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Ranpirnase - Orgenesis

Drug Profile

Ranpirnase - Orgenesis

Alternative Names: Amphibian ribonuclease A; Onconase; P-30 protein - Alfacell; P-30 ribonuclease

Latest Information Update: 02 Sep 2020

At a glance

  • Originator Alfacell Corporation
  • Developer Alfacell Corporation; Orgenesis; Tamir Biotechnology
  • Class Antineoplastics; Antivirals; Eye disorder therapies; Ribonucleases
  • Mechanism of Action Apoptosis stimulants; Protein synthesis inhibitors; Ribonuclease replacements
  • Orphan Drug Status

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

    Yes - Mesothelioma; Ebola virus infections
  • New Molecular Entity No
  • Available For Licensing Yes

Highest Development Phases

  • Phase I/II Genital warts
  • Clinical Phase Unknown COVID 2019 infections
  • Preclinical Ebola virus infections; HIV infections
  • No development reported Zika virus infection
  • Discontinued Acute myeloid leukaemia; Brain cancer; Chronic lymphocytic leukaemia; Mesothelioma; Neuroblastoma; Non-small cell lung cancer; Pancreatic cancer; Prostate cancer; Renal cell carcinoma

Most Recent Events

  • 11 May 2021 Orgenesis plans a phase II trial for Genital warts in 2021.
  • 20 Aug 2020 Orgenesis intends to submit IND application for Genital warts
  • 20 Aug 2020 Orgenesis plans a phase II trial for Genital warts

Development Overview

Introduction

Ranpirnase is a natural homologue of ribonuclease A isolated from the eggs of the frog Rana pipiens, is being developed by Orgenesis, for the treatment of genital warts associated with human papilloma virus (HPV), Ebola virus infections, Zika virus infections, COVID-19 infections, HPV infections and HIV infections. Ranpirnase primarily degrades cellular transfer RNA with a substrate specificity for uridine-guanidine base-pair sequences, resulting in inhibition of protein synthesis thus blocking viral replication. Ranpirnase is shown to target tRNA and premiRNA. This agent also activates caspase-9 in mitochondria, resulting in tumour cell apoptosis. Clinical development of a topical formulation for the treatment of genital warts associated with human papilloma virus and systemic formulation for COVID-19 infections, is underway in Australia. Preclinical development for Ebola virus infections, Zika virus infections, HPV infections and HIV infections is underway in the US.

The compound (under the brand name of onconase), was being developed by Alfacell Corporation for non-small cell lung cancer, malignant mesothelioma, brain cancer, pancreatic cancer, prostrate cancer, renal cell carcinoma, neuroblastoma, chronic lymphocytic leukaemia and acute myeloblastic leukaemia. However, in April 2010, Alfacell Corporation changed its name to Tamir Biotechnology and underwent restructuring leading to the discontinuation of development of ranpirnase for all the oncology indications. Tamir Biotechnology, later in 2013-2014 shifted its focus to develop ranpirnase as an antiviral therapeutics.

An ophthalmic formulation of ranpirnase for the treatment of adenoviral conjunctivitis, is being developed by Okogen, under a license from Tamir Biotechnology [see Adis Insight Drug Profile 800048677]

As at March 2020, no recent reports of development had been identified for preclinical development in Zika-virus-infection in USA (Parenteral).

Company Agreements

In August 2020, Orgenesis entered into a services agreement with Therapeutics for the development of ranpirnase for the treatment of external genital warts. According to the agreement, the teams will investigate enhanced intracellular targeting of ranpirnase using Orgenesis Bioxomes™ technology. The companies plan to seek US FDA guidance for a phase II clinical study of topical ranpirnase for external genital warts in early 2021. [1]

In April 2020, Orgenesis completed an asset purchase agreement to acquire the assets of Tamir Biotechnology including ranpirnase and TamirBio’s broad spectrum antiviral platform. The acquisition included total stock and cash consideration of approximately $US21 million, based on the value of the stock at closing. In turn, Orgenesis plans to combine ranpirnase with its co-developed Bioxome™ technology for enhanced payload delivery directly to cells. [2]

In September 2009, Alfacell (now Tamir) and Par (the parent company of Strativa) entered into a Termination and Mutual Release Agreement. Under the terms of the termination all rights to ranpirnase were returned to Alfacell and Par gained royalty rights to the compound. Previously, Alfacell Corporation and Strativa Pharmaceuticals, entered into an agreement for the commercialisation of ranpirnase in the US. Strativa was to have exclusive marketing, sales and distribution rights to ranpirnase for the treatment of cancer in the US and its territories [3] [4] .

Genesis Pharma S.A. signed an exclusive licence and distribution agreement in December 2006 with the originator company, Alfacell Corporation, for ranpirnase in southeast Europe. This area includes the countries of Greece, Cyprus, Bulgaria, Romania, Slovenia, Croatia, Serbia and Macedonia. Rights to member states of the EU have been retained by Alfacell [5] .

A distribution agreement between Alfacell Corporation and MegaPharm Ltd regarding ranpirnase was formed in July 2008, whereby MegaPharm received exclusive rights to market, sell and distribute the drug in Israel. Alfacell will receive 50% of the revenue from sales [6] .

In July 2007, Alfacell entered into a marketing and distribution agreement with USP Pharma Spolka Z.O.O. (USP Pharma), an affiliate of US Pharmacia, for the commercialisation of ranpirnase in Eastern Europe, including Poland, Belarus, Ukraine, Estonia, Latvia and Lithuania. Under the terms of the agreement, Alfacell received $US1.5 million consisting of an up-front fee and equity investment [7] .

Alfacell entered into a purchase and supply agreement with Scientific Protein Laboratories LLC in January 2008 for the commercial production of ranpirnase. In the same month, Alfacell also signed a distribution agreement with BL&H Co. Ltd for the commercialisation of ranpirnase in South Korea, Taiwan and Hong Kong. Alfacell granted BL&H exclusive rights in the defined territory for the marketing, sales and distribution of ranpirnase, and Alfacell received an up-front fee of $100 000 and is eligible for milestone payments based on the achievement of certain regulatory approvals and net sales. Alfacell will also receive 50% of all net sales in the territory. In addition, Alfacell will manufacture and supply the product to BL&H, while BL&H will be responsible for all activities and costs related to regulatory filings and commercial activities in the territory [8] [9] .

Key Development Milestones

In April 2020, Orgenesis and TamirBio plans to combine ranpirnase with Bioxomes™ technology, which have demonstrated the ability to fuse with cell membranes and deliver an intracellular cargo, in a similar manner to natural exosomes [10] .

Anogenital warts associated with Human papillomavirus (HPV)

Based on the positive results obtained in a phase I/II trial conducted in immunocompromised people with HPV infections in Bolivia, Tamir intends to file a request with the US FDA to schedule a pre-IND meeting in the second quarter of 2017. The company anticipates an accelerated time-line for receiving the IND approval in HPV infections [11] .

In March 2017, Tamir released positive clinical data from a phase I/II trial that evaluated the efficacy and safety of a topical formulation of ranpirnase for the treatment of anogenital warts (TAMIR1402HPV; NCT02535104). The trial was completed in September 2016. The randomised, double-blind, placebo-controlled trial was initiated in February 2016, and enrolled 75 patients in Bolivia [11] [12] .

It also intends to initiate a larger proof-of concept trial for ranpirnase in the treatment of HPV infections, to be conducted in Colombia and/or Mexico [13] [14] [15] .

Tamir initiated enrolment in a phase I trial outside the US for a topical formulation of ranpirnase for anogenital warts. Results from the trial were reported in April 2015 [13] .

Tamir released positive efficacy results from the preclinical studies in Draize animal models in March and April 2015 [13] [16] .

Zika virus infections

Tamir Biotechnology, in February 2016, announced that ranpirnase exhibited anti-zika activity in preclinical animal models. The preclinical studies were carried out in collaboration with the Institute of Antiviral Research at Utah State University [17] .

Ebola virus infections

In August 2017, Tamir Biotechnology announced that ranpirnase received orphan drug designation from the US FDA for the treatment of Ebola virus infections. The designation was based on laboratory and animal data, which showed the safety and efficacy as both treatment and prevention of Ebola virus infection [18] .

In February 2016, Tamir Biotechnology announced that ranpirnase was found to be effective against Ebola viral infections in NIH-sponsored preclinical studies [17] .

Treatment with ranpirnase was associated with increased survival rates in Ebola infected mice. The preclinical data were released in July 2016 [19] .

HIV infections

Ranpirnase demonstrated in vitro activity against two chronic strains of HIV-1 in two independent laboratory studies conducted by the National Institutes of Health (NIH) and its collaborators. The drug appeared to preferentially degrade viral RNA without affecting normal cellular ribosomal and messenger RNA. These findings were confirmed using a third strain of HIV, according to data presented at the Congress of the German Society for Virology in April 2002, by Dr M. Michaelis from the Johann Wolfgang University in Frankfurt, Germany. Ranpirnase demonstrated activity at two stages in the HIV life-cycle: at the viral replication initiation stage, ranpirnase degraded the tRNA (Lys3) isoform and selectively degraded the spectrum of HIV-1 RNA species. Additionally, the study had found that ranpirnase is also a potent inhibitor of enteroviruses such as Echovirus type-7 and Coxsackie Virus A [20] .

Discontinued development

Non-small cell lung cancer (NSCLC)

Ranpirnase was being developed for non-small cell lung cancer. However, Tamir later discontinued development to focus on developing ranpirnase as an antiviral therapeutic (Tamir Biotechnology pipeline, July 2014)

Tamir (formerly Alfacell) completed the phase I portion of a phase I/II trial of ranpirnase in patients with treatment-refractory NSCLC. The phase II part (NCT01184287), which was investigating ranpirnase in combination with pemetrexed and carboplatin in patients with non-squamous NSCLC, was commenced in July 2010 and recruitment in the trial was completed in October 2010 [21] [22] [23] . Earlier in the same month, Tamir announced that it had selected Pharmatech Oncology as the Clinical Research Organisation to conduct the phase II trial [24] .

In October 2009, Alfacell Corpopration entered into a private placement agreement with undisclosed investors in which it raised $US3.25 million in gross proceeds to support planned phase II development of ranpimase for the treatment of non-small cell lung cancer [25] .

Preclinical results showed that ranpirnase increased the radiation response by inducing inhibition of oxygen consumption in tumour cells in vitro, and significantly increased the radiation-induced tumour growth delay of A549 human NSCLC tumours in vivo. Earlier preclinical data demonstrated that ranpirnase enhanced the sensitivity of tumour cells, including non-small cell lung cancer cells, to radiation. Furthermore, findings suggested the agent may be a good candidate for the treatment of gefitinib-resistant NSCLC. Non-invasive imaging biomarkers were identified in a separate in vivo study, these may be of use as a therapeutic predictor of the product in patients with NSCLC [26] [27] [28] [29] . The compound was also found to be effective when given in combination with standard of care treatments in vivo [30] .

Unresectable malignant mesothelioma (UMM)

at a pre-NDA meeting in January 2009, the FDA informed Alfacell that prior to the submission of an NDA for UMM, it was recommending that an additional clinical trial of ranpirnase (plus doxorubicin) should be conducted in patients with UMM who had failed one prior chemotherapy regimen. Alfacell reported that its financial situation did not permit it to conduct an additional clinical trial unless other sources of funding became available. The company chose not to seek funding an additional trial in this indication and development for UMM was discontinued.

Alfacell completed a phase IIIb trial for ranpirnase in combination with doxorubicin in UMM. The trial (NCT00003034) was conducted at sites in the US, Germany, Italy and Poland. A preliminary statistical analysis of data from the phase IIIb trial showed that the primary endpoint (overall survival) did not meet statistical significance. However, there was a statistically significant improvement in survival in patients treated with ranpirnase who had previously failed one prior chemotherapy regimen. Updated results, presented at ASCO 2009, supported these preliminary findings [31] [32] [33] [34] .

Ranpirnase has been granted fast track status in the US, and orphan drug status in the US, EU, and Australia for this indication [35] [36] .

Alfacell completed a phase III trial of single-agent ranpirnase in patients with UMM in April 1999. The efficacy of ranpirnase was compared with that of doxorubicin (head-to-head). The primary objectives were overall survival, progression-free survival and quality of life.

Neuroblastoma

preclinical studies conducted by Alfacell in colaboration with the Johann Wolfgang University of Frankfurt, have shown that ranpirnase is active against naive and chemoresistant neuroblastoma cells in vitro and in vivo. Ranpirnase inhibits neuroblastoma cell growth and induces caspase-independent cell death in neuroblastoma cells independently of P-gp expression or p53 status, which has been shown to contribute to multi-drug resistance in neuroblastoma as well as other human cancers. Transmission electron microscope investigations suggest that ranpirnase induces autophagy in neuroblastoma cells which leads to apoptosis. Antitumour activity of ranpirnase against drug-sensitive and chemoresistant neuroblastoma xenografts has been confirmed in animal models [37] .

Chronic lymphocytic leukaemia (CLL)/acute myeloblastic leukaemia (AML)

in preclinical studies, ranpirnase in combination with standard chemotherapeutic agents showed antitumour activity in leukaemia cells isolated from patients with CLL or AML [38] .

Other cancers

phase III trials of ranpirnase monotherapy in pancreatic cancer were discontinued because of lack of efficacy compared with gemcitabine and fluorouracil. Phase I/II studies of ranpirnase in combination with tamoxifen have been completed in prostate cancer and renal cell carcinoma (RCC) patients. A phase I/II trial of ranpirnase in combination with 13-cis-retinoic acid and interferon-α in patients with metastatic RCC was completed in 2001. Development for prostate cancer, pancreatic cancer, and RCC has been discontinued.

In preclinical studies, ranpirnase demonstrated significant activity against rhabdomyosarcoma and chemotherapy-resistant variants of these cancer cells. Development for these indications has been discontinued.

A National Institutes of Health-funded in vitro study carried out by the University of Vermont and published in the Molecular Cancer Therapeutics journal, demonstrated that ranpirnase in combination with rosiglitazone, synergistically induced apoptosis in ovarian, prostate, lung and breast cancer cell lines [39] .

Preclinical investigations conducted by Alfacell showed synergistic anti-tumour effects between ranpirnase and proteasome inhibitors. However, development in this area has been discontinued.

Other indications

Alfacell intended to undertake preclinical studies to investigate ranpirnase's ability to downregulate the protein produced by the multidrug resistance 1 (MDR1) gene [21] .

Alfacell announced in May 2003 that it was to provide ranpirnase to the federal severe acute respiratory syndrome (SARS) testing programme for evaluation against the human coronavirus implicated in the disease. No further development has been reported.

Patent Information

Alfacell has received twelve US and four European patents for ranpirnase. Patents issued in the US range from a 1996-issued patent (No. 5 559 212) covering the amino acid sequence of ranpirnase (expires 2013), to a patent (No. 6 175 003 B1) issued in 2001 and expiring in 2019 that protects the gene sequences of the compound plus another genetically engineered variant, effectively protecting the company's proprietary technology. In July 2002, Alfacell received a US patent (No. 6 423 515 B1) entitled "Methods of Making Nucleic Acids Encoding Ribonucleases". This patent is effective until 2019. US Patent No. 7 229 824 B1, issued in June 2007, covers a vector containing DNA encoding a genetically engineered variant of ranpirnase, and expires in 2024.

European patent EP 0 440 633 which covered ranpirnase and the process technology for making it, expired in March 2009. There are two non-US patents, expiring in October 2010 and July 2013 respectively, that cover combinations of ranpirnase with certain other pharmaceuticals (EP 0 500 589 in Europe or JP 2 972 334 in Japan, and EP 0 656 783 in Europe or JP 3 655 628 in Japan). A patent that covers a variant of ranpirnase expires in June 2016 (EP 0 837 878 in Europe or JP 3 779 999 in Japan).

Drug Properties & Chemical Synopsis

  • Route of administration IV, Parenteral, Topical
  • Formulation Infusion, Liquid, unspecified
  • Class Antineoplastics, Antivirals, Eye disorder therapies, Ribonucleases
  • Target Apoptosis; Protein synthesis; Ribonuclease
  • Mechanism of Action Apoptosis stimulants; Protein synthesis inhibitors; Ribonuclease replacements
  • WHO ATC code

    J05 (Antivirals for Systemic Use)

    J05A-X (Other antivirals)

    L01X (Other Antineoplastic Agents)

  • EPhMRA code

    J5B9 (Antivirals, others)

    J5C (HIV antivirals)

    L1X (All Other Antineoplastics)

  • Molecular formula C520 H810 N142 O155 S9
  • CAS Registry Number 196488-72-9

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Acute myeloid leukaemia + doxorubicin or cytarabine Combination therapy Discontinued (Preclinical) USA IV / Infusion Tamir Biotechnology 25 Jun 2015
Brain cancer - - Discontinued (Preclinical) USA IV / Infusion Alfacell Corporation 06 Sep 2006
COVID 2019 infections - - Clinical Phase Unknown USA Parenteral / unspecified Orgenesis 22 Jun 2020
Chronic lymphocytic leukaemia + cladribine, fludarabine or doxorubicin Combination therapy Discontinued (Preclinical) USA IV / Infusion Tamir Biotechnology 25 Jun 2015
Ebola virus infections - - Preclinical USA Parenteral / unspecified Tamir Biotechnology 22 Feb 2016
Genital warts associated with Human papilloma virus - Phase I/II Bolivia Topical / Liquid Tamir Biotechnology 01 Feb 2016
HIV infections - - Preclinical USA Parenteral / unspecified Tamir Biotechnology 22 Sep 2017
Mesothelioma - - Discontinued (III) Australia, Brazil, Canada, Mexico, New Zealand, Romania, Russia IV / Infusion Tamir Biotechnology 31 Dec 2009
Mesothelioma With doxorubicin Combination therapy Discontinued (III) Germany, Italy, Poland, USA (fast track) IV / Infusion Tamir Biotechnology 31 Dec 2009
Neuroblastoma - - Discontinued (Preclinical) USA IV / Infusion Tamir Biotechnology 25 Jun 2015
Non-small cell lung cancer - - Discontinued (II) USA IV / Infusion Tamir Biotechnology 04 Jul 2014
Pancreatic cancer - - Discontinued (III) USA IV / Infusion Alfacell Corporation 15 Jul 1998
Prostate cancer - - Discontinued (II) USA IV / Infusion Alfacell Corporation 06 Sep 2006
Renal cell carcinoma - - Discontinued (II) USA IV / Infusion Alfacell Corporation 06 Sep 2006
Zika virus infection - - No development reported (Preclinical) USA Parenteral / unspecified Tamir Biotechnology 28 Mar 2020

Priority Development Status

Type Region Indication
Fast Track USA Mesothelioma

Orphan Status

Indication Patient Segment Country Organisation Event Date
Ebola virus infections - USA Tamir Biotechnology 08 Aug 2017
Mesothelioma - Australia Tamir Biotechnology 28 Mar 2005
Mesothelioma - European Union Tamir Biotechnology 29 Mar 2001

Commercial Information

Involved Organisations

Organisation Involvement Countries
Alfacell Corporation Originator USA
Orgenesis Owner USA
Tamir Biotechnology Owner USA
Leidos Holdings Collaborator USA

Licensing Availability

Licensing Organisation Available Indication Available Phase Region Date
Tamir Biotechnology - Unspecified - 24 Apr 2019

Brand Names

Brand Name Organisations Indications Countries
Onconase Tamir Biotechnology Mesothelioma USA

Scientific Summary

  • Adverse Events Frequent: Asthenia; Oedema
    Occasional: Alopecia; Anaphylaxis; Fatigue; Hypotension; Nausea; Proteinuria; Vomiting
    Rare: Eczema

Adverse Events

Malignant mesothelioma

Phase III

doxorubicin + ranpirnase and doxorubicin alone appeared to have similar tolerability profiles in patients with unresectable mesothelioma enrolled in a phase III trial (NCT00003034; n=413). The most frequently reported adverse events included nausea, alopecia and fatigue [31] .

Ranpirnase was generally well-tolerated in a phase III clinical trial; only 5/63 patients had their treatment terminated due to adverse events [51] .

Phase II

of the 105 patients with malignant mesothelioma participating in a phase II trial of ranpirnase, only five discontinued treatment because of drug intolerance [49] .

Treatment was discontinued in 16 patients (15.2%) due to adverse events. Ranpirnase-related grade 3-4 adverse effects were experienced by 21 patients, with asthenia, peripheral oedema and arthralgia being the most common events. In this open-label multicentre study, 105 patients with clinically progressive malignant mesothelioma received once-weekly infusions of ranpirnase 480 µg/m2 [46] .

Pancreatic cancer

Phase I

ranpirnase was well tolerated in phase I clinical trials. The tolerability of P 30 + tamoxifen has been reported in 50 patients with advanced pancreatic cancer. Patients received IV P 30 at doses of 60 µg/m2 (n = 3), 120 µg/m2 (9), 240 µg/m2 (8), 360 µg/m2 (6), 480 µg/m2 (9) or 720 µg/m2 (15) every week + tamoxifen 40 mg/day. The maximum tolerated dose of ranpirnase was 720 µg/m2. Grade 3-4 adverse events included: asthenia (6), peripheral oedema (4), decreased CrCl (4), vomiting (1), reversible hypotension (1), anaphylactic reaction (1) and albuminuria (1) [52] .

Human papilloma virus infections

Phase I:

Interim results from the phase I trial of ranpirnase in human papilloma virus infections demonstrated that treatment in one of the patients had to be discontinued due to an eczematous skin reaction [13] .

Pharmacodynamics

Summary

Mechanism of action

An in vitro study demonstrated that silencing the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene in human lung adenocarcinoma A549 cells by small interfering RNA (siRNA) was effectively prevented by ranpirnase. Transfection of cells with GAPDH siRNA reduced expression of this protein by nearly 70% and the expression was restored in the cells exposed to ranpirnase for 48 or 72 hours [56] .

Treatment with ranpirnase suppressed the generation of reactive oxygen intermediates (ROI) and promoted their degradation in both normal and tumour cell lines in vitro, thus reducing intracellular oxidative stress. The observed antioxidant activity of the drug may be important to its antiproliferative/cytotoxic activity towards cancer cells, and is a possible mechanism of synergism with other anticancer agents [41] .

Ranpirnase was more effective, in terms of cytotoxic and cytostatic effects, than a variety of genetically engineered variants of the product in several tumour cell lines, including NCI-H2452 (mesothelioma), K-562 (chronic myelogenous leukaemia) and A-253 (epidermoid carcinoma). Results confirmed previous findings which showed that the product's cytotoxic and cytostatic effects are predominantly due to its catalytic activity rather than conformational stability [42] .

Ranpirnase regulated the fundamental molecular control mechanisms of cancer cell growth. Human histiocytic lymphoma U937 cells treated with ranpirnase were arrested in the G1 phase, which resulted in a significant inhibition of proliferation and apoptotic cell death. These effects were observed after 24-72h incubation with P 30 [50] .

In mammalian cells, ranpirnase exhibited marked specificity for tRNA which it subsequently degraded. Similar to DNA damage, the tRNA degradation signal activated caspase expression that resulted in the activation of the apoptotic pathway. This activity was independent of p53 status and strongly suggested that the nonmutagenicity of RNA is an effective target for this compound [48] .

Preclinical studies

Ranpirnase in combination with purine analogues (cladribine or fludarabine) and doxorubicin showed significant cytotoxic effects and pro-apoptotic activity, respectively, in leukemia cells isolated from 36 untreated patients with chronic lymphocytic leukaemia. Combination of ranpirnase and doxorubicin demonstrated an increased activity compared to single agent treatment. Ranpirnase in combination with doxorubicin or cytarabine arabinoside showed significant activity against leukaemia cells isolated from 22 patients with acute myeloblastic leukaemia. Ranpirnase and doxorubicin showed synergistic activity [38] .

Ranpirnase + lovastatin showed synergistic cytostatic and cytotoxic effects against the ASPC-1 pancreatic carcinoma, A-549 lung adenocarcinoma and HT-520 squamous cell lung carcinoma cell lines which are relatively resistant to tamoxifen and trifluoperazine. Similar degrees of growth suppression were seen with lovastatin alone and in combination with ranpirnase. The inhibitory effects of lovastatin alone or in combination with ranpirnase, were reversed by mevalonate indicating that HMG-CoA reductase inhibition is the primary mechanism of lovastatin action. Ranpirnase + lovastatin seems to offer a new therapeutic approach against resistant human solid tumours [55] .

Ranpirnase inhibited the tumour growth of A549 human non-small cell lung cancer (NSCLC) cells, and induced apoptosis. The compound also enhanced the cytotoxic effects of cisplatin and carboplatin when both drugs were administered simultaneously, or when either was added after ranpirnase administration. Ranpirnase also increased cisplatin-induced growth delay. In the treatment of large-size tumours, ranpirnase showed inhibition of tumour growth, while cisplatin and carboplatin were ineffective [44] [45] .

In an in vitro study, pretreatment with ranpirnase significantly increased the sensitivity of A549 human NSCLC cells to radiation and decreased the accumulation of damaged cells that could potentially rebuild themselves. In vivo, in athymic nude mice, administration of ranpirnase prior to radiation significantly decreased tumour growth compared with radiation alone. While, there were significant increases in tumour blood flow, no alteration in muscle blood flow was observed [26] .

In vitro

, ranpirnase induced inhibition of oxygen consumption in A549 human NSCLC cells, increasing the radiation response. Apoptosis was increased by ranpirnase; this effect was dependent upon the dose and length of exposure to the agent. In vivo, ranpirnase significantly increased the radiation-induced tumour growth delay of A549 human NSCLC tumours [29] .

In vivo,

ranpirnase significantly increased the radiation-induced tumour growth delay of lung tumours compared with radiation therapy alone. Furthermore, ranpirnase significantly reduced the tumour hypertension that is the major physiological barrier to therapeutic delivery to solid tumours, resulting in increased tumour penetration of the agent and selectively increased tumour blood flow [28] .

Ranpirnase significantly increased the radiation-induced growth delay of lung tumours in vivo without increases in skin reaction when compared with radiation alone. Ranpirnase increased apoptosis in several NSCLC cell lines. In vitro, radiation repair mechanisms which lead to radiation resistance in tumours were significantly inhibited by ranpirnase [27] .

An in vitro study demonstrated that ranpirnase in combination with rosiglitazone, synergistically decreased cell viability and increased apoptosis in ovarian, prostate, lung and breast cancer cell lines. This was achieved by targeting and decreasing the expression of two phosphatidylinositol 3-kinase downstream proteins, Fra-1 and Survivin [39] .

Ranpirnase has an additive/synergistic effect when given in combination with either cisplatin or a carboplatin-pemetrexed doublet in Biomerk Tumorgraft models derived from individual patients with non-small cell lung cancer. Tumour growth inhibition increased from 33% to 42%. When given in combination with the carboplatin-pemetrexed doublet, tumour inhibition was increased from 67% to 85% [30] .

Results from in vitro analyses of the two main HPV types (HPV 11 and HPV 16), HPV 11 was found to be highly sensitive to ranpirnase [13] .

Ebola virus infection:

In in vitro studies conducted in Ebola infected VeroE6 cells, increasing concentrations of ranpirnase produced a clear dose dependent response. In in vivo studies conducted in Ebola infected mice, treated mice were protected against Ebola, compared with placebo treated mice. No virus were detected in the serum of ranpirnase treated mice beyond day 6, compared with controls [19] .

Antimicrobial Activity

Summary

Ranpirnase inhibited 99.9% of HIV-1 replication in H9 cells at a concentration of 10-7 mmol/L and was also active at 10-8 mmol/L. The RNase activity of ranpirnase was essential for antiviral activity. Another member of the RNase family, bovine seminal RNase, also inhibited HIV-1 replication but to a lesser degree than ranpirnase [53] .

Therapeutic Trials

Malignant mesothelioma

Phase III

preliminary results from a phase IIIb clinical trial in 428 patients (320 evaluable) with unresectable malignant mesothelioma showed there was not a statistically significant improvement in evaluable patients who received ranpirnase plus doxorubicin. Median survival time was 11.1 months compared with 10.7 months for patients treated with doxorubicin monotherapy. Statistically significant results were seen in patients who had previously failed a prior chemotherapy regimen (n=122). Median survival time for these patients who received ranpirnase and doxorubicin was 10.5 months compared with 8.7 months for patients who received doxorubicin as a single agent [34] .

Interim results from the phase IIIb study showed that at one year, 47% of the ranpirnase + doxorubicin-treated patients were alive, compared with 36% of the patients treated with doxorubicin alone [43] .

Based on an updated intent-to-treat analysis (n=413), doxorubicin + ranpirnase did not significantly increase overall survival (primary endpoint), compared with doxorubicin alone, in patients with unresectable mesothelioma (11.1 vs 10.7 months; hazard ratio 1.02, 95% CI 0.82, 1.26). However, doxorubicin + ranpirnase significantly increased overall survival in a subset of pretreated patients (10.5 vs 9 months; HR 1.49; 95% CI 1.02, 2.17) [31] .

Preliminary results from a phase III trial suggested that ranpirnase may prolong survival, compared with doxorubicin, in target groups of patients with unresectable mesothelioma. Median survival duration was 17.8 versus 9.9 months in P 30 versus doxorubicin recipients when only patients with a performance status of 0 and epithelioid histology were included in the analysis. Both 1- and 2-year survival rates were higher in the ranpirnase arm when poor-prognosis patients were excluded. Adverse events were manageable and reversible in both groups [47] .

Thirty-seven percent of 63 patients with malignant mesothelioma treated with ranpirnase showed evidence of objective clinical activity and had median survival times of 10.1 months from day 1 of treatment and 24.7 months from date of diagnosis. Of the 63 patients, 4 achieved partial responses, 3 achieved minor responses, and 16 demonstrated stabilisation of disease for a minimum of 3 months [51] .

Phase II

of the 105 patients with malignant mesothelioma enrolled in a phase II trial of ranpirnase, 39% experienced a reduction in tumour size or had disease stabilisation after treatment. The 1- and 2-year survival rates were 34.3 and 21.1%, respectively. Overall median survival time was approximately 6 months, but for patients who demonstrated clinical activity (39%), the median survival time was 17.1 months. These patients had 1- and 2-year survival rates of 61 and 31.7% respectively. Patients with abdominal involvement had a median survival time of 12 months and 1- and 2-year survival rates of 48 and 35.6%, respectively [49] [46] .

Weekly administration of ranpirnase was well tolerated and improved survival in patients with advanced unresectable malignant mesothelioma. In an open-label multicentre study, 105 such patients with clinically progressive disease received once-weekly infusions of ranpirnase 480 µg/m2. At the time of the analysis, a mean of 13.3 doses (range 1 to >109) had been administered. Overall median survival time was 6 months and the 1- and 2-year survival rates were 34.3 and 21.6% respectively. Of the 81 evaluable patients, 4 achieved partial responses, 2 achieved minor regression of disease and a further 35 patients experienced stabilisation of previously progressive disease. Median survival time in these 41 patients was 18.5 months, with all 4 patients who experienced partial responses surviving >24 months [46] .

Pancreatic cancer

Phase I

The efficacy of ranpirnase plus tamoxifen has been reported in 50 patients with advanced pancreatic cancer. Patients received IV P 30 at doses of 60 µg/m2 (n = 3), 120 µg/m2 (9), 240 µ/m2 (8), 360 µg/m2 (6), 480 µg/m2 (9) or 720 µg/m2 (15) every week + tamoxifen 40 mg/day. One patient had a complete response lasting > 30 months and 8 had stable disease lasting 3 to > 17 months. 40 patients died with a median survival duration of 91 days [52] .

Renal cell carcinoma

Phase II

Among the 14 patients with refractory metastatic kidney cancer receiving ranpirnase 480 µg/m2 weekly, no responses were seen. In this phase II trial, the median survival was 16 months (range 2 to 28 months) [54] .

Human papilloma virus infections

In a phase I/II trial in 75 patients with HPV infections, at week eight a 71% mean area loss was observed for topical ranpirnase versus 33% mean area loss for vehicle (p < 0.0025). 61% of ranpirnase treated subjects showed loss of 80% of lesion area, compared with 34% of placebo treated patients (p < 0.0194) [11] [12] .

Phase I:

Interim results from the compassionate use phase I trial in human papilloma virus infections demonstrated that all patients who completed an eight-week treatment showed clearance of lesions. The time for clearance of lesions ranged from two weeks to 33 days. At visit 4, 4 of the patients (30.8%) had no warts, 6 (46.2%) had a 50% improvement, and 3 (23.1%) had a 25% improvement. At week 8, none of the patients who returned for evaluation had any warts. All patients achieved a complete remission [16] [13] .

Future Events

Expected Date Event Type Description Updated
31 Dec 2021 Trial Update Orgenesis plans a phase II trial for Genital warts in 2021. [40] 11 May 2021

Development History

Event Date Update Type Comment
11 May 2021 Trial Update Orgenesis plans a phase II trial for Genital warts in 2021. [40] Updated 11 May 2021
20 Aug 2020 Regulatory Status Orgenesis intends to submit IND application for Genital warts [1] Updated 02 Sep 2020
20 Aug 2020 Trial Update Orgenesis plans a phase II trial for Genital warts [1] Updated 25 Aug 2020
22 Jun 2020 Phase Change - Clinical Clinical trials in COVID-2019 infections in USA (Parenteral), prior to June 2020 Updated 28 Jun 2020
22 Jun 2020 Regulatory Status Orgenesis and Leidos anticipate US FDA marketing approval of ranpirnase for COVID-19 infections Updated 28 Jun 2020
27 Apr 2020 Licensing Status Orgenesis aquires an assets of ranpirnase including its antiviral platform from Tamir Biotechnology [2] Updated 04 May 2020
17 Apr 2020 Licensing Status Orgenesis enters into an asset purchase agreement with Tamir Biotechnology to acquire the ranpirnase including its antiviral platform [10] Updated 17 Apr 2020
13 Apr 2020 Active Status Review Preclinical development in Ebola-virus-infections is ongoing in USA (Parenteral) [10] Updated 17 Apr 2020
28 Mar 2020 Phase Change - No development reported No recent reports of development identified for preclinical development in Zika-virus-infection in USA (Parenteral) Updated 28 Mar 2020
24 Apr 2019 Licensing Status Ranpirnase is available for licensing as of 24 Apr 2019. http://tamirbio.com/partnering/ Updated 24 Apr 2019
22 Sep 2017 Phase Change - Preclinical Preclinical trials in HIV infections in USA (Parenteral) (Tamir Biotechnology pipeline, September 2017) Updated 24 Apr 2019
08 Aug 2017 Regulatory Status Ranpirnase receives Orphan Drug status for Ebola virus infections in USA [18] Updated 11 Aug 2017
08 Mar 2017 Scientific Update Efficacy data from a phase I/II trial in Genital warts and Human papillomavirus infections released by Tamir Biotechnology [11] Updated 09 Mar 2017
01 Sep 2016 Trial Update Tamir Biotechnology completes a phase I/II trial in Genital warts and Human papillomavirus infections in Bolivia (NCT02535104) Updated 28 Sep 2016
28 Jul 2016 Scientific Update Pharmacoynamic data from preclinical trials in Ebola virus infections released by Tamir Biotechnology [19] Updated 02 Aug 2016
22 Feb 2016 Phase Change - Preclinical Preclinical trials in Ebola virus infections in USA (Parenteral) before February 2016 [17] Updated 24 Feb 2016
22 Feb 2016 Phase Change - Preclinical Preclinical trials in Zika virus infection in USA (Parenteral) before February 2016 [17] Updated 24 Feb 2016
01 Feb 2016 Phase Change - I/II Phase-I/II clinical trials in Genital warts in Bolivia (Topical) (NCT02535104) Updated 11 Mar 2016
01 Sep 2015 Trial Update Tamir Biotechnology plans a phase II trial for Genital warts in Bolivia (NCT02535104) Updated 01 Sep 2015
25 Jun 2015 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Acute myeloid leukaemia (Combination therapy) in USA (IV) before June 2015 Updated 25 Jun 2015
25 Jun 2015 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Chronic lymphocytic leukaemia (Combination therapy) in USA (IV) before June 2015 Updated 25 Jun 2015
25 Jun 2015 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Neuroblastoma in USA (IV) before June 2015 Updated 25 Jun 2015
25 Jun 2015 Phase Change - I Phase-I clinical trials in Genital warts (Topical) Updated 25 Jun 2015
25 Jun 2015 Phase Change - I Phase-I clinical trials in Human papillomavirus infections (Topical) Updated 25 Jun 2015
08 Apr 2015 Trial Update Tamir Biotechnology plans a clinical proof-of-concept trial in Human papilloma virus infections in Colombia and/or Mexico [13] Updated 25 Feb 2016
08 Apr 2015 Scientific Update Interim pharmacodynamics data from a preclinical study in Genital warts released by Tamir Biotechnology [13] Updated 24 Feb 2016
08 Apr 2015 Scientific Update Interim therapeutics efficacy and adverse events data from a phase I trial in Human papilloma virus infections released by Tamir Biotechnology [13] Updated 24 Feb 2016
08 Apr 2015 Trial Update Tamir Biotechnology plans a phase I/II trial in Human papilloma virus infections in USA [13] Updated 24 Feb 2016
04 Jul 2014 Phase Change - Discontinued(II) Discontinued - Phase-II for Non-small cell lung cancer in USA (IV) Updated 25 Jun 2015
19 Nov 2010 Scientific Update Pharmacodynamics data from a preclinical trial in Non-small cell lung cancer presented at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR-2010) [30] Updated 29 Nov 2010
11 Oct 2010 Trial Update Tamir Biotechnology completes enrolment in its phase II trial for Non-small cell lung cancer in USA Updated 27 Oct 2010
19 Jul 2010 Phase Change - II Phase-II clinical trials in Non-small cell lung cancer in USA (IV) Updated 19 Jul 2010
27 Apr 2010 Company Involvement Alfacell Corporation is now called Tamir Biotechnology Updated 09 Jul 2010
31 Dec 2009 Phase Change - Discontinued(III) Discontinued - Phase-III for Mesothelioma in Brazil, Mexico, Romania, Russia, Australia, New Zealand, Canada (IV) Updated 24 Apr 2019
31 Dec 2009 Phase Change - Discontinued(III) Discontinued - Phase-III for Mesothelioma in Germany (IV) Updated 09 Jul 2010
31 Dec 2009 Phase Change - Discontinued(III) Discontinued - Phase-III for Mesothelioma in Italy (IV) Updated 09 Jul 2010
31 Dec 2009 Phase Change - Discontinued(III) Discontinued - Phase-III for Mesothelioma in Poland (IV) Updated 09 Jul 2010
31 Dec 2009 Phase Change - Discontinued(III) Discontinued - Phase-III for Mesothelioma in USA (IV) Updated 09 Jul 2010
08 Sep 2009 Licensing Status Par (Strativa) terminates its licence for ranpirnase in USA Updated 03 Feb 2011
02 Jun 2009 Scientific Update Efficacy and adverse events data from a phase IIIb trial in patients with unresectable mesothelioma were presented at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO-2009) [31] Updated 04 Jun 2009
27 Jan 2009 Regulatory Status FDA advises Alfacell that an additional phase III trial in patients with unresectable malignant mesothelioma is required prior to NDA submission Updated 11 Mar 2009
10 Dec 2008 Phase Change - Preclinical Preclinical trials in Acute myeloid leukaemia in USA (IV) Updated 18 Dec 2008
10 Dec 2008 Phase Change - Preclinical Preclinical trials in Chronic lymphocytic leukaemia in USA (IV) Updated 18 Dec 2008
21 Jul 2008 Phase Change Early research in Cancer in USA (unspecified route) Updated 23 Jul 2008
21 Jul 2008 Scientific Update In vitro study results in Cancer released by Alfacell [39] Updated 23 Jul 2008
15 Jul 2008 Licensing Status Ranpirnase licensed to MegaPharm Ltd in Israel Updated 21 Jul 2008
09 Jun 2008 Trial Update Alfacell Corporation completes a Phase-I trial in Non-small cell lung cancer in USA Updated 30 Jul 2008
28 May 2008 Scientific Update Preliminary efficacy data from a phase IIIb trial in unresectable malignant mesothelioma released by Alfacell Corporation [34] Updated 30 May 2008
16 Apr 2008 Scientific Update Pharmacodynamics data from a preclinical trial in NSCLC presented at the 99th Annual American Association for Cancer Research (AACR-2008) [27] Updated 17 Apr 2008
22 Jan 2008 Licensing Status Ranpirnase licensed to BL & H in South Korea, Taiwan and Hong Kong Updated 29 Jan 2008
15 Jan 2008 Licensing Status Ranpirnase licensed to Strativa Pharmaceuticals in US Updated 17 Jan 2008
01 Nov 2007 Scientific Update Preclinical data added to the Cancer pharmacodynamics section [28] Updated 01 Nov 2007
15 Oct 2007 Trial Update Alfacell completes enrolment in its phase III trial for unresectable malignant mesothelioma Updated 26 Oct 2007
27 Aug 2007 Scientific Update Preclinical data added to the Cancer pharmacodynamics section [29] Updated 27 Aug 2007
26 Aug 2007 Regulatory Status Ranpirnase receives orphan drug status for mesothelioma in the US Updated 26 Oct 2007
23 Aug 2007 Scientific Update Preclinical data added to the Cancer pharmacodynamics section [41] Updated 23 Aug 2007
26 Jul 2007 Licensing Status Ranpirase licensed to USP Pharma in Eastern Europe Updated 26 Oct 2007
25 Jul 2007 Scientific Update Preclinical data added to the Cancer pharmacodynamics section [42] Updated 25 Jul 2007
21 Dec 2006 Licensing Status Ranpirnase licensed to Genesis Pharma in Southeast Europe Updated 08 Jan 2007
21 Nov 2006 Scientific Update Preclinical data added to Cancer pharmacodynamics section [26] Updated 21 Nov 2006
06 Sep 2006 Phase Change - Discontinued(II) Discontinued - Phase-II for Prostate cancer in USA (unspecified route) Updated 06 Sep 2006
06 Sep 2006 Phase Change - Discontinued(II) Discontinued - Phase-II for Renal cell carcinoma in USA (IV) Updated 06 Sep 2006
06 Sep 2006 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Brain cancer in USA (unspecified route) Updated 06 Sep 2006
01 May 2006 Scientific Update Interim results from a phase IIIb clinical trial in patients with malignant mesothelioma have been added to the Cancer therapeutic trials section [43] Updated 01 May 2006
01 Mar 2006 Trial Update Alfacell has completed worldwide enrolment in a phase IIIb trial for unresectable malignant mesothelioma Updated 01 Mar 2006
21 Oct 2005 Scientific Update Preclinical data from a media release have been added to the Cancer pharmacodynamics section [44] Updated 21 Oct 2005
01 Sep 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Brazil (IV) Updated 01 Sep 2005
01 Sep 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Mexico (IV) Updated 01 Sep 2005
01 Sep 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Romania (IV) Updated 01 Sep 2005
01 Sep 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Russia (IV) Updated 01 Sep 2005
30 Mar 2005 Regulatory Status Ranpirnase has received orphan drug status for malignant mesothelioma in Australia Updated 30 Mar 2005
16 Mar 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Australia (IV) Updated 16 Mar 2005
16 Mar 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Canada (IV) Updated 16 Mar 2005
16 Mar 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Germany (IV) Updated 16 Mar 2005
16 Mar 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Italy (IV) Updated 16 Mar 2005
16 Mar 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in New Zealand (IV) Updated 16 Mar 2005
16 Mar 2005 Phase Change - III Phase-III clinical trials in Mesothelioma in Poland (IV) Updated 16 Mar 2005
28 Feb 2005 Scientific Update Preclinical data from a media release have been added to the Cancer pharmacodynamics section [45] Updated 28 Feb 2005
09 Feb 2005 Phase Change - I/II Phase-I/II clinical trials in Non-small cell lung cancer in USA (IV) Updated 09 Feb 2005
18 Nov 2003 Active Status Review This compound is still in active development for HIV infections treatment in the US Updated 18 Nov 2003
10 Nov 2003 Phase Change - Preregistration Preregistration for Mesothelioma in USA (IV) Updated 10 Nov 2003
23 Dec 2002 Regulatory Status Ranpirnase has received fast-track designation for malignant mesothelioma in combination with doxorubicin in the USA Updated 23 Dec 2002
02 Oct 2002 Company Involvement Alfacell and the NCI have expanded their collaboration allowing the NCI to study ranpirnase as a radiation enhancer Updated 02 Oct 2002
18 Feb 2002 Scientific Update A clinical study in malignant mesothelioma has been added to the Cancer therapeutic trials and adverse events sections [46] Updated 18 Feb 2002
29 Jan 2002 Phase Change - Preclinical Preclinical development for Neuroblastoma in USA (Unknown route) Updated 29 Jan 2002
05 Sep 2001 Scientific Update A phase II study in metastatic renal cell carcinoma has been added to the Cancer therapeutic trials section Updated 05 Sep 2001
26 Feb 2001 Regulatory Status Alfacell received a patent protecting gene sequences of Onconase® Updated 26 Feb 2001
26 Feb 2001 Regulatory Status Orphan medicinal product designation granted to Onconase® in Europe for malignant mesothelioma Updated 26 Feb 2001
27 Sep 2000 Scientific Update A phase III study has been added to the cancer therapeutic trials section [47] Updated 27 Sep 2000
15 Aug 2000 Licensing Status Onconase® is available for licensing (http://www.alfacell.com) Updated 15 Aug 2000
15 Aug 2000 Phase Change - II Phase-II clinical trials for Prostate cancer in USA (IV) Updated 15 Aug 2000
15 Aug 2000 Phase Change - Preclinical Preclinical development for Brain cancer in USA (Unknown route) Updated 15 Aug 2000
22 Jun 2000 Scientific Update A preclinical study has been added to the pharmacodynamics section [48] Updated 22 Jun 2000
30 Mar 1999 Scientific Update A phase II clinical trial has been added to the therapeutic trials and adverse events sections [49] Updated 30 Mar 1999
01 Dec 1998 Phase Change - II Phase-II clinical trials for Renal cell carcinoma in USA (IV) Updated 01 Dec 1998
21 Aug 1998 Scientific Update A preclinical study has been added to the pharmacodynamics section [50] Updated 21 Aug 1998
15 Jul 1998 Phase Change - Discontinued(III) Discontinued-III for Pancreatic cancer in USA (IV) Updated 15 Jul 1998
27 May 1997 Scientific Update A study has been added to the adverse events and Cancer therapeutic trials sections [51] Updated 27 May 1997
23 May 1997 Phase Change - III Phase-III clinical trials for Mesothelioma in USA (IV) Updated 23 May 1997
17 Jul 1996 Scientific Update Preliminary results in patients with breast cancer have been added to the therapeutic trials section Updated 17 Jul 1996
31 May 1996 Phase Change - II Phase-II clinical trials for Mesothelioma in USA (IV) Updated 31 May 1996
31 May 1996 Scientific Update Data in patients with malignant mesothelioma have been added to the therapeutic trials section Updated 31 May 1996
16 Aug 1995 Phase Change - III Phase-III clinical trials for Pancreatic cancer in USA (IV) Updated 16 Aug 1995
28 Nov 1994 Scientific Update A clinical study has been added to the adverse events section [52] Updated 28 Nov 1994
28 Nov 1994 Scientific Update A study has been added to the Cancer therapeutic trials section [52] Updated 28 Nov 1994

References

  1. Orgenesis Selects Therapeutics, Inc. as CRO to Support Development and Planned Phase 2 Clinical Study of Ranpirnase for the Treatment of External Genital Warts.

    Media Release
  2. Orgenesis Completes Acquisition of Tamir Biotechnology, Inc. Assets Including Broad Spectrum Antiviral Platform.

    Media Release
  3. Alfacell Corporation Licenses ONCONASE(R) U.S. Commercial Rights to Strativa Pharmaceuticals.

    Media Release
  4. Strativa Pharmaceuticals Acquires Commercialization Rights to Onconase(R) from Alfacell Corporation.

    Media Release
  5. Alfacell Corporation and GENESIS Pharma S.A. Announce Exclusive Licensing Agreement for ONCONASE in Southeast Europe.

    Media Release
  6. Alfacell Announces ONCONASE(R) Distribution and Marketing Agreement with Megapharm for Israel.

    Media Release
  7. Alfacell Reports Fiscal Fourth Quarter and Year-End 2007 Financial Results.

    Media Release
  8. Alfacell Announces ONCONASE(R) Distribution and Marketing Agreement With BL&H for South Korea, Taiwan and Hong Kong.

    Media Release
  9. Alfacell Announces ONCONASE(R) Purchase and Supply Agreement with Scientific Protein Laboratories.

    Media Release
  10. Orgenesis Announces Agreement to Acquire Assets of Tamir Biotechnology, Inc. Including Broad Spectrum Antiviral Platform.

    Media Release
  11. Topical Ranpirnase Demonstrates Effective Treatment Of HPV Associated Genital Warts.

    Media Release
  12. Phase I/II Clinical Study, Double Blinded, Multicentric, Controlled Against Placebo, in Parallel Groups, to Evaluate the Efficacy and Safety of a Topical Product Containing Ranpirnase in Genital Warts - HPV

    ctiprofile
  13. Tamir Biotechnology:New Antiviral Medication For HPV Infection Shows Promise.

    Media Release
  14. Phase I/II trial of Ranpirnase in patients with HPV infections

    ctiprofile
  15. Proof-of-concept study of Ranpirnase in patients with HPV infections

    ctiprofile
  16. Antiviral Promising in Early HPV Trial.

    Media Release
  17. Ranpirnase Exhibits Anti-Zika Activity.

    Media Release
  18. Ranpirnase Receives Orphan Drug Designation from US FDA for Treatment of Ebola Virus Disease.

    Media Release
  19. Ranpirnase Shows Antiviral Effect Against Ebola.

    Media Release
  20. Alfacell's ONCONASE (R) significantly inhibits RNA viruses including HIV-1; data presented at the Congress of the German Society for Virology.

    Media Release
  21. Alfacell Provides Shareholder Update.

    Media Release
  22. Alfacell Corporation Expands ONCONASE(R) Clinical Program.

    Media Release
  23. A Phase II Trial of Addition of Ranpirnase(ONCONASE) to Permetrexed Plus Carboplatin in Patientes With Non-Squamous Non-Small Cell Lung Cancer

    ctiprofile
  24. Tamir Biotechnology, Inc. Announces Selection of CRO.

    Media Release
  25. Alfacell Corporation Announces Closing of $3.25 Million Private Placement.

    Media Release
  26. Study Reinforces Potential Utility of ONCONASE(Rm) in Non-Small-Cell Lung Cancer.

    Media Release
  27. Alfacell's ONCONASE(R) Shows Potential as Radiation Sensitizer for Lung Cancer Treatment.

    Media Release
  28. Alfacell's ONCONASE(R) Shows Promise as Radiation Sensitizer for Lung Cancer Treatment.

    Media Release
  29. Paper in Advances in Experimental Medicine and Biology Reports Alfacell's ONCONASE(R) Enhances Effect of Radiation in Non-Small Cell Lung Cancer.

    Media Release
  30. Bruckheimer EM, Strawn SJ, Wick MJ, Nieves F, Saxena S, Ardelt W, et al. Anti-cancer activity of onconase, a cytotoxic amphibian ribonuclease, in combination with standard of care agents in non-small cell lung tumorgraft models. 22nd-EORTC-NCI-AACR-2010 2010; abstr. 433.

    Available from: URL: http://www.ecco-org.eu
  31. Reck M, Krzakowski M, Jassem J, Eschbach C, Kozielski J, Costanzi JJ, et al. Randomized, multicenter phase III study of ranpirnase plus doxorubicin (DOX) versus DOX in patients with unresectable malignant mesothelioma. 45th-ASCO-2009 2009;383 abstr. 7507.

    Available from: URL: http://www.abstract.asco.org
  32. Alfacell Reports Financial Results for First Quarter of Fiscal 2009.

    Media Release
  33. Alfacell Provides ONCONASE(R) NDA Submission Update.

    Media Release
  34. Alfacell Corporation Announces Preliminary Results From ONCONASE(R) Phase IIIb Clinical Trial.

    Media Release
  35. Alfacell Provides Update on the ONCONASE Phase IIIb Registration Trial.

    Media Release
  36. Alfacell Corporation Files for U.S. Orphan Drug Designation for ONCONASE (Rm).

    Media Release
  37. In Vitro and In Vivo Data Show Alfacell's ONCONASE(R) is Active Against Naive and Chemoresistant Neuroblastoma Cells.

    Media Release
  38. Alfacell's ONCONASE(R) and R-Amphinase Show Anti-Tumor Activity in Chronic Lymphocytic Leukemia and Acute Myeloblastic Leukemia Cells.

    Media Release
  39. Paper in Molecular Cancer Therapeutics Reports that a Novel Combination of Alfacell's ONCONASE(R) and Rosiglitazone Induces a Synergistic Apoptotic Effect in Several Cancer Cell Lines.

    Media Release
  40. UNITED STATES SECURITIES AND EXCHANGE COMMISSION FORM 10 K ORGENESIS INC. Internet-Doc 2021;.

    Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1460602/000149315221005653/form10-k.htm
  41. Paper in International Journal of Oncology Reports Alfacell's ONCONASE(R) Suppresses Intracellular Oxidative Stress.

    Media Release
  42. Paper in Cancer Biology & Therapy Confirms In Vitro Cytotoxic Effect of Alfacell's ONCONASE(R).

    Media Release
  43. Alfacell Provides Update on ONCONASE Phase IIIb Confirmatory Registration Trial; Releases First Interim Analysis Data.

    Media Release
  44. New ONCONASE(R) Non-Small Cell Lung Cancer Data Presented at ASTRO Annual Meeting.

    Media Release
  45. Key ONCONASE(R) Findings Presented at AACR Special Lung Cancer Conference.

    Media Release
  46. Mikulski SM, Costanzi JJ, Vogelzang NJ, McCachren S, Taub RN, et al. Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J-Clin-Oncol 2002;20274-281.

    PubMed | CrossRef Fulltext
  47. Vogelzang N, Taub R, Shin D, Costanzi J, Pass H, et al. Phase III randomized trial of onconase vs. doxorubicin in patients with unresectable malignant mesothelioma: analysis of survival. 36th-Proc-Am-Soc-Clin-Oncol 2000;19577.

  48. Iordanov MS, Ryabinina OP, Wong J, Dinh T-H, Newton DL, et al. Molecular determinants of apoptosis induced by the cytotoxic ribonuclease onconase: evidience for cytotoxic mechanisms different from inhibition of protein synthesis. Cancer-Res 2000;601983-1994.

    PubMed | CrossRef Fulltext
  49. Alfacell announces phase II malignant mesothelioma results.

  50. Alfacell's Oncase shown to control cancer cell growth.

  51. ALFACELL initiates phase III clinical trial for asbestos-related cancer.

  52. Costanzi J, Chun H, Mittelman A, Puccio C, Coombe N, et al. Phase I/II clinical trial of onconase plus tamoxifen in patients with advanced pancreatic carcinoma. 30th-ASCO 1994;13205.

    PubMed
  53. Youle RJ, Wu Y-N, Mikulski SM, et al. RNase inhibition of human immunodeficiency virus infection of H9 cells. Proc-Natl-Acad-Sci-U-S-A 1994;916012-6016.

    PubMed
  54. Vogelzang NJ, Aklilu M, Stadler WM, Dumas MC, Mikulski SM. A phase II trial of weekly intravenous ranpirnase (Onconase Rm), a novel ribonuclease in patients with metastatic kidney cancer. Invest-New-Drugs 2001;19255-260.

    PubMed | CrossRef Fulltext
  55. Mikulski SM, Viera A, Darzynkiewicz Z, Shogen K. Synergism between a novel amphibian oocyte ribonuclease and lovastatin in inducing cytostatic and cytotoxic effects in human lung and pancreatic carcinoma cell lines. Br-J-Cancer 1992;66304-310.

    PubMed
  56. Paper in Cell Cycle Reports Alfacell's ONCONASE(R) Targets siRNA.

    Media Release
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