nausea (37%/0%), rash (38%/5%) and pruritus (skin itching: 36%/1%) – the majority of AEs were mild-to-moderate.1
Coordinating investigator Professor Keunchil Park, Division of Hematology & Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, South Korea commented, "These data further validate BI 1482694 as a potential treatment for lung cancer patients who encounter resistance to 1st- or 2nd-generation EGFR targeting treatments. Being able to improve outcomes of EGFR mutation-positive patients with minimum burden on their overall wellbeing is the goal for both patients and oncologists, so we eagerly await the duration of response and progression-free survival data from this study, as well as results of the broader clinical programme which is underway."
The pivotal clinical development programme of BI 1482694 in lung cancer, ELUXA, encompasses multiple trials including Phase III studies starting in 2016. The first pivotal Phase II trial (ELUXA 1/HM-EMSI-202) is designed to further investigate the efficacy and safety of BI 1482694 in patients with NSCLC with acquired T790M-mediated resistance after first-line EGFR TKIs.3
Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented, "The clinical trial results we have seen so far for BI 1482694 are very encouraging and have led to the FDA Breakthrough Designation and a first regulatory submission in Korea. The T790M mutation is the most common resistance mechanism found in about half of the patients previously treated with currently available EGFR TKIs. Our aim at Boehringer Ingelheim is to prolong the continuum of treatment with targeted therapies for patients with EGFR mutation-positive lung cancer with a treatment that could potentially be efficacious even after the inevitable occurrence of resistance to the initial treatment."
Regulatory update
Boehringer Ingelheim aims to achieve first market authorisation for BI 1482694 in patients with T790M-positive NSCLC in 2017.
In December 2015, the US FDA granted BI 1482694 with Breakthrough Therapy Designation
In October 2015, a New Drug Application for HM61713 / BI 1482694, was filed to the Korean Ministry of Food and Drug Safety.
About the HM-EMSI-101 study
This is a Phase I/II, multicenter study of BI 1482694 in Korean patients. All patients included in the trial had been previously treated with at least one EGFR TKI and may have received additional lines of chemotherapy or other systemic treatments. At the recommended Phase II dose (RP2D: 800mg qd), all eligible patients had to have confirmed T790M mutation in the tumour. The primary endpoint was OR; secondary endpoints included duration of response, disease control rate, progression-free survival (PFS) and safety.
About the ELUXA 1 (HM-EMSI-202) study
ELUXA 1 is an ongoing pivotal Phase II global clinical trial. It is designed to further investigate the efficacy and safety of BI 1482694 in patients with NSCLC whose tumours acquired T790M-mediated resistance after first-line EGFR TKIs. The ELUXA 1 trial is part of a broad ELUXA pivotal trial programme, which will include the initiation of Phase III studies in 2016.
Month: December 2015
Merck’s KEYTRUDA® (pembrolizumab) Significantly Improves Survival Compared to Chemotherapy in Previously-Treated Patients with Non-Small Cell Lung Cancer Whose Tumors Express Any Level of PD-L1
On December 19, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported results from the pivotal KEYNOTE-010 study, the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with advanced non-small cell lung cancer (NSCLC) (Press release, Merck & Co, DEC 19, 2015, View Source [SID:1234508607]). In the Phase 2/3 study, KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, significantly improved overall survival (OS) compared to chemotherapy in patients with any level of PD-L1 expression, as defined by a tumor proportion score (TPS) of 1 percent or more. The results were published in The Lancet and will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia 2015 Congress.
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"Because lung cancer remains one of the most common and most challenging cancers to treat, understanding the role that KEYTRUDA can play in helping patients was essential to our development program. In this study in patients with PD-L1 expression of one percent or greater, KEYTRUDA demonstrably improved overall survival compared to chemotherapy in previously-treated patients with non-small cell lung cancer, including both squamous and non-squamous histologies," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.
Merck plans to submit a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration for KEYTRUDA based on findings from KEYNOTE-010 by the end of 2015. The Company plans to submit a Marketing Authorization Application to the European Medicines Agency in early 2016.
Overall Survival Findings from KEYNOTE-010
The Phase 2/3 KEYNOTE-010 study included 1,034 patients with advanced NSCLC with PD-L1 expression (TPS of 1% or more). Similar findings were shown in patients who received the FDA-approved dose of KEYTRUDA (pembrolizumab) (2 mg/kg every three weeks) (n=345) and an investigational dose of KEYTRUDA (10 mg/kg every three weeks) (n=346). Both groups of patients who received KEYTRUDA were compared to patients who received docetaxel (n=343). PD-L1 expression was assessed by the immunohistochemistry companion diagnostic test PD-L1 IHC 22C3 PharmDx, made by Dako North America, Inc., an Agilent Technologies Company. The findings from KEYNOTE-010 are based on the final study analysis. The median follow-up was 13.1 months (IQR, 8.6-17.7).
In the total study population (all levels of PD-L1 expression), both doses of KEYTRUDA studied significantly improved OS compared with docetaxel. Specifically, KEYTRUDA resulted in a 29 percent improvement in OS for the 2 mg/kg dose (HR 0.71, P=0.0008; 95% CI, 0.58-0.88) and a 39 percent improvement in OS for the 10 mg/kg dose (HR 0.61, P<0.0001; 95% CI, 0.49-0.75), compared to docetaxel. The estimated 1-year OS rates for KEYTRUDA were 43.2 percent and 52.3 percent, respectively, compared to 34.6 percent for docetaxel. Median OS for KEYTRUDA were 10.4 months (95% CI, 9.4-11.9) and 12.7 months (95% CI, 10.0-17.3), respectively, compared to 8.5 months for docetaxel (95% CI, 7.5-9.8).
Among patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater), OS was superior for both KEYTRUDA doses compared with docetaxel. Specifically, KEYTRUDA improved OS by 46 percent for the 2 mg/kg dose (HR 0.54, P=0.0002; 95% CI, 0.38-0.77) and by 50 percent for the 10 mg/kg dose (HR 0.50, P<0.0001; 95% CI, 0.36-0.70), compared to docetaxel. Median OS for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) was 14.9 months (95% CI, 10.4 to not reached) and 17.3 months (95% CI, 11.8 to not reached), compared to 8.2 months for docetaxel (95% CI, 6.4-10.7).
"This is an exciting time, and studies such as KEYNOTE-010 with KEYTRUDA are paving the way to a better understanding of how to identify the right medicine for each patient," said Dr. Roy Herbst, Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. "These study findings show KEYTRUDA provided superior overall survival in patients with advanced lung cancer who had positive PD-L1 expression, and support its potential in the treatment of this disease."
Additional Findings from KEYNOTE-010
In the total study population, KEYTRUDA (pembrolizumab) prolonged progression-free survival (PFS) at both doses, though statistical significance was not met (HR 0.88 [95% CI, 0.74-1.05], P=0.07 for 2 mg/kg; HR 0.79 [95% CI, 0.66-0.94], P=0.004 for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 3.9 months (95% CI, 3.1-4.1) and 4.0 months (95% CI, 2.7-4.3), compared to 4.0 months for docetaxel (95% CI, 3.1-4.2).
Patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater) who were treated with KEYTRUDA had significantly prolonged PFS compared to docetaxel (HR 0.59 [95% CI, 0.44-0.78, P=0.0001] for 2 mg/kg; HR 0.59 [95% CI, 0.45-0.78, P<0.0001] for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 5.0 months (95% CI, 4.0-6.5) and 5.2 months (95% CI, 4.1-8.1), compared to 4.1 months for docetaxel (95% CI, 3.6-4.3).
Additionally, the safety of KEYTRUDA was consistent with what has been seen in previous trials among advanced lung cancer patients. Grade 3-5 treatment-related adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: decreased appetite (n=3, n=1), fatigue (n=4, n=6), nausea (n=1, n=2), rash (n=1, n=1), diarrhea (n=2, n=0), asthenia (n=1, n=2), stomatitis (n=0, n=1), and anemia (n=3, n=1). The most common immune-mediated adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: hypothyroidism (8% [n=28], 8% [n=28]), hyperthyroidism (4% [n=12], 6% [n=20]), and pneumonitis (5% [n=16], 4% [n=15]). There were three treatment-related deaths among patients receiving KEYTRUDA at the 2 mg/kg dose (pneumonitis [n=2], pneumonia [n=1]) and three treatment-related deaths among patients receiving KEYTRUDA at the 10 mg/kg dose (myocardial infarction [n=1], pneumonia [n=1], and pneumonitis [n=1]).
About KEYNOTE-010 and the KEYTRUDA Development Program
KEYNOTE-010 is a global, open-label, randomized, pivotal Phase 2/3 study (ClinicalTrials.gov, NCT01905657) evaluating two doses of KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to docetaxel (75 mg/m^2 every three weeks) in 1,034 patients with squamous and non-squamous NSCLC who experienced disease progression after platinum-containing systemic therapy and whose tumors expressed PD-L1. The primary endpoints were OS and PFS. Tumor response was assessed at week 9, then every 9 weeks thereafter per RECIST 1.1 criteria by independent, central, blinded, radiographic review and investigator-assessed, immune-related response criteria.
The KEYTRUDA program currently addresses more than 30 tumor types in more than 160 clinical trials, including more than 80 combinations of KEYTRUDA with other cancer treatments. In lung cancer, KEYTRUDA is being studied across lines of therapy, both as a monotherapy and in combination with chemotherapy. Registration-enabling trials of KEYTRUDA (pembrolizumab) are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer, Hodgkin lymphoma, multiple myeloma and other tumors, with further trials in planning for other cancers.
10-K – Annual report [Section 13 and 15(d), not S-K Item 405]
(Filing, 10-K, Aeolus, DEC 18, 2015, View Source [SID:1234508612])
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Isis Pharmaceuticals Changes Name to Ionis Pharmaceuticals
On December 18, 2015 Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) reported that the company has changed its name to Ionis Pharmaceuticals, Inc (Press release, Ionis Pharmaceuticals, DEC 18, 2015, View Source;p=irol-newsArticle&ID=2124010 [SID:1234509110]). Ionis (pronounced "eye-OH-nis") Pharmaceuticals is an original name that the Company has chosen to represent its innovative culture and heritage as both the pioneer and leader in the RNA-targeted therapeutic space for the past 26 years. Ionis is focused on bringing its late-stage Phase 3 drugs, nusinersen, volanesorsen and IONIS-TTRRx to the market and advancing its pipeline of high value drugs that have the potential to be first-in-class or best-in-class drugs to treat patients with life-threatening or serious diseases.
Ionis Pharmaceuticals
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"Our goal is to create medicines that will save patients’ lives, and we are proud to be at the forefront of creating innovative medicines," said Lynne Parshall, chief operating officer at Ionis Pharmaceuticals. "We decided to change our company name because, when people see or hear our name, we want them to think about the life-saving medicines we are developing."
In conjunction with the corporate name change, the Company will trade on the NASDAQ Global Select Market under the new ticker symbol "IONS". The new ticker symbol will become effective at the open of the market on December 22, 2015. In addition, the Company will have a new website address: www.ionispharma.com.
Midatech agrees to acquire marketed oncology product, Zuplenz®, from Galena Biopharma, Inc.
On December 18, 2015 Midatech Pharma reported that it has entered into an agreement to acquire Zuplenz (ondansetron), a marketed anti-emetic oral soluble film from Galena Biopharma for the prevention of chemotherapy-induced nausea and vomiting (CINV), radiotherapy-induced nausea and vomiting (RINV), and post-operative nausea and vomiting (PONV), (the "Acquisition") (Press release, Midatech, DEC 18, 2015, View Source [SID:1234508918]).
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Zuplenz, launched in the United States in July 2015, is an anti-emetic, which does not need to be injected or swallowed, offering patients a differentiated alternative. Midatech expects that the acquisition of Zuplenz will leverage its commercial infrastructure in the United States, following the acquisition of DARA BioSciences, and is complementary to Midatech’s three existing marketed oncology products. With patent protection until at least 2029, Zuplenz is targeting an estimated $4.6bn market by 2018[1] and is expected to add to Midatech’s growing revenues.
Midatech will pay a total up front consideration of $3.75 million in cash, with further cash payments, totalling up to $26 million, becoming payable if certain sales milestones are achieved, which are expected to be self-financed by milestone-generated cashflow. Following the Acquisition, Management expects cash reserves to be c.£16 million at the financial year-end. The transaction is expected to be completed on or prior to Thursday, December 24, 2015, subject to customary closing conditions.
Since closure of the DARA BioSciences acquisition, significant integration has already occurred and the resultant benefits are already evident in the enlarged group with increased revenues.
Commenting on the announcement, Dr. Jim Phillips, CEO of Midatech Pharma, said: "The acquisition of Zuplenz is a highly-complementary addition to our newly-acquired, marketed oncology portfolio. With Zuplenz expected to add to our fast-growing revenue, we believe this acquisition will help drive the Group further towards profitability."