 |
.December
2003, (Vermarktung eines Gentherapieproduktes
in China) |
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Last update: September 21, 2005 |
This page is regularly updated since December 3, 2003
with facts, comments & reactions on this event. |
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'Gendicine' Mystery
partly solved The use of recombinant
adenoviruses carrying a 'healthy' version of the tumor
suppressor gene p53 for the treatment of human cancers has
been widely investigated (several hundred papers in the
official publication database). In a very recent review article (including an editorial by J Wilson) in the journal Human Gene Therapy, Dr. Peng officially discloses many of the features of the clinical trials that were the basis of the approval by chinese authorities. The data confirm that the crucial trial involved less than 130 patients but seem quite convincing about a significant therapeutic effect. In the accompanying editorial, J. Wilson mentions that there have been over 2600 patients treated with Gendicine since the approval and that something like 50'000 should be treated before the end of 2006. Although all this is quite promising, only the powered numbers will finally tell whether the therapeuticeffect is as good as in the original clinical phase II/III that prompted approval. If the effect is proven, then we all should be extremely thankful to the Chinese scientists and their regulatory bodies for their courage and vision. If not, than we shall continue in our quest for better vectors and better treatments in gene therapy. |
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Chronology of events
Facts and questions after this disclosure
Gendicine: is this a case of good news, moderately good news, or just bad news?
Comments by Sandro Rusconi to the prospected commercialisation of Gendicine
After posting this news-page on the NFP37 WEB site I have received
several messages from patients
seeking for the information of how and where to get this medicine.
Thus, I must conclude that, even
if I took my best efforts to point out that 'Gendicine' remains so
far for the official medicine in the
realm of the 'unproven methods', patients or their relatives
remain eager to get alternative treatments,
even if these are poorly documented.
This eagerness is easily understandable because when people are so
deeply suffering, there is litle room
left for rational thinking. I have lost myself my father several
years ago on colon cancer and I know
what it means when the medical doctors tell you the 'no option'
news.
We all had tremendous troubles accepting it. At that time I had just
initiated my PhD studies and I felt
miserably useless in spite of all the science that I had proudly
learned over those years.
Similarly useless I feel when I have to respond to all the patients
that contact our WEB site in search of
some hope.
Personally I dont know if Gendicine is really such a good
concotion, and from
my humble experience and from talking to many world specialists I
must remain extremely skeptical.
Nonetheless, it is 'moderately good news' that one can say at least
that one gene therapy drug is finally
approved. Perhaps it is not better than the other Adeno-p53 drugs,
but nobody expects gene therapy
to start with perfect drugs. After all, our airplanes were not that
safe and reliable at the beginning of the flight-era.
But there are also some 'bad news', besides the lack of current
official information.
Indeed, the worst that can happen is that somebody may exploit the
restricted availability in China
and start offering 'Gendicine' at overwhelming prices over some
obscure channels in the rest of the world,
taking cynical advantage of the desperation of patients and their
families.
Even worse, some fake products could be offered, adding fraud to
cynisism.
Independent of technology, the perverse effects are always caused
by human greed and ambition,
which are diseases that cannot be cured.
www.eurekalert.org/pub_releases/
2003-11/ns-fgt112603.php (www.newscientist.com)
Public release date: 26-Nov-2003
Contact: Claire Bowles claire.bowles@rbi.co.uk, 44 207 331 2751, New
Scientist
First gene therapy approved
Cancer gene therapy is first to be approved
11:36 28 November 03 Exclusive from New Scientist Print Edition. Subscribe and get 4 free issues.
For the first time, a gene therapy-based treatment has been given the go-ahead by regulatory authorities. China's medicines authority approved the cancer therapy after it achieved promising results in a clinical trial.
The treatment, called Gendicine, will be launched commercially in January by SiBiono GeneTech of Shenzhen, Guangdong province. The results of the trial will be published in December in China's national medical journal, says Zhaohui Peng, the company's founder and head, and he plans to translate the paper into English to submit to an international journal.
Gendicine's approval was announced over a month ago but has gone largely unnoticed outside China. Most gene therapy experts contacted by New Scientist knew nothing about it. But French Anderson of the University of Southern California, a renowned gene therapy pioneer, visited SiBiono earlier in 2003 and also met the head of the Chinese drug approval agency. "The Chinese did evaluate this in considerable detail, so this was not a trivial approval," he says. "This was a serious in-depth analysis."
Run amok
The treatment consists of an adenovirus designed to insert a gene
called p53. This gene codes for a protein that triggers cell suicide
when cells start to run amok, preventing them becoming cancerous.
Many tumours arise after the mutation or inactivation of p53, and in
cancers of this type restoring the protein should kill the tumour
cells. This approach has already been tried in the US, with mixed
results.
SiBiono decided to test the treatment on head and neck squamous cancers, as p53 is known to be mutated in over 60 per cent of these tumours. This form of cancer is also particularly common in China. In the largest clinical trial, 120 patients with nasopharyngeal cancer were given either radiotherapy alone, or Gendicine and radiotherapy. The p53-carrying viruses were injected directly into tumours once a week for eight weeks, and most patients were monitored for more than a year afterwards. In 64 per cent of patients given Gendicine there was complete regression of primary tumours, a rate three times as great as that in the radiotherapy-only group. Peng hopes the virus will work against other kinds of cancers too.
Simple is better
The only side effect, he says, was fever in around a third of
patients. He does not expect any long-term adverse effects because
the virus does not integrate into the genome of cells - unlike the
viruses used in the French gene therapy trial halted in 2002 after
two boys developed leukaemia.
Anderson, who has agreed to become an unpaid adviser to SiBiono, says the company's adenovirus is relatively simple compared with the gene-delivery systems being developed in the west. "But sometimes simple is better," he says. A dose will cost just 3000 yuan ($360), Peng told New Scientist, and can easily be administered by any doctor. The development has been hailed in China as another sign of how the country is forging ahead in scientific research. However, the approval of Gendicine is also likely to provoke criticism from western researchers who think it is too early to bring gene therapy to patients, especially after such a small trial.
With 300,000 new cases of head and neck squamous cancers each year, China clearly thinks the benefits outweigh the risks. If Gendicine proves successful, SiBiono plans to launch the therapy in south-east Asia before seeking approval elsewhere.
Sylvia Pagán Westphal
http://www.nbsc.com
MTNEWS RELEASE NEW BRUNSWICK SCIENTIFIC CO.,
INC.
BOX 4005 o 44 TALMADGE RD. o EDISON, NJ 08818-4005 o 732-287-1200
FAX 732-287-4222 o Internet: http://www.nbsc.com o E-mail:
bioinfo@nbsc.com
Samuel Eichenbaum Mike Sattan
The World's First Commercially-Licensed Gene Therapy Drug
Produced
In NBS CelliGen Plus® Packed-Bed Bioreactor
Edison, NJ -- November 5, 2003 &endash; New Brunswick Scientific Co., Inc. (NBS) (NASDAQ: NBSC) announced today that approval to produce the world's first commercially-licensed gene therapy medication, a treatment for head and neck squamous cell carcinoma (HNSCC), has been granted to the Shenzhen SiBiono Gene Technologies Co. Ltd. (SiBiono) using New Brunswick Scientific's CelliGen® Plus bioreactor. The drug license was issued on October 16th, 2003 by the State Food and Drug Administration of China after more than five years of clinical trials, providing hope to about 300,000 new patients in China who are diagnosed with this malignancy each year. HNSCC predominantly strikes men after age 50, and until now prognosis for survival had been poor, despite combined surgery and chemotherapy or radiation therapy. Marketed under the name "Gendicine", SiBiono's new drug is expected to become commercially available in January 2004, and with further testing, may prove effective in treating a wide range of cancers. It is the first gene therapy drug in the world approved for sale in what is predicted to be a $100 million market in 2004. SiBiono, founded in 1998, specializes in the development of gene therapy products for the treatment of a variety of cancers and cardiovascular diseases. Their new 16,000 square foot cGMP (current good manufacturing practices)-compliant facility is equipped with expert staff and state-of-the-art equipment.
This new injectable medication, developed using an adenoviral vector, was first produced in roller bottles and parallel-plate reactor systems, before being approved for production using the NBS CelliGen Plus cGMP-compliant packed-bed perfusion bioreactor. According to Dr. Zhaohui Peng, SiBiono's founder and CEO, "NBS' packed-bed bioreactor was selected because of its ability to produce extremely high quantities of secreted products, as many as 2 x 1015 viral particles using a 14 L autoclavable vessel". NBS senior cell culture scientist and principal designer of the packed-bed basket, Dr. Guozheng Wang, explained that the CelliGen Plus utilizes Fibra-Cel® disks, a cell growth support matrix, which provides a very high surface area-to-volume ratio, enabling higher yields of biomass and therefore secreted products than competing microcarrier systems. The packed-bed design provides a low-shear, highly-oxygenated environment to facilitate cell growth, and is currently available in 2.2 &endash; 130 liter configurations.
About Gendicine
Gendicine was used in clinical trials on patients with late-stage HNSCC. After 8 weeks of therapy involving 1 injection per week, 64% of patients' tumors experienced complete regression and 32% experienced partial regression. In combination with chemo- and radiotherapy, Gendicine improved treatment efficacy more than 3-fold. Over more than three years of follow-up, no patient relapsed. Unlike the gene therapies using retroviral vector delivery systems which led to complications, and ultimately the halt of further clinical trials in the US, Gendicine uses an adenoviral vector + p53 tumor suppressor gene delivery system, with the only side effect being grade I or II self-limited fever.
Applications for gene therapy are far-reaching, with the potential to eventually cure diseases such as cancers, coronary artery disease, genetic diseases, AIDS and other health problems. With only a decade of clinical trials as its history, gene therapy has built enormous momentum in the fields of medicine and healthcare, because of its ability to precisely deliver therapeutic genes at the site of the disease and express the therapeutic protein. This precise localization of therapeutics is thought to be among the most effective means to guarantee sufficient levels of the therapeutics in the target tissue of the patient, without the risk of toxicity elsewhere in the body.
David Freedman, New Brunswick Scientific's Chairman and CEO, summarized this groundbreaking news by stating, "our cell culture technology has been well received throughout the world and has been successfully used to produce a large variety of antibiotics, vaccines and other products within the pharmaceutical and immunology fields. We are very proud that our equipment played a part in this latest, exciting medical breakthrough."
New Brunswick Scientific Co., Inc. designs and manufactures a wide variety of research equipment and scientific instruments for the life sciences with particular orientation towards equipment used to develop and manufacture vaccines, antibiotics and therapeutic products for human and animal healthcare.
2
This press release includes statements that may constitute
forward-looking statements made pursuant to the Safe Harbor provision
of the Private Securities Litigation Reform Act of 1995. This
information may involve risks and uncertainties that could cause
actual results to differ materially from the forward-looking
statements. Although the Company believes that the expectations
reflected in such forward-looking statements are based on reasonable
assumptions, such statements are subject to risks and uncertainties
that could cause actual results to differ materially from those
projected. Further information concerning risk factors is described
in the Company's Securities and Exchange Commission filings.
o Dr. Zhaohui Peng, E-mail: zhpeng@sibiono.com
o NBS CelliGen Plus Packed-Bed Bioreactor &endash; www.nbsc.com/gt.htm
www.laboratorytalk.com/news/new/new108.html
Case study/Application note received on 7 November 2003
from New Brunswick Scientific (UK) (contact details)
World's first gene therapy medicine
Approval to produce the world's first commercially-licensed gene therapy medication, a treatment for head and neck squamous cell carcinoma, has been granted to SiBiono
New Brunswick Scientific reports that approval to produce the world's first commercially-licensed gene therapy medication, a treatment for head and neck squamous cell carcinoma (HNSCC), has been granted to the Shenzhen SiBiono Gene Technologies (SiBiono) using New Brunswick Scientific's CelliGen Plus bioreactor.
The drug license was issued on 16 October 2003 by the State Food and Drug Administration of China after more than five years of clinical trials, providing hope to about 300,000 new patients in China who are diagnosed with this malignancy each year.
HNSCC predominantly strikes men after age 50, and until now prognosis for survival had been poor, despite combined surgery and chemotherapy or radiation therapy.
Marketed under the name Gendicine, SiBiono's new drug is expected to become commercially available in January 2004, and with further testing, may prove effective in treating a wide range of cancers. It is the first gene therapy drug in the world approved for sale in what is predicted to be a $100 million market in 2004.
SiBiono, founded in 1998, specialises in the development of gene therapy products for the treatment of a variety of cancers and cardiovascular diseases. Their new 16,000 square foot cGMP (current good manufacturing practices)-compliant facility is equipped with expert staff and state-of-the-art equipment.
This new injectable medication, developed using an adenoviral vector, was first produced in roller bottles and parallel-plate reactor systems, before being approved for production using the NBS CelliGen Plus cGMP-compliant packed-bed perfusion bioreactor. According to Zhaohui Peng, SiBiono's founder and CEO, "NBS's packed-bed bioreactor was selected because of its ability to produce extremely high quantities of secreted products, as many as 2x1015 viral particles using a 14L autoclavable vessel".
NBS senior cell culture scientist and principal designer of the packed-bed basket, Guozheng Wang, explained that the CelliGen Plus utilises Fibra-Cel disks, a cell growth support matrix, which provides a very high surface area-to-volume ratio, enabling higher yields of biomass and therefore secreted products than competing microcarrier systems.
The packed-bed design provides a low-shear, highly-oxygenated environment to facilitate cell growth, and is currently available in 2.2 - 130litre configurations.
http://www.china.org.cn/english/China/78182.htm
First Gene Therapy Medicine on Sale Soon
A gene therapy medicine made in Shenzhen obtained a drug license from China's State Food and Drug Administration (SFDA) Oct. 16 and is expected to hit the market early next January.
Called Gendicine, the new drug is being produced by Shenzhen SiBiono GeneTech Co., Ltd. It is expected to be effective in the treatment of a range of diseases including cancer, some genetic diseases, cardiovascular diseases and AIDS. It is claimed to be the first gene therapy medicine in the world. The news was released at a press conference held in Wuzhou Guesthouse on Wednesday.
Many scientific research organizations from home and abroad have congratulated Dr. Peng Zhaohui, chairman and CEO of SiBiono. W. French Anderson, reputed to be the father of gene therapy who leads the Gene Therapy Laboratories in the United States, also sent his congratulations to Dr. Peng.
Dr. Wang, president of the Sino-American Pharmaceutical Professionals Association West Regional Branch, said in his congratulation letter: "This is indeed a great breakthrough in the biotech industry and I was very excited to hear this good news."
Dr. Peng has devoted himself to gene therapy research since 1990. On Christmas Eve, 1997, Peng returned from the United States and established SiBiono in Shenzhen later in 1998. As a lead product of SiBiono, Gendicine has undergone clinical trials for four years and the results have been successful. Most of the patients involved in the trials were nasopharyngeal cancer patients.
(Shenzhen Daily October 23, 2003)
http://science.orf.at/science/news/97437
China genehmigt weltweit erste Gentherapie
Als erstes Land der Welt hat China ein Medikament für die kommerzielle Anwendung genehmigt, das eine krankhafte genetische Veränderung beim Menschen heilen soll - und zwar bei einer bestimmten Krebsart.
Die chinesischen Gesundheitsbehörden lizensierten bereits im Oktober eine Therapie zur Behandlung bestimmter Tumore im Kopf- und Halsbereich, wie das britische Wissenschaftsmagazin "New Scientist" am Mittwoch berichtete.
"p53" entscheidend bei Tumoren im Kopf- und Halsbereich
Diese Tumorarten lassen sich dem Bericht zufolge in 60 Prozent der Fälle auf eine Veränderung des Gens p53 zurückführen, das ein unkontrolliertes Zellwachstum auslöst. Das Biotech-Unternehmen SiBiono aus der südchinesischen Wirtschaftsmetropole Shenzhen in der Provinz Guangdong soll ab Jänner kommenden Jahres das Präparat Gendicine kommerziell vertreiben dürfen, das diesen Gendefekt beheben soll.
Viren als Vehikel, Kosten: 300 Euro
Bei der Behandlung mit Gendicine wird dem Patienten ein therapeutisches Virus gespritzt, in das ein gesundes p53-Gen geschleust wurde, wie "New Scientist" weiter berichtete. Mit Hilfe der Viren als Vehikel lassen sich die Gene dann an die erkrankten Zellen transportieren. Eine Behandlungsdosis soll 3.000 Yuan (rund 300 Euro) kosten und könne von jedem Arzt leicht verabreicht werden, heißt es in dem Bericht.
Studie: Dreimal höhere Heilungsquote - repräsentativ?
In der größten klinischen Studie mit Gendicine wurden 120 Patienten mit Tumoren an Nase oder im Rachenbereich in zwei Gruppen behandelt, berichtete "New Scientist" weiter. Die eine erhielt eine reine Strahlentherapie, der zweiten Gruppe wurde zusätzlich das Gentherapie-Präparat verabreicht. Nach der Behandlung zeigten die Patienten der zweiten Gruppe eine dreimal höhere Heilungsquote. Nach westlichen Standards gilt diese Studie aber als nicht repräsentativ. Das Magazin aber zitierte den US-Gentherapiespezialisten French Anderson, der nach eigenen Woten unentgeltlich für SiBiono als Berater tätig ist, mit den Worten: "Dies war keine leichtfertige Genehmigung. Dem ging eine ernsthafte und gründliche Analyse voraus."
Bisher eher bescheidene Erfolge
In Nordamerika und Europa ist die Anwendung von Gentherapien ausgesprochen umstritten. Bisherige klinische Versuche wurden nur an kleinen Patientengruppen gestattet und führten bisweilen zu schweren Misserfolgen. In den USA etwa starb 1999 der 18-Jährige Jesse Gelsinger nach einer Gentherapiean Organversagen. 2002 wurde in Frankreich die Gentherapieeines so genannten schweren kombinierten Immundefekts (SCID) bei Babys gestoppt, nachdem sich bei zwei der kleinen Patienten eine Leukämie-ähnliche Erkrankung gezeigt hatte.
http://de.news.yahoo.com/031126/286/3rxvt.html
London (AFP)
China genehmigt weltweit erste Gentherapie
Als erstes Land der Welt hat China eine Medikament genehmigt, das einen krankhafte genetische Veränderung beim Menschen heilen soll. Bereits im Oktober lizensierten die chinesischen Gesundheitsbehörden eine Therapie zur Behandlung bestimmter Tumore im Kopf- und Halsbereich, berichtet das Wissenschaftsmagazin "New Scientist". Diese Tumorarten lassen sich dem Bericht zufolge in 60 Prozent der Fälle auf eine Veränderung des Gens p53 zurückführen, das ein unkontrolliertes Zellwachstum auslöst. Das Biotech-Unternehmen SiBiono soll ab Januar das Präparat Gendicine kommerziell vertreiben dürfen, das diesen Gendefekt beheben soll.
Bei der Behandlung mit Gendicine wird dem Patienten ein therapeutisches Virus gespritzt, in das ein gesundes p53-Gen geschleust wurde, wie "New Scientist" weiter berichtete. Mit Hilfe der Viren als Vehikel lassen sich die rettenden Gene dann an die erkrankten Zellen transportieren. Eine Behandlungsdosis soll 3000 Yuan (gut 300 Euro) kosten und könne von jedem Arzt leicht verabreicht werden.
In der größten klinischen Studie mit Gendicine wurden 120 Patienten mit Tumoren an Nase oder im Rachenbereich in zwei Gruppen behandelt, berichtete "New Scientist" weiter. Die eine erhielt eine reine Strahlentherapie, der zweiten Gruppe wurde zusätzlich das Gentherapie-Präparat verabreicht. Nach der Behandlung zeigten die Patienten der zweiten Gruppe eine dreimal höhere Heilungsquote.
Nach westlichen Standards gilt diese Studie als nicht repräsentativ. Das Magazin indes zitierte den US-Gentherapiespezialisten French Anderson, der nach eigenen Woten unentgeltlich für SiBiono als Berater tätig ist, mit den Worten: "Dies war keine leichtfertige Genehmigung. Dem ging eine ernsthafte und gründliche Analyse voraus."
In Nordamerika und Europa ist die Anwendung von Gentherapien ausgesprochen umstritten. Bisherige klinische Versuche wurden nur an kleinen Patientengruppen gestattet und führten bisweilen zu schweren Misserfolgen. In den USA etwa starb 1999 der 18-Jährige Jesse Gelsinger nach einer Gentherapie an Organversagen. 2002 wurde in Frankreich die Gentherapie eines so genannten schweren kombinierten Immundefekts (SCID) bei Babys gestoppt, nachdem sich bei zwei der kleinen Patienten eine Leukämie-ähnliche Erkrankung gezeigt hatte.
http://www.washtimes.com/upi-breaking/20031126-053535-5743r.htm
SHENZHEN, China, Nov. 26 (UPI)
China to begin gene-based cancer therapy
China has officially approved a new gene-based cancer therapy it says achieved promising results in clinical trials.
New Scientist magazine reported Wednesday the treatment, called gendicine, will be launched commercially in January by SiBiono GeneTech of Shenzhen, in China's Guangdong province. The results of the clinical trials are expected to be published next month in China's national medical journal.
Gendicine's approval was announced more than a month ago, but went largely unnoticed outside China. However, French Anderson of the University of Southern California, a renowned gene therapy pioneer, visited SiBiono earlier this year and also met the head of the Chinese drug approval agency. Said Anderson: "The Chinese did evaluate this in considerable detail, so this was not a trivial approval. This was a serious in-depth analysis."
The treatment consists of an adenovirus designed to insert a gene called p53. This gene codes for a protein that triggers cell suicide when cells start to run amok, preventing them becoming cancerous.
http://www.gesundheit.de/static/news/031126190944.ojc6i7kh.shtml
29.11.03
China genehmigt weltweit erste Gentherapie
- Präparat Gendicine soll bestimmte Krebsarten heilen
Als erstes Land der Welt hat China eine Medikament genehmigt, das einen krankhafte genetische Veränderung beim Menschen heilen soll. Bereits im Oktober lizensierten die chinesischen Gesundheitsbehörden eine Therapie zur Behandlung bestimmter Tumore im Kopf- und Halsbereich, berichtet das Wissenschaftsmagazin "New Scientist". Diese Tumorarten lassen sich dem Bericht zufolge in 60 Prozent der Fälle auf eine Veränderung des Gens p53 zurückführen, das ein unkontrolliertes Zellwachstum auslöst. Das Biotech-Unternehmen SiBiono soll ab Januar das Präparat Gendicine kommerziell vertreiben dürfen, das diesen Gendefekt beheben soll.
Bei der Behandlung mit Gendicine wird dem Patienten ein therapeutisches Virus gespritzt, in das ein gesundes p53-Gen geschleust wurde, wie "New Scientist" weiter berichtete. Mit Hilfe der Viren als Vehikel lassen sich die rettenden Gene dann an die erkrankten Zellen transportieren. Eine Behandlungsdosis soll 3000 Yuan (gut 300 Euro) kosten und könne von jedem Arzt leicht verabreicht werden.
In der größten klinischen Studie mit Gendicine wurden 120 Patienten mit Tumoren an Nase oder im Rachenbereich in zwei Gruppen behandelt, berichtete "New Scientist" weiter. Die eine erhielt eine reine Strahlentherapie, der zweiten Gruppe wurde zusätzlich das Gentherapie-Präparat verabreicht. Nach der Behandlung zeigten die Patienten der zweiten Gruppe eine dreimal höhere Heilungsquote.
Nach westlichen Standards gilt diese Studie als nicht repräsentativ. Das Magazin indes zitierte den US-Gentherapiespezialisten French Anderson, der nach eigenen Woten unentgeltlich für SiBiono als Berater tätig ist, mit den Worten: "Dies war keine leichtfertige Genehmigung. Dem ging eine ernsthafte und gründliche Analyse voraus."
In Nordamerika und Europa ist die Anwendung von Gentherapien ausgesprochen umstritten. Bisherige klinische Versuche wurden nur an kleinen Patientengruppen gestattet und führten bisweilen zu schweren Misserfolgen. In den USA etwa starb 1999 der 18-Jährige Jesse Gelsinger nach einer Gentherapie an Organversagen. 2002 wurde in Frankreich die Gentherapie eines so genannten schweren kombinierten Immundefekts (SCID) bei Babys gestoppt, nachdem sich bei zwei der kleinen Patienten eine Leukämie-ähnliche Erkrankung gezeigt hatte.
© AFP Agence-France-Presse GmbH / Powered by Cocomore
http://www.3sat.de/3sat.php?http://www.3sat.de/nano/news/53666/
28.11.03
China genehmigt erste Gentherapie
"Gendicine" soll Krebs heilen
Als erstes Land der Welt hat China eine Medikament genehmigt, das einen krankhafte genetische Veränderung beim Menschen heilen soll. Das berichtet das britische Wissenschaftsmagazin "New Scientist".
In aller Stille lizensierten die chinesischen Gesundheitsbehörden bereits im Oktober eine Therapie zur Behandlung bestimmter Tumore im Kopf- und Halsbereich. Diese Tumorarten lassen sich dem Bericht zufolge in 60 Prozent der Fälle auf eine Veränderung des Gens p53 zurückführen, das ein unkontrolliertes Zellwachstum auslöst. Das Biotech-Unternehmen SiBiono aus der südchinesischen Wirtschaftsmetropole Shenzhen in der Provinz Guangdong soll ab Januar das Präparat Gendicine kommerziell vertreiben dürfen, das diesen Gendefekt beheben soll.
Bei der Behandlung mit Gendicine wird dem Patienten ein therapeutisches Virus gespritzt, in das ein gesundes p53-Gen geschleust wurde, wie "New Scientist" weiter berichtete. Mit Hilfe der Viren als Vehikel lassen sich die rettenden Gene dann an die erkrankten Zellen transportieren.
Eine Behandlungsdosis soll 3000 Yuan (gut 300 Euro) kosten und könne von jedem Arzt leicht verabreicht werden, heißt es in dem Bericht. In der größten klinischen Studie mit Gendicine wurden 120 Patienten mit Tumoren an Nase oder im Rachenbereich in zwei Gruppen behandelt, berichtete "New Scientist" weiter. Die eine erhielt eine reine Strahlentherapie, der zweiten Gruppe wurde zusätzlich das Gentherapie-Präparat verabreicht. Nach der Behandlung zeigten die Patienten der zweiten Gruppe eine dreimal höhere Heilungsquote. Nach westlichen Standards gilt diese Studie als nicht repräsentativ.
Das Magazin indes zitierte den US-Gentherapiespezialisten French Anderson, der nach eigenen Worten unentgeltlich für SiBiono als Berater tätig ist, mit den Worten: "Dies war keine leichtfertige Genehmigung. Dem ging eine ernsthafte und gründliche Analyse voraus." In Nordamerika und Europa ist die Anwendung von Gentherapien ausgesprochen umstritten.
Bisherige klinische Versuche wurden nur an kleinen Patientengruppen gestattet und führten bisweilen zu schweren Misserfolgen. In den USA etwa starb 1999 der 18-Jährige Jesse Gelsinger nach einer Gentherapie an Organversagen. 2002 wurde in Frankreich die Gentherapie eines so genannten schweren kombinierten Immundefekts (SCID) bei Babys gestoppt, nachdem sich bei zwei der kleinen Patienten eine Leukämie-ähnliche Erkrankung gezeigt hatte.
<http://www.3sat.de/images/tStrich.gif>
28.11.2003
http://www.sciencepresse.qc.ca/archives/2003/cap0112038.html
Le 3 décembre 2003
Thérapie génique: avantage à la Chine
(Agence Science-Presse) - Tandis que plusieurs pays s'interrogent sur l'avenir et les risques de la thérapie génique, la Chine fonce: en janvier 2004, elle sera la première nation à disposer d'une thérapie génique dûment approuvée par ses autorités médicales.
Bien que différentes thérapies géniques fassent l'objet d'essais cliniques depuis 1990, aucune n'a en effet été jugée assez sécuritaire pour approbation. Des dérives et même des décès ont, en 2001-2003, refroidi les ardeurs des plus enthousiastes promoteurs de cette stratégie extrêmement complexe et risquée (lire Le naufrage de la thérapie génique).
La thérapie génique consiste à corriger un gène défectueux directement dans les cellules du corps.
La Food and Drug Administration chinoise a autorisé le traitement en octobre, mais la nouvelle n'a trouvé écho dans les médias occidentaux que tout récemment, sur le site du magazine britannique The New Scientist. Il s'agit d'une thérapie anti-cancer appelée Gendicine. Elle a été mise au point par le docteur Peng Zhaohui qui travaille sur les thérapies géniques depuis 1990.
La Gendicine permettrait de corriger le gène p53, dont la mutation ou l'inactivation est la cause de nombreux cancers. Ce gène a pour rôle premier d'ordonner le suicide de toute cellule anormale; s'il n'agit pas, cette cellule peut donc proliférer, créant du fait même une tumeur. La Gendicine, qui est en fait un adénovirus modifié, pénètre dans les cellules pour y introduire une copie normale de ce gène p53.
Lors des essais cliniques, qui ont porté sur 120 patients, ceux qui ont reçu le traitement à la Gendicine en association avec la radiothérapie ont vu leur tumeur disparaître dans 64 % des cas, soit trois fois mieux qu'avec la seule radiothérapie. La plupart souffraient d'un cancer du nasopharynx, un cancer particulièrement fréquent en Chine. Ces résultats seront publiés en décembre dans le journal médical national de Chine.
Malgré ces résultats encourageants, la Chine est-elle allée trop vite? Interrogé par le New Scientist, le Dr French Anderson, pionnier de la thérapie génique, qui s'est rendu sur place, répond: "ce n'est pas une approbation faite à la légère; il s'agit d'une sérieuse analyse en profondeur. "
Les expériences interrompues en Europe en 2002 (voir ce texte) utilisaient des rétrovirus. Le docteur Peng Zhaohui assure que son adénovirus ne s'intègre pas à l'ADN des cellules humaines, ce qui diminuerait les risques d'effets indésirables à long terme.
La Chine donne donc une raison supplémentaire à l'Occident de tourner les yeux vers le soleil levant...
http://www.medpoint.ch/frame.asp?ru=dokument&ArtikelID=15023
Mo 8. Dez. 2003
MEDIKAMENT
China: Gendicine zur Behandlung von Krebserkrankungen zugelassen
Erstmals wurde einem auf Gentherapie basierenden Behandlungsverfahren von offiziellen Stellen die Genehmigung zum Einsatz erteilt. Laut Newscientist hat die chinesische Bundesbehörde zur Überwachung von Nahrungs- und Arzneimitteln (SFDA) Gendicine nach viel versprechenden Ergebnissen in klinischen Tests zur Behandlung von Krebserkrankungen zugelassen.
Die Ergebnisse der Studie sollen im nächsten Monat in einer nationalen chinesischen Fachzeitschrift veröffentlicht werden. Eine Übersetzung ins Englische ist angekündigt. Im Januar nächsten Jahres wird Gendicine von SiBiono GeneTech auf den Markt gebracht.
Die Behandlung besteht aus einem Adenovirus, der für das Einfügen des Gens p53 vorgesehen ist. Dieses Gen kodiert ein Protein, das den Zelltod bei unkontrolliertem Wachstum auslöst und verhindert so, dass sie kanzerös werden. SiBiono entschied das neue Verfahren bei Plattenepithelkarzinomen im Kopf- und Nackenbereich zu testen. p53 verfügt bei über 60 Prozent dieser Tumore über Mutationen. Es handelt sich dabei um eine Krebsform, die in China besonders verbreitet ist.
Am grössten klinischen Versuch nahmen 120 Patienten mit nasopharyngealem Krebs teil. Sie erhielten entweder nur eine Strahlenbehandlung oder eine Kombination von Gendicine und Strahlenbehandlung. Die p53 tragenden Viren wurden acht Wochen lang wöchentlich direkt in die Tumore injiziert. Die meisten Teilnehmer wurden anschliessend mehr als ein Jahr lang beobachtet. Bei 64 Prozent der Patienten führte Gendicine zu einer kompletten Regression der primären Tumore. Dieser Wert war drei Mal so hoch wie bei der Gruppe, die nur eine Bestrahlung erhalten hatte.
Der Chef des Unternehmens Zhaohui Peng hofft, dass das Virus auch bei anderen Krebsarten wirksam ist. Als einzige Nebenwirkung wurde bei rund einem Drittel der Patienten Fieber beobachtet. Nachdem das Virus nicht in das Genom von Zellen integriert wird, sei auch nicht mit Langzeitbeeinträchtigungen zu rechnen. Eine Dosis wird laut Peng 360 Dollar kosten und kann einfach durch jeden Arzt verabreicht werden.
FACTS: 4.12.2003
Premiere aus Fernost: Krebs In China kommt die erste
Gentherapie
zur Tumor-Behandlung auf den Markt. Die westliche Fachwelt ist
skeptisch.
Von Odette Frey
GEN-FÄHRE: Das Erkältungsvirus wird zusammen mit dem Therapie-Gen den Krebspatienten gespritzt.
Wenn die Verheissung stimmt, steht eine Sensation bevor: Eine chinesische Firma namens Sibiono Genetech will im Januar die weltweit erste Gentherapie zur Krebsbehandlung auf den Markt bringen. Von ihr sollen Patienten profitieren, die an einem Tumor im Hals-Nasen-Ohren- Bereich erkrankt sind.
Gentherapie, eine Behandlung, bei der den Patienten gesundes Erbmaterial injiziert wird, weckte in den Neunzigerjahren grosse Hoffnungen unter Medizinern. Menschen mit Erbkrankheiten wie Diabetes- Typ-1, aber auch mit Leiden wie Alzheimer oder eben Krebs, könnten geheilt werden, lautete die These. Doch obwohl die Genmedizin seit über zehn Jahren an Patienten getestet wird, ist der grosse Durchbruch ausgeblieben. Die Genmediziner mussten gar herbe Rückschläge einstecken: 1999 starb in den USA der 18-jährige Jesse Gelsinger an den Nebenwirkungen, und in diesem Jahr löste die experimentelle Behandlung bei zwei Kindern an einem Pariser Spital Leukämie aus.
In die gedämpfte Stimmung platzt nun die Nachricht aus Fernost. Bereits vor einigen Wochen, berichtet das britische Wissenschaftsmagazin «New Scientist» in seiner neusten Ausgabe, habe die chinesische Gesundheitsbehörde grünes Licht für die Gentherapie gegeben. In klinischen Tests war die Methode, die zusätzlich zur normalen Bestrahlung angewandt wurde, bei 64 Prozent der Patienten erfolgreich. Ihre Tumore verschwanden. Ohne Genspritze verbesserte sich der Zustand nur bei jedem fünften Kranken. Gewicht erhalten die Behauptungen von Sibiono durch den kalifornischen Gentherapie- Pionier French Anderson, der als wissenschaftlicher Berater der Firma fungiert. «Die chinesischen Behörden haben das genau geprüft», sagt er.
Schweizer Gentherapie-Experten sind skeptisch. Zwar ist das Prinzip der Sibiono-Therapie auch im Westen bekannt: Beim verabreichten Erbmaterial handelt es sich um das p53-Gen, das die Selbstzerstörung von Krebszellen bewirkt. Es soll das bei vielen Krebspatienten defekte p53 ersetzen. Zusammen mit den Therapie-Genen werden Erkältungsviren, so genannte Adenoviren, gespritzt, die das p53 in die Zellen einschleusen. DOCH DIE ERFOLGE waren bis anhin gering. So testeten Mediziner am Berner Inselspital vor einigen Jahren ein solches Gen- Viren-Konstrukt an Patienten. «Bei den meisten hat es nichts gebracht», sagt Onkologe Martin Fey. «Nur bei wenigen wurde der Tumor kleiner.» Das Projekt wurde darauf sistiert.
Auch Sandro Rusconi von der Universität Freiburg, der das Nationalfondsprogramm «Somatische Gentherapie» leitete, reagiert verhalten: «In der Vergangenheit war das Problem der Gentherapie, dass man zu früh zu viel versprochen hat. Das hat den Ruf des Gebietes ruiniert.» Bevor die chinesischen Forscher die Details ihrer Daten nicht der westlichen Fachwelt unterbreiten und damit überprüfbar machen, wollen weder Fey noch Rusconi in den Triumphchor aus Fernost einstimmen.
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nbt/journal/v22/n1/full/nbt0104-3.html
3 January 2004 Volume 22 Number 1 pp 3 - 4
China approves first gene therapy
Sue Pearson, Hepeng Jia & Keiko Kandachi
China became the first country to approve the commercial production of a gene therapy, and it is due to hit the market in early January. Despite technical hurdles and the wary attitude of regulatory authorities outside China, other countries are expected to soon follow suit.
On October 16, 2003, Shenzhen SiBiono GenTech (Shenzhen, China), obtained a drug license from the State Food and Drug Administration of China (SFDA; Beijing, China) for its recombinant Ad-p53 gene therapy for head and neck squamous cell carcinoma (HNSCC)&emdash;a cancer that accounts for about 10% of the 2.5 million annual new cancer patients in China. Sold under the brand name Gendicine, the world's first commercial gene therapy uses an adenoviral vector and cost the company more than RMB 80 ($9.6) million to develop in addition to research grants they received from government.
"We have had more than five years of clinical trials, and the only side effect of Gendicine is self-limited fever," says Zhaohui Peng, chairman and CEO of SiBiono. After eight weeks of a joint treatment of radiotherapy and weekly gene therapy injections, 64% of late-stage HNSCC tumors experienced complete regression and 32% experienced partial regression.
"SiBiono's approach is not a trivial one," Jean-François Carmier, CEO of Transgene (Strasbourg, France) comments. "Introgen has been using a similar strategy for head and neck cancer and their product is showing encouraging results in Phase 3 trials" (see Table 1).
The success of SiBiono was in overcoming difficulties in developing the right system for delivering its adenoviral vector&emdash;considered an effective way of introducing a gene into tumor cells&emdash;without integrating the gene in the host cells' chromosomes and creating genetic alterations. SiBiono has addressed safety concerns by carefully dosing the injection (injecting a weekly dose of 1 1012 viral particles) and closely monitoring reactions of participants during the clinical trials and subsequently following up with them for one to five years, according to Peng.
So why did the first commercial gene therapy treatment get produced and approved in China? "In China, where hundred of thousands die of diseases such as cancer without access to the clinical opt-ions available to patients in the US and Europe, the potential for a one-time treatment that is relatively simple to administer is very appealing," says Mark Kay, a director of the human gene therapy program at Stanford University (Stanford, CA, USA). Size matters as well. "Due to its large population, the Chinese can recruit enough patients for a trial in a short time and can therefore generate statistically significant amounts of clinical data very rapidly," says Carmier.
And because China has not been blighted by failure&emdash;as happened in the United States with the death of Jesse Gelsinger of an inherited nitrogen metabolism disorder (Nat. Biotechnol. 18, 1136 2000) and more recently in Europe with the X-linked, severe combined immunodeficiency syndrome trials (Nat. Biotechnol. 21, 121, 2003)&emdash;the Chinese regulatory authorities may be more receptive to the technology.
But some suggest that the regulatory process is much more lax in China than elsewhere. "The recently approved gene therapy in China had only 120 people in clinical trials, whereas the same therapy in the US has hundreds of people and yet it has not been approved," says Hitoshi Kotani, senior vice president of gene therapy firm AnGes MG (Osaka, Japan).
But Peng refutes Genedicine was approved because of the allegedly looser regulation of the Chinese authorities, a sentiment that is echoed by Peng Shang, vice director of cell engineering research center at the Fourth Military Medical University (Xi'an, China). "In fact, the SFDA had a routine practice not to approve any new kind of medicine if the kind of drug was not authorized by the US FDA," Shang says. Peng has been lobbying SFDA for years and the agency gradually changed its attitude since early this year, as shown by the approval of the new gene therapy and, on November 22, by giving a green light to clinical trails for a new SARS vaccine developed by Sinovac (Beijing).
Many scientists involved in gene therapy say there are no major regulatory issues in the US and Europe preventing gene therapy trials from getting the go ahead. Massimo Cristofanilli, associate professor at the University of Texas M.D. Anderson Cancer Center, (Houston), a principle investigator of Introgen's Advexin to treat breast cancer, agrees: "The process for getting gene therapy into clinic in the US is conservative. The concerns with safety are stringent but also fair."
By comparison, clinical trials for gene therapy in Japan could take longer than a regular treatment. The Ministry of Health, Labor and Welfare (Tokyo, Japan) requires A "confirming application" (referring to basic quality of the medicine and results of animal experiments) in addition to the standard application for clinical trials. And healthy humans usually won't take part in phase 1 clinical trials because of the higher risk involved with an experimental therapy.
Whatever the reason China was first to approve a gene therapy, this success story can only help make the technology become more accepted.
http://www.bioscinews.com/files/news-detail.asp?newsID=6771
August 1, 2004
First gene therapy medicine hits market this month
The world's first gene therapy medicine Genedicine will hit the market in China this month, according to top company sources.
Gene therapy uses new genes to curb the growth of tumor cells.
"We got sales permission from the State Food and Drug Administration (SFDA) in late January and the drug Genedicine will be available for cancer therapy in grade A level hospitals this month," said Peng Zhaohui, chairman of Shenzhen SiBiono Gene Technologies Co Ltd. SiBiono developed the world's first gene therapy medicine, which is called Recombinant Ad-p53 Anti-cancer Injection, also known as Genedicine. This new injectable medication, uses an adenoviral vector and p53 tumor suppressor gene. It is a new treatment for head and neck cancer, also called squamous cell carcinoma (HNSCC).
Gendicine was used in clinical trials on patients with late-stage HNSCC. After eight weeks of therapy involving one injection per week, about 64 per cent of patients' tumors experienced complete regression and 32 per cent experienced partial regression. In combination with chemo- and radiotherapy, Gendicine improved treatment efficacy more than 3-fold.
The new drug will be sold at around 3,000 yuan (US$362) per injection. An average cancer patient needs to use six to eight injections, Peng told China Business Weekly during an exclusive interview last week. The annual gene therapy market worldwide is expected to reach US$9.9 billion by 2007. In China, the annual market for the therapy was at least 4 billion yuan (US$483 million) at the beginning, Peng estimated.
In China, there are 2.5 million new cancer patients and 7 million are treated every year. Peng estimated that 3 per cent of the 7 million cancer patients would try Genedicine, as there is no other competitive drug in the Chinese market. But the privileged status of Genedicine as the only gene therapy treatment available may not last long. H101 Adenovirus Injection, another biodrug against cancer developed by Shanghai Sunway Biotech Co Ltd is in its third phase of clinical trials. Liang Min, chief scientist of Sunway, told China Business Weekly that H101 is expected to get SFDA drug authorization in a short period.
Other gene therapy medicines in clinical trial in China include Thymidine Kinase Cyto by Shanghai Institute of Cancer, Recombinant Adeno-associated Virus-2 Human Factor by Beijing-based AGTC Gene Technology Co, and Recombinant Interleukin-2 Adenovirus Antitumor Injection by Chengdu Centre of Gene Technologies.
But Peng said that the upcoming competition is not a major threat to Genedicine. Technically, these medicines still need more time to get SFDA approval. SiBiono could utilize the period of time to develop more uses for Genedicine and new products related to the gene therapy medicine. To date there are more than 700 gene therapy medicines in clinical trial but Genedicine is the only one with approval to commercialize.
The appearance of more gene therapy medicines can help doctors and patients understand the concept more clearly, which will benefit Chinese patients as well as gene therapy drug makers in China, Peng said. Another advantage Sibiono has is that many venture capitalists rushed to sign deals with the company after it obtained the drug licence. "The Shenzhen government will support Peng to list Sibiono in NASDAQ. With a good conception of the world's first gene therapy drug, the company is expected to collect tens of millions of dollars," said Zhou Hui, a senior official of Shenzhen government.
Source: China Daily via FDA News, 13 March 2004
The Genesis of Gendicine: The Story Behind the First Gene Therapy
In this BioPharm International exclusive interview, SiBiono's founder relates the science and manufacture of his company's innovative cancer therapy.
By: Zhaohui Peng, BioPharm International
http://www.biopharm-mag.com/biopharm/article/articleDetail.jsp?id=95485&pageID=1&sk=&date=
May 1, 2004
In October 2003, Shenzhen SiBiono GeneTech made history by becoming the first company approved to market a gene therapy medication. China's State Food and Drug Administration (SFDA) approved Gendicine for treatment of head and neck squamous cell carcinoma (HNSCC). SiBiono believes that continued clinical trials will prove Gendicine to be effective as a wide-spectrum anticancer agent.
In March, BioPharm International interviewed Dr. Zhaohui Peng, SiBiono's founder, chairman, and CEO, to learn more about the science behind gene therapy, the clinical experience with Gendicine, and the processes involved in manufacturing this ground-breaking new therapy. An English translation of "Points to Consider for Human Gene Therapy and Product Quality Control," a technical guide for gene therapy research, development, and commercialization written by SiBiono and adopted by the SFDA, can be found here.
Table 1. Production Apparatus Comparison
In addition to a distinguished academic career, Dr. Peng served as director of a research institute at The First Medical University in Guangzhou and as a visiting professor at both the University of Chiba in Japan and the University of California. He also conducted research at two US biotech companies. Dr. Peng has devoted more than ten years to gene therapy research, development, and commercialization.
GENE THERAPY BASICS
BPI: You have used the term adenoviral vector +p53 tumor suppressor-gene delivery system. Will you briefly describe the science behind this?
Peng: Gendicine is a gene therapy product. To be more specific, it is a replication-incompetent, recombinant, human adenovirus of serotype 5 engineered to contain the human wild-type p53 tumor-suppressor gene. The Ad5-p53 virus particles are approximately 90 nm in diameter.
Gendicine is produced using SBN-Cel, which is a cell line that was subcloned from the human embryonic kidney (HEK) cell line 293. Gendicine is a sterile, slightly-white-to-clear liquid. A Gendicine vial contains 1 x 1012 viral particles in 1 mL of WFI (water for injection) buffered with Tris (made by Amresc) and glycerol. We store it frozen in a single-use vial at -20°C.
BPI: What is the role of the p53 gene?
Peng: The p53 gene is one of the most important tumor-suppressor genes existing in normal cells. In normal cells, the expression level of p53 protein is very low. p53 expression is activated upon oncogene activation, growth-factor deprivation, hypoxia, and DNA damage. The upregulation of p53 gene expression occurs at the posttranslational level and is achieved through stabilization of the expressed protein. The activation of p53 gene expression results in either cell cycle arrest or apoptotic cell death.
Table 2. The Initial Clinical Stage of Patients with HNSCC
The p53 gene is mutated or deleted (null) in approximately 50% to 70% of human tumors. Mutant forms of the p53 gene are not necessarily inactive and can gain oncogenic functions that contribute to tumorigenicity. Most importantly, mutant p53 proteins have been associated with the upregulation of the multidrug resistance (MDR) gene, which results in tumor resistance to a variety of chemotherapeutics. Introduction of exogenous wild-type p53 gene and subsequent over-expression of the p53 protein has been shown to control and eliminate tumor cell growth by growth cycle arrest or apoptosis. In addition, over-expresion of wild-type p53 protein has been demonstrated to have a synergistic effect with radiotherapy and chemotherapy.
BPI: What role does the adenoviral vector play?
Peng: Upon intratumor injection, Gendicine binds to the coxsakie adenovirus receptor (CAR) on tumor cells. Subsequently, Gendicine enters tumor cells via receptor-mediated endocytosis and begins to over-express the encoded exogenous p53 gene. The over-expressed p53 protein triggers multiple tumor fighting functions.
First, it induces tumor cell cycle arrest or apoptosis by functioning as a sequence-specific transcriptional-regulator that up-regulates the expression of some anticancer genes and downregulates the expression of some oncogenes. Second, it can directly induce tumor cell apoptosis.
Table 3. Comparison of Tumor Shrink Rates
Third, it can function as a tumor-antigen by stimulating human immune cells (cytotoxic T cells) to selectively kill cancer cells that over-express the p53 gene. It can also activate natural killer cells to kill uninfected cancer cells via bystander effects.
Fourth, the expressed p53 protein can downregulate the expression of vascular endothelial growth factor (VEGF) genes and MDR genes, which are involved in tumor progress, metastasis, and chemo-drug resistance. The expression of p53 gene is not activated in normal cells because its DNA is undamaged, thus minimizing the side effects of Gendicine treatment.
SiBiono and New Brunswick Scientific
MATTERS OF SAFETY
BPI: What are the results of toxicity tests with Gendicine?
Peng: Two groups of rhesus monkeys received intramuscular injections of Gendicine, based on weight, at doses 7.5-fold and 75-fold the proposed clinical dose for 16 successive days. On the 14th day, a neutralizing antibody to Gendicine appeared in all animal sera. A mild pathological effect was observed in kidney tissues in 2 out of the 12 animals at the end of the study. Gendicine can be detected in lung, liver, and kidney tissues by polymerase chain reaction (PCR) analysis. The expressed exogenous p53 protein can be detected by immunohistochemistry analysis in the intestines, lungs, bladders, and kidneys. At three weeks postinjection, the p53 gene and the expressed p53 protein were still detectable in the above-mentioned organs and tissues.
BPI: Did you conduct any genetic toxicology tests?
Peng: In our tests, no genetic toxicity was observed. Results from both a Chinese hamster lung (CHL) cell-chromosome-aberration test and mouse bone-marrow micronucleus assay were negative. Gendicine will not replicate in the infected cells and is incapable of multi-cycle infection and of spreading to the neighboring cells. Therefore, Gendicine will not cause horizontal adenovirus infection or environmental contamination. More importantly, infected adenoviral DNA will not integrate into the human host cell genome. Consequently, Gendicine poses no genetic toxicity.
BPI: What are the distribution and pharmacokinetic parameters?
Peng: In vivo animal studies demonstrated that Gendicine entered tumor cells within one hour after injection, whether administrated locally or systemically. A detectable amount of p53 protein is expressed from the transduced p53 gene at three hours postinjection. The level of p53 protein expression increased to 47% at the 12th hour, reached the highest level (100%) at the 72nd hour, and subsequently descended to 30% at the 120th hour postinjection. However, a detectable amount of p53 protein expression was still observed at the 14th day. At three weeks postinjection, recombinant Gendicine DNA began to diminish and eventually became undetectable. When injected locally, Gendicine is distributed mainly in the local tissues with minimal distribution in other organs and tissues. No Gendicine DNA was detected in excrements of urine, stool, or bile.
CLINICAL TRIALS
BPI: When did you begin researching Gendicine?
Peng: We started in 1989. That is about 14 years ago.
BPI: How have clinical trials proceeded?
Peng: One hundred thirty-five patients with late-stage HNSCC took part in phase 2 and 3 trials during the period from November 2000 to May 2003. The results showed complete regression of tumors in 64% of the patients after eight weekly intratumoral injections of Gendicine in combination with radiation therapy; 29% of the patients experienced partial regression. Among all the patients, about 75% suffered from advanced nasopharyngeal carcinoma, which is a sub-indication of head-and-neck cancer. Statistically, 80% of the worldwide cases are in China. Tables 2, 3, and 4 show our clinical trial results as of October 2002.
Another 240-plus patients with late-stage HNSCC or terminal-stage non-HNSCC tumors were treated with Gendicine during the period from June 2003 to the present, continuing the phase 2 and 3 clinical trials. Like the previous data, these trials also showed the safety and efficacy of Gendicine.
We find that in combination with chemo- and radiotherapy, Gendicine can improve treatment efficacy by 3.4-fold. Furthermore, this combination not only improves treatment efficacy, but it also appears to alleviate the toxic side effects normally associated with chemotherapy and radiation therapy. We have no test criteria proving reduced side effects, just anecdotal comments from patients or their doctors. Seven scientific papers reporting on the safety and efficacy of the clinical trials have also been published in National Medicine Journal of China (December 10, 2003).
BPI: Are there any side effects?
Peng: Clinical results indicate that Gendicine is safe and efficacious. Some patients experienced self-limiting Grade I and II fevers lasting approximately three hours. No other serious side effects were observed.
BPI: Is Gendicine a wide-spectrum anticancer agent?
Peng: In clinical trials, Gendicine has been used to successfully treat cancers of the digestive tract (esophageal, gastric, intestine, liver, pancreas, gallbladder, rectum), lung cancer, sarcoma, thyroid-gland cancer, breast cancer, cervical cancer, and ovarian cancer. Although Gendicine has not been formally approved by SFDA for indications other than HNSCC, terminal patients with no other avenue of treatment have been allowed, on a case-by-case basis, to receive Gendicine with permission from the SFDA, along with a request from the patient, the patient's family, and the agreement of the patient's doctor. We also insist that the patient, family, and the doctor-in-charge carefully read and endorse the informed consent forms.
BPI: What is the incidence of relapse?
Peng: During more than three years of follow-up for the twelve patients with mid-to-late-stage laryngeal cancer who received Gendicine therapy in phase 1 clinical trials, no patient has relapsed. By contrast, among patients who received only surgery, the three-year relapse rate is approximately 30%.
BPI: What is the duration of treatment?
Peng: Patients do not stay on the drug for the rest of their lives. A patient receives one injection per week for four to eight weeks consecutively as a treatment cycle. A standard dose is 1 x 1012 viral particles (VP).
GENDICINE AVAILABILITY
BPI: Are you receiving requests for Gendicine from outside of China?
Peng: Yes. Requests are coming from the US, Germany, Denmark, Thailand, the Philippines, Greece, Canada, the UK, Singapore, Russia, Rumania, and Turkey. Patients must come to China to be treated. So far, about 400 patients have been treated.
BPI: How much do you plan to produce in 2004?
Peng: In 2004, 200,000 to 500,000 doses. Gendicine is expected to bring relief to millions of cancer patients over the coming years. We also expect it to accelerate the commercialization of other gene therapy products and to create a significant social and economic impact.
BPI: Is Gendicine currently available?
Peng: Yes. It will be formally launched in late March 2004. Right now, it is just for HNSCC.
MANUFACTURING AND SCALE-UP
BPI: Your manufacturing facility was built in 2000. How is Gendicine produced and how was the process developed?
Peng: Our facility passed GMP approval by SFDA on February 13, 2004. We produced research quantities in roller bottles and parallel-plate reactor systems. However, roller bottles were found unsuitable for production of gene therapeutics using an adenoviral vector.
I used the Cell-Cube (parallel-plate reactor) system in the lab, but yields were too low, and we had cell growth problems. We produced approximately 1 x 1014 VP in a medium sized Cell-Cube (21,250 cm2 surface area). When we installed a 14-L CelliGen Plus packed-bed bioreactor (from New Brunswick Scientific) in our manufacturing facility, we produced 15 times more than in the Cell-Cube system. Approximately 2 x 1015 VP can be produced in a 14-L bioreactor that is partially loaded with 200-g Fibra-Cel disks, and 1 x 1015 VP adenoviral vector in a 5-L bioreactor loaded with 100-g disks. We observed two periods of peak virus release into the supernatant &emdash; on day 3 and day 5 postinfection, respectively. The viral bursts of 40,000 to 50,000 viral particles/cell were attained on day 3 postinfection.
A complete panel of lot-release quality-control criteria for the final product has been established. Those criteria include vector purity, particle concentration, infectivity, gene expression, potency, and product safety criteria such as sterility, adventitious viruses, and level of replication-competent adenovirus (RCA). For example, our released final product has the following quality characteristics: IU/VP ratio of about 4.8%, purity over 97%, and less than 1 RCA in 3 x 1010 VP
BPI: What is the source of cells?
Peng: Gendicine is based on an E1-deleted adenoviral vector containing the p53 tumor-suppressor gene. Engineered cells expressing adenovirus E1 proteins are required to produce Gendicine. Usually, people use the HEK 293 cell line for this purpose. We have subcloned a cell line called SBN-Cel from the 293 cell line. SBN-Cel is much better than the 293 cells for the production of Gendicine. Compared to standard 293 cells, SBN-Cel has a shorter doubling time and a more uniform, better morphology and attachment to the culture surface in the DMEM [Dulbecco's Modified Eagle Medium] media. Production of Gendicine using the SBN-Cel is carried out in NBS's CelliGen Plus perfusion bioreactor.
A production process under development will use suspension cells instead of attachment-dependent cells. We have been using the NBS CelliGen Plus bioreactor with packed-bed basket for production during the past four years. The suspension process is referred to internally as the second-generation process. We will apply to SFDA for a change to the suspension process if it results in higher productivity (Table 1).
For the production of Gendicine, the most important raw material items are the master and working cell banks and the working virus bank we have prepared. The adenoviral vectors produced from the bioreactors are processed further by clarification, ultrafiltration, and diafiltration, and they are finally purified using an automated bioprocessing system. The overall downstream-processing vector recovery rate is approximately 65%. The purified and formulated viral product is filled into sterile glass vials using an automated filling machine and stored frozen for future use.
INSIDE THE COMPANY
BPI: What can you tell us about Shenzhen SiBiono GeneTech?
Peng: Chinese scholars returning to China from the US founded SiBiono in early 1998. We are privately held and currently have more than 50 employees.
SiBiono is a leader and pioneer in gene therapy research, development, and commercialization in China. We have developed two technology platforms for the research, development, and commercialization of gene therapy: viral and nonviral gene-delivery systems. In China, we authored the first comprehensive book covering gene therapy, commissioned the first cGMP facility equipped with validated state-of-the-art equipment for the production of gene therapy products, and established a complete set of quality-control assays and production processes following international regulations and standards.
SiBiono owns five innovative patents issued by the China Intellectual Property Ministry covering production process, products, and a subcloned cell line. SiBiono is the recipient of a number of national high-tech biotechnology grants, Science and Technology Development Foundation grants, and grants from Guangdong Province and Shenzhen municipal projects.
BPI: What other challenges has SiBiono faced?
Peng: China is a huge market, and we need to increase our production capacity in order to meet the market demand. For large-scale production, SiBiono is building a new production facility in Shenzhen. Manufacturing capacity will reach approximately two million doses per year when we commission this new facility in mid-2005.
We also need to make changes in our product formulation to facilitate transition to commercial-scale production. We are consistently improving our quality system to maintain a leading position in the Chinese market. The "Points to Consider for Human Gene Therapy and Product Quality Control" document [click here] is an example of our achievement.
We are building our marketing and product distribution network. Currently, there are about 15 companies participating in the distribution of Gendicine in China.
PARTNERING
BPI: What criteria do you use in selecting business partners?
Peng: SiBiono has established collaborations with a few domestic and overseas research organizations and universities during Gendicine's development period.
We are currently looking for strategic partners. Potential partners include well-known organizations, foundations, and biotech corporations. We are seeking a partner that, together with SiBiono, can jointly lead and promote worldwide gene therapy development. The partner is expected to collaborate with SiBiono, however; we are not interested in a merger partner. This partner has to be large enough to deal with China's huge market.
BPI: Did you have any other consulting help?
Peng: Dr. W. French Anderson, director of the Gene Therapy Laboratories at the University of Southern California and widely considered the father of gene therapy, serves as a free advisor to SiBiono. He plans to visit here once a year in an advisory capacity.
Gendicine: The First Commercial Gene Therapy Product; Chinese Translation of Editorial
James M. Wilson
Human Gene Therapy. Sep 2005, Vol. 16, No. 9: 1014-1015
Title
Current Status of Gendicine in China: Recombinant Human Ad-p53 Agent for Treatment of Cancers
Zhaohui Peng
Human Gene Therapy. Sep 2005, Vol. 16, No. 9: 1016-1027
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