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)