On September 11, 2019 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has accepted for review its supplemental New Drug Application (sNDA) for neratinib in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have failed two or more prior lines of HER2-directed therapy (third-line disease) (Press release, Puma Biotechnology, SEP 11, 2019, View Source [SID1234539435]). The FDA has informed the Company that it is not currently planning to hold an advisory committee meeting to discuss this application. The FDA confirmed that the review will have an action date of late April, 2020.

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"The FDA’s acceptance of our sNDA marks another important regulatory milestone for my team," said Alan H. Auerbach, Chief Executive Officer and President of Puma. "We look forward to working with the FDA during its review of this submission, which targets patients with HER2-positive metastatic breast cancer who have progressed on two or more prior treatments and who need additional treatment options."

Neratinib was originally approved by the U.S. Food and Drug Administration in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer following adjuvant trastuzumab-based therapy and is marketed in the United States as NERLYNX tablets. In September 2018 NERLYNX was granted marketing authorization by the European Commission for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy.

The sNDA is supported by the results of the Phase III NALA trial, a randomized controlled trial of neratinib plus capecitabine versus Tykerb (lapatinib) plus capecitabine in patients with third-line HER2-positive metastatic breast cancer.

About HER2-Positive Breast Cancer

Approximately 20 to 25 percent of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

About NALA

The NALA trial is a randomized controlled Phase III trial of neratinib plus capecitabine versus Tykerb (lapatinib) plus capecitabine in patients with third-line HER2-positive metastatic breast cancer. The trial enrolled 621 patients who were randomized (1:1) to receive either neratinib plus capecitabine or lapatinib plus capecitabine. The trial was conducted globally at sites in North America, Europe, Asia-Pacific and South America. The co-primary endpoints of the trial are centrally confirmed progression free survival (PFS) and overall survival (OS). An alpha level of 1% was allocated to the PFS and 4% allocated to OS. The study was to be considered positive if either of the co-primary endpoints was positive. Puma reached agreement with the FDA under a Special Protocol Assessment (SPA) for the design of the Phase III clinical trial and the European Medicines Agency (EMA) also provided follow-on scientific advice (SA) consistent with that of the FDA regarding the Company’s Phase III trial design and endpoints used in the trial.

On September 11, 2019 Gracell Biotechnologies Co., Ltd. ("Gracell"), a clinical-stage immune cell therapy company, reported a positive continued clinical readout of a multi-center pilot study designed to evaluate the safety and efficacy of Gracell’s first-in-class FasT CAR-19 (GC007F) investigational cell gene therapy (Press release, Gracell Biotechnologies, SEP 11, 2019, View Source [SID1234539452]). The results were announced during the CAR-TCR Summit held from 10-13 September in Boston.

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At present, anti-CD19 CAR-T bioprocessing takes on average two weeks to manufacture and seven days to pass quality testings. However, with Gracell’s FasT CAR solution, customized treatments which genetically modifies patient’s T-cells to express CD19-specific chimeric antigen receptor (CAR), preparation time can be cut to one day, with a manufacturing success rate of 26/26 (100%) without patient loss. FasT CAR technology can also be utilized on other immune cell programs, such as the treatment of multiple myeloma (MM) and Non-Hodgkin Lymphoma (NHL). With these advantages, FasT CAR-19 is highly cost-effective and has considerable potential to establish a new standard in CAR-T treatment for r/r B-ALL.

The multi-center investigational study enrolled 26 adolescent and adult patients aged from 14 to 70 years, with relapsed or refractory B-ALL, and had failed to respond to multiple prior lines of therapy. As of Sep. 4, all patients received a single infusion of FasT CAR-19 following lymphoid depleting chemotherapy. FasT CAR-19 was administered at three dose levels from low to high, equivalent to 1/30-1/10 of the conventional CAR-T therapy dose for B-ALL, respectively.

The treatment efficacy was assessed in 24 treated patients over 28 days of follow-up, of which:

23 (95.8%) achieved complete remission with or without complete blood count recovery (CR/CRi);
21 (87.5%) achieved undetectable minimal residual disease (uMRD) (< 10-4 detectable leukemic cells in bone marrow).
During the over three month-durable remission period, FasT CAR-19 demonstrated a good level of persistence. In terms of safety, all 26 patients well tolerated the single infusion of FasT CAR-19 at different dose levels. The most common safety concerns were cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) where mild to moderate side effects were observed.

In comparison to the high dose group, patients administered low to middle dose levels experienced mild adverse events. Across 20 patients in the low to mid doses group, only 2 (10%) Grade 3 CRS and 2 (10%) manageable Grade 3 ICANS were reported; while in the 6 patients of the high dose group, there were 5 (83.3%) Grade 3 CRS and 1 (16.7%) Grade 1-2 ICANS, indicating a dose-limiting toxicity.

Taking FasT CAR-T Further: GC012F and GC022F

CAR-T immunotherapy uses patients’ own immune cells to treat disease. In this form of therapy, immune cells are collected from a patient’s blood; engineered in a laboratory to create a chimeric antigen receptor cells (CAR) that target cancer cells and then reinfused back into the patient. However, such therapy is time-consuming, highly personalized. Furthermore, it can only target a single tumor antigen, which limits efficacy.

To combat this, treatments containing two separate CARs and dual transduction (GC012 targeting BCMA and antigen X, and GC022 targeting CD19 and CD22), which were expected to have a higher safety profile and ability to control and prevent relapse compared to single CAR-T cells were developed. As both programs (GC012F and GC022F) hold similar characteristics to GC007F, there is potential to enhance the therapies through the FasT CAR platform, enabling GC012F and GC022F to perform better than the conventionally manufactured dual CAR-T cells.

The results from in vitro studies have already shown that GC012F and GC022F provide a higher portion of centry memory T cells with less exhaustion, higher proliferation capacity, and killing ability similar to conventional CAR-T cells at the same cell basis. While in vivo studies, show lower dose poses higher potency, greater efficiency and better ability to eradicate tumor cells.

"We are very excited to see that the patients with refractory or relapsed B-ALL in this study gained substantial clinical benefit from FasT CAR-19" said CEO Dr. William CAO. "Dual CAR-T cells manufactured using the FasT CAR platform has the potential to offer more clinical benefits. The next stage will be to unlock these benefits with first-in-human trials."

About FasT CAR-19

FasT CAR-19, or GC007F, is an investigational CD19-targeted CAR-T cell therapy for adolescent and adult patients with refractory or relapsed B-ALL, as well as aggressive non-Hodgkin lymphoma. Thanks to Gracell’s patented FasT CAR technology, the bioprocessing of GC007F has been significantly reduced to 24 hours with substantially lower cost. The younger and less exhausted T cell phenotype exhibited superior proliferation capabilities, potency, and extensive bone marrow migration making GC007F a potential best-in-class therapy for refractory or relapsed B-ALL.

About ALL

Acute lymphoblastic leukemia (ALL), although rare, is one of the most common forms of cancer in children between the ages of two and five and adults over the age of 50[1]. In 2015, ALL affected around 876,000 people globally and resulted in 110,000 deaths worldwide[2]. It is also the most common cause of cancer and death from cancer among children. ALL is typically treated initially with chemotherapy aimed at bringing about remission. This is then followed by further chemotherapy carried out over several years.

About MM

Multiple myeloma (MM) is a cancer that forms in a type of white blood cell known as a plasma cell. Plasma cells help fight infection by making antibodies. MM causes cancer cells to accumulate in the bone marrow, where they crowd out healthy blood cells. Rather than producing antibodies, the cancer cells produce abnormal proteins which cause complications (myeloma cells).

On September 11, 2019 MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), reported that Yuichi Iwaki, MD, PhD, President and Chief Executive Officer, and Geoffrey O’Brien, JD/MBA, Vice President and Executive Officer, will present a corporate overview at the Ladenburg Thalmann 2019 Healthcare Conference on Tuesday, September 24, 2019 at 10:30 am at the Sofitel Hotel in New York City (Press release, MediciNova, SEP 11, 2019, View Source [SID1234539470]). Management will be available for one-on-one meetings at this conference and investors may request a one-on-one meeting through Ladenburg Thalmann.

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On September 11, 2019 Veracyte, Inc. (Nasdaq: VCYT) reported the publication of new data demonstrating the clinical and analytical validity of its Afirma Xpression Atlas (XA) genomic test, which is used to help guide surgery and treatment decisions for patients with likely or confirmed thyroid cancer (Press release, Veracyte, SEP 11, 2019, View Source [SID1234539437]). The new findings appear online in the journal Frontiers in Endocrinology.

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The Afirma XA uses RNA whole-transcriptome sequencing to detect expressed DNA variants and RNA fusion partners in over 500 genes that are associated with thyroid cancer. The test is performed on fine needle aspiration (FNA) samples of thyroid nodules deemed suspicious for cancer by Veracyte’s Afirma Genomic Sequencing Classifier (GSC), as well as those that are suspicious for or have been diagnosed as cancer based on cytopathology. Importantly, the Afirma XA is performed on the same FNA sample as the Afirma GSC, obviating the need for patients to undergo an additional FNA procedure to obtain this genomic information about their thyroid.

To evaluate the Afirma XA’s clinical validity, researchers compared the test’s ability to identify genomic variants in an FNA sample’s transcriptome to currently accepted methods of targeted DNA and RNA sequencing. Using 943 blinded FNA samples, they found the Afirma XA had high positive predictive agreement (PPA) with targeted DNA sequencing (88 percent) and targeted RNA sequencing (89 percent). Similarly, using 695 blinded FNA samples to look for RNA fusions, the Afirma XA had an 82 percent PPA with targeted RNA sequencing. Conversely, 95 percent or more of variants and fusions identified by Veracyte’s RNA whole-transcriptome sequencing test were also identified by the reference method.

"Our findings suggest that the Afirma XA is sensitive and accurate in identifying gene alterations that are associated with thyroid cancer and confirm that the test can do this using one patient sample for all molecular testing," said Trevor E. Angell, assistant professor of clinical medicine at the Keck School of Medicine of USC and lead author of the new paper. "The extensive genomic-alteration information provided by the Afirma test can help physicians tailor initial treatment for patients with likely or confirmed cancer and also provides information about the potential benefits of targeted therapies for those cancers that don’t respond to standard treatment."

The researchers also investigated the reproducibility of the Afirma XA across laboratories and reagent lots. Using 69 variant-positive FNA samples, they found that the Afirma XA showed high accuracy between two different labs with different personnel for detecting variants (90 percent) and fusions (94 percent).

"The use of pre-operative molecular testing with minimally invasive FNA samples is expanding beyond cytologically indeterminate thyroid nodules to include those nodules with clear malignancy. Our findings demonstrate that physicians can be confident in the Afirma XA’s results at the time of diagnosis, which help guide surgery and treatment decisions," said Richard T. Kloos, M.D., medical director of endocrinology for Veracyte and an author of the new study.

On September 11, 2019 Merck KGaA, Darmstadt, Germany, a leading science and technology company, which operates its biopharmaceutical business as EMD Serono in the US and Canada, reported that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for the investigational targeted therapy tepotinib* in patients with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations who progressed following platinum-based cancer therapy (Press release, Merck KGaA, SEP 11, 2019, View Source [SID1234539439]).

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"Tepotinib was associated with robust objective responses with durability that has not previously been seen in patients with metastatic NSCLC harboring MET exon 14 skipping alterations, selected by either tissue or liquid biopsy approaches," said Luciano Rossetti, Global Head of Research & Development for the Biopharma business of Merck KGaA, Darmstadt, Germany. "This breakthrough therapy designation further underscores the potential of tepotinib, and we aim to advance this program and deliver this medicine as quickly as possible to NSCLC patients who may benefit."

Lung cancer is the most common type of cancer worldwide, with 2 million cases diagnosed annually.1 Alterations of the MET signaling pathway are found in various cancer types, including 3-5% of NSCLC cases, and correlate with aggressive tumor behavior and poor clinical prognosis.2-4

Discovered in-house at Merck KGaA, Darmstadt, Germany, tepotinib is an investigational oral MET kinase inhibitor that is designed to be highly potent and selective5 and to inhibit the oncogenic signaling caused by MET (gene) alterations, including both MET exon 14 skipping alterations and MET amplifications, or MET protein overexpression.

In March 2018, tepotinib’s potential was recognized by the Japanese Ministry of Health, Labour and Welfare (MHLW), which granted SAKIGAKE ‘fast-track’ designation for tepotinib in advanced NSCLC harboring MET exon 14 skipping alterations. SAKIGAKE designation promotes research and development in Japan, aiming at early practical application for innovative pharmaceutical products, medical devices and regenerative medicines.

Tepotinib is also being investigated in the INSIGHT 2 study (NCT03940703) in combination with the tyrosine kinase inhibitor (TKI) osimertinib in epidermal growth factor receptor (EGFR) mutated, MET amplified, locally advanced or metastatic NSCLC having acquired resistance to prior EGFR TKI.

The Breakthrough Therapy Designation is based on data from the ongoing VISION study (NCT02864992), showing preliminary clinical evidence that tepotinib may offer an improvement over available therapy in patients with metastatic NSCLC harboring MET exon 14 skipping alterations detected by liquid biopsy (LBx) or tissue biopsy (TBx) across different lines of treatment.

Results from an interim analysis of the ongoing VISION study in 73 efficacy-evaluable patients with NSCLC with MET exon 14 skipping alterations identified by LBx or TBx testing demonstrate overall objective response rate (ORR) of 50.0% for LBx-identified patients as assessed by Independent Review Committee (IRC), and 55.3% as assessed by investigators. The ORR for TBx-identified patients was 45.1% and 54.9%, respectively. The overall median duration of response (DOR) was 12.4 months and 17.1 months among LBx-identified patients, as assessed by IRC and investigators, respectively, while among TBx-identified patients, 15.7 and 14.3 months were observed, respectively.

Most treatment-related adverse events (TRAEs) were Grade 1 and 2. No Grade 4 or 5 TRAEs were observed. Any grade TRAEs reported by ≥10% of 87 patients evaluable for safety were peripheral edema (48.3%), nausea (23.0%) diarrhea (20.7%) and increased blood creatinine (12.6%). Other relevant TRAEs of any grade include increased lipase (4.6%), fatigue (3.4%) and vomiting (3.4%). TRAEs led to permanent discontinuation in four patients (two patients due to peripheral edema, one due to interstitial lung disease, one due to diarrhea and nausea).

Results from this study were presented in an oral presentation at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.6 The use of both LBx and TBx to identify patients for the VISION study is intended to support improved patient selection and is consistent with the company’s focus on patient-centric drug development.

*Tepotinib is the recommended International Nonproprietary Name (INN) for the MET kinase inhibitor (MSC2156119J). Tepotinib is currently under clinical investigation and not approved for any use anywhere in the world.

About Breakthrough Therapy Designation

Breakthrough Therapy Designation is designed to expedite the development and review of drugs which are intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). The FDA’s granting of the Breakthrough Therapy Designation for advanced NSCLC does not alter the standard regulatory requirement to establish the safety and effectiveness of a drug through adequate and well-controlled studies to support approval.

About Non-Small Cell Lung Cancer

With 2 million cases diagnosed annually, lung cancer (including trachea, bronchus and lung) is the most common type of cancer worldwide, and the leading cause of cancer-related death, with 1.7 million mortality cases worldwide.1 Alterations of the MET signaling pathway, including MET exon 14 skipping alterations and MET amplifications, occur in 3-5% of NSCLC cases.2-4

About Tepotinib

Tepotinib, discovered in-house at Merck KGaA, Darmstadt, Germany, is an investigational oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations, including both MET exon 14 skipping alterations and MET amplifications, or MET protein overexpression. It has been designed to have a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations.

Tepotinib is currently being investigated in NSCLC and Merck KGaA, Darmstadt, Germany is actively assessing the potential of investigating tepotinib in combination with novel therapies and in other tumor indications.ray F, et al. CA Cancer J Clin. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 2018;68(6):394–424. View Source View Source.
Reungwetwattana T, et al. Lung Cancer 2017;103:27-37.
Mo HN, et al. Chronic Dis Transl Med 2017; 3(3):148-153.
Lutterbach B, et al. Cancer Res 2007;67:2081–8.
Bladt, F, et al. Clin Cancer Res 2013;19:2941-2951.
Paik P, et al. J Clin Oncol 2019;37: (suppl; abstr 9005).
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