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.

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.

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