12 juli 2012: Wie advexin intypt in pubmed krijgt keur aan studies, maar veelal laboratorium of dierstudies. Als u geinteresseerd bent in dit vaccin kunt u wellicht eens in deze selectie zoeken. http://www.ncbi.nlm.nih.gov/pubmed?term=advexin
d.d. 17 sept. 2003: Zoals Gleevec lijkt nu Advexin gepresenteerd te worden als een doorbraak in het behandelen van kanker. De FDA heeft een versnelde toelating voor Advexin bij hoofd- en halstumoren toegelaten. Gebaseerd op studies die zouden uitwijzen dat Advexin een hoog significant verschil maakt in overleving in vergelijking met de tot nu toe geldende eerste lijns behandelingen bij hoofd- en halstumoren. Een studieomschrijving ter controle van de gemelde resultaten hebben we nergens kunnen vinden. Wel kunt u hier op deze website van Clinical Oncology Research een zeer uitgebreid, maar wel in medische taal geschreven overzichtsartikel lezen over ontwikkelingen van gentherapie en dan vooral over deze p53 gebaseerde gentherapie. Wie echter klikt op de op genoemde website aanwezige deeplink naar clinical trials ziet dat de resultaten toch wel erg pover zijn tot nu toe.
Hier een artikel met beschrijving van patenten enz. van gentherapie met Advexin en verwante immuuntherapeutische middelen, allemaal gerelateerd aan het p53 gen.
1: Drugs R D. 2007;8(3):176-87.
INGN 201: Ad-p53, Ad5CMV-p53, adenoviral p53, p53 gene therapy--introgen, RPR/INGN 201.
[No authors listed]
Introgen and its wholly owned European subsidiary Gendux AB are developing an adenoviral p53 gene therapy as a treatment for cancer in the US and Europe, respectively. Phase III trials in patients with head and neck cancer are ongoing, and a number of clinical trials in other cancer indications have been completed. INGN 201 is being reviewed by the EMEA for approval in Li-Fraumeni syndrome (LFS) under the provisions of exceptional circumstance; the therapy is available on a compassionate use basis to eligible LFS cancer patients under a protocol authorised by the US FDA. The p53 tumour suppressor gene is deleted or mutated in many tumour cells and is one of the most frequently mutated genes in human tumours. The p53 protein is one of the most intricate elements in the apoptotic signalling cascade, and a mutation in the gene encoding it is believed to result in a decreased ability of a cell to apoptose. Thus replacing this gene via adenovirally-mediated p53 gene therapy is hoped to result in increased apoptosis where it is administered.INGN 201 is available for licensing, although Introgen favours retaining partial or full rights to the therapy in the US.Introgen entered into a license agreement with The University of Texas System and MD Anderson Cancer Center in 1994. The technologies licenced include p53 and fus1 (INGN 401). The collaboration has yielded exclusive patent and licensing rights to numerous technologies.Introgen entered into a collaboration with Rhône-Poulenc Rorer Pharmaceuticals (now sanofi-aventis) to develop therapeutics based on p53 inhibition in October 1994. However, in June 2001 this relationship was restructured and Introgen assumed responsibility for the worldwide development of all p53 products including INGN 201, and acquired all marketing and commercialisation rights with respect to those products.Introgen initiated two phase III trials in head and neck cancer (in June 2000 and May 2001) at about 80 sites in the US, Canada and Europe; the first is a comparative study of INGN 201 and IV methotrexate in 240 patients with refractory head and neck cancer. The second is for the combination of INGN 201 and standard chemotherapy, compared with standard chemotherapy alone, in 288 patients with recurrent squamous cell carcinoma of the head and neck. Introgen expects to complete regulatory filings for advanced recurrent head and neck cancer in the US and EU within 2007.Favourable phase II data of INGN 201 in a subpopulation of patients with recurrent, unresectable head and neck cancer (SCCHN) prompted Introgen to seek accelerated approval for INGN 201 in December 2004. The company has filed a request with the FDA to accept a 'rolling Biologics License Application', the first regulatory step in the accelerated approval process. Introgen requested immediate initiation of the Accelerated Approval rolling BLA, with completion of the filing process expected before the end of 2005.Introgen had presented combined results from three multicentre (US and Europe) phase II studies of INGN 201 in 217 patients with recurrent squamous cell carcinoma of the head and neck confirming previous safety and efficacy results of the treatment.In April 2004, the Southwest Oncology Group initiated a similar clinical trial using INGN 201 for the treatment of stage III or IV squamous cell carcinoma of the oral cavity, or oropharynx, that is able to be removed surgically. The study assessed the feasibility, efficacy and safety of administering INGN 201 at the time of surgery for suppression of remaining tumour cells, followed by a combination of chemotherapy and radiation therapy. The previous trial was a phase II study that afforded Introgen access to surgical specialists in cancer and complemented the company's ongoing pivotal phase III studies in advanced recurrent disease. Sixty patients with head and neck cancer will undergo surgery at ten US sites and receive INGN 201 intraoperatively (and not postoperatively as used in the former trial) followed by a combination of chemo- and radiotherapy.In September 2003, INGN 201 was granted designation as a Fast Track Drug Product development programme by the FDA for prolonging survival and delaying time to disease progression in patients with recurrent, unresectable squamous cell carcinoma of the head and neck. Previously, in February 2003, INGN 201 received orphan drug designation from the FDA for head and neck cancer.Phase I trials in the US for the treatment of non-small-cell lung cancer have been completed. Sanofi-aventis (formerly Rhône-Poulenc Rorer Gencell) initiated phase II trials in the US, Europe and Canada for non-small-cell lung cancer.Intratumoral injection of RPR/INGN 201 in patients with recurrent glioblastomas was safe and resulted in expression of the p53 protein. Direct administration of RPR/INGN 201 to the lower airways of patients with bronchioalveolar cell lung carcinoma resulted in symptomatic improvement and improved lung function in some patients.In November 2003, according to a Clinical Trials Agreement between the Division of Cancer Treatment and Diagnosis (DCTD) of the National Cancer Institute (NCI) and Introgen, a 6-month phase I/II study with p53 gene therapy administered in the form of an oral rinse or mouthwash for patients with oral premalignancies has been initiated. This is the first trial to investigate the effect of this treatment on oral lesions that are at high risk for developing into full blown cancers.In September 2006, the EMEA granted orphan drug status to INGN 201 for the treatment of LFS, following Gendux's application for the designation. The company intends to provide the therapy on a compassionate use basis to qualifying patients in Europe.INGN 201 has been successfully used in the treatment of a LFS patient on a compassionate use basis under a protocol authorised by the FDA. Based on these interim findings, Introgen has decided to continue making the therapy available through a compassionate use programme to eligible LFS patients who have relapsed after standard treatment as part of physician-sponsored protocols at qualifying institutions in the US.A worldwide, exclusive license to a family of US patents covering a combination therapy comprised of INGN 201 in combination with several inhibitors of epidermal growth factor receptors (EGFr) such as Erbituxtrade mark Vectibixtrade mark and Tarcevatrade mark was granted to Introgen by The University of Texas MD Anderson Cancer Center in November 2006.In February 2006, Introgen exclusively licenced a broad patent (US Patent No. 6 989 375), originally issued to to the Board of Regents of The University of Texas System; the patent covers any therapeutic gene-based therapy when applied in combination with conventional cancer therapy such as radiation or chemotherapy.Introgen Therapeutics was awarded a patent from the US Patent and Trademark Office in June 2005 that directly covers many of the special features of its INGN 201 molecular therapy. US Patent No. 6,905,873 is one of a family of patents that cover INGN 201 that have been issued to the Board of Regents of The University of Texas System and exclusively licensed to Introgen. To date, Introgen controls 30 issued patents relevant to the product covering compositions, therapeutic methods of administering the product in virtually any form, alone and in conjunction with the most widely used chemotherapeutic and radiation treatments, as well as its production, and has a large number of pending patent applications in the US and in foreign countries relating to its ADVEXIN((R)) therapy.In December 2004, the US Patent and Trademark Office issued Patent No. 6,830,749 entitled Recombinant p53 Adenovirus Methods and Compositions. Importantly, the patent is the broadest adenoviral p53 patent to date, covering any adenovirus carrying the p53 gene under the control of any promoter. Previously, Patent No. 6,805,858 covering methods for the administration of INGN 201 to cancer patients including virtually all of those routes currently being used for adenoviral delivery was awarded. In addition, US Patent No. 6,740,320, which broadly covers adenoviral vectors with the tumour suppressor p53 in pharmaceutical compositions, was awarded. This patent extends Introgen's patent coverage for its adenoviral p53 gene therapy product to the year 2021, not taking into account possible patent extensions.In February 2003, the US Patent and Trademark Office issued patent No. 6,511,847, entitled Recombinant p53 Adenovirus Methods and Compositions, covering any adenoviral DNA molecule that encodes the p53 gene positioned under the control of a promoter.US patents issued in 2002 include Patent No. 6,410,010, broadly covering all adenoviral p53 compositions (including ADVEXIN((R))) that express adequate p53 in amounts sufficient to suppress the growth of or kill cancer cells in patients. The patent also covers adenoviral p53, which incorporates a specific type of promoter that helps cells to express the p53 tumour suppressor gene. Introgen has a number of US patents that relate to the clinical use of adenoviral p53 gene therapy in cancer as monotherapy or in combination with one or more chemotherapeutic drugs, radiation therapies or other agents that have a damaging effect on the DNA or survival of (i.e. 2-methoxyestradiol, Patent No. 6,410,029) cancer cells.A patent with broad claims directed to combination therapy with the p53 gene and conventional chemotherapy or radiation was issued in China in August 2005. Patent No. ZL95192776.0, entitled Compositions Comprising DNA Damaging Agents and p53, was issued to the Board of Regents of The University of Texas System and was exclusively licenced to Introgen. (ABSTRACT TRUNCATED)
PMID: 17472413 [PubMed - indexed for MEDLINE]
Introgen Receives FDA Fast Track Designation for Advexin(R)
AUSTIN, Texas, Sept. 17 /PRNewswire-FirstCall/ -- Introgen Therapeutics, Inc.
(Nasdaq: INGN) announced today that its investigational cancer therapy, Advexin,
was granted designation as a Fast Track Drug Product development program by the
U.S. Food and Drug Administration (FDA) for its effect on prolonging survival
and on prolonging the time to loco-regional disease progression in patients with
recurrent, unresectable squamous cell carcinoma of the head and neck. Each year
approximately 40,000 Americans are affected with head and neck cancer.
By designating Advexin as a Fast Track product, the FDA will take such actions
as are appropriate to expedite the development and review of the application for
approval of Advexin. FDA may also evaluate for filing and commence review of
portions of an application for approval of a Fast Track product under certain
conditions. The FDA previously granted Advexin orphan drug status in head and
"We are extremely pleased by today's news since it confirms Advexin's
potential to treat a devastating disease for which there is no approved biologic
or drug treatment. It also reflects the FDA's leadership in the war on cancer
by providing biotechnology and pharmaceutical sponsors with assistance in
accelerating the development and approval of essential therapies," said Dr. Max
Talbott, Introgen's senior vice president of worldwide commercial development.
Introgen currently has two ongoing phase 3 studies of Advexin in head and neck
cancer. In one study the effect on survival time (primary endpoint) of Advexin
mono-therapy is compared to that of methotrexate. Secondary endpoints are
objective response rate, time to progression and tumor growth control. In the
second study, a combination of Advexin with platinum and 5-fluorouracil is
compared to that of the combined chemotherapies. The primary endpoint in this
study is time to progression. Secondary endpoints include survival time,
objective response rate and tumor growth control.
Two Advexin phase 2 studies have been completed in which patients with
recurrent head and neck cancer received injections of Advexin at two dose levels
into local and regional disease. In these studies, patients receiving a higher
dose, consistent with the dose used in Introgen's phase 3 studies, experienced
an 88 percent improvement in median survival time compared to historical
controls, as well as an increased survival compared to patients receiving the
lower dose of Advexin. Additionally, 73 percent of the tumors that were
injected with Advexin stopped growing or diminished in size.
Clinical responses were observed in patients whose tumors were resistant to
previous chemotherapy. Both phase 2 studies were conducted using Advexin alone,
as a mono-therapy. The most common adverse events in both studies were fever
without infection, pain on injection, and nausea. There were no significant
bone marrow, liver or kidney toxicities observed in patients in either study.
In addition to demonstrating the potential to treat head and neck cancer,
Advexin has shown indication of effectiveness in other cancers. Data published
in the January 2003 issue of the journal Clinical Cancer Research of a phase 2
study of patients with non-small cell lung cancer treated with Advexin and
radiotherapy showed over 60 percent of patients' primary tumors regressed or
disappeared after the combination therapy, as assessed by both biopsies and by
CT scans three months after treatment. Additionally, Advexin administration did
not appear to increase the side effects caused by radiation treatment.
Preliminary data from a phase 2 study in patients with locally advanced breast
cancer indicated that Advexin can be safely combined with two standard
chemotherapies, Taxotere(R), marketed by Aventis, and Adriamycin(R), marketed by
Pfizer (Pharmacia). Interim evaluation demonstrated that ninety percent of the
patients in the study had complete or partial (greater than 50 percent)
responses in treated lesions. Pathological examination revealed only scattered
residual tumor cells. No patients had progressive disease. These data were
published at the 39th annual meeting of the American Society of Clinical
Advexin supplies p53 protein in very high concentrations in cancer tissue and
selectively kills cancer cells while not harming the surrounding normal cells.
p53 is a normal constituent of cells and is known as a tumor suppressor because
it provides a powerful halt signal on cell growth. One of the major roles of
this protein is to recognize when the cell has been damaged by mutation and stop
cell growth to initiate repair. If the cell is damaged beyond repair, p53
initiates the cell death pathway to prevent the cell from growing out of