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Trabedersen - Autotelic/Oncotelic

Drug Profile

Trabedersen - Autotelic/Oncotelic

Alternative Names: AP 2/09-DS; AP-12009; AP-2/09; OT-101; OT-201; Personalised dosing TGF-beta antisense; TGF-beta antisense

Latest Information Update: 30 Apr 2020

At a glance

  • Originator Antisense Pharma
  • Developer Autotelic; Oncotelic
  • Class Antineoplastics; Antisense oligonucleotides; Antivirals; Immunotherapies; Oligodeoxyribonucleotides; Thionucleotides
  • Mechanism of Action Transforming growth factor beta2 inhibitors; Virus replication inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - Pancreatic cancer; Glioma
  • New Molecular Entity Yes

Highest Development Phases

  • Phase III Glioblastoma
  • Phase II/III Malignant melanoma; Pancreatic cancer
  • Preclinical COVID 2019 infections; Ovarian cancer; Pneumonia
  • No development reported Colorectal cancer
  • Discontinued Anaplastic astrocytoma

Most Recent Events

  • 30 Apr 2020 Mateon Therapeutics plans a phase II trial for COVID-2019 infections and associated Pneumonia in USA
  • 27 Apr 2020 Mateon Therapeutics files an IND application with the US FDA in for COVID-2019 infections
  • 09 Apr 2020 Mateon Therapeutics files a pre-IND application with the US FDA for COVID-19

Development Overview

Introduction

Trabedersen, a single-stranded phosphorothioate antisense oligodeoxynucleotide (18-mer) that specifically targets mRNA encoding transforming growth factor-β2 (TGFβ2), is being developed by Autotelic, in partnership with Oncotelic (a subsidiary of Mateon Therapeutics), for the treatment of cancer and COVID-2019 infections. Trabedersen is believed to reverse TGF-'s immunosuppressive effects by reversing tumour induced immuno-blockade, reactivating the immune response, inhibiting tumour cell growth, and reducing migration and metastases. Trabedersen is a potent inhibitor of SAR-CoV-2 replication and also targets the lethal clinical sequelae of COVID-19, including pneumonia and fibrosis. Trabedersen through inhibition of TGFβ-Tgfbr1 pathway reduce internalisation of the epithelial sodium channel (ENaC) by alveolar epithelial cells which results in improved alveolar fluid reabsorption in ARDS, and reduction in pulmonary oedema in patients with severely ill COVID-2019 infections. Clinical development in glioblastoma is underway worldwide. Clinical development for pancreatic cancer and melanoma is underway in Germany. Preclinical development for the treatment of pneumonia associated with COVID-2019 and COVID-2019 infections is underway in the US.

The proposed mechanism and actions for trabedersen against COVID-19 infections include inhibition of cellular binding, inhibition of viral replication and suppression of viral induced pneumonia [1] .

Development in anaplastic astrocytoma/glioblastoma was terminated at phase III, and later discontinued. No recent reports of development have been identified for clinical development in colorectal cancer in Germany.

Oncotelic is also developing a personalised dosing regimen of its TGFβ antisense nucleotide, designated as OT 201, which is under preclinical development (Oncotelic pipeline, September 2016).

Trabedersen originated with Antisense Pharma, which was renamed as Isarna Therapeutics in September 2013; subsequently the drug was acquired by Autotelic [2] .

In April 2019, Oncotelic was acquired by Mateon Therapeutics [3] .

Company Agreements

In July 2017, Marina Biotech entered into a license agreement with Oncotelic under which the former licensed its SMARTICLES platform for the delivery of antisense DNA therapeutics and its conformationally restricted nucleotide (“CRN”) technology with respect to TGF-beta. Under the terms of the agreement, Oncotelic will invest $US250 000 in Marina at a share price of $0.51. Marina Biotech could receive sales milestones of up to $US90 million based on commercial sales of licensed products. Further details of the agreement were not disclosed. In addition, if Oncotelic determines to pursue further development and commercialisation of products under the agreement, Oncotelic will purchase shares of Marina Biotech's common stock for an aggregate purchase price of $US500 000, with the purchase price for each share of Marina common stock being the greater of $US0.51 or the volume weighted average price of the Marina common stock at the time of purchase. [4] [5]

In October 2015, Isarna Therapeutics signed an asset sale and purchase agreement with Autotelic, whereby Autotelic gained full and worldwide rights to develop trabedersen. Financial terms of the agreement were not disclosed [6] .

Key Development Milestones

As at September 2016, phase II/III development of trabedersen is ongoing for pancreatic cancer, melanoma and glioblastoma (Oncotelic pipeline, September 2016).

Monotherapy:

Anaplastic astrocytoma/glioblastoma

In September 2019, Mateon Therapeutics announced that the US FDA granted Rare Pediatric Disease Designation to trabedersen for the treatment of diffuse intrinsic pontine glioma (DIPG) [7] .

In December 2008, Isarna Therapeutics initiated a phase III trial to investigate the safety and efficacy of trabedersen in patients with recurrent or refractory anaplastic astrocytoma or secondary glioblastoma (SAPPHIRE; NCT00761280; EudraCT2007-005802-38; G005). The study was intended to enrol approximately 27 patients from sites in Europe, Canada, Mexico, and Asia. Trabedersen was to be compared with standard chemotherapy (temozolomide or BCNU) in the trial. The primary endpoint would be the survival rate at 24 months. However, the trial was discontinued in March 2012 due to lack of patient recruitment (no safety or efficacy issues) [8] [9] [10] .

In April 2003, Isarna Therapeutics initiated a dose finding phase II trial to evaluate the safety and efficacy of two doses of trabedersen compared to standard chemotherapy (temozolomide or PCV) in patients with recurrent or refractory anaplastic astrocytoma or secondary glioblastoma (NCT00431561; AP 12009-G004). The trial was completed in March 2009 and enrolled 141 patients in Austria, Georgia, Germany, India, Israel and Russia. Results from the study in 141 patients with recurrent or refractory glioma demonstrated that trabedersen administered intratumourally was well tolerated and equivalent to chemotherapy with temozolomide or PCV (combination therapy of procarbazine, lomustine and vincristine). In addition, a sub-population analysis demonstrated trabedersen improved overall response rate and survival in 39 patients with anaplastic astrocytoma. Results from a 24-month follow-up were reported in April 2010. In March 2019, data from the trial showed improved survival was achieved by repeated exposure to temozolomide/alkylating agent, which were presented at the 110th Annual Meeting of the American Association for Cancer Research (AACR-2019). This was further enhanced by trabedersen and consistent with the proposed MOA of trabedersen/Chemo as reactivation of immunity during TGF-β suppression and subsequent xenogenization by temozolomide [11] [9] [12] [13] [14] [15] [16] [17] .

Antisense was targeting approval of trabedersen in this indication in the EU where the product candidate has orphan drug status. The Scientific Advice Working Party of the EMEA had accepted the 24 month survival rate as the primary study endpoint for the phase III study. Given the rarity of the disease, the surrogate endpoint of 14 month progression rate would have been accepted as the endpoint for conditional approval in anaplastic astrocytoma by the EMEA, provided this was supported by the survival data [14] .

A good safety and tolerability profile was reported for trabedersen following a phase I/II clinical trial in Germany and Europe in mid-2002. There were no drug related clinically relevant adverse events and six of eighteen patients showed stabilisation or response [18] .

Other solid tumours

In November 2011, Antisense Pharma completed an open-label phase I/II trial of trabedersen in patients with pancreatic carcinoma, malignant melanoma, or colorectal cancer (NCT00844064; AP 12009-P001; P-001). This trial was initiated in January 2005 and completed enrolment of 61 patients in Germany [19] . Oncotelic released results from the trial in April 2017, September 2016 and March 2016 [20] [21] [22] [23] [24] . In August 2017, the company presented the results of the trial at the 42nd European Society for Medical Oncology Congress (ESMO-2017) [25] . In March 2019, updated efficacy results from the trial were presented at the 110th Annual Meeting of the American Association for Cancer Research (AACR-2019) [26] .

The development plans for trabedersen were revised by Isarna in September 2013, with the focus on a Responder Patient Profiling Program (RPPP). The RPPP was assessing the genetic profile and responder biomarkers in patients with cancer to find a correlation between tumour biology and response to anti-TGF-β oligonucleotides and preclinical development was ongoing [2] . The company had reported in its June 2015 corporate presentation that it planned to advance the RPPP towards an IND/CTA.

In February 2013, Antisense revised its development plan for trabedersen to focus on the systemic intravenous administration. The decision was based on preliminary data from the SAPPHIRE trial showing serious adverse events that might be associated with the local administration of the compound in the trial. The decision was further supported by the data from a phase I/II trial in solid tumour where treatment was safe and well tolerated following intravenous administration of trabedersen. There were encouraging survival outcome data in patients with pancreatic cancer or malignant melanoma compared with historical controls. Antisense plans to conduct a phase II trial to investigate systemic intravenous trabedersen in the treatment of malignant melanoma, pancreatic cancer and other tumours.

Oncotelic released data from preclinical study of trabedersen in human melanoma xenograft in athymic nude mice, in February 2016 [27] .

In September 2009, both the EMEA and the FDA granted orphan drug status for trabedersen in the treatment of pancreatic carcinoma [28] .

In April 2002, Antisense Pharma received orphan drug status for the treatment of high-grade glioma in the EU. Orphan drug status was granted by the US FDA in July 2002 for the same indication.

Combination therapy

In March 2016, Oncotelic reported its plans to initiate multiple phase II combination trials followed by pivotal phase III registrational trials in several indications including pancreatic cancer, melanoma and glioblastoma [21] .

In September 2017, Autotelic presented results from preclinical studies of trabedersen in combination with chemotherapy in tumour models at the 42nd European Society for Medical Oncology Congress (ESMO-2017) [29] .

COVID-2019 infections

In April 2020, Mateon Therapeutics submitted an Investigational New Drug (IND) application with the US FDA seeking approval to evaluate trabedersen for the treatment of COVID-2019 infections. A pre-IND application was submitted by the company to the US FDA in the same month for COVID-19 infections. The company has requested US FDA to allow the referencing of OT-101’s oncology IND in order to streamline the IND submission for OT-101 against COVID-19 [30] [31] . Earlier In March 2020, Mateon Therapeutics released the preclinical results of trabedersen for the treatment of COVID-19 infections. Trabedersen showed significant activity against COVID-19 and SARS with safety index >500. Trabedersen inhibited virus binding to its target, thereby stopping the virus from replicating itself and stopping viral induced pneumonia, which often leads to patient complications. The proposed mechanism and actions for trabedersen against COVID-19 include inhibition of cellular binding, inhibition of viral replication and suppression of viral induced pneumonia [32] [1] .

In March 2020, Mateon Therapeutics reported that it is developing trabedersen for the treatment of pneumonia associated with coronavirus infectious disease (COVID-2019) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The company believe that replication of SARS-Co-2 virus release TGF-β which further potentiate the viral replication. The progressive increase in TGF-β with increasing viral load results in increased permeability and failed fluid reabsorption in lungs, leading to persistent and severe pulmonary oedema and ARDS. TGF-β through Tgfbr1-mediated signaling pathway cause internalisation of the epithelial sodium channel (ENaC) by alveolar epithelial cells with marked reduction in the cell-surface abundance of ENaC on lung epithelial cells thereby rapidly and substantially impairing alveolar fluid reabsorption in ARDS patients, which culminate in pulmonary oedema. Thus, inhibition of TGF-β with trabedersen can reduse pulmonary oedema with inhibition of SARS-CoV-2 virus replication and improve ARDS in patients with severe COVID-2019 infections [33] [34] .

Drug Properties & Chemical Synopsis

  • Route of administration Intratumoural, IV, Parenteral
  • Formulation Infusion, unspecified
  • Class Antineoplastics, Antisense oligonucleotides, Antivirals, Immunotherapies, Oligodeoxyribonucleotides, Thionucleotides
  • Target Transforming growth factor beta2; Virus replication
  • Mechanism of Action Transforming growth factor beta2 inhibitors; Virus replication inhibitors
  • WHO ATC code

    J05A-X (Other antivirals)

    L01 (Antineoplastic Agents)

  • EPhMRA code

    J5B (Antivirals, excluding anti-HIV products)

    J5B9 (Antivirals, others)

    L1 (Antineoplastics)

  • Molecular formula C177 H225 N60 O94 P17 S17
  • CAS Registry Number 925681-61-4

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

anaplastic astrocytoma

not specified

TGFB2

1

anaplastic astrocytoma

Exclusion

TGF-beta

1

colorectal cancer

not specified

TGF-beta

1

colorectal cancer

Outcome Measure

TGFB2

1

glioblastoma

not specified

TGFB2

1

glioblastoma

Exclusion

TGF-beta

1

glioma

not specified

TGFB2

1

malignant melanoma

not specified

TGF-beta

1

malignant melanoma

Outcome Measure

TGFB2

1

pancreatic cancer

not specified

TGF-beta

1

pancreatic cancer

Outcome Measure

TGFB2

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Trabedersen - Autotelic/Oncotelic TGF-beta Exclusion
TGFB2 Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Anaplastic astrocytoma - Late-stage disease, Recurrent, Second-line therapy or greater Discontinued (III) Argentina, Austria, Brazil, Canada, France, Germany, Hungary, India, Mexico, Poland, Russia, South Korea, Spain, Taiwan, USA, United Kingdom Intratumoural / Infusion Autotelic, Oncotelic 07 Sep 2016
Anaplastic astrocytoma - Late-stage disease, Recurrent, Second-line therapy or greater Discontinued (II) Georgia, Israel Intratumoural / Infusion Autotelic, Oncotelic 07 Sep 2016
COVID 2019 infections - - Preclinical USA Parenteral / unspecified Autotelic, Oncotelic 18 Mar 2020
Colorectal cancer - Second-line therapy or greater No development reported (I/II) Germany IV / Infusion Autotelic, Oncotelic 11 Aug 2015
Glioblastoma - Late-stage disease, Recurrent, Second-line therapy or greater Phase III Argentina, Austria, Brazil, France, Germany, Hungary, India, Poland, Russia, South Korea, Spain, Taiwan, USA, United Kingdom Intratumoural / Infusion Autotelic, Oncotelic 01 Dec 2008
Glioblastoma - Late-stage disease, Recurrent, Second-line therapy or greater Phase II/III Georgia, Israel Intratumoural / Infusion Autotelic, Oncotelic 07 Sep 2016
Glioblastoma - Combination therapy Preclinical USA IV / Infusion Autotelic 08 Sep 2017
Malignant melanoma - Second-line therapy or greater Phase II/III Germany IV / Infusion Autotelic, Oncotelic 07 Sep 2016
Malignant melanoma - Combination therapy Preclinical USA IV / Infusion Autotelic 08 Sep 2017
Ovarian cancer - Combination therapy Preclinical USA IV / Infusion Autotelic 08 Sep 2017
Pancreatic cancer - Second-line therapy or greater Phase II/III Germany IV / Infusion Autotelic, Oncotelic 07 Sep 2016
Pancreatic cancer - Combination therapy Preclinical USA IV / Infusion Autotelic 08 Sep 2017
Pneumonia Associated with COVID-2019 - Preclinical USA Parenteral / unspecified Autotelic, Oncotelic 02 Mar 2020

Orphan Status

Indication Patient Segment Country Organisation Event Date
Glioma - USA Autotelic 22 Jul 2002
Glioma - European Union Autotelic 18 Apr 2002
Pancreatic cancer - European Union Autotelic 14 Sep 2009
Pancreatic cancer - USA Autotelic 14 Sep 2009

Commercial Information

Involved Organisations

Organisation Involvement Countries
Antisense Pharma Originator Germany
Autotelic Owner USA
Oncotelic Licensee USA
Adhera Therapeutics Technology Provider USA
Mateon Therapeutics Collaborator USA

Scientific Summary

Pharmacokinetics

Results of the phase I/II trial of trabedersen in patients with pancreatic cancer demonstrated increasing peak levels of IL-8 and IL-15 response on day 2 of trabedersen treatment. ANCOVA models for two feedback interactions with pharmacokinetics (PK) parameters showed significant model fits (F3,7 = 7.89, P = 0.012 for simulated Vz mean; F3,7 = 8.18, P = 0.011 for simulated Cl mean) and the interaction effects resulted in lower p-values for the correlation of overall survival (OS) versus IL-8 levels [25] . The PK profile of trabedersen, described by a two-compartment model, showed large distribution of the drug in the peripheral tissues. The influence of age, gender, BMI, height, cancer type and treatment schedule on the PK of trabedersen was not identified. Total body clearance observed was 0.17 mL/h, distribution volume of the central compartment was 4.69L, inter-compartmental clearance was 3.31 L/h and distribution volume of the peripheral compartment was 5046.44 L. Body weight was identified as a covariate on trabedersen inter-compartmental clearance, with KBW as -ve 1.48. With exclusion of protocol deviations, a total of 1 444 plasma sample concentration data, obtained from a phase I/II trial, from 100 patient cycles were examined. The study evaluated the safety and tolerability of trabedersen in 61 patients with pancreatic cancer (n = 37), malignant melanoma (n = 19) and colorectal carcinoma (n = 5) [20] [19] .

Adverse Events

Glioblastoma and anaplastic astrocytoma

Trabedersen was well tolerated in a phase IIb trial in 145 patients with recurrent or refractory glioblastoma, including 39 patients with anaplastic astrocytoma (AA). Patients received chemotherapy (N=33, AA patients=12), or trabedersen 10µM (N=28, AA=12) or 80µM (N=34, AA=15) via convection-enhanced delivery for up to 11 2-week cycles (7 days receiving treatment, followed by 7 days off). In the total population, drug related serious adverse events were observed in only three patients in the trabedersen 80µM group. In the AA subpopulation, there was a higher incidence of SAEs in the trabedersen groups (67% each) compared with the control group (25%), but these were often procedure related and mostly reversible; no serious adverse events were drug related. Two cases of neutropenia in the 90 patients was reported in trabedersen group versus 8, 10, and 8 patients with leukopenia, neutropenia and thrombocytopenia, respectively, among 45 patients treated with temozolomide (2% vs. 56%, p < 0.0001) [11] [14] [16] [15] [42] [18] [17] .

In three phase I/II studies, 27 adult patients with recurrent high-grade glioma and MRI evidence of tumour progression received a 113-fold dose escalation of trabedersen. The drug was administered by convection enhanced delivery, using an indwelling pump system. All doses were rated as safe by an independent Data and Safety Monitoring Board. Six patients had adverse events which were possibly related to treatment. There were no changes in haematological parameters or other laboratory values [46] .

Solid tumours

Trabedersen had a good safety and tolerability profile, based on interim results from a phase I/II trial in patients pancreatic cancer, malignant melanoma and colorectal cancer. At the time of the interim analysis, 25 patients in 6 cohorts had been treated in two dosing regimens. The maximum tolerated dose was established as 160 mg/m2/day, when trabedersen is given via IV infusion for the first 7 days of a 14 day cycle. Dose limiting toxicities, including two grade 3 thrombocytopenia and grade 3 exanthema, were observed at the 240 mg/m2/day dose level. In the second dosing schedule, trabedersen IV is given in the first 4 days of a 14 day cycle; dose escalation was ongoing in this schedule at the time of interim analysis [41] [23] . Additional data from this phase I/II trial showed that trabedersen was associated with a maximum tolerated dose (primary endpoint) of 160 mg/m2/day in the 7 days on-7 days off schedule and 140 mg/m2/day in the 4 days on-10 days off schedule in patients with pretreated advanced pancreatic cancer, colorectal cancer or malignant melanoma. Non-serious, moderate and transient thrombocytopenia was the only expected adverse reaction observed [36] .

Animal toxicology

After short-term infusion of trabedersen 5-160 mg/kg to cynomolgus monkeys there were no observed adverse effects reported for cardiovascular, clotting and haematological parameters. In mice, a single IV bolus dose of trabedersen was also well tolerated [48] [50] .

Pharmacodynamics

Summary

Treatment with trabedersen as a single agent significantly reduced lymph node metastasis (p = 0.023), tumour growth (p = 0.0084), and tumour angiogenesis (p < 0.0001) in mice model of human L3.6pl pancreatic cancer (PAC), as compared with untreated control. Trabedersen, in combination with dacarbazine (DTIC), demonstrated synergy in tumour growth inhibition and increased survival in human metastatic C8161 melanoma model (p = 0.038), as compared with DTIC alone. Synergistic effects in tumour growth inhibition and increased survival were also reported with combination therapy of trabedersen and paclitaxel (PTX) in SC glioblastoma (U87) (p = 0.001) and SC ovarian (SKOV-3) tumour models (p < 0.05), as compared with PTX alone. Trabedersen and gemcitabine combination therapy did not demonstrate synergy in PAC model. The combination regimen tested was effective and achieved significant antitumour activity at HED of 80 mg/m2/day, which is well below the optimised clinical dose used for intravenous infusion of patients at 140 mg/m2/day [29] .

Treatment with trabedersen resulted in antitumour activity in a mouse model of metastatic pancreatic cancer. A significant reduction in tumour weight (0.7 versus 1.4g, p=0.0084) and cell proliferation (p=0.028) occurred in the treatment arm relative to control animals. Furthermore, lymph node (2/10 mice) and liver metastasis (4/10) was lower in the treatment group than the control group (7/9 and 5/9 mice, respectively). Tumours showed a significant reduction in angiogenesis in the treatment group (p=0.0001) [38] .

Trabedersen efficiently targeted colorectal cancer cells and significantly reduced TGF-β2 expression in a dose-dependent manner. In functional assays, trabedersen inhibited colorectal carcinoma cell proliferation by up to 60% compared with controls. Trabedersen also reversed TGF-β2-mediated immunosuppression in an allogenic system with WiDr cells targeted by IL-2-activated peripheral blood mononuclear cells (LAK cells) derived from healthy donors. LAK cell cytoxicity was increased in a donor-dependent manner up to 190% after treatment with trabedersen [40] .

Tumour cells treated with trabedersen secreted reduced amounts of TGFβ2 and trabedersen abrogated TGFβ-dependent mechanisms of tumour progression. Moreover, when human glioma cells were exposed to trabedersen, the anti-tumour response of LAK effector cells was enhanced. This effect is related to downregulation of TGFβ synthesis in vitro. Glioma cell proliferation and migration was also inhibited by trabedersen in a dose dependent manner [49] .

TGFβ2 secretion was inhibited in several human pancreatic cancer cell lines by trabedersen. Trabedersen reversed TGFβ2-mediated immunosuppression, reduced pancreatic cancer cell proliferation up to 76% in a dose-dependent manner, and completely blocked pancreatic cancer cell migration [44] .

In a human glioma cell line (A-172), trabedersen potently inhibited TGFβ2 expression and barely affected TGFβ1 expression when the cell culture medium contained serum. However, under serum-free conditions, both isoforms were inhibited. The inhibitory effects of trabedersen on TGFβ1 expression was reversed by addition of rhTGFβ2. Specific inhibition of TGFβ2 expression by trabedersen down-regulated TGFβ1 and also interrupted the cross-regulatory loop whereby TGFβ induces the expression of TGFβ1 [37] .

Trabedersen inhibited TGF-2 secretion and proliferation of human malignant melanoma cell cultures (Mel-Juso, MER 116, and RPMI 7951) and cell migration from MER spheroids. Combination of trabedersen and dacarbazine (DTIC) induced a synergistic effect (p<0.001) on tumour inhibition in the C8161 melanoma xenograft in athymic nude mice [27] .

In an in vitro antiviral testing, trabedersen showed an 50% effective concentration (EC50) of 7.6 µg/mL and was not toxic at the highest dose of 1000 µg/mL giving a safety index (SI) value of >130, which is considered highly active [1] .

Therapeutic Trials

Glioblastoma and anaplastic astrocytoma

Phase II

Trabedersen showed equal efficacy to chemotherapy with temozolomide or PCV (combination therapy of procarbazine, lomustine and vincristine) in an open label, randomised phase IIb trial of 145 patients with recurrent or refractory high grade glioblastoma. Patients either received chemotherapy or trabedersen 10 or 80µM intratumourally via convection-enhanced delivery for up to 11, 2-week cycles comprising 7 days treatment, followed by 7 days off. The overall response rate (complete or partial response) at 12 months, based on 134 evaluable patients was 3%, 7%, and 0% in the chemotherapy (N=33), trabedersen 10 (N=28) and 80µM groups (N=34), respectively. In addition, there were more survivors after 1.5 and 2 years in the trabedersen groups compared with the control group. The 2-year survival rates were 83%, 53% and 42%, respectively, in the trabedersen 10µMol, 80µMol and standard chemotherapy groups, respectively. Furthermore, the duration of response was approximately three-times longer in the 10µMol group than in the standard chemotherapy group (29.1 vs 8.0 months) and the median survival duration in the trabedersen 10µMol group was 17.4 months [39] . In a subpopulation analysis of patients with recurrent anaplastic astrocytoma, trabedersen therapy was associated with a higher survival rate and overall response rate compared with the chemotherapy analysis. The overall response rate at 14 months and survival rate at 24 months was 34% and 83% in the trabedersen 10µM group (N=12), respectively, 20% and 53% in the trabedersen 80 µM group (N=15), respectively and 0% and 42% in the control group (N=12), respectively. Furthermore, the median survival time was 37.2 and 21.7 months in the trabedersen 10µM and control groups, respectively. In the trabedersen 10µM group, there was a steady increase in overall tumour response over 14 months, whereas the response rate in the chemotherapy group decreased from 25% to 0% [9] [12] [14] [15] [23] [42] [43] [17] .

In a phase I/II dose escalation trial of trabedersen showed that six out of 18 patients achieved an objective response or disease stabilisation [18] . Another patient had a complete response after one course without any other anti-tumour therapy [47] .

In three phase I/II studies, 27 adult patients with recurrent high-grade glioma and MRI evidence of tumour progression received a 113-fold dose escalation of trabedersen. The drug was administered by convection enhanced delivery, using an indwelling pump system. In the 20 evaluable patients, median overall survival results for trabedersen therapy versus literature values for temozolomide therapy were 77.0 vs 42 weeks for anaplastic astrocytoma and 42.4 vs 32 weeks for glioblastoma. 13 patients who had received temozolomide prior to trabedersen had median overall survival results of 106.4 weeks for anaplastic astrocytoma and 46.1 weeks for glioblastoma [46] . In follow-up results, the median overall survival time of patients from start of the first trabedersen treatment was 90 weeks and 44 weeks for anaplastic astrocytoma and glioblastoma respectively compared to 42 weeks and 32 weeks for those receiving temozolomide therapy for anaplastic astrocytoma and glioblastoma respectively. The mean overall survival for 16 patients that received temozolomide before trabedersen was 146.6 weeks for anaplastic astrocytoma and 46.1 weeks for glioblastoma. One patient had a complete response in all tumour sites after one cycle of trabedersen. He survived for 195 weeks until his death due to myocardial infarction. A similar tumour reduction of more than 80% for a second patient has been documented. This patient is still alive and has to date received 12 cycles of trabedersen [45] .

Other solid tumours

Updated results from a phase I/II trial in patients with pancreatic cancer demonstrated that the median OS (mOS) for 18 second-line patients (OT 101/SC) was 9.4months compared with 2.8 months in 19 patients on OT 101/best supportive care (BSC) (p = 0.0004). Patients with only liver metastasis had a mOS of 9.5 months versus 4.7 months(p = 0.0077) in those with liver metastasis and others. Complete response beyond 77.3 months was reported in one patient and another had stable disease with OS of 40.3 months in the former group. For liver metastasis only group with OT 101/SC OS was 12.4 months compared with 1.9 months (p = 0.0006). Disease control (DC) was reported in 16 of 37 patients with a mOS of 9.7 months versus 3 months (p < 0.0001). In the DC group OS was higher for with OT-101/SC being 11.8 months versus 5 months (p = 0.0021). A spike was observed in IL-8 level which returned to basal level when the treatment was stopped. The R2 relating the IL-8 spike and OS were 0.8522 (p = 0.0011) and 0.9895 (p = 0.0053) for patients treated subsequently with SC and BSC, respectively [26] . Earlier it was shown that When stratified for patients with and without chemotherapy, R2 increased to 0.99 and 0.77 respectively. Similar results were observed for IL-15, with R2 = 0.93 in patients with chemotherapy and R2 = 0.50 in those without therapy [25] . Anti-cancer activity was demonstrated in patients with pancreatic carcinoma, malignant melanoma and colorectal cancer. In the first dosing schedule, trabedersen was administered for the first 7 days of a 10 day cycle, the maximum tolerated dose (MTD) was established as 160 mg/m2/day, whereas MTD was not reached on 4/10 regimen (n = 27) even at highest dose of 330 mg/m2/d. There were 16 second-line patients and 11 third-line and beyond on 4/10 regimen. The progression free survival/overall survival (PFS/OS) of the second line patients in months were: 1.87/5.60 (n = 6), 1.87/9.93 (n = 11) and 2.72/11.80 (n = 5) at increasing mean dose of 140, 167 and 196 mg/m2/d, respectively. The OS of 9.93 and 11.80 months were higher (range = 2.50-9.20/median = 5.50 months). The corresponding progression free survival (PFS) values were in line (range = 0.00-7.65/median = 2.43 months). The OS of 4/10 cohort treated with subsequent chemotherapies was 14.7 and 2.93 months with and without subsequent chemotherapies, p = 0.0023. Chemotherapy on second line followed with subsequent trabedersen 4/10 regimen as third line was ineffective with OS of 2.80 months (n = 9) versus 9.93 months (n = 11), p = 0.046. Of the five malignant melanoma patients treated with trabedersen, one from the first schedule showed stable disease and lived for 13.8 months, three patients from the second schedule are still alive. Median overall survival (OS) for advanced pancreatic carcinoma patients in the first schedule was 6.8 months; one patient showed a complete response and is still alive 45.6 months (as of Feb 2009) after receiving trabedersen therapy. The median OS for pancreatic carcinoma patients in the first cohort of five patients in the second schedule is 13.4 months (as of Aug 2009); one patient is still alive with stable disease 19 months (as of April 2009) after start of study treatment. Additional data showed that trabedersen administered at the maximum tolerated dose of 160 mg/m2/day (7 days on 7 days off) or 140 mg/m2/day (4 days on, 10 days off) was active in all patients. Updated results from the trial showed an IL-8 spike during first cycle of therapy resulting in improved overall survival in pancreatic cancer patients treated with trabedersen [21] [35] [28] [41] [23] [36] [19] .

In a phase I/II melanoma study, trabedersen treatment resulted in improved overall survival (OS) which was not supported by progression-free survival (PFS). The effect was observed when chemotherapies were used as subsequent therapies following trabedersen treatment [22] .

Development History

Event Date Update Type Comment
30 Apr 2020 Trial Update Mateon Therapeutics plans a phase II trial for COVID-2019 infections and associated Pneumonia in USA [30] Updated 30 Apr 2020
27 Apr 2020 Regulatory Status Mateon Therapeutics files an IND application with the US FDA in for COVID-2019 infections [30] Updated 30 Apr 2020
09 Apr 2020 Regulatory Status Mateon Therapeutics files a pre-IND application with the US FDA for COVID-19 [31] Updated 09 Apr 2020
25 Mar 2020 Regulatory Status Mateon Therapeutics announces intention to submit IND application to the US FDA for COVID-2019 infections [32] Updated 27 Mar 2020
18 Mar 2020 Phase Change - Preclinical Preclinical trials in COVID-2019 infections in USA (Parenteral) prior to March 2020 [1] Updated 20 Mar 2020
18 Mar 2020 Regulatory Status Mateon Therapeutics intends to work with the US FDA to conduct clinical trials of Trabedersen for COVID-19 infections [1] Updated 20 Mar 2020
18 Mar 2020 Trial Update Mateon Therapeutics plans clinical trials for COVID-19 infections [1] Updated 20 Mar 2020
02 Mar 2020 Phase Change - Preclinical Preclinical trials in Pneumonia in USA (Parenteral) [34] Updated 06 Mar 2020
23 Sep 2019 Regulatory Status The US FDA grants Rare Pediatric Disease Designation for diffuse intrinsic pontine glioma [7] Updated 25 Sep 2019
09 Sep 2019 Trial Update Mateon Therapeutics plans a expanded access program for Pancreatic cancer Updated 12 Sep 2019
25 Apr 2019 Company Involvement Oncotelic has been acquired by Mateon Therapeutics Updated 02 May 2019
25 Apr 2019 Trial Update Oncotelic plans multiple phase III registration trials of OT 101 in Glioblastoma and Pancreatic cancer [3] Updated 30 Apr 2019
29 Mar 2019 Scientific Update Updated safety data from a phase IIb trial in Glioma presented at the 110th Annual Meeting of the American Association for Cancer Research (AACR-2019) [11] Updated 18 Apr 2019
29 Mar 2019 Scientific Update Updated efficacy data from a phase I/II trial in Pancreatic cancer presented at the 110th Annual Meeting of the American Association for Cancer Research (AACR-2019) [26] Updated 16 Apr 2019
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
08 Sep 2017 Scientific Update Pharmacodynamics data from a preclinical trial in Malignant melanoma, Pancreatic cancer, Glioblastoma and Ovarian cancer (Combination therapy) presented at the 42nd European Society for Medical Oncology Congress (ESMO-2017) [29] Updated 16 Oct 2017
08 Sep 2017 Phase Change - Preclinical Preclinical trials in Pancreatic cancer, Ovarian cancer, Glioblastoma and Malignant melanoma (Combination therapy) in USA (IV) [29] Updated 14 Oct 2017
31 Aug 2017 Scientific Update Efficacy and pharmacokinetic data from a phase I/II trial in Pancreatic cancer presented at the 42nd European Society for Medical Oncology Congress (ESMO-2017) [25] Updated 11 Oct 2017
17 Jul 2017 Licensing Status Oncotelic in-licenses conformationally restricted nucleotide (CRN) technology from Marina Biotech [5] Updated 31 Jul 2017
01 Apr 2017 Scientific Update Pharmacokinetics data from a phase I/II trial in Malignant melanoma, Pancreatic cancer and Colorectal cancer presented at the 108th Annual Meeting of the American Association for Cancer Research (AACR-2017) [20] Updated 19 Apr 2017
07 Sep 2016 Active Status Review Trabedersen is still in phase II/III trials for Glioblastoma in Georgia and Israel (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Active Status Review Trabedersen is still in phase II/III trials for Malignant melanoma in Germany (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Active Status Review Trabedersen is still in phase II/III trials for Pancreatic cancer in Germany (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Active Status Review Trabedersen is still in phase III trials for Glioblastoma in Argentina, Austria, Brazil, France, Germany, Hungary, India, Poland, Russia, South Korea, Spain, Taiwan, USA and United Kingdom (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Phase Change - Discontinued(II) Discontinued - Phase-II for Anaplastic astrocytoma (Late-stage disease, Recurrent, Second-line therapy or greater) in Israel, Georgia (Intratumoural) (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Phase Change - Discontinued(III) Discontinued - Phase-III for Anaplastic astrocytoma (Late-stage disease, Recurrent, Second-line therapy or greater) in United Kingdom, Taiwan, Spain, Poland, South Korea, Hungary, France, Brazil, Argentina, USA, India, Russia, Germany, Mexico, Canada, Austria (Intratumoural) (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Phase Change - II/III Phase-II/III clinical trials in Glioblastoma (Late-stage disease, Recurrent, Second-line therapy or greater) in Georgia, Israel (Intratumoural) before September 2016 (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Phase Change - II/III Phase-II/III clinical trials in Malignant melanoma (Second-line therapy or greater) in Germany (IV) before September 2016 (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
07 Sep 2016 Phase Change - II/III Phase-II/III clinical trials in Pancreatic cancer (Second-line therapy or greater) in Germany (IV) before September 2016 (Oncotelic pipeline, September 2016) Updated 07 Sep 2016
02 Sep 2016 Scientific Update Efficacy data from a phase I/II trial in Pancreatic cancer released by Oncotelic [21] Updated 09 Sep 2016
02 Sep 2016 Trial Update Oncotelic and Autotelic plan multiple phase II combination trials and pivotal phase III trials for Pancreatic cancer, Melanoma and Glioblastoma [21] [3] Updated 09 Sep 2016
16 Apr 2016 Scientific Update Efficacy data from a phase I trial in Solid tumours presented at the 107th Annual Meeting of the American Association for Cancer Research (AACR-2016) [35] Updated 19 Apr 2016
09 Mar 2016 Scientific Update Efficacy data from a phase I/II trial in Malignant melanoma released by Oncotelic [22] Updated 09 Sep 2016
09 Feb 2016 Scientific Update Pharmacodynamics data from a preclinical trial in Solid tumours released by Oncotelics [27] Updated 09 Sep 2016
14 Oct 2015 Licensing Status Autotelic acquires trabedersen from Antisense Pharma [6] Updated 07 Sep 2016
11 Aug 2015 Phase Change - No development reported(I/II) No recent reports on development identified - Phase-I/II for Colorectal cancer (Second-line therapy or greater), Pancreatic cancer (Second-line therapy or greater) and Malignant melanoma (Second-line therapy or greater) in Germany (IV) Updated 11 Aug 2015
04 Nov 2014 Trial Update Isarna Therapeutics terminates phase III trial in Glioblastoma and Anaplastic astrocytoma in USA, Argentina, Austria, Brazil, France, Germany, Hungary, India, Poland, Russia, South Korea, Spain, Taiwan and United Kingdom (NCT00761280) Updated 07 Sep 2016
31 Oct 2014 Licensing Status Trabedersen is available for licensing to a regional partner - http://www.isarna-therapeutics.com Updated 13 Jan 2015
26 Oct 2013 Company Involvement Antisense Pharma is now called Isarna Therapeutics Updated 26 Oct 2013
30 Sep 2013 Phase Change - Preclinical Preclinical trials in Cancer in Germany (IV) Updated 18 Apr 2012
28 Mar 2012 Phase Change - Discontinued(III) Discontinued - Phase-III for Anaplastic astrocytoma/Glioblastoma in Asia (Intratumoural) Updated 18 Apr 2012
28 Mar 2012 Phase Change - Discontinued(III) Discontinued - Phase-III for Anaplastic astrocytoma/Glioblastoma in Canada (Intratumoural) Updated 18 Apr 2012
28 Mar 2012 Phase Change - Discontinued(III) Discontinued - Phase-III for Anaplastic astrocytoma/Glioblastoma in Europe (Intratumoural) Updated 18 Apr 2012
28 Mar 2012 Phase Change - Discontinued(III) Discontinued - Phase-III for Anaplastic astrocytoma/Glioblastoma in Mexico (Intratumoural) Updated 18 Apr 2012
18 Nov 2011 Trial Update Antisense Pharma completes a phase I/II trial in Malignant melanoma, pancreatic cancer and colorectal cancer in Germany (NCT00844064) Updated 18 Jan 2012
06 Apr 2011 Scientific Update Interim safety and efficacy data from a phase I/II trial in Solid tumours presented at the 102nd Annual Meeting of the American Association for Cancer Research (102nd-AACR-2011) [36] Updated 21 Apr 2011
16 Nov 2010 Scientific Update Preclinical pharmacodynamics data presented at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR-2010) [37] , [38] Updated 03 Dec 2010
10 Nov 2010 Trial Update Antisense Pharma completes enrolment in its phase I/II trial for Malignant melanoma, pancreatic cancer & colorectal cancer in Germany (NCT00844064) Updated 28 Apr 2011
08 Nov 2010 Licensing Status Trabedersen is available for licensing in USA, Japan, Europe as of 03 Feb 2003. http://www.antisense-pharma.com Updated 08 Nov 2010
20 Apr 2010 Scientific Update Two-year efficacy data from a phase IIb trial in Glioma presented at the 101st Annual Meeting of the American Association for Cancer Research (AACR-2010) [39] Updated 10 May 2010
19 Oct 2009 Regulatory Status Antisense Pharma receives approval from Health Canada for the phase III SAPPHIRE trial in anaplastic astrocytoma [8] Updated 21 Oct 2009
14 Sep 2009 Regulatory Status Trabedersen received Orphan Drug status for Pancreatic cancer in European Union Updated 16 Sep 2009
14 Sep 2009 Regulatory Status Trabedersen received Orphan Drug status for Pancreatic cancer in USA Updated 16 Sep 2009
02 Jun 2009 Scientific Update Interim efficacy data from a phase I trial in Solid tumours presented at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO-2009) Updated 10 Jun 2009
01 Jun 2009 Scientific Update Efficacy data from a phase IIb trial in Glioma presented at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO-2009) [12] Updated 22 Jun 2009
27 Apr 2009 Phase Change - III Phase-III clinical trials in Anaplastic astrocytoma in Asia (Intratumoural) Updated 28 Apr 2009
22 Apr 2009 Scientific Update Pharmacodynamics data from a preclinical trial in Colorectal cancer presented at the 100th Annual Meeting of the American Association for Cancer Research (AACR-2009) [40] Updated 14 May 2009
01 Mar 2009 Trial Update Iserna Therapeutics completes a phase II trial in Glioblastoma and Anaplastic astrocytoma in Austria, Georgia, Germany, India, Israel and Russia (NCT00431561) Updated 07 Sep 2016
31 Dec 2008 Phase Change - III Phase-III clinical trials in Anaplastic astrocytoma in Mexico (Intratumoural) Updated 21 Oct 2009
31 Dec 2008 Phase Change - III Phase-III clinical trials in Anaplastic astrocytoma in Canada (Intratumoural) Updated 04 Mar 2009
31 Dec 2008 Phase Change - III Phase-III clinical trials in Anaplastic astrocytoma in Europe (Intratumoural) Updated 04 Mar 2009
01 Dec 2008 Phase Change - III Phase-III clinical trials in Anaplastic astrocytoma (Late-stage disease, Recurrent, Second-line therapy or greater) in India, Russia, Germany (Intratumoural) (NCT00761280) Updated 07 Sep 2016
01 Dec 2008 Phase Change - III Phase-III clinical trials in Anaplastic astrocytoma (Late-stage disease, Recurrent, Second-line therapy or greater) in United Kingdom, Taiwan, Spain, Poland, South Korea, Hungary, France, Brazil, Argentina, USA (Intratumoural) (NCT00761280) Updated 07 Sep 2016
01 Dec 2008 Phase Change - III Phase-III clinical trials in Glioblastoma (Late-stage disease, Recurrent, Second-line therapy or greater) in Austria, India, Germany, Russia (Intratumoural) (NCT00761280) Updated 07 Sep 2016
01 Dec 2008 Phase Change - III Phase-III clinical trials in Glioblastoma (Late-stage disease, Recurrent, Second-line therapy or greater) in United Kingdom, Taiwan, Spain, Poland, South Korea, Hungary, France, Brazil, Argentina, USA (Intratumoural) (NCT00761280) Updated 07 Sep 2016
03 Jun 2008 Scientific Update Interim adverse events and efficacy data from a phase II study in recurrent or refractory Glioblastoma, including anaplastic astrocytoma, and a phase I/II trial in Solid tumours presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO-2008) [14] , [41] , [15] , [16] , [23] Updated 10 Jun 2008
06 Jul 2007 Scientific Update Data presented at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO-2007) added to the adverse events and Cancer therapeutic trials sections [42] Updated 06 Jul 2007
01 Feb 2007 Licensing Status AP 12009 is available for licensing in the USA, Europe and Japan for high-grade glioma and pancreatic cancer (http://www.antisense-pharma.com) Updated 01 Feb 2007
01 Feb 2007 Phase Change - Discontinued(I/II) Discontinued - Phase-I/II for Glioblastoma in Germany (Intratumoural) Updated 01 Feb 2007
01 Feb 2007 Phase Change - Discontinued(II) Discontinued - Phase-II for Glioblastoma in India (Intratumoural) Updated 01 Feb 2007
01 Feb 2007 Phase Change - Discontinued(II) Discontinued - Phase-II for Glioblastoma in Israel (Intratumoural) Updated 01 Feb 2007
05 Dec 2006 Phase Change - II Phase-II clinical trials in Anaplastic astrocytoma in Europe (Intratumoural) Updated 05 Dec 2007
05 Dec 2006 Phase Change - II Phase-II clinical trials in Anaplastic astrocytoma in Germany (Intratumoural) Updated 05 Dec 2007
01 Dec 2006 Scientific Update Data presented at the 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR-2006) added to the Cancer therapeutic trials section [43] Updated 01 Dec 2006
18 May 2006 Phase Change - I/II Phase-I/II clinical trials in Colorectal cancer in Germany (Intratumoural) Updated 09 Jun 2006
18 May 2006 Phase Change - I/II Phase-I/II clinical trials in Malignant melanoma in Germany (Intratumoural) Updated 09 Jun 2006
30 Nov 2005 Other Antisense Pharma raised $US18 million in private equity from German venture capital investor MIG Funds Updated 05 Dec 2005
06 May 2005 Trial Update Antisense Pharma has completed enrolment in a phase IIb trial for high grade glioma in Germany Updated 06 May 2005
04 May 2005 Phase Change - I/II Phase-I/II clinical trials in Pancreatic cancer in Germany (Intratumoural) Updated 04 May 2005
04 May 2005 Scientific Update Data presented at the 96th Annual Meeting of the American Association for Cancer Research (AACR-2005) have been added to the Cancer pharmacodynamics section [44] Updated 04 May 2005
07 Jul 2004 Phase Change - II/III Phase-II/III clinical trials in Glioblastoma in Europe (Intratumoural) Updated 09 Jul 2004
18 May 2004 Scientific Update Data presented at the 56th Annual Meeting of the American Academy of Neurology (AAN-2004) have been added to the Cancer therapeutic trials section [45] Updated 18 May 2004
09 Oct 2003 Scientific Update Data presented at the 12th European Cancer Conference (ECCO-2003) have been added to the adverse events and therapeutic trials sections [46] Updated 09 Oct 2003
01 Sep 2003 Phase Change - II Phase-II clinical trials in Glioblastoma in Europe (Intratumoural) Updated 01 Sep 2003
01 Sep 2003 Phase Change - II Phase-II clinical trials in Glioblastoma in India (Intratumoural) Updated 01 Sep 2003
01 Sep 2003 Phase Change - II Phase-II clinical trials in Glioblastoma in Israel (Intratumoural) Updated 01 Sep 2003
01 Sep 2003 Scientific Update Data from a media release have been added to the Cancer therapeutic trials section [47] Updated 01 Sep 2003
01 Apr 2003 Phase Change - II Phase-II clinical trials in Anaplastic astrocytoma (Late-stage disease, Recurrent, Second-line therapy or greater) in Russia, Israel, India, Georgia (Intratumoural) (NCT00431561) Updated 07 Sep 2016
01 Apr 2003 Phase Change - II Phase-II clinical trials in Glioblastoma (Late-stage disease, Recurrent, Second-line therapy or greater) in Russia, Germany, Georgia (Intratumoural) (NCT00431561) Updated 07 Sep 2016
11 Mar 2003 Scientific Update A study has been added to the Cancer therapeutic trials section [18] Updated 11 Mar 2003
03 Feb 2003 Licensing Status AP 12009 is available for licensing for the treatment of Glioma (http://www.antisense-pharma.de/) Updated 03 Feb 2003
09 Oct 2002 Scientific Update A clinical study has been added to the adverse events section [18] Updated 09 Oct 2002
09 Oct 2002 Scientific Update A preclinical study has been added to the adverse events section [48] Updated 09 Oct 2002
09 Oct 2002 Scientific Update A preclinical study has been added to the Cancer pharmacodynamics section [49] Updated 09 Oct 2002
22 Jul 2002 Regulatory Status AP 12009 has received Orphan Drug Status for high grade glioma in the USA Updated 22 Jul 2002
18 Apr 2002 Regulatory Status AP 12009 has received Orphan Drug Status for high grade glioma in the EU Updated 18 Apr 2002
16 Jul 2001 Phase Change - I/II Phase-I/II clinical trials for High-grade glioma in Germany and Europe (Intratumoural administration) Updated 16 Jul 2001

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