Sorry, that note to "Janet" in the middle of the post, was from me to my daughter who does basic ( very basic ) medical research. I just put the wrong address on it. Nita Flemco- wrote: > The point is Novartis spent nearly $1Billion on this technology. > Dramatically more than the pittance the US government is proposing and we > keep drooling over. Let's face it. If you want anything done, the > government is not the place to look. > > Larry Fleming > 54/51 > [log in to unmask] > http://homepages.msn.com/HobbyCt/flemco > > -----Original Message----- > From: Parkinson's Information Exchange Network > [mailto:[log in to unmask]] On Behalf Of Nita Andres > Sent: Thursday, October 28, 1999 1:57 PM > To: [log in to unmask] > Subject: Re: Gene Therapy > > Janet, more on Novartis and gene therapy. How much time do drug companies > spend > on developing drugs before they throw in the towel? Really strange, it > seems to > me that it would take a lot of time. Love, Mother > > Flemco- wrote: > > > Researchers Get Dose of Reality > > As Logistics Stymie Gene Therapy > > By ROBERT LANGRETH and STEPHEN D. MOORE > > Staff Reporters of THE WALL STREET JOURNAL > > Eight years ago, Swiss drug maker Sandoz AG was dazzled by a tiny U.S. > > biotechnology firm doing promising work in the new field of gene therapy. > > Genetic Therapy Inc. and government scientist French Anderson, its > > co-founder, claimed that injecting healthy genes into the body to replace > > damaged or defective ones would revolutionize medicine by letting doctors > > attack the causes of diseases such as cancer and cystic fibrosis, rather > > than just the symptoms. > > Sandoz, which would merge with Swiss rival Ciba-Geigy AG in 1996 to form > > Novartis AG, bought into this bold new vision. It began amassing GTI > shares > > in 1991; in 1995, it bought the Gaithersburg, Md., company outright, > > bringing its total investment in GTI to more than $300 million. By 1997, > > Sandoz, looking for new technologies to fuel its profits, also had > invested > > $548 million to acquire SyStemix Inc., which was developing a related > > process. > > These days, however, gene therapy looks unlikely to pay off in a big way > > anytime soon. And Novartis is scrambling to salvage its nearly $1 billion > > investment in the technology. All but one of the human gene-therapy > testing > > programs once under way at GTI and SyStemix have been scrapped or > > temporarily halted. And none of the hundreds of human studies conducted > > elsewhere around the globe so far have offered clear proof that gene > therapy > > works in any significant way to fight disease. > > "This has been an overhyped area that has failed to reach its promise for > > very obvious technical reasons," says George Poste, a top research > executive > > at British pharmaceutical maker SmithKline Beecham PLC. > > 'We Were Naive' > > Even Dr. Anderson has tempered his enthusiasm. "We were naive to think we > > could revolutionize medicine in 10 years," says the researcher, who now > > doubts that major gene-therapy drugs will reach the market before 2004 or > > 2005. > > Indeed, the sudden death last month of a patient undergoing experimental > > treatment for a rare liver disorder at the University of Pennsylvania -- > the > > first death apparently linked to gene therapy -- has raised questions > about > > whether scientists have been in too big a hurry to test such therapy on > > humans. As a precaution, federal regulators since have ordered U.S. drug > > maker Schering-Plough Corp., which wasn't involved in the University of > > Pennsylvania research project, to temporarily stop enrolling new patients > in > > certain gene-therapy trials for cancer. > > Back in 1990, though, gene therapy was generating enormous excitement. Dr. > > Anderson and his colleagues at the National Institutes of Health treated a > > young girl with a rare and potentially fatal immune disorder called ADA > > deficiency, or "boy-in-the-bubble" disease. Dozens of hospitals and > medical > > schools sought government approval for human trials for other illnesses. > > Boosters went so far as to predict that the first gene therapies would hit > > the market as early as 1996. > > Sandoz, one of the pharmaceutical industry's most aggressive investors in > > the new field, had high hopes of using gene therapy to treat the deadliest > > form of brain cancer, glioblastoma, and other cancers. But in 1998, > Novartis > > quietly abandoned its flagship gene-therapy project after a large-scale > > human test failed to prove that the therapy was effective. And, earlier > this > > year, the drug maker undertook a painful overhaul of its entire > gene-therapy > > research program. Now, Michael Perry, who has run both GTI and SyStemix > > since their operations were combined last fall, says no new human tests > are > > planned until a host of technical issues are resolved. > > A Crucial 24 Months > > "Novartis is not proud of it right now," Dr. Anderson says of the program. > > "Something has got to show up on the radar screen in the next 24 months or > > some really serious decisions are going to be made" says the researcher, > who > > serves on GTI's board and is now a University of Southern California > medical > > school professor. > > Even so, Novartis Chief Executive Daniel Vasella says his company remains > > committed to the field. "There isn't a single major drug on the market > that > > hasn't been close to the grave at some point," he says. If gene therapy > > ultimately fails to produce a major product, "I'd still say fair enough. > > That's our business. If you don't spend big money and take big risks, you > > shouldn't be in the pharmaceutical industry," adds Mr. Vasella, who notes > > that gene therapy accounts for a small fraction of Novartis's annual > > health-care research budget of more than $2 billion. > > >From the beginning, the therapy's main difficulty has been a logistical > one: > > how to deliver enough healthy genes to the appropriate site and get them > to > > stay there long enough to cure or alleviate a disease. For example, > > researchers estimate that to cure cystic fibrosis, a hereditary > respiratory > > disorder, new genes would have to be permanently placed in a billion > > defective cells in the lung's airways. Researchers often use genetically > > engineered viruses as vehicles for such genes. For example, an adenovirus > > was used as the carrier in the University of Pennsylvania trial in which > the > > patient died. But the technique has its drawbacks: Sometimes a patient's > > immune system, wary of foreign invaders, tries to fight off the viral > > vehicles. To be sure, gene-therapy researchers recently have made progress > > in some areas, such as treating heart disease or hemophilia. But overall, > > the therapy's short-term applications seem narrower than they did a few > > years ago. > > Confident of a Breakthrough > > After Sandoz and GTI began working together in November 1991, GTI > scientists > > were confident of achieving a breakthrough. The feeling was: "We are going > > to do something very important here," says Alan McClelland, a former GTI > > research manager now at rival Avigen Inc. > > GTI's showcase gene-therapy effort, aimed at treating glioblastoma, was > > conceived by colleagues of Dr. Anderson at NIH. It involved inserting > > so-called suicide genes into the DNA of tumor cells to make them sensitive > > to the antiviral drug ganciclovir; doctors could then give patients the > > antiviral to kill the tumor cells. > > The first human test was conducted in the early 1990s at the NIH, with GTI > > as a partner. Initial results seemed highly encouraging. The first > patient's > > tumor shrank dramatically following the treatment. Although distant tumors > > eventually killed him eight months later, the original tumor never came > > back. A second patient showed no response. A third patient's tumor also > > shrank significantly, though only temporarily. Overall, the tumors of six > of > > the 15 patients studied showed some shrinking in response to the therapy; > in > > one case, the tumor disappeared entirely and the patient seemed to fully > > recover, a rare outcome in glioblastoma. > > GTI executives didn't wait for all the data to come in before they began > > planning a second test on a few dozen patients at the University of > > Washington and elsewhere. But even as these new tests were launched, > Edward > > Oldfield, an NIH neurosurgeon, was analyzing the results of the first > trial, > > which he had led, and he was growing increasingly skeptical of the > therapy. > > It seemed the new genes penetrated only a tiny fraction of tumor cells in > > the immediate vicinity of the injection. While this killed nearby cancer > > cells, a phenomenon dubbed "the bystander effect," it seemed to have no > > impact on cells farther afield. And Dr. Oldfield wasn't convinced that the > > one patient's recovery was fully a result of the gene treatment. > > "We didn't think it had enough activity to be meaningful. Based on what we > > had seen, I saw no hope of distributing the gene where it needed to go," > > says Dr. Oldfield, a surgical chief at the National Institute of > > Neurological Diseases and Stroke. > > By 1994, Sandoz had decided to expand its collaboration with GTI to > include > > the glioblastoma work. It started its own small human test in Europe. The > > initial results were mixed, and oncologist Athos Gianella-Borradori, the > > Sandoz official helping coordinate the trial, says he had doubts the > > treatment would work. He says he told his superiors at Sandoz and > officials > > at GTI of his reservations, aware they might be interpreted "as a betrayal > > of our cause." > > He had another concern: By late 1995, several prominent gene-therapy > trials > > elsewhere had failed, leading some to question the validity of the entire > > approach. Dr. Gianella-Borradori, who left Sandoz a few years ago and now > > works at Bavarian Nordic GmbH in Germany, says he didn't want another such > > failure. > > That same year, an NIH committee set up to review gene therapy concluded > > that problems remained "in all basic aspects" of the technology. Top > > researchers were reporting disappointing results. Scientists at the > > University of North Carolina in Chapel Hill disclosed that a trial for > > cystic fibrosis produced side effects and didn't alleviate the disease. > > Another trial, at Ohio State University, found that a muscular-dystrophy > > treatment didn't improve muscle strength. > > Still, GTI and Sandoz forged ahead. Although gene therapy affected only a > > limited number of cancer cells directly in the glioblastoma project, > Sandoz > > was impressed by the fact that a handful of patients in the various trials > > appeared to be among the rare long-term survivors of the disease. > > Researchers theorized that the new genes had triggered an immune response > > against the cancer. A neurosurgeon who led the University of Washington > > trial says he was so taken by his results that he flew to Switzerland, to > > urge Sandoz to continue the program. > > Comparative Study > > In 1996, Sandoz, soon to become Novartis, launched a large trial that > would > > compare the effectiveness of gene therapy combined with standard treatment > > to that of standard treatment alone. It would be by far the largest > > gene-therapy trial to date, with more than 200 patients. > > Novartis development chief Joerg Reinhardt says the company was fully > aware > > of the high risk of failure. But given the reports of patients who seemed > to > > respond to treatment, Novartis felt larger brain-cancer trials were in > > order. The test began in the summer of 1996 at hospitals in Europe and the > > U.S. > > Meanwhile, GTI's gene-therapy treatments for other diseases were running > > into problems. When Sandoz bought it out in August 1995, GTI was involved > in > > early-stage human tests of therapies for cystic fibrosis, breast cancer > and > > several rare genetic diseases. But these efforts were halted, one by one, > as > > it became clear that existing gene-delivery technology couldn't deliver > > enough genes to do the job. Novartis says Sandoz wasn't counting on any of > > these preliminary tests to succeed when it bought GTI. > > Different Concepts of Time > > As project after project stumbled, Novartis grew worried that GTI's > approach > > was too scattered. There were "too many things going on, and not enough > > focus," says Paul Herrling, Novartis's research director. Novartis > attempted > > to impress its deliberate decision-making style on GTI, but ended up > > frustrating some researchers there. A running joke was that at GTI the > clock > > ticked in days, but at Novartis it ticked in quarters. Dr. Herrling says > > there were clashes. "We had no experience with this biotechnology; they > had > > no experience with drug development." > > In another setback, the U.S. Federal Trade Commission, reviewing the > > proposed Sandoz-Ciba merger in 1996, demanded -- as a condition for > > approving the deal -- that rights to key GTI patents be offered to rival > > companies. Sales of gene-therapy drugs, the FTC predicted, could reach $45 > > billion a year by 2010 -- a figure that today seems highly unrealistic. > > By early 1998, preliminary results of the large-scale comparative trials > on > > brain-cancer patients were rolling in. They didn't look good. Patients who > > underwent gene therapy didn't live longer than those receiving standard > > treatment. For Novartis, it was the final straw. > > Returning a Verdict > > In mid-1998, the panel of scientists that reviews Novartis's research each > > year took a hard look at gene therapy. Its verdict: Improved gene-delivery > > methods were needed in order to give human tests a better chance of > success. > > Soon thereafter, Novartis combined GTI and SyStemix. Many GTI officials > were > > shocked when GTI bore the brunt of the cuts, which included most of GTI's > > senior managers for drug development. Roughly 90 employees, or about 20% > of > > the two units' combined staffs, were laid off, the vast majority of them > at > > GTI. Mr. Perry, a Novartis insider who had been running SyStemix for more > > than a year, was chosen to head the combined operation from SyStemix's > Palo > > Alto, Calif., laboratory. The decision, Mr. Perry says, didn't reflect on > > the quality of GTI's researchers. > > Dr. Anderson sees it differently. GTI was "charging off in various > > directions" and not always conforming to Novartis's corporate goals. > > Novartis had tried to rein in the company, but "wasn't successful." > > Novartis has since scaled back or eliminated many gene-therapy research > > projects. "It is not on my high priority list to go into the clinic now," > > Mr. Perry says. But he says he is "positive" that gene therapy will play a > > major role in medicine, and that Novartis's past experience will give it > an > > edge. "Certainly, there is pressure" to produce a return on Novartis's > > investment, he says. "It is a question of when, not if." > > > > Larry Fleming > > [log in to unmask] > > http://homepages.msn.com/HobbyCt/flemco