Partial Clinical Hold Lifted and Enrollment Resumes for Aduro Biotech LADD Clinical Trials

On November 21, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported that the U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold placed on its clinical trials evaluating the LADD (live, attenuated double-deleted) immunotherapy platform, enabling patient enrollment to resume in all Aduro-sponsored clinical studies (Press release, Aduro BioTech, NOV 21, 2016, View Source [SID1234516707]).

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"We are pleased to come to a rapid agreement with the FDA to resume new patient enrollment in our LADD clinical studies," said Stephen T. Isaacs, chairman, president and CEO of Aduro Biotech. "With slight protocol modifications implemented, we remain on track to initiate a Phase 2 clinical study using our LADD-based therapy CRS-207 in combination with an anti-PD-1 compound for patients with mesothelioma in the first half of 2017. Additionally, we continue to make significant progress with our STING Pathway Activator and B-select Antibody programs and with our three diverse immunotherapy platforms, we believe we are uniquely positioned to bring innovative therapies to patients with late-stage cancers."

In agreement with the FDA, Aduro’s LADD-based clinical trial protocols have been modified to include extended patient surveillance, to exclude patients with certain prosthetic devices that are not easily removed, and to add guidance to administer prophylactic antibiotics following LADD-based treatment for patients who may receive immune-suppressive treatments.

Cellthera Presents Preclinical Data at SITC Using Argos’ Individualized Immunotherapy

On November 18, 2016 Argos Therapeutics Inc. (Nasdaq:ARGS) ("Argos"), an immuno-oncology company focused on the development and commercialization of individualized immunotherapies based on the Arcelis technology platform, and its partner Cellthera Pharm ("Cellthera"), a subsidiary of Pharmstandard focused on personalized therapeutics, reported the presentation of data on a murine ("mouse") model developed by Cellthera to determine functional activity of a therapy modeled after Argos’ AGS-003 individualized immunotherapy (Press release, Argos Therapeutics, NOV 18, 2016, View Source [SID1234516678]). The data were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 31st Annual Meeting, which was held November 11-13 in National Harbor, Maryland.

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The data presented demonstrated the favorable effects of the AGS-003-like therapy as a single agent and in combination with sunitinib and a PD-1 checkpoint inhibitor in a murine model of renal cell carcinoma (RCC). "Our model provides some exciting survival data using an AGS-003-like therapy in a murine kidney cancer model that has proven useful in exploring combinations with other agents in a relevant preclinical setting," said Dr. Alexander Shuster, chairman of Cellthera. In this experiment the agents were administered alone or together 7 days prior to the inoculation of tumor cells and then each group was followed for tumor reduction and survival. Dr. Shuster continued, "The prophylactic mouse data show the superiority of the AGS-003-like therapy as a single agent versus control in both survival and enhanced control of tumor growth. Furthermore, the AGS-003-like therapy when combined with sunitinib or a PD-1 checkpoint inhibitor outperformed each agent alone, and the combination of all three therapies demonstrated the strongest survival advantage."

Argos is currently evaluating AGS-003 in combination with standard of care agents in the pivotal ADAPT Phase 3 clinical trial for the treatment of metastatic renal cell carcinoma (mRCC). Enrollment in this 462-patient study was initiated in February 2013 and completed in July 2015. The Independent Data Monitoring Committee (IDMC) for this study most recently recommended continuation of the study following a meeting in June 2016, with the next IDMC meeting planned for February 2017. In addition, AGS-003 is being studied in Phase 2 investigator-initiated clinical trials as neoadjuvant therapy for RCC and for the treatment of non-small cell lung cancer (NSCLC).

"These mouse data support the expectation of enhanced clinical benefit for the combination of AGS-003 with checkpoint inhibitors and, importantly, also show that amplified total tumor RNA is essential to the anti-tumor activity of Arcelis-derived dendritic cells," noted Dr. Charles Nicolette, chief scientific officer and vice president of research and development at Argos. "Additionally, the observation in mice that the AGS-003-like therapy and sunitinib are each active separately and lead to improved control of tumor growth when combined bodes well for our ongoing Phase 3 ADAPT trial in advanced renal cell carcinoma where AGS-003 is initially being combined with sunitinib."

A copy of this and other Argos-related publications can be found at:
View Source

About the Arcelis Technology Platform
Arcelis is a precision immunotherapy technology that captures both mutated and variant antigens that are specific to each patient’s individual disease. It is designed to overcome immunosuppression by producing a specifically targeted, durable memory T-cell response without adjuvants that may be associated with toxicity. The technology is potentially applicable to the treatment of a wide range of different cancers and infectious diseases and is designed to overcome many of the manufacturing and commercialization challenges that have impeded other personalized immunotherapies. The Arcelis process uses only a small disease sample or biopsy as the source of disease-specific antigens and the patient’s own dendritic cells, which are optimized from cells collected by a leukapheresis procedure. The proprietary process uses RNA isolated from the patient’s disease sample to program dendritic cells to target disease-specific antigens. These activated, antigen-loaded dendritic cells are then formulated with the patient’s plasma and administered via intradermal injection as an individualized immunotherapy.

Peptide-based vaccination against VEGF results in efficient antitumor activity

On November 18, 2016 Immunovo reported on the successful development of a peptide-based vaccine enabling a successful active anti-tumor immunization therapy targeting the growth hormone Vascular Endothelial Growth Factor (VEGF) (Press release, Immunovo, NOV 18, 2016, View Source [SID1234516684]). An academic research team, in collaboration with Immunovo, has established that treatment with vaccine caused suppression of tumor growth in mice. These encouraging preclinical results were published last week in the leading international journal "Proceedings of the National Academy of Sciences of the USA" (PNAS). An exploratory Phase I/II studie in patients is now well underway at VU Medical Center (Amsterdam, The Netherlands).

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The vascular endothelial growth factor (VEGF) is a pivotal growth factor for angiogenesis (blood vessel formation) in tumor tissue. Therefore, it has been frequently investigated as a target in anticancer therapy. Its inhibition by the monoclonal anti-VEGF antibody bevacizumab (Avastin) has already demonstrated improved survival in patients with several types of cancer.

There are, however, limitations to the effectiveness of this passive immunotherapy strategy since it does not stimulate a patient’s immune system to actively respond to a disease in the way a vaccine does. The starting point of the research now reported in PNAS is that a VEGF vaccination has the potential to outperform the current clinical anti-VEGF treatment strategies.

Vaccination will not only provide durable VEGF suppression, it is also expected that the induced antibodies will have superior VEGF-neutralizing ability in comparison to bevacizumab. Furthermore, vaccination requires only a few intramuscular injections and reduces the number of hospital visits in comparison to treatment with bevacizumab.

However, vaccination with intact VEGF has major drawbacks such as unwanted biological activity and weak immunogenicity. The strategy pursued in the current research therefore is to use a VEGF mimicking peptide as a vaccine. The major challenge here was to identify the minimal peptide able to generate antisera with potent VEGF-neutralizing capacity and tumor-reducing capabilities.

A total of 33 peptide mimics of VEGF with varying levels of structural complexity (linear, conformational, and discontinuous) were designed, synthesized, and tested for the ability to generate potent antisera. It was established that induction of neutralizing antibodies with tumor-growth-inhibiting power was only successful for a 3D-structured 79-mer peptide with a fully intact cysteine-knot fold (covering the complete discontinuous binding site of bevacizumab).

Eradication of tumor growth using this peptide was demonstrated in two different tumor models (mice). It thus became clear that enforcing a native-like, secondary structure in the peptide is the key to success for inducing neutralizing anti-VEGF antibodies with tumor-inhibiting power.

Joost van Bree, CEO of Immunovo explains: "At Immunovo, we think that clinical benefit could be enhanced by inducing a humoral immune response against VEGF through active immunization with VEGF-based peptides. In this study we demonstrated the successful development of a unique synthetic vaccine with potent in vitro and in vivo VEGF-neutralizing activities, as shown in passive and active immunization tumor models. We strongly believe that this strategy has the exciting potential to outperform the current clinical anti-VEGF treatment strategies"

The research team included Professor Peter Timmerman of Pepscan Systems BV and the University of Amsterdam’s Van’t Hoff Institute for Molecular Sciences (HIMS) and Madelon Wentink and Professor Arjan Griffioen, both of VU Medical Center Amsterdam.

Agios Announces Phase 1 Data from Dose Expansion Cohorts of AG-120 in Patients with IDH1 Mutant Positive Glioma and Chondrosarcoma

On November 18, 2016 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of cancer metabolism and rare genetic metabolic disorders, reported the first data from the dose expansion cohorts of the Phase 1 study evaluating single agent AG-120 in isocitrate dehydrogenase-1 (IDH1) mutant positive glioma and chondrosarcoma (Press release, Agios Pharmaceuticals, NOV 18, 2016, View Source [SID1234516677]). The glioma data were presented today at the Society for Neuro-Oncology (SNO) Annual Meeting in Scottsdale, AZ and the chondrosarcoma data were presented last week at the annual meeting of the Connective Tissue Oncology Society (CTOS) in Lisbon, Portugal.

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"Glioma and chondrosarcomas are extremely difficult-to-treat diseases where patients are in need of new therapies," said Chris Bowden, M.D., chief medical officer at Agios. "These Phase 1 dose expansion data are encouraging, as they continue to demonstrate a well-tolerated safety profile for AG-120 at a fixed daily dose of 500 mg. The prolonged stable disease in both patient populations is encouraging in light of AG-120’s unique differentiation mechanism of action. In addition, our initial experience utilizing centralized volumetric assessments in patients with glioma has been informative, and along with our ongoing AG-881 Phase 1 trial, will help determine the next steps in clinical development."

"In glioma, AG-120 has the potential to help a large number of patients with IDH1 mutations," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "The SNO presentation is the first look at data for AG-120 in a defined cohort of glioma patients where we evaluated the potential for volumetric analyses to improve our understanding of the response patterns beyond the conventional bi-dimensional methods. This methodology could be instrumental in developing more effective, targeted therapies for patients with this disease."

The Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, intrahepatic cholangiocarcinoma (IHCC) and chondrosarcomas that harbor an IDH1 mutation. The dose-escalation phase was followed by four expansion cohorts in the following patient groups.

Low grade glioma with ≥ 6 months prior scans
High grade (metastatic) chondrosarcoma
2nd-line cholangiocarcinoma
Solid tumors not eligible for cohorts 1-3
Enrollment is now complete for the dose escalation and expansion cohorts.

Glioma Expansion Data Presented at SNO Annual Meeting

As of the August 1, 2016 data cut off, 66 patients have been treated with single agent AG-120, and 28 patients (42%) remain on treatment.

Data reported are from 20 patients who received AG-120 administered from 200 mg to 1200 mg total daily doses in the dose-escalation phase.
Forty-six patients who received 500 mg daily doses of AG-120 administered in two expansion cohorts, including 24 patients enrolled in a cohort with non-enhancing glioma and 22 glioma patients with enhancing disease enrolled in a basket cohort.
The median age of these patients is 41 (ranging from 21-71).
The median number of prior therapies was two (ranging from one to six) and included temozolomide (71%). Seventy-four percent of patients received radiotherapy.
A safety analysis conducted for all 66 treated patients as of the data cut-off demonstrated that AG-120 was well-tolerated with a favorable safety profile in glioma patients.

No dose limiting toxicities have been observed.
The majority of adverse events reported by investigators were mild to moderate, with the most common being headache, nausea, diarrhea and vomiting.
There were 11 patients with serious adverse events (SAE) and none of them were drug-related.
Efficacy data from 65 response-evaluable patients as of the data cut-off showed:

Two patients had a minor response according to the Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG).
Forty-one (63%) patients had stable disease, including 27 with non-enhancing disease; the median treatment duration for non-enhancing glioma was 8.1 months (ranging from 1.4 – 17.8 months).
Volumetric analysis conducted centrally demonstrated stabilization or a decrease in tumor growth rate compared to the pretreatment rate in 64% (n=14 of 22) of glioma patients with non-enhancing disease receiving AG-120 and requires further development as a response evaluation tool.
Chondrosarcoma Expansion Data Presented at CTOS Annual Meeting

Agios also analyzed data from 21 chondrosarcoma patients as of September 23, 2016 in the dose escalation (n=12) and expansion cohorts (n=9) and 7 remain on treatment.

Doses received were 100 mg twice daily, and 300, 400, 500, 600, 800, 900 and 1200 mg once a day. Expansion cohort patients received 500 mg once a day. Median treatment duration was 2.6 months (ranging from 0.0–24.4 months).
Prior therapy included surgery (57%), radiotherapy (33%) and chemotherapy (24%). The median number of prior systemic therapies was one (ranging from one to five).
No dose-limiting toxicities were reported; the majority of adverse events reported by investigators were mild to moderate, with the most common being diarrhea, nausea, decreased appetite, QT prolongation and fatigue.
Most SAEs were considered unrelated to treatment with one case of hypophosphatemia (low phosphorous blood level) considered to be possibly related to treatment.
Of 20 response-evaluable patients, 11 (55%) experienced stable disease as their best response; the 3-month progression-free survival rate was 58%.
Baseline plasma levels of the oncometabolite D-2-hydroxyglutarate (2-HG) were elevated above the healthy volunteer range. Treatment with AG-120 resulted in significant reduction of plasma 2-HG compared to baseline. Up to 99.7% tissue 2-HG reduction was documented in paired biopsies obtained from 3 patients treated with AG-120. Together these data indicate the on-target pharmacodynamic effects of AG-120.
About Glioma
Glioma presents in varying degrees of tumor aggressiveness, ranging from slower growing (low grade glioma) to rapidly progressing (high grade glioma-Glioblastoma Multiforme). Common symptoms include seizures, memory disturbance, sensory impairment neurologic deficits and seizures. The long-term prognosis is poor with a five-year survival rate of 33 percent. Median survival is 12-15 months for glioblastoma and 2-5 years for anaplastic glioma. IDH1 mutations are highly prevalent, accounting for approximately 68-74 percent of low grade glioma and secondary glioblastoma.

About Chondrosarcoma
Chondrosarcoma is a heterogeneous group of cancers that arise from cartilage in the bone and joint. It is the most common type of bone cancer with 700-1,000 people diagnosed per year in the U.S. IDH1/2 mutations occur in approximately 46-63 percent of central chondrosarcomas. The prognosis is based on disease burden – for localized disease, there is curative potential with surgery, but metastatic disease has a low five-year survival rate. Radiation is not effective, and chemotherapy is of limited benefit. Treatment for metastatic disease is mainly palliative.

ICLUSIG® Tablets 15 mg Now Available in Japan for Patients with Chronic Myeloid Leukemia and Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

On November 18, 2016 Otsuka Pharmaceutical Co., Ltd. reported that it has commenced sales as of November 21 in Japan of ICLUSIG Tablets 15 mg (ponatinib hydrochloride), a tyrosine kinase inhibitor (TKI) indicated to treat patients with chronic myeloid leukemia (CML) who are resistant or intolerant to previous treatments and patients with recurrent or refractory Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) (Press release, Otsuka, NOV 18, 2016, View Source [SID1234516673]).

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Although TKIs are used as a first-line treatment for CML and Ph+ ALL, mutation of BCR-ABL genes can develop during the treatment period and indicates resistance to the currently used TKI. In addition, intolerance to the side effects of existing TKI treatments can lead to a discontinuation of treatment.

ICLUSIG, discovered in the U.S. by ARIAD Pharmaceuticals, Inc., is a TKI that targets BCR-ABL expressed in CML and Ph+ ALL. This drug is a new chemically synthesized oral TKI, and is specifically designed to inhibit mutated TK caused by a T315I mutation which induces resistance to the currently used TKI. ICLUSIG demonstrates efficacy in CML patients with resistance to or with intolerance to currently available TKIs. ICLUSIG was approved in the U.S. in 2012, in Europe in 2013, and in 2014 Otsuka obtained the rights to commercialize and develop ICLUSIG in ten Asian countries and regions.*2
ICLUSIG was designated as an orphan drug in Japan and regulatory approval was granted in September 2016. New Drug Applications have been submitted in South Korea and Taiwan