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Clinical Study

Our technology has been validated in study after study and we continue to pursue active research to further new formulation development and confirm benefit in disease indices where we can have a positive impact.

NEO100-01 GBM TRIAL

In April 2017, NeOnc began the first human clinical trial of its NEO100 formulation. The study was conducted to determine the drug’s therapeutic survivability impact and tolerance capacity when used as an intranasal transport mechanism for delivering therapeutics to the brain for treating brain-based glioblastomas (GBM). As a result of this part of the trial, NeOnc showed an improvement with this therapy in patients with an IDH1 mutation. Phase 2a of the trial is now underway, focusing on the IDH1 mutation component related to GBM treatment.

Background

Glioblastoma (GBM, WHO grade IV glioma) is the most common primary malignant brain tumor among adults.

Regardless of the treatment regimen, many patients relapse and are faced with limited treatment options. The aggressive infiltration of GBM throughout the brain typically limits the efficacy of repeat surgical resection, and tumor cells frequently acquire resistance to further cytotoxic therapy. Therefore, recurrent GBM does not respond well to repeat surgery, re-irradiation, and additional rounds of chemotherapy. At the same time, these interventions may moderately increase overall survival, but the prognosis for these patients remains exceptionally poor.

Given the persistent medical need for improved treatments, NeOnc began investigating a type of intervention, intranasal delivery of perillyl alcohol (POH, NEO100), for patients with recurrent GBM. Extensive preclinical studies provided strong evidence of POH’s natural anticancer potential. Though the exact mechanism of POH’s anticancer effect is unclear, it most likely results from the pleiotropic effects including cell cycle arrest, endoplasmic reticulum stress, and induction of apoptosis.

Protocol

In the two-year study conducted at the Cleveland Clinic at the University of Washington/Seattle, the University of Wisconsin, and the University of Southern California study, 12 patients were enrolled and divided into four cohorts. Candidates for the clinical study needed to meet the following criteria:

  • Were 18 years of age or older.
  • Had a confirmed progression or recurrent grade IV Glioma.
  • Had been on a stable dose of steroids for at least five days.
  • Had failed previous radiation and Temozolomide treatment.
  • Had an ECOG1 performance status of 0-2, or;
    • Had Karnofsky’s 2 performance status ≥60.
    • Had an expected survival rate of at least 3 months.
    • Showed a baseline MRI with gadolinium within two weeks of trial.
    • Had seizures which were being controlled on a stable dose of anti-epileptics for two weeks prior to
      enrollment.

        The cohorts in the study were divided into four groups.  Each group was given a specific dosage of NEO100 administered by intranasal delivery using a nebulizer and nasal mask for 28 days. Dosages were 96 mg/dose (384 mg/day) for Group 1, 144 mg/dose (576 mg/day) for Group 2, 192 mg/dose (768 mg/day) for Group 3, and 288 mg/dose (1152 mg/day) for Group 4.

        Patients stayed in the trial for as long as there was no disease progression.

        The patients underwent gadolinium-enhanced brain MRI as part of standard care. Baseline tumor measurement was performed within two weeks of registration and assessed by RANO criteria (Response Assessment in Neuro-Oncology). MRIs were repeated after every 28-day cycle (i.e., cycles 2, 4, and 6) and whenever disease progression was suspected based on clinical symptoms. Tumor response was assessed using the MacDonald and the RANO response criteria for high-grade gliomas, which considers radiologic imaging, neurological status, and steroid dosing.

        Safety was evaluated throughout the trial by the incidence of adverse events (AE), physical examination findings, vital signs, and clinical laboratory test results. AE were graded for severity using NCI Common Terminology Criteria for Adverse Events v.4.0.

        Results

        Phase 1 of the study showed that Intranasal NEO100 was well tolerated at all dose levels, and no severe adverse events were reported.

        • 30% of patients had no disease progression after six months
        • There was a 100% survival rate after 12 mo. with patients who received a minimum of 4 cycles
        • In one patient, there was complete remission of the disease at the two-year mark
        • Another patient who continued to receive NEO100 after the conclusion of the trial was still alive at the three-year mark
        • The overall survival rate and survival time of patients who received NEO100 was significantly higher vs.
          similar GBM studies using traditional
          chemotherapeutic drugs and delivery methods.
        • All subjects well tolerated the therapy.
        • Only minor side effects were noted, such as fatigue, headaches, and runny nose.

        As a result, NEO100 demonstrated an ability to provide improved survivability when compared to historical controls. It points to the potential that this novel intranasal approach could be helpful in treating recurrent GBM.

        Publishing

        This part of the NEO100GBM Study concluded in 2020 and the results were published in 2021 in the Neuro-Oncology Advances Journal (NOAJ). The NOAJ is a quarterly journal under the auspices of the Oxford University Press, the largest university press in the world, and its printing history dates to the 1480s. 

        The study was authored by Axel Schonthal PhD3, David M Peereboom4, Naveed Wagle5, Rose Lai6, Anna J Mathew7, Kyle M Hurth8, Vincent F Simmon9, Steven P Howard10, Lynne P Taylor11, Frances Chow12, Clovis Orlando da FonsecaNeOnc Technologies, Inc., Los Angeles, California and Department of General and Specialized Surgery, Antonio Pedro University Hospital, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil[/efn_note], and Dr. Thomas C Chen13

        IDH1 Mutation

        One of the important findings in the first part of the NEO100 GBM study was the data that was acquired showing that NEO100 not only had a positive impact on survivability for those patients with GBM but that those who showed an Isocitrate dehydrogenase 1 (IDH1) biomarker mutation the results were even more positive with patients surviving 25% longer than those whose gliomas show wild-type IDH1.

        IDH1 is one of the key components in cancer cell homeostasis as it catalyzes the oxidative decarboxylation of isocitrate, which is necessary for releasing the energy needed for cell growth. Cancer cell growth can be hindered or stopped by slowing or stopping an IDH1 mutation’s ability to function.

        Expanding the Study

        As a result of this finding, NeOnc has expanded its initial NEO100 GBM Study into phase 2a to specifically target the ability of NEO100 inhalation treatment to impact patients with Grade III, IV glioma with IDH1 Mutation. This next part of the study is anticipated to run through 2025  in up to twelve affinity sites across the United States.

        Protocol

        The protocols for this part of the study remain the same, except that prospective candidates for the trial must show the IDH1 mutation biomarker in their tumor. The study will be conducted at up to twelve qualified and vetted university and hospital locations. Patients in the study will be given 288 mg of NEO100 intranasally four times a day (1152 mg total) to determine the impact on their gliomas. An interim analysis will be conducted every six months and follow-up for one more year past the study’s conclusion.

        Status

        The study protocols have been approved, and site enrollment is underway.

        Desired Outcome

        We believe data generated from this part of the trial may allow NeOnc to seek approval from the FDA to treat IDH1 mutant tumors (Grade III and IV) based on NeOnc having successfully identified a life-extending biomarker and a successful therapy for treating the same. The FDA approved Avastin with a three-month survival. This approval makes NeOnc’s management optimistic that the FDA will approve NEO100 for the market.

        GBM Phase I Survival Data

        The following charts show some of the data that was gathered during the first part of the NEO100 GBM Study.

        OVERALL SURVIVAL

        The chart shows the survival rate of all
        patients within the first 24 months of the trial.

        The chart shows specific highlights of survival at 12 months (OS 12) and 24 months (OS 24) vs. Median OS at 15 months.

        CYCLE SURVIVAL

        The chart shows the survival rate of all patients within the first 24 months based on the number of treatment cycles they completed.

        Patients who completed >5 cycles demonstrated a higher survival rate.

        – COMPLETED <5 CYCLES

        – COMPLETED

        IDH1 SURVIVAL

        The chart above shows the survival rate of patients based on the indication of IDH1 in their profile. Studies show that people with IDH1 biomarkers tend to do better with disease resistance.

        – HAS IDH1 MUTATIONS

        – NO IDH1 MUTATION

        NEO100 PHASE I SURVIVAL RATE vs. STANDARD of CARE for RECURRENT HIGH-GRADE GLIOMAS

        The chart below shows the Kaplan Meier curves representing the probability of survival of recurrent GBM patients undergoing different treatment regimens.

        Blue Line: Results for intranasal NEO100 treatment (n=12) obtained from Phase I part of the NEO100 GBM trial. This shows that the subjects had a higher survival rate vs. current Standard of Care.

        Purple Line: This shows a single institution retrospective of the real-world clinical experience with bevacizumab (n=74).

        Grey Line: This line shows the historical comparison from 1998 which monitored the survival of patients after surgical resection of recurrent tumors (n=46).

        Red Line: This represents the data from a randomized Phase III trial published in 2013, where patients (n=65) received Lomustine. The percentages refer to OS 12- and 2-year survival (OS 24) of the different treatment regimens after diagnosis of recurrence.

         

        Differentiators

        NEO100 provides several key differentiators that set it apart from the current state-of-the-art in the pharma-based treatment of CNS-based disease.

         

        Current Standard of Care for Recurrent High-Grade Gliomas

        Repeat
        Surgery

        Oral
        Lomustine

        Bevacizumab
        (Avastin)

        Novocure

        Gamma
        Tiles

        Gliadel
        Wafers

        No Surgery Required

        Bone Marrow Unaffected

        Normal Wound Healing

        Radiation Not Required

        No Systemic Side
        effects

        Easy to Administer
        Treatment