On April 8, 2019 Inovio Pharmaceuticals, Inc. (NASDAQ: INO) reported that it achieved a third indication milestone from AstraZeneca resulting from dosing a patient in a Phase 2 combination trial evaluating MEDI0457 (formerly called INO-3112) in combination with durvalumab targeting cervical, anal, penile, and vulvar cancers associated with the human papilloma virus (HPV) (Press release, Inovio, APR 8, 2019, View Source [SID1234535049]). The milestone achievement for this multi-indication trial is the third MEDI0457-related Phase 2 milestone from AstraZeneca; two previous milestone payments resulted from initiating Phase 2 combination trials targeting head and neck and cervical cancers. Financial arrangements were not disclosed.

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Dr. J. Joseph Kim, Inovio’s President and Chief Executive Officer, said, "This Phase 2 milestone stresses the potential breadth of MEDI0457 in treating multiple HPV-associated cancers. Inovio’s goal is to lead the HPV-treatment market from pre-cancers with its lead product VGX-3100 to cancers with MEDI0457 along with our partner AstraZeneca."

In several on-going Phase 2 cancer-indication trials, AstraZeneca is evaluating MEDI0457 in combination with durvalumab, an anti-PD-L1 immune checkpoint inhibitor, in patients with HPV-associated head and neck, cervical, anal, penile, and vulvar cancers. Inovio is developing its HPV monotherapy VGX-3100 for pre-cancerous indications in a Phase 3 trial for cervical dysplasia; and in Phase 2 trials for vulvar and anal dysplasia.

About MEDI0457 and VGX-3100

MEDI0457 (formerly called INO-3112 (VGX-3100, plus IL-12) which AstraZeneca in-licensed from Inovio) is under evaluation by AstraZeneca to treat HPV-associated cancers. Inovio is investigating VGX-3100, a DNA-based immunotherapy for the treatment of HPV-16 and HPV-18 infection and pre-cancerous lesions of the cervix (Phase 3) and vulva (Phase 2) and anal (Phase 2). VGX-3100 has the potential to be the first approved treatment for HPV infection of the cervix and the first non-surgical treatment for pre-cancerous cervical lesions. VGX-3100 works by stimulating a specific immune response to HPV-16 and HPV-18, which targets the infection and causes destruction of pre-cancerous cells. In a randomized, double-blind, placebo-controlled Phase 2b study in 167 adult women with histologically documented HPV-16/18 cervical HSIL (CIN2/3), treatment with VGX-3100 resulted in a statistically significantly greater decrease in cervical HSIL and clearance of HPV infection vs. placebo. The most common side effect was injection site pain, and no serious adverse events were reported. VGX-3100 utilizes the patient’s own immune system to clear HPV-16 and HPV-18 infection and pre-cancerous lesions without the increased risks associated with surgery, such as loss of reproductive health and negative psychosocial impacts.

Under the 2015 agreement, AstraZeneca acquired exclusive rights to Inovio’s INO-3112, now called MEDI0457. MEDI0457 targets cancers caused by HPV types 16 and 18 which are responsible for more than 70 percent of cervical pre-cancers and cancers and are involved in the development of other tumors. Within the broader license and collaboration agreement, AstraZeneca and Inovio are co-developing one additional DNA-based cancer therapy product not included in Inovio’s current product pipeline, which AstraZeneca has exclusive rights to develop and commercialize. Inovio will receive development, regulatory and commercialization milestone payments for these additional cancer vaccine products and will be eligible to receive royalties on worldwide net sales.

About Durvalumab

Durvalumab, a human monoclonal antibody directed against PD-L1, blocks PD-L1 interaction with PD-1 and CD80 on T cells, countering the tumor’s immune-evading tactics and inducing an immune response. As part of a broad development program, durvalumab is being investigated as monotherapy and in combination with IO, small molecules, and chemotherapies across a range of tumors and stages of disease.

On April 8, 2019 PharmaMar (MSE:PHM) reported that attended the third bi-annual meeting on small cell lung cancer, organized by the International Association for the Study of Lung Cancer (IASLC) (Press release, PharmaMar, APR 8, 2019, View Source [SID1234535048]). During this meeting, Anna Farago M.D., Ph.D., coPrincipal Investigator of the ATLANTIS trial from Massachusetts General Hospital in Boston, presented the latest data from the ATLANTIS trial with Zepsyre (lurbinectedin) in combination with doxorubicin for the treatment of recurrent small cell lung cancer, in an oral presentation on Friday 5th April. This is a specialized meeting, which presents information on the clinical trials of the most promising therapies for the treatment of small cell lung cancer.

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The ATLANTIS trial of lurbinectedin in combination with doxorubicin compared to topotecan or the combination CAV (cyclophosphamide, adriamycin and vincristine), randomized 1 to 1, recruited 613 patients in 160 centers in 20 countries, with Spain, Germany and the United States the countries with the highest number of patients recruited. The primary objective of the study is overall survival (OS).

Also for the treatment of second line small cell lung cancer, PharmaMar recently announced positive results for its monotherapy trial with lurbinectedin. The results of this study will be made public during an oral presentation at the next ASCO (Free ASCO Whitepaper) congress.

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On April 8, 2019 OncoSec Medical Incorporated (OncoSec) (NASDAQ: ONCS), a company developing intratumoral cancer immunotherapies, reported an update on recent pipeline and regulatory progress during a Key Opinion Leader (KOL) Symposium focused on the potential of TAVO (IL-12 / tavokinogene telseplasmid) on Friday, April 5, 2019 in New York City (Press release, OncoSec Medical, APR 8, 2019, View Source [SID1234535045]). The KOL Symposium featured presentations from Adil Daud, M.D. and H. Kim Lyerly, M.D.

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Dr. Daud is the lead U.S. investigator for KEYNOTE-695, Clinical Professor of Medicine and Dermatology at University of California, San Francisco (UCSF), and Director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center. Dr. Lyerly is the George Barth Geller Professor for Research in Cancer at Duke University Medical Center and Director of the Duke Comprehensive Cancer Center. Both Dr. Daud and Dr. Lyerly have worked extensively with IL-12 for the past 20 years. Each presentation provided key insights on the importance of IL-12. Dr. Daud also provided his observations regarding TAVO’s two ongoing KEYNOTE clinical trials and Dr. Lyerly highlighted his upcoming work combining TAVO with HER2 in breast cancers.

Discussing KEYNOTE-695, Dr. Daud noted the following:

A key differentiating factor with KEYNOTE-695 relative to other studies which have published data regarding checkpoint non-responder is that KEYNOTE-695 is enrolling only those patients who have definitively progressed on anti-PD-1 therapy by RECIST v1.1. The expected response rate to anti-PD-1 therapy in the KEYNOTE-695 patient population is approximately 6% and therefore the responses having been observed thus far on the study are encouraging. Dr. Daud commented, "There are checkpoint non-responders and then there are other checkpoint non-responders and I just want to highlight the rigor of the patients that are being enrolled here [in KEYNOTE-695]. We are talking about patients who have had RECIST progression on PD-1 treatment and then go on our trial where they have PD-1 plus TAVO, and then have a RECIST response, so it’s just a different kind of population."
Responding patients on KEYNOTE-695 had extensive progressive disease prior to TAVO+ KEYTRUDA treatment and responses have been observed in both treated and untreated lesions. The duration of response is consistent with an immunologic response. Dr. Daud stated, "So what we’ve seen so far and what’s been publicly disclosed has been pretty encouraging. … These are patients with extensive progressive disease and we’ve seen responses both in treated and in untreated lesions on them. And the duration of response is consistent with an immunologic response, not an ablative response to treatments."
TAVO’S safety profile continues to be encouraging and there are no apparent systemic side effects. Dr. Daud commented, "Our safety profile continues to be excellent. One of the impressive things about TAVO treatment is that, remember I told you that cytokine treatment is toxic and systemic cytokine treatment is pretty toxic. What is interesting about TAVO is that patients can have TAVO treatment and basically 30 minutes later go back to work. There isn’t any nausea, there are no systemic side effects to speak of. There can be some grade 1 lesion pain or lesion discomfort, some bleeding, some local redness and irritation, but that is pretty much it in terms of side effect profile. So you could imagine that it’s combinable."
KEYNOTE-695 is approximately 40% enrolled and on track to complete enrollment by year-end.
Dr. Daud also commented on KEYNOTE-890, OncoSec’s Phase 2 clinical trial for the treatment of late-stage triple negative breast cancer (TNBC) with TAVO in combination with Merck’s KEYTRUDA (pembrolizumab). Dr. Daud stated, "So just to give you a highlight on another trial that’s ongoing, that’s the KEYNOTE-890, which is a breast cancer trial combining TAVO plus KEYTRUDA, and patients with breast cancer. And again, these seem – without going too far into details about patients, so these are patients who have visceral disease, who have also had skin disease. And also have accessible treatable lesions. And we’ve just seen some amazing responses in this trial and will be presenting these as the year goes on."

Dr. Lyerly discussed the importance of IL-12 and OncoSec’s technology:

Dendritic cells are the critical cells necessary for transferring antigens and stimulating antigen specific T cells again, which is the basis for cancer immunotherapy. The key cytokine for activated and fully matured dendritic cells is IL-12 production. Systemic use of IL-12 generated systemic toxicities, which seemed to preclude its use, requiring a technical solution to exquisite delivery. OncoSec’s technology affords a potential solution to the problem of systemic use of IL-12.
A variety of IL-12 delivery mechanisms, including viruses and other strategies for direct gene transfer have been explored; however, OncoSec’s plasmid delivery system directs IL-12 expression to the tumor microenvironment which has advantages over these other mechanisms.
In his independent research, he has previously demonstrated the power of IL-12 as a therapeutic against breast cancer and could be foundational, even as primary treatment in early stages of cancer.
"Imagine if you will that if you had the opportunity to deliver IL-12, stimulate systemic antitumor immunity that would provide lifetime benefit to you," said Dr. Lyerly, "Would you not include that in your initial treatment regime? So rather than simply thinking about the treatment of end-stage cancers, we began to explore the potential of IL-12 delivery and really developing systemic antitumor immunity to prevent recurrences and attack these cancers and again this is ongoing work with one of the reasons we were excited about the potential for the OncoSec technical solution."

For a full transcript of the KOL Symposium, please visit www.oncosec.com. An archived replay of the webcast is available in the Investor Relations section of OncoSec’s website at ir.oncosec.com.

On April 8, 2019 Curis, Inc. (Nasdaq: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported that it has begun dosing patients in the 5th cohort (200mg BID; total daily dose of 400mg) in the Phase 1 trial of CA-4948, an orally available small molecule inhibitor of IRAK4, for treatment of patients with non-Hodgkin lymphoma, including those with MYD88 alterations (Press release, Curis, APR 8, 2019, View Source [SID1234535043]).

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"This is an important milestone in the execution of our clinical program," said James Dentzer, the Company’s President and Chief Executive Officer. "Last fall, we re-organized the company to heighten focus on clinical execution and laid out an aggressive goal to advance to the 5th cohort (200mg BID) in time for a midyear 2019 release of initial data. We are pleased to announce that we have begun dosing the 5th cohort sooner than expected and we re-iterate our plan to report initial clinical data this summer."

About CA-4948, a Small-Molecule Inhibitor of IRAK4

Innate immune responses orchestrated through Toll-like receptors or certain interleukin receptors are important mediators of the body’s initial defense against foreign antigens, while their dysregulation is associated with certain inflammatory conditions. Toll-like receptor and interleukin receptor signaling through the adaptor protein MYD88, results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NFκB. More recently, components of this pathway are recognized to be genetically altered and have important roles in specific human cancers. MYD88 gene mutations are shown to occur in approximately 30% of Activated B-Cell (ABC) subtype of diffuse large B-cell lymphomas (DLBCL)1,2 and in over 90% of the B-cell malignancy Waldenstrom’s macroglobulinemia.3 Due to IRAK4’s central role in these signaling pathways, it is considered an attractive target for generation of therapeutics to treat these B-cell malignancies as well as certain inflammatory diseases.

1 Nature. 2011; 470(7332):115–119
2 Immunology and Cell Biology. 2011; 89(6):659–660
3 N Engl J Med. 30, 2012; 367(9):826–833

On April 8, 2019 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), currently developing pelareorep, an intravenously delivered immuno-oncolytic virus, reported that the first patient has been treated in the AWARE-1 window of opportunity (WOO) study that is being conducted in collaboration with SOLTI, an academic research group dedicated to clinical and translational research in breast cancer (Press release, Oncolytics Biotech, APR 8, 2019, View Source [SID1234535041]). Patients will receive the appropriate intervention for their breast cancer sub-type, plus pelareorep, with or without Tecentriq (atezolizumab), followed by surgery.

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"We are pleased to have treated the first patient in our window of opportunity study that will yield important results confirming both our recently identified biomarker and pelareorep’s ability to prime an antitumor immune response," said Matt Coffey, President and Chief Executive Officer of Oncolytics Biotech. "This short study could significantly de-risk our late-stage metastatic breast cancer program, resulting in a smaller, less expensive study with a higher likelihood of success. Beyond the biomarker data, the study will also inform whether we should add a checkpoint inhibitor arm to the phase three registration study. We look forward to initial data from this study in this highly-prevalent cancer indication later this year."

This study, which is being sponsored by Oncolytics and facilitated by SOLTI, is a WOO study in the early treatment setting for breast cancer. Patients will receive the appropriate intervention for their breast cancer sub-type plus pelareorep, with or without Tecentriq. Patients are biopsied on day one, followed immediately by treatment and a final biopsy after three weeks, on the day of their mastectomy. The study is being coordinated by Dr. Aleix Prat, Head of Medical Oncology at the Hospital Clínic of Barcelona, Associate Professor of the University of Barcelona and the Head of the Translational Genomics and Targeted Therapeutics in Solid Tumors Group at August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and member of Oncolytics’ Scientific Advisory Board.

Pelareorep received FDA Fast Track Designation for the treatment of metastatic breast cancer in May 2017.

About Pelareorep
Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.