On November 16, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported the presentation of preliminary clinical data from an ongoing Phase 1/2 trial of its investigational PARP inhibitor, pamiparib, in combination with radiation therapy (RT) and/or temozolomide (TMZ) in patients with newly diagnosed or recurrent/refractory (R/R) glioblastoma multiforme (GBM) (Press release, BeiGene, NOV 16, 2018, View Source;p=irol-newsArticle&ID=2377491 [SID1234531392]). These data are being presented at the 23rd Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO), being held November 15 to 18 in New Orleans, LA. Discovered by BeiGene scientists in Beijing, pamiparib is currently in Phase 3 trials globally and in China as a monotherapy and in Phase 1/2 trials in combination with chemotherapy or immunotherapy for a variety of solid tumors.

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"There are limited treatment options available for patients with newly diagnosed and recurrent/refractory glioblastoma. This trial was designed to evaluate the potential synergies between DNA damaging therapies and/or agents and our investigational PARP inhibitor, pamiparib, which in pre-clinical studies has demonstrated brain penetration and PARP trapping activity. We are excited to continue to assess the potential of pamiparib combinations for a variety of difficult-to-treat cancers where there is urgent global need," commented Amy Peterson, M.D., Chief Medical Officer for Immuno-Oncology at BeiGene.

"While response data are still maturing, these preliminary results demonstrated signs of antitumor activity of pamiparib in combination with radiation therapy in patients with newly diagnosed glioblastoma, as well as in combination with low-dose TMZ in patients with recurrent/refractory glioblastoma including those who previously progressed on TMZ, and support the continued development of these combinations," said Kent Shih, M.D., Senior Investigator of the Neuro-Oncology Program at Sarah Cannon Research Institute.

Summary of Preliminary Results

This open-label, multi-center global Phase 1b/2 multiple-dose and dose-escalation trial of pamiparib plus RT and/or TMZ (NCT03150862) was designed to evaluate the safety, efficacy and clinical activity of the combination in patients with newly diagnosed or R/R GBM. Patients with newly diagnosed GBM with unmethylated MGMT promoter status (Arm A) received pamiparib (60 mg twice a day) over escalating time periods (two, four, or six weeks) in combination with RT over six to seven weeks. Patients with R/R GBM (Arm C) received pamiparib (60 mg twice a day) continuously plus TMZ administered on Days 1 to 21 of each 28-day cycle. After evaluation of safety and tolerability from Arm A and C, Arm B will enroll patients with newly diagnosed GBM and treat them with the triple combination of RT, pamiparib, and TMZ.

As of September 14, 2018, a total of 18 patients with newly diagnosed GBM were enrolled in Arm A (n=3, 6 and 9 in the two-, four-, and six-week cohorts respectively). The median study follow-up duration is 19 weeks (2-54). Five grade >3 adverse events (AE) (chills, diarrhea, fatigue, nausea, vertigo, one [5.6%] each) were considered related to pamiparib or RT. Dose-limiting toxicities of fatigue, vertigo, and chills (one each) were reported.

As of the data cutoff date, 15 of the 18 patients were evaluable for response per modified response assessment in neuro-oncology (mRANO) criteria. Two of 15 patients achieved a partial response (PR, one was confirmed) and six patients achieved stable disease (SD); the disease control rate was 53.3% (95% CI: 26.6-78.7).

In Arm C, eight patients received TMZ at a fixed dose of 40 mg for 21 of 28 days and seven patients received 20 mg TMZ. The median study follow-up duration is 12.9 weeks (0.3-31.4). Grade >3 AEs included anemia (20%), fatigue (13.3%), and decreased lymphocyte (13.3%), which were considered related to pamiparib or TMZ. Dose-limiting toxicities of nausea and neutropenia were reported. The combination of 21 days of 40 mg TMZ with pamiparib was not tolerable; a lower 20 mg TMZ dose evaluation in combination with pamiparib is ongoing.

Ten of the 15 patients were evaluable per mRANO criteria and there were two PRs (one unconfirmed and one confirmed after data cutoff) and three SD.

About Glioblastoma Multiforme
Glioblastoma multiforme, also called glioblastoma, is an aggressive type of cancer where malignant grade IV tumors occur in the brain or spinal cord.2 These are the most common type of malignant brain tumors among adults.3 Symptoms include worsening headaches, nausea, vomiting and seizures. Patients can also present with neurological symptoms which are dependent on the tumor location (for example, weakness or sensory changes of face, arm or leg, balance difficulties and neurocognitive/memory issues).4 Glioblastoma can occur at any age but tends to occur more often in older adults. The five-year relative survival rates for patients with glioblastoma are: 19 percent (age 20-44), eight percent (age 44-54), and five percent (age 55-64).5

About Pamiparib
Pamiparib (BGB-290) is an investigational inhibitor of PARP1 and PARP2 which has demonstrated pharmacological properties such as brain penetration and PARP-DNA complex trapping in preclinical models. Discovered by BeiGene scientists in Beijing, pamiparib is currently in global clinical development as a monotherapy and in combination with other agents for a variety of solid tumor malignancies.

On November 16, 2018 VBL Therapeutics (Nasdaq: VBLT), is reported its results today from its Phase 3 GLOBE study in patients with recurrent glioblastoma (rGBM) which was designed to evaluate VB-111 in combination with bevacizumab (Avastin) (`treatment arm`), compared to bevacizumab (`control arm`) (Press release, VBL Therapeutics, NOV 16, 2018, View Source [SID1234531393]). In March 2018, VBL announced top-line data for the study, which did not demonstrate a benefit in overall survival (OS) or progression-free survival for the treatment arm relative to the bevacizumab control.

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The GLOBE data are being presented today at the 2018 Society for Neuro-Oncology Annual Meeting by Dr. Timothy Cloughesy, MD, Professor of Clinical Neurology and Director of the Neuro-Oncology Program, UCLA School of Medicine and principal investigator of the GLOBE trial. The data include further analyses of the GLOBE data including baseline prognostic factors and subgroups analysis. Data show that the baseline tumor volume, which is a significant prognostic factor in rGBM, was higher in the treatment arm compared to the control arm. Overall, the subjects in the study had relatively high tumor volume, as large-volume tumors were not an exclusion criterion. It is of interest that patients with smaller tumors (<15 cm3) appeared to respond better to the treatment arm, with numerically higher response rate and overall survival observed. Furthermore, a trend towards greater survival was observed in patients treated with VB-111 who reported fever. VB-111 was well tolerated, with a similar early termination rate in both the treatment and control arms. Most frequent adverse event was self-limited fever, starting several hours post therapy and usually resolving by 24 hours. As expected, a higher rate of SAEs and grade >=3 AEs was reported in the combination treatment arm.

Subsequent analyses have focused on the potential reasons for the major differences in outcomes between the positive VB-111 Phase 2 clinical trial in rGBM and the unsuccessful GLOBE results. The Phase 2 trial of VB-111 met the primary endpoint of OS benefit with median OS (mOS) of 13.6 months upon treatment with VB-111 as a single drug (`priming`) followed by adding bevacizumab to VB-111 upon further progression, compared to mOS of 6.8 months for the treatment arm in GLOBE (co-administration of VB-111 and bevacizumab, without any VB-111 monotherapy `priming` period).

Thorough analyses of the baseline risk factors of the Phase 2 and the Phase 3 treatment groups did not reveal any differences. Therefore, patient selection or different patient populations could not explain the difference between the results of the two studies. The only significant change between the Phase 2 and Phase 3 treatment cohorts was in the treatment regimen – the regimen for Phase 2 trial included priming with VB-111 whereas the regimen for GLOBE trial did not.

To test the hypothesis that concomitant treatment with bevacizumab may have a negative effect on VB-111 activity, the Company investigated this combination in a pre-clinical tumor model. The results indicate that treatment with VB-111 in combination with bevacizumab appears to block the anti-tumor the effect of VB-111, compared to VB-111 monotherapy. In addition, a retrospective analysis of a small cohort of 10 patients who were treated concomitantly with VB-111 and bevacizumab for safety evaluation (no priming), was inferior to what was observed with VB-111 priming in the Phase 2 study.

To better understand these results, the Company is collaborating with UCLA scientists in performing thorough analyses of MRI scans for VB-111-primed combination arm patients from the Phase 2 trial, compared to the un-primed combination arm patients in the GLOBE trial.

"Our initial exploratory analyses demonstrate clear radiologic responses over time in rGBM patients treated with VB-111 in the Phase 2 trial, both on VB-111 monotherapy and in combination with bevacizumab after priming with VB-111 alone, which were translated to overall survival. We are currently analyzing the GLOBE MRI scans to see if this signature of VB-111 activity is lost in the GLOBE combination group and will report the outcome upon completion of the analysis," said Dr. Cloughesy.

"The new analyses we have been conducting provide insight into how the VB-111 treatment regimen may influence its anti-tumor effect and help us understand why the positive Phase 2 data were not replicated in the GLOBE Phase 3 study," said Dror Harats, M.D., Chief Executive Officer of VBL Therapeutics. "We believe that priming with VB-111 without bevacizumab may be critical for the immune and vascular-disruptive/anti-angiogenic mechanism of VB-111 in rGBM. We continue to have confidence in the ongoing OVAL Phase 3 study of VB-111 in platinum-resistant ovarian cancer patients, whose protocol takes into account lessons learned from our GBM trial. The OVAL Phase 3 study is evaluating VB-111 in combination with chemotherapy rather than Avastin. The combination of VB-111 with paclitaxel worked well both in pre-clinical settings and in our Phase 2 for ovarian cancer, including in patients whose tumors progressed on prior treatment with Avastin. In OVAL, we are repeating exactly the same successful Phase 2 regimen."

For a link to the GLOBE presentation at SNO see: LINK

About the GLOBE study

The GLOBE pivotal Phase 3 trial was a randomized, controlled, double-arm, open-label study of VB-111 dosed every two months in combination with bevacizumab dosed every two weeks, compared to bevacizumab monotherapy. Key inclusion criteria included first or second progression of glioblastoma following standard of care treatment with temozolomide and radiation, a histologically confirmed diagnosis of glioblastoma and measurable disease by RANO criteria at progression.

The study was conducted under a Special Protocol Assessment (SPA) granted by the FDA, with full endorsement by the Canadian Brain Tumor Consortium (CBTC). VB-111 has received orphan drug designation in the United States and Europe and was granted Fast Track designation by the FDA for promising and meaningful long-term survival in patients with glioblastoma that has recurred following treatment with standard chemotherapy and radiation.

About Ofranergene Obadenovec (VB-111)

VB-111, a potential first-in-class anticancer therapeutic candidate, is the Company’s lead oncology product currently being studied in a Phase 3 trial for ovarian cancer. VB-111 has received orphan drug designation in both the US and Europe, and fast track designation in the US for prolongation of survival in patients with rGBM. In addition, VB-111 successfully demonstrated proof-of-concept and survival benefit in Phase 2 clinical trials in radioiodine-refractory thyroid cancer and recurrent platinum-resistant ovarian cancer. VB-111 has received an Orphan Designation for the treatment of ovarian cancer by the European Medicines Agency (EMA).

On November 16, 2018 Stemline Therapeutics, Inc. (Nasdaq: STML), a biopharmaceutical company focused on the development and potential commercialization of novel oncology therapeutics, reported that data from the Phase 2 trial of SL-701 in patients with second-line glioblastoma (GBM) were selected for oral presentation at the 23rd Annual Meeting of the Society of Neuro-Oncology (SNO) being held November 15-18, 2018 in New Orleans, LA (Press release, Stemline Therapeutics, NOV 16, 2018, View Source [SID1234531394]).

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Details on the presentation are as follows:

Title: Phase 2 trial of SL-701 + bevacizumab in patients with previously treated glioblastoma (GBM) meets primary endpoint of OS-12, with preliminary correlation between long-term survival and target-specific CD8+ T cell immune response
Presenter: David Peereboom, MD; Cleveland Clinic
Abstract: ATIM-06
Date/Time: Friday, November 16, 2018 – 4:25 PM CT

A copy of the oral presentation will be available on the Stemline website (www.stemline.com), under the Scientific Presentations tab, following the SNO presentation.

On November 16, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its updated data from the ongoing Phase 1 study evaluating single agent AG-881 in advanced glioma (Press release, Agios Pharmaceuticals, NOV 16, 2018, View Source [SID1234531460]). The data were featured in an oral presentation at the Society for Neuro-Oncology (SNO) Annual Meeting in New Orleans. AG-881 is an investigational, oral, selective, potent inhibitor of the mutant isocitrate dehydrogenase-1 (IDH1) and IDH2 enzymes and was designed for enhanced brain penetrance for development in IDH-mutant glioma.

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"With additional follow-up, the AG-881 Phase 1 dose-escalation data continue to show a favorable safety profile at the doses selected for the perioperative study. Longer treatment duration and a reduction in tumor growth rates are encouraging signs of clinical activity in low-grade glioma," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "Ultimately, use of an IDH inhibitor in this difficult-to-treat disease has the potential to improve the current treatment paradigm by delaying the multiple rounds of surgery, radiation and chemotherapy that many patients endure."

"With no curative or approved targeted therapies and a high frequency of IDH1 mutations in low-grade glioma, we are committed to advancing one of our IDH inhibitors to a registrational study in this disease," said Chris Bowden, M.D., chief medical officer at Agios. "We are continuing to collect clinical data for both ivosidenib and AG-881, along with feedback from regulators and the neuro-oncology community, to make an internal decision on our glioma pivotal strategy by the end of this year."

Study Status

AG-881 is being evaluated as a single agent in an ongoing Phase 1 dose-escalation trial in IDH1/2 mutant advanced solid tumors, including glioma. Enrollment was completed in June 2017. Dose escalation data as of March 29, 2018 were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. As of the updated July 20, 2018 data cut-off, study design, enrollment and baseline characteristics of the 52 glioma patients remain unchanged, as reported below.

Forty-eight percent of patients (n=25) had World Health Organization (WHO) classified Grade 2 tumors, 42% (n=22) had Grade 3 tumors, 8% (n=4) had Grade 4 tumors and 2% (n=1) was unknown.
The median age of these patients is 42.5 years (ranging from 16-73 years).
Patients received a median of two prior systemic therapies (ranging from one to six).
Seventy-three percent of patients (n=38) had previously received temozolomide and 58% percent (n=30) had previously received radiotherapy.
Patients received daily doses of AG-881 ranging from 10 mg to 300 mg.
Updated safety and efficacy data on the 52 patients with enhancing and non-enhancing glioma, including an exploratory tumor volume growth rate analysis, are reported below.

Fourteen patients remain on treatment, including 13 patients with non-enhancing disease.
Of the 38 patients who discontinued treatment, 76.3% (n=29) discontinued for disease progression and 5.2% (n=2) discontinued due to an AE.
The median treatment duration was 6.3 months (ranging from 0.2-32 months) for all glioma patients, 15 months (ranging from 1-32 months) for non-enhancing glioma and 3.25 months (ranging from 0.2- 32 months) for patients with enhancing disease.
Thirty-seven percent of patients (n=19, including 15 patients with non-enhancing disease) remained on treatment for ≥1 year.
Safety Data

The safety analysis conducted for all 52 glioma patients as of the data cut-off demonstrated that AG-881 continues to have a favorable safety profile at dose levels below 100 mg.

The majority of adverse events (AEs) reported by investigators were mild to moderate, with the most common (>30%) being increases in alanine aminotransferase (ALT) (n=23), increases in aspartate aminotransferase (AST) (n=21), headache (n=19) and fatigue (n=17).
Grade 3 or higher AEs were observed in 19% of all patients (n=10). AEs occurring in more than one patient included seizure (n=4), ALT increases (n=3) and AST increases (n=2).
As reported in June, dose limiting toxicities (DLTs) of Grade 2 or higher elevated transaminases occurred in five glioma patients at the higher dose levels (≥100 mg) and resolved to Grade ≤1 with dose modification or discontinuation. There were no new DLTs reported as of the new data cut-off or any treatment-related on-treatment deaths.
Doses of 10 mg and 50 mg are under evaluation in an ongoing perioperative study in non-enhancing glioma.
Efficacy Data

Efficacy data from the 52 glioma patients (22 with non-enhancing and 30 with enhancing disease) as of the data cut-off showed:

One patient with non-enhancing disease and a 1p19q co-deletion had a confirmed / sustained partial response according to the investigator by Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG) and remains on treatment.
One patient with non-enhancing disease and a 1p19q co-deletion had a confirmed / sustained minor response according to the investigator by RANO-LGG and remains on treatment.
Sixty-nine percent of patients (n=36) had a best response of stable disease, including 82% (n=18) patients with non-enhancing disease.
For non-enhancing patients with available data (n=18), the average volumetric six-month tumor growth was 6.8% following treatment with AG-881; pre-treatment volumetric growth rates were not available for these patients. For a similar population of IDHm low-grade glioma patients in the ongoing Natural History study, the average six-month volumetric growth prior to treatment was 24.5%.
Ongoing Glioma Perioperative Study Presented in Trials in Progress Poster
A perioperative ‘window’ trial with ivosidenib and AG-881 (10 mg and 50 mg) in up to 45 IDH1m non-enhancing low-grade glioma patients is ongoing and being presented today as part of a trials in progress poster. The goal of the trial is to confirm CNS penetrance and tumor 2-HG suppression of ivosidenib and AG-881 as part of the strategy to finalize internal pivotal development plans by year-end 2018.

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 and neurologic deficits. The long-term prognosis is poor with a five-year survival rate of 33 percent. Approximately 11,000 low-grade glioma patients are diagnosed annually in the U.S. and EU and approximately 80 percent have an IDH1 mutation.

On November 16, 2018 Savara Inc. (NASDAQ:SVRA), an orphan lung disease company, reported that Rob Neville, Savara’s Chief Executive Officer, will participate in a fireside chat at the Evercore ISI HealthCONx Conference in Boston on Tuesday, November 27, 2018 at 11:45 a.m. ET in the South Atlantic Room at the Boston Harbor Hotel in Boston (Press release, Savara, NOV 16, 2018, View Source [SID1234531395]).

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Interested parties can access a live audio webcast of the fireside chat on the Investors page of Savara’s website at View Source Please connect to the company’s website at least 15 minutes prior to the start of the presentation to ensure sufficient time for any software download that may be required for the webcast. An archived presentation of the webcast will be available on Savara’s website for 30 days.