Betting on Better Organs
1 Patients are left with less tissue to function as intestine, which can complicate things even further. Some studies have also linked the procedure to a slightly higher risk of cancer.
Performing this procedure in older adults, who have relatively fewer years left to develop complications, is one thing. But what about the children who could live with jerry-rigged bladders for decades? This is a question Anthony Atala asked himself as a surgical resident training in pediatric urology. "These children had an 80-year life expectancy," he says. "They are going to have a lot of problems."
The ideal solution, Atala reasoned, was to provide children with new tissue from their bladders, not their intestines. This meant growing a vast amount of new, autologous bladder cells. In 1990, out of "pure ignorance" of how hard it would be, Atala started experimenting with biopsies, media, and scaffolds. Naturally, this took a while. "It was failure, and failure, and failure," he says. "I just kept going after something others couldn't do."
What he was looking for were smooth muscle and urothelial progenitor cells that could multiply ad infinitum. He eventually found them among the batches of cells that scientists typically discarded, since they lacked the properties of adult bladder cells. The next step was finding a "soup," or group of growth factors that would encourage the progenitor cells to proliferate indefinitely. Eventually, he began experimenting with ordinary serum, adding back one ingredient at a time to find the right combination. There was never one "eureka" moment or event, just a lot of small lines of reasoning that eventually, and serendipitously, converged. "There were many times when I thought this was a lost cause," says Atala, now director of the Wake Forest Institute for Regenerative Medicine. "But we just kept at it."
Eventually, after 10 years of tweaking, he was ready to try the technique in a handful of people.2 Finding volunteers wasn't an issue, he says. "There were many patients who wanted to do this." In 2006, Atala published results from the first human clinical trial with engineered bladders in the April 15 issue of The Lancet. Among seven children and teenagers who received an autologous bladder, all displayed good renal function for an average follow-up of four years. Moreover, they experienced good end-filling pressure, which signaled that the bladder was properly pliable, able to expand when needed.3 The new bladders become innervated, but patients can't simply sit on a toilet; they need to continue intermittent catheterization, in which they insert a tube through the urethra to drain the bladder. Atala continues to get reports from the patients' doctors, who all say the pressure value has stayed low, which is where they want it. One patient has now lived with the new organ for eight years.
Between sips of Diet Coke, Tengion's chief financial officer, Gary Sender, describes the company's early days. He's tall and thin, and has a habit of nodding empathically when I ask a question, as if he's heard it many times from equally incredulous observers. "The first reaction people often have is: 'This sounds like something I would see in Star Trek. You can't possibly be growing new organs for patients,'" he says. His goal is to "try, in every way we can, to convince people that this is very real. There's really hard science behind it."
Right off the bat, Tengion's executives realized they had a hard sell. But they also had an advantage over most biotechs: early human data, albeit unpublished (until 2006). They also knew that, to make more than a handful of autologous bladders at a time, they needed an airtight manufacturing process that the Food and Drug Administration would approve. They quickly hired the best people they could find: Allen Smith, who was the head engineer at Wyeth's € 1.8 billion, 111,500 square meter biopharmaceutical campus in Grange Castle, Ireland; and Don Bergmann, former general manager of the biopharmaceuticals business unit at GlaxoSmithKline, a man who walks and talks quickly, in the powerful manner of someone who's accomplished a lot.
This emphasis on manufacturing distinguishes Tengion from other startups, most of which outsource that process. "Most venture capitalists would prefer putting their money towards R&D than bricks and mortar," says Sender. But when what you're manufacturing is human tissue, the process you use becomes critical, so Tengion made the decision to do it themselves. Sender won't say how much the company has spent on building the new facility in the Philadelphia region, but he places it in the range of "tens of millions" of dollars. Tengion has already hired 25 people to begin testing the equipment. "That number should double in the next year," Sender predicts.
Of course, medicine is about much more than science. Even if the company can choreograph the intricate dance involved in mass producing human organs, it has to ensure that this intervention is something patients - and insurers - can afford. Tengion has already assembled a preliminary figure for what each bladder might cost, but the company refuses to release it. (The company also refused our request to take photos of the facility, aside from some generic images.)
Sender won't even provide a range of what the bladder might cost, but insists that the company has done enough calculations to make sure they've entered a "viable business" - meaning, a technology that insurance will pay for. But it won't be cheap: "Humans are expensive," he says. Each time a surgeon performs a radical cystectomy, another type of surgery that uses intestinal tissue to repair a bladder, the cost is $70,000. The annual cost of these procedures exceeds $500 million in the United States alone, without factoring in the cost of any complications that might subsequently arise.
A "logical place to start" when formulating an estimate of the cost of autologous organs is to look at "how much does the system pay for organs today," Sender says. He mentions, for instance, heart transplant: One hospital, just to procure the donor organ, pays $70,000 to whomever provides it, and that's before the surgery. All told, a single heart transplant costs half a million dollars, "nowhere near" what patients will have to pay for an autologous bladder, Sender says. But he won't say more. "It's premature for us to provide any information on what we think this is going to cost," he adds. "We believe that the data will be very compelling, and this will be an important medical need. We also know that these [bladders] are very expensive to manufacture."
Even without a precise estimate of what these bladders would cost, investors had reason to believe the product could eventually turn a profit. The company received $39 million in Series A financing in 2004, and another $50 million in Series B two years later. In October, it closed another $33 million in Series C funding. Brenda Gavin, a partner at the Philadelphia-based firm Quaker BioVentures, which invested in Tengion, says the firm received a tentative cost projection, but declined to specify what she saw. "We were comfortable that the pricing was not out of line, given the current procedures" now used in organ repair, she says. For instance, she projects that the procedure will likely cost less than bone marrow replacement, which racks up $200,000 in charges (when autologous). Growing and implanting an autologous bladder may be more expensive than current forms of cystoplasty, she adds, but it could reduce the risk of extensive (and expensive) complications.
Ting Pau Oei, a partner at New York-based L Capital Partners, which also invested in Tengion, says he learned of the company while at Johnson & Johnson Development Corporation, the company's venture capital subsidiary, which funded Tengion when the company was "just a glimmering gleam" in Atala's eye. He says it was unusual to come across a company with human data, and he was impressed by the "breakthrough potential" of the technology. Oei, too, says he saw cost projections from Tengion, and his firm also did "due diligence" in looking at prices for comparable procedures. However, no other procedure is quite similar to what Tengion (and its scientific founder, Anthony Atala) is doing. "I think the question is still out in terms of the cost-benefit analysis," Oei notes. Gavin agrees that early cost projections are never reliable. "If an early-stage company comes in and gives me a cost estimate, I wouldn't believe it," she says.
Tengion isn't the first to try to capitalize on tissue regeneration, and it has a reputation to beat. In 2002, the first two firms to mass produce engineered skin for chronic wounds filed for bankruptcy, citing regulatory bottlenecks. A number of tissue-engineered products have been abandoned, even after some success in Phase II trials. 4
One reason attempts using skin may have failed is that the alternative - transplanting skin from cadavers - works fairly well, Sender says. An autologous bladder, however, carries the promise that it might work better than a bladder cobbled together from other tissue. "This isn't just some magical elixir being sold on cable television; this is real science that has robust preclinical and clinical data behind it," Sender says. "Over the medium to long term, people pay for the products that give the most value."
It "would be wonderful" to have a technology that could provide patients with bladders that their bodies would accept, says Dominic Frimberger, a researcher based at the University of Oklahoma Health Sciences Center in Oklahoma City. Frimberger is currently working on another technique for growing autologous bladders, and has so far gotten good - but inconsistent - results in animals. "I'm all for tissue-engineered bladders," he says.
Atala may be the one to do it, says Steve Chung, a urologist based in Ottawa, Illinois, who wrote an editorial accompanying The Lancet paper. Atala has been researching tissue engineering "probably more than any other urologist," says Chung, and his scaffold - a biodegradable mix of collagen and polyglycolic acid (PGA) - is "just as good as the best scaffolds out there." (Chung himself is currently trying to use nanotechnology to obtain a better scaffold.)
Still, there are reservations. "Will [this technique] be the future?" asks Chung. "I think, in due time. There are obstacles that need addressing." For one, Atala used two different scaffolds in The Lancet paper: The first four patients received a scaffold made of homologous decellularized bladder submucosa. Atala says his team continued to tweak the formulas as they went along, and now all procedures use the PGA and collagen scaffold.
One factor that may limit how many patients could benefit from the procedure is the nature of the patient population. Thousands of patients who have bladder surgery every year do so because of a diagnosis of bladder cancer. In these cases, Tengion's technology won't work, since any bladder grown from a diseased bladder might also develop a tumor.
Even for those with spina bifida, Chung sees the patients as Atala did: Children who could live for decades. So although up to five years of follow-up data in The Lancet is impressive, it's not enough. "I don't think five years can be considered long term in this context," Chung says. If the technology doesn't last as long as it needs to, Frimberger cautions, patients may need another operation - perhaps an intestinal replacement, the very procedure they sought to avoid. The technique "has to be scientifically more valid before it's ready for everybody," he says.
The Phase II trials currently underway include children with spina bifida and adults with spinal cord injury. If that goes as planned, the company will schedule a larger, Phase III trial. What happens then is still somewhat unclear. The FDA has never been asked to approve an autologous human organ. What safety criteria will it consider? What kind of quality control procedures and infrastructure will the company need to employ? "It's not like we're stamping out a million pills a day," says Sender. "We have to custom-grow a new organ for every patient."
One of the reasons Tengion may be the first to attempt mass producing autologous organs, he speculates, is the enormous upfront investment, with no guarantee of success. "I think the task of trying to commercialize this type of custom-made organ for patients is pretty daunting." From the beginning, the company interacted with the agency to educate it about how the technology works, scheduling "at least five" pre-IND meetings. "The FDA had to create new sets of standards for us," Sender says. A handful of bladders is one thing; mass producing them is quite another. "You can probably understand maybe doing one at a time, two at a time, three at a time," says Sender. "Now imagine having to grow thousands of organs a year. Or maybe thousands at one time."
Atala agrees that five years of follow-up is not long enough to know definitively if the results will last decades, but he feels more confident with every year that passes. He purposely waited for a longer period than usual before releasing The Lancet data, just to be sure. In the case of bladder cancer, Atala envisions a day in which scientists might eventually be able to use progenitor cells from the kidney and coax them to become a healthy, pliable bladder. Even excluding bladder cancer patients, there is a need for something new: Since writing the editorial, Chung says he has received "endless phone calls from patients with dysfunctional bladders, and they don't care about the lack of long-term data."
Atala, too, says he is cautiously optimistic about Tengion's plan to mass produce autologous bladders. It's one thing to gingerly grow a small group of bladders at a time; it's another to mass produce them. So for the time being, Atala is waiting for data that show the quality won't change. "Obviously, I'm happy that the technology will reach more patients," he says. But for now, "I'm still cautious."
For a Tengion video showing the bladder construction process, References