On April 1, 2019 AstraZeneca and MSD, Inc., Kenilworth, NJ, US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for the MEK 1/2 inhibitor and potential new medicine selumetinib (Press release, AstraZeneca, APR 1, 2019, View Source [SID1234534817]).

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This designation is for the treatment of paediatric patients aged three years and older with neurofibromatosis type 1 (NF1) symptomatic and/or progressive, inoperable plexiform neurofibromas (PN), a rare, incurable genetic condition.

José Baselga, Executive Vice President, Research and Development, Oncology, said: "Selumetinib shows promise in the treatment of NF1-related plexiform neurofibromas, a rare and debilitating disease with no approved medications to date. The Breakthrough Therapy Designation acknowledges the significant unmet need of these patients and the potential benefit of selumetinib in this setting."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, at MSD Research Laboratories, said: "This new designation validates our ongoing development of selumetinib. As a result of this, selumetinib has the potential to receive expedited regulatory review and we hope to bring this medicine to patients as soon as possible."

The BTD is based on Phase II data from the SPRINT trial, testing selumetinib as an oral monotherapy in paediatric patients, aged three years or older with inoperable NF1-related PN. The results of the trial were presented by the National Cancer Institute (NCI) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

This is the ninth BTD that AstraZeneca has received from the FDA since 2014. BTD is designed to expedite the development and regulatory review of medicines that are intended to treat a serious condition and that have shown encouraging early clinical results, which may demonstrate substantial improvement on a clinically-significant endpoint over available medicines.

Selumetinib was granted Orphan Drug Designation for the treatment of NF1 by the US FDA in February 2018 and the European Medicines Agency in August 2018.

Selumetinib is a MEK 1/2 inhibitor and potential new medicine licensed by AstraZeneca from Array BioPharma Inc. in 2003. AstraZeneca and MSD entered a co-development and co-commercialisation agreement for selumetinib in 2017.

The NF1 gene provides instructions for making a protein called neurofibromin, which negatively regulates the RAS/MAPK pathway, helping to control cell growth, differentiation and survival. Mutations in the NF1 gene may result in dysregulations in RAS/RAF/MEK/ERK signalling, which can cause cells to grow, divide and copy themselves in an uncontrolled manner, and may result in tumour growth. Selumetinib inhibits the MEK enzyme in this pathway, potentially leading to inhibition of tumour growth.

Selumetinib is being assessed as a monotherapy and in combination with other treatments in ongoing trials.

About SPRINT

The SPRINT trial is a US Cancer Therapy Evaluation Program (CTEP) NCI-sponsored Phase I/II trial. The Phase I trial was designed to identify the optimal Phase II dosing regimen, and the results were published in the New England Journal of Medicine.1

About NF1

Neurofibromatosis type 1 (NF1) is an incurable genetic condition that affects one in 3,000 to 4,000 individuals.2,3 It is caused by a spontaneous or inherited mutation in the NF1 gene and is associated with many symptoms, including soft lumps on and under the skin (cutaneous neurofibromas), skin pigmentation (so-called ‘cafe au lait’ spots) and, in 20-50% of patients, tumours develop on the nerve sheaths (plexiform neurofibromas). These plexiform neurofibromas can cause clinical issues such as pain, motor dysfunction, airway dysfunction, bowel/bladder dysfunction and disfigurement as well as having the potential to transform into malignant peripheral nerve sheath tumours (MPNST).

People with NF1 may experience a number of complications such as learning difficulties, visual impairment, twisting and curvature of the spine, high blood pressure, and epilepsy. NF1 also increases a person’s risk of developing other cancers, including malignant brain tumours, MPNST and leukaemia. Symptoms begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years.4

About the AstraZeneca and MSD Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza (olaparib), the world’s first PARP inhibitor and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On April 1, 2019 EDAP TMS SA (Nasdaq: EDAP), the global leader in therapeutic ultrasound, reported that the University of Chicago Medicine became the first medical center in the Midwest to offer focal therapy to men with localized prostate cancer, using Focal One, the only advanced robotic ultrasound technology available to target and ablate diseased prostate tissue (Press release, EDAP TMS, APR 1, 2019, View Source [SID1234534834]).

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Focal One HIFU (high intensity focused ultrasound) makes it possible for doctors to deliver a non-invasive precision treatment to the prostate-without removing it-reducing the likelihood of negative side effects like incontinence and impotence commonly related to surgical treatments.

UChicago Medicine is the fifth medical center in the U.S. to acquire Focal One since the new system for prostate tissue ablation received 510(k) clearance from the FDA in June 2018.

"Focal One specifically targets the diseased tissue and allows the patient to retain his prostate and his quality of life," said Arieh Shalhav, MD, Fritz and Mary Lee Duda Family Chair, Chief, Section of Urologic Surgery, Professor of Surgery and the Comprehensive Cancer Research Center Director of Robotic Surgery at the University of Chicago. "Within a 90-minute procedure, we can pinpoint and destroy diseased tissue with minimal collateral damage. It bridges the gap between active surveillance and whole gland therapy."

"We are honored to add the University of Chicago Medicine to the growing roster of prestigious U.S. medical institutions utilizing Focal One," said Marc Oczachowski, Chief Executive Officer of EDAP. "UChicago Medicine raises the standard for hospitals across the Midwest, bringing in the latest noninvasive robotic technology to treat prostate disease. Men with localized prostate disease who wish to maintain their quality of life post-treatment can now seek HIFU treatment with Focal One at UChicago Medicine."

About UChicago Medicine

The University of Chicago Medicine, with a history dating to 1927, is a not-for-profit academic medical health system based on the campus of the University of Chicago in Hyde Park, and with hospitals, outpatient clinics and physician practices throughout Chicago and its suburbs. UChicago Medicine unites five organizations to fulfill its tripartite mission of medical education, research and patient care: Pritzker School of Medicine, Biological Sciences Division, Medical Center, Community Health and Hospital Division, and UChicago Medicine Physicians.

On April 1, 2019 Sensei Biotherapeutics, Inc., a clinical-stage biopharmaceutical company developing precision immuno-oncology therapies, reported new data from two programs targeting a novel tumor specific embryonic antigen, human aspartate β-hydroxylase (ASPH), including preclinical data on SNS-723, a first-in-class CAR-T cell therapy demonstrating effective killing of tumor cells by a series of ASPH-specific CAR-Ts as well as additional data from its Phase 1 study on the long-term effects of SNS-301, a first-in-class cancer immunotherapy demonstrating that all patients experienced dose-dependent and durable ASPH-specific immune responses (Press release, Sensei Biotherapeutics, APR 1, 2019, View Source [SID1234534850]). These data were presented in two poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Atlanta, Georgia from March 29 – April 3, 2019.

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"We are excited to share these first preclinical data for SNS-723," said Hossein Ghanbari, Ph.D., Chief Scientific Officer of Sensei Biotherapeutics. "This novel CAR-T is designed to elicit tumor cell destruction where ASPH is expressed, which includes both solid tumors and hematological malignancies. Given that ASPH is not found on the surface of normal tissues at any detectable levels, we believe SNS-723 offers a substantial opportunity to improve on the safety profile of today’s approved cell therapies."

"These long-term data from our phase 1 study of SNS-301 are consistent with our earlier findings of strong dose-dependent APSH-specific immunogenicity in patients and provide additional insights into our Phase 2 dosing strategy," said Ildiko Csiki, M.D., Ph.D., Chief Medical Officer of Sensei Biotherapeutics. "Given the promise of targeting ASPH as a new strategy for treating cancer, we remain focused on initiating Phase 2 trials of SNS-301 in various hematological malignancies and solid tumors in 2019."

In a poster titled "CAR-T Cell Therapies Targeting Aspartyl β-hydroxylase (ASPH)," Sensei researchers examined multiple ASPH-specific CAR constructs for CAR expression, cell-killing efficacy and cytokine response. Key SNS-723 data (poster #2306) highlights included:

Significant expression of three different evaluated ASPH-specific CARs was observed in human T-cells.
Dose-dependent cell-killing of ASPH-expressing H460 lung carcinoma cells by two of the ASPH-specific CAR constructs was observed concomitant with cytokine release. In contrast, untransduced T-cells or T-cells transduced to express a non-relevant CAR did not kill target cells of or activate cytokine production.
CARs binding two different, non-overlapping epitopes on ASPH both displayed cell killing efficacy.
In a poster titled "Long-term Immunogenicity Results from a First-in-human Study Evaluating the Anti-ASPH Cancer Vaccine, SNS-301," Sensei researchers examined both short- and long-term immune responses to SNS-301. Previous data from the Phase 1 clinical trial of SNS-301 were presented in 2018, demonstrating rapid and significant antigen-specific B-cell and T-cell responses induced by SNS-301. In the extension of the Phase 1 study, the 12 enrolled patients received between 8 and 23 doses of the vaccine delivered via an intradermal injection every 21 days. The additional key SNS-301 data (poster #1454) highlights included:

All patients continued to experience long-term, dose-dependent and durable ASPH-specific immune responses, including B-cell, T-cell, and antibody responses.
A fluctuation in the peak immune responses following the first six cycles was seen, suggesting the possibility of immune fatigue and a potential benefit from increased spacing between boosting doses after the first 6 cycles.
Anti-phage antibody responses were generally much lower at the low- and mid-doses than the high dose. Based on the ratio of ASPH-specific immune response to anti-phage immune response, the mid-dose is the recommended Phase 2 dose.
Based on the data presented today, Sensei plans to initiate multiple multi-site Phase 2 clinical trials in mid-2019 to evaluate the immunogenicity and preliminary clinical activity of SNS-301 in various malignancies. Sensei also plans to continue preclinical development and begin IND-enabling studies for SNS-723 in the second half of 2019.

About SNS-723

SNS-723 is a first-in-class CAR-T cell therapy that is currently in preclinical development targeting human aspartate β-hydroxylase (ASPH), a cell surface enzyme that is normally expressed during fetal development. The recognition domain of the CAR is the scFv portion of a high affinity, fully human, anti-ASPH antibody. SNS-723 is designed to overcome one of the major hurdles in T-cell therapy, targeting T-cells to tumors in the absence of non-tolerable and/or off-target toxicities to essential tissues and organs. Experiments to further characterize ASPH-targeted CAR-T cells are ongoing with the goal of moving these promising therapeutics into clinic.

About SNS-301

SNS-301 is a first-in-class cancer immunotherapy targeting human aspartate β-hydroxylase (ASPH), a cell surface enzyme that is normally expressed during fetal development. Following fetal development, the protein is no longer expressed. Expression of ASPH is uniquely upregulated in more than 20 different cancer types and promotes cancer cell growth, cell motility and invasiveness. ASPH expression levels in various tumors are inversely correlated with tumor resistance and patient survival. Through enhanced antigen presentation and other engineered immunotherapeutic features, SNS-301 is designed to overcome self- tolerance and induce robust and durable ASPH-specific humoral and cellular immune responses. SNS-301 is paired with a companion diagnostic to select antigen-positive patients and is delivered intradermally for ease of administration.

On April 1, 2019 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported promising preclinical data at the annual AACR (Free AACR Whitepaper) meeting from its next generation SPEAR T-cell targeting MAGE-A4 (Press release, Adaptimmune, APR 1, 2019, View Source;p=RssLanding&cat=news&id=2392937 [SID1234534869]). This next generation SPEAR T-cell, known as ADP-A2M4CD8, expresses the CD8α co-receptor alongside the engineered TCR that targets MAGE-A4.

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Co-expression of CD8α is anticipated to broaden the immune response against solid tumors and increase antitumor activity by converting CD4+ helper cells into CD8+ killer or cytotoxic T-cells. The preclinical data demonstrate that the addition of CD8a with the engineered TCR in vitro improved engagement and function in CD4+ T-cells that may support clonal expansion of CD8+ T-cells, differentiation into effector and memory T-cells, as well as engage the wider immune system in antitumor responses.

"Our next generation programs are designed to enhance our existing SPEAR T-cells, to improve their ability to target and kill solid tumors. The preclinical data we presented at AACR (Free AACR Whitepaper) indicate that adding CD8a to our ADP-A2M4 candidate may help broaden the antitumor immune response against additional tumor antigens. Further, the CD8a co-receptor may enhance the ability of CD4+ SPEAR T-cells to kill cancer cells through the engineered TCR targeting MAGE-A4," said Rafael Amado, Adaptimmune’s President of Research & Development.

Poster presentation details:

Title: Enhanced activity of second-generation MAGE-A4 SPEAR T-cells through co-expression of a CD8α homodimer
Session Title: Adoptive Cell Therapy 2
Session Date and Time: Monday Apr 1, 2019 1:00 PM – 5:00 PM ET
Location: Georgia World Congress Center, Exhibit Hall B, Poster Section 22
Poster Board Number: 12
Abstract Number: 2313

On April 1, 2019 Inovio Pharmaceuticals, Inc. (NASDAQ: INO) reported that its Phase 1/2 immuno-oncology trial in patients with newly diagnosed glioblastoma (GBM) has completed its enrollment three months ahead of schedule (Press release, Inovio, APR 1, 2019, View Source [SID1234534818]). The 52-patient trial is designed to evaluate Inovio’s INO-5401 T cell activating immunotherapy encoding multiple antigens expressed by GBM and INO-9012, an immune activator encoding IL-12, in combination with cemiplimab-rwlc (also known as Libtayo or REGN2810), a PD-1 inhibitor developed by Regeneron Pharmaceuticals in collaboration with Sanofi. This trial information will be presented today at Phase I-III Trials in Progress session at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) being held in Atlanta.

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Inovio expects to report interim results from this study before the end of this year evaluating safety, immunological impact, progression-free survival and overall survival (see www.clinicaltrials.gov, identifier NCT03491683).

Dr. J. Joseph Kim, Inovio’s President and Chief Executive Officer, said, "We sincerely thank the patients and their doctors for participating in our innovative combination trial. This is an important step for Inovio’s cancer combination strategy using our T cell-generating therapies in combination with PD-1/PD-L1 inhibitors for GBM and for multiple other cancers to improve overall efficacy of immunotherapy. We have previously shown in a Phase 1 head and neck cancer clinical study, combining Inovio’s T cell-generating immunotherapy MEDI0457 along with checkpoint inhibitors have resulted in two complete responders who remain cancer free for over two years. In this GBM trial, our goal is to increase the overall survival of patients facing a disease where neither the standard of care, nor clinical outcomes have changed in a clinically significant way in more than a decade."

Inovio holds clinical partnerships with AstraZeneca for MEDI0457 (in HPV-related cancers) and collaborations with Roche/Genentech and Regeneron for INO-5401 (in bladder cancer and GBM), each providing for clinical evaluation of Inovio immunotherapies combined with checkpoint inhibitors. In particular, the INO-5401 collaborations are based on a strong scientific rationale to combine two immunotherapies: INO-5401, which generates antigen-specific killer T cells, and a checkpoint inhibitor, which augments T cell activity.

About Glioblastoma

Glioblastoma (GBM) is the most common and aggressive type of brain cancer and remains a devastating disease for both patients and caregivers. Its prognosis is extremely poor, despite a limited number of new therapies approved over the last 10 years. The median overall survival for patients receiving standard of care therapy is approximately 15 months and the average five-year survival rate is less than five percent.

About INO-5401

INO-5401 includes Inovio’s SynCon antigens for hTERT, WT1, and PSMA, and has the potential to be a powerful cancer immunotherapy in combination with checkpoint inhibitors. The National Cancer Institute previously highlighted hTERT, WT1, and PSMA among a list of important cancer antigens, designating them as high priorities for cancer immunotherapy development. These three antigens are known to be over-expressed, and often mutated, in a variety of human cancers, and targeting these antigens may prove efficacious in the treatment of patients with cancer.