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Cancer immunotherapeutics, including vaccines, may hit the market by the end of this decade. They promise longer survival and perhaps indefinite remission at a more favorable cost-benefit ratio than that of oncologics now in use. They also may fuel dramatic changes in how healthcare is delivered and financed.
William Coley, MD, may have had it right when he claimed that malignant tumors could be killed by vaccination. At least that’s what several small biotechs and even some big pharmaceutical companies are banking on.
When Coley, a surgeon, injected a vaccine made from live streptococcal organisms into patients with advanced cancer more than 100 years ago, he reasoned that the body, in forming an immune response to fight the infection, also would shrink or kill the cancerous cells. His results, published in 1893, showed that of 17 patients injected, 4 were permanently cured, and 10 showed improvement.
But some patients also died, so Coley hit on the idea of developing a vaccine made from dead bacterial byproducts. This new “mixed toxins” vaccine — known as Coley’s toxins — produced some modest successes well into the 20th century, but was finally relegated to quackery after its illegalization under the U.S. Food and Drug Administration’s 1962 drug amendments.
Searching for the Holy Grail drives discovery, and the idea that a vaccine could not only treat but also possibly prevent cancer was never entirely abandoned. It took the birth of biologics 30 years ago to put the development of cancer immunotherapeutics into high gear.
At least 90 cancer vaccines are now in the pipeline. More than two thirds are in late development, according to IMS Health, and the cancer vaccine market could be worth $8 billion by 2012. In all, 245 pure vaccines and 11 combination vaccines for various diseases are in development, according to Price-WaterhouseCoopers, creating a potential market of $42 billion by 2025.
“There’s an incredible hunger for vaccine candidates,” says Anthony Farino, partner and U.S. pharmaceutical and life sciences advisory services leader at PWC. “What you see now is part of a trend that has been going on for quite some time. People are saying that the pipeline is drying up. I don’t think that paints an accurate picture; we are working at the limits of human understanding of the underlying science, and the diseases that need to be addressed are very complex. That extends development time frames.”
Vaccine is a misleading term because it denotes prevention along with protection — like that given by smallpox and flu vaccines, which are properly called prophylactic vaccines. The new immunologic drugs being developed to treat various cancers are therapeutic vaccines, given once cancer sets in to shrink tumorous cells and establish immunity so more cancer cells don’t develop. But with the FDA’s approval of Merck’s Gardasil and the expected approval of Glaxo-SmithKline’s Cervarix to prevent cervical cancer, vaccine will likely become an all-purpose term.
“Although Gardasil really isn’t a therapeutic cancer vaccine,” says H. Kim Lyerly, MD, director of the Duke University Comprehensive Cancer Center, “we now understand more about cancer and preventing genetic events that lead to cancer progression.”
Imagine cancer as a process. As genetic changes occur throughout that process (“The only time you are ever normal is when you’re born,” Lyerly offers), then all healthcare inter ventions are, in some sense, therapeutic. Typically, he says, genetic mutations put cancer patients at high risk, “and those [mutations] could be targeted, which would be considered therapeutic, even though you’re preventing the clinical manifestations of that process.”
So what is the difference between injecting a patient with a targeted therapy, based on a genetic profile, or giving lapatinib (Tykerb) or imatinib (Gleevec) to treat the disease?
“We never tell patients that all they need is radiation therapy or surgery,” Lyerly says. “With Gleevec, Tykerb, or tamoxifen, you give those as a therapy. The therapy is what you give. In a vaccine strategy, the vaccine triggers your body to do the work.”
Immunotherapeutics won’t replace an entire therapeutic regimen, Lyerly cautions, but exploration could begin to determine what specific treatments might be replaced by vaccinations. “Is it lifelong Gleevec administration? Is it that you don’t have to give Avastin for a year because you’ve been immunized?” The economic argument can be powerful, he adds, because the patient’s body creates the therapeutic product. “It’s going to be much more scalable and cost effective, so the potential benefit could be very high.”
Other factors are also pushing cancer vaccine development.
According to PWC’s Pharma 2020 report, political, social, and economic factors are driving a shift from treatment to prevention and cure in an effort to control healthcare costs. Private initiatives to stop disease pandemics, such as that by the Bill and Melinda Gates Foundation, as well as government efforts to combat bioterrorism, are gaining momentum. Against this backdrop, big pharma, losing patents and revenue, sees vaccines as a potentially lucrative growth area. Their participation in programs associated with national security and pandemic preparedness, Farino says, presents manufacturers with a short-term business opportunity, but also indirectly hands them a long-term advantage through creation of a platform for making vaccines.
“Pharmas and biotechs are competing for those contracts very, very aggressively,” he says.
Vaccine development also will hit the manufacturer and payer communities in ways not yet determined. Vaccines present many challenges, not the least of which is the question of underwriting. If a patient shows a positive immune response for a defined period but later loses immunity and the disease returns or progresses, who assumes liability for subsequent health care costs? For personalized vaccines, it’s been suggested that manufacturers would be on the hook.
As William Sullivan, president and founder of Orlando-based Specialty Pharmacy Solutions puts it, “I’ve had conversations with some of my clients exactly on this topic. They cross their eyes and say, ‘Boy, I thought it was complicated before.’”
Cancer vaccines come in two basic forms: autologous or patient-specific, which are made from killed tumor cells taken from the patient to be treated, and allogeneic or “off the shelf,” grown in a lab from cancer cells and injected into a patient with adjuvants designed to boost the immune system. Allogeneic vaccines can be DNA-, antigenic protein or peptide-, dendritic cell-, and viral vector based, depending on the technology used, and all require a mechanism to deliver the vaccine to the target.
Avtar Dhillon, MD, CEO of San Diego-based Inovio Biomedical, offers an easy-to-follow explanation of how vaccines work and why his company is involved in DNA-based immunotherapeutics. Inovio has developed an intracellular delivery mechanism called electroporation for DNA-based vaccines, and is collaborating with Merck and the University of Southampton, United Kingdom, on phase 1/2 trials of a combination vaccine designed to treat lung, breast, ovarian, or colorectal cancer and a prostate cancer vaccine, both to be delivered via electroporation.
“Let’s go back to the conventional vaccines that you and I have had —mumps, rubella, tetanus,” Dhillon says. “For most of these, you grow the bugs, you inactivate or attenuate them, kill them, and [inject] them into the body, and the immune system recognizes these bugs as foreign and forms an immune response.” But it’s much more sophisticated — and effective — Dhillon says, to inject a DNA segment taken from the offending bug. Then, when the body produces proteins from it, “You mount an antibody and a white cell response to that protein. Those cells, then, are ready to fight the real disease.”
With patient-specific vaccines, the cancer cells are removed from the patient. Then, Dhillon says, “You attach some bells and whistles, put them back in, they make a lot of noise, and the immune system wakes up.” That triggers a broad immune response to the cancer cells already in the body and helps to eliminate them.
Vaccine development not only takes a long time, it’s also a gamble, and Dhillon cites some of the pitfalls. With DNA vaccines, if there’s an immune response — antibodies and white cells — then the DNA has made the proteins. From there, different DNA sequences are tried to develop the ideal vaccine.
Dhillon offers an example of how this mix-and-match exercise plays out, using the Inovio/Southampton trials as an example. These are focused on men who have prostate cancer and who express high levels of prostate-specific membrane antigen, or PSMA.
“We’re trying to make an immune response to PSMA. As with any clinical trial, he says it’s possible that research will eventually show that PSMA was not “the right protein to pick. We picked PSMA, but maybe it should’ve been PSMA plus PSA.” That, he says, means that “Vaccine developers will have to work with different combinations of the DNA sequences or different combinations of proteins to help trigger an immune response strong enough to wipe out the cancer or chronic disease” being targeted.
DNA vaccines can be delivered in various ways. One way is to use viruses, and another is to use a lipid vesicle. Both present issues of synthesis, delivery, and toxicity. Electroporation, Inovio’s technology, puts DNA into the tissue, pulses it for less than a second — increasing the permeability of the cells — and the DNA is in. The only other effective delivery technology for DNA vaccines, he claims, is PowderMed’s gene gun, now owned by Pfizer.
The last thing to consider in a vaccine is an immune kicker. “You’ve got your DNA, you’ve got your delivery — now you need [an adjuvant] to make sure the immune system has a better chance of reacting to the protein that you are trying to hit,” says Dhillon. You might, for example, combine a DNA sequence with an immune-stimulating cytokine, such as interleukin 12 or interleukin 2 (ProLeukin). When the cytokines are released, the immune system joins them. Electroporation, he says, can act as an adjuvant, because as the electricity passes through tissue, it causes a disturbance that signals the immune system to mount a stronger inflammatory response.
Favrille, a small biotech also based in San Diego, has developed FavId, a patient-specific vaccine to treat follicular lymphoma. John P. Longnecker, PhD, director, president, and CEO, admits that even sophisticated investors link the word vaccine with prevention. “Our policy has been to direct people to use the term immunotherapy, even though it has more syllables.”
FavId is now in phase 3 studies, enrolling two patient populations simultaneously to treat the indolent form of follicular lymphoma. Says Daniel Gold, PhD, Favrille’s chief scientific officer, “It’s incurable, but patients live a long time with it — an average of 7 to 10 years. FavId is intended to prolong remissions, which may translate into survival.” Years ago, Gold says, most patients would get either no therapy or chemotherapy. That changed with the advent of rituximab (Rituxan). “We’re trying to move FavId up into the front line where it would be used in combination with Rituxan to prolong the remission that was induced with Rituxan.” Trial data are expected by next July, with a regulatory filing soon thereafter.
The vaccine is tied in with a patient’s genetic makeup and contains a recombinant protein that’s slightly different in every patient. “We identify the gene [associated with] that protein, and we isolate the one that exactly fits the particular tumor expressed by the patient, and we make a protein off of that. So, we start with a patient’s tumor and go from there,” says Gold.
Favrille manufactures sufficient product to treat a patient for up to three years. “The beauty of it is, because we start with genetic information, we basically ‘vial’ that info and store it. If the patient comes up on the three-year [mark] and needs more, it’s easy for us to go back [to] that genetic bit stored away [and] recrank that product for another three years’ worth,” Gold says.
“The general interpretation of [therapeutic] vaccines is that they will be office administered,” says William Sullivan, president and founder of Specialty Pharmacy Solutions. (Sullivan excludes patient-specific vaccines, which would have to be handled differently.) The justification for specialty pharmacy involvement is that these new-generation vaccines are likely to fall well outside the traditional vaccine pricing structure. This presents an opportunity for the SP to act as a conduit to distribute the vaccines and also to address the patient’s other pharmacy needs.
With traditional vaccines, “The doctor draws it up into a syringe, pops it into the patient’s arm, gives the patient a lollipop, and sends the patient off,” says Sullivan. These vaccines won’t be that simple, he says, because of the potential for administration issues and postadministration follow-up. “There are so many ‘what-ifs’ associated with this that the SPs I have been talking with are struggling to guess what those issues will be. It’s too early to form a strategy other than ‘Let’s keep our pulse on this and figure it out as soon as something tangible is ready to hit the market.’”
Immunotherapy presents a logistical issue that SPs can manage efficiently. “Best-run offices won’t want to carry inventory for expensive vaccines because a patient may or may not come in Wednes-day morning at 10 o’clock for a scheduled appointment. Easily, that could be hundreds of dollars sitting on the shelf,” Sullivan says.
McKesson Specialty Pharmacy is taking a ‘wait-and-see’ attitude, at least for now, but is optimistic about service opportunities. “We think these vaccines fit naturally in our operations and in the way that our pharmacy care design is established,” says Robert Reilly, vice president of operations. “We have strong reimbursement expertise and deep clinical resources, especially in oncology, so that we’re able to customize our SP programs to support physicians’ therapy plans and counsel patients on side-effect management and medication safety.”
Filling the script may be simple. The SP opportunity will be in follow-on and supportive care services, which may also open the door to 3 to 10 other prescriptions these patients usually have. “SPs are smart enough to know where their bread is buttered,” says Sullivan. “If a regular pattern of referrals begins to take place between Dr. Jones and the pharmacy down the street, it doesn’t really matter what the margin opportunity on a vaccine might be if it creates what they all want —the number 1 position on the fax machine.”
Moreover, says Longnecker, Favrille can manufacture on a small scale — a recombinant product for each patient. “We use a proprietary system of a baculovirus and insect cells that allow us to do this in a very short time. The time we receive a biopsy to [the time we could] send the drug back to the physician is about eight weeks. That’s a dramatic improvement over work in the 1990s that took nine months or more to produce a product like this.”
As for cost, the company is positioning to offer a per-vial price. The treatment protocol for the first year is nine doses, in the second year it drops to about six doses, and in the third year it’s four doses. Over time, the cost gradually decreases.
“Based on our analysts’ projecting, we will certainly not be as high priced as some cancer biologics now on the market,” Gold asserts.
Even for nearly 20 doses, cancer therapies are sustained, and that extends to therapeutic vaccines. Most, if not all, will require booster shots, says Duke’s Lyerly, “because of the types of immune responses you are generating. I think most people [understand] that boosting is going to be a major part of this.”
With FavId, “We give six monthly induction doses, and then we boost them to maintain the level of immunity that was established with the first six doses,” says Gold.
Dhillon, at Inovio, agrees that whether a vaccine is personalized or off the shelf, the priming dose would be followed by subsequent injections “because our immune system forgets about it after 10 years.” Once the regimen is determined, he says, “You keep on hitting it, again and again, and each time you’re looking to see how fired up the immune system gets. Hopefully 3 shots or 4 shots may do it.”
The many years of vaccine research and development are costly. Oncophage, Antigenics’ kidney cancer vaccine, took 12 years to develop at a cost of $300 million, only to have the FDA send a nonapprovable letter and request more efficacy and safety data. Other biotechs face the same uphill battle and expense. Dendreon’s sipuleucel-T (Provenge) also was denied FDA approval because, the agency said, the trials were not well designed. On the other hand, Northwest Biotherapeutics’ DCVax, a personalized brain cancer vaccine that prevents recurrence, in development for more than 10 years, has now been cleared for commercial launch in Switzerland. Several clinical trials are in progress for cancer immunotherapeutics (Table, pages 26 and 27), though the data won’t be in for most until 2009 and beyond.
Complicating the picture is the inequality of cancers. Will prostate cancer or melanoma be more easily treatable with immunotherapies than pancreatic cancer?
“The hope is that some of the mechanisms of action might enable us to explore the utility of these refractory cancers,” says Lyerly at Duke, which is working with the Center for HIV/AIDS Vaccine Immunology on vaccines for hemomalignancies and breast, colorectal, brain, and skin cancers.
Many developers have targeted melanoma because it is often refractory to chemotherapy, even though interleukin 2 was seen as marginally beneficial, Lyerly says. “We are learning that the innate immune and adaptive immune responses may really influence the behavior of malignant cells, and if we can manipulate them somehow, we think we can provide a good outcome,” he says. “That is in the realm of cancer immunology and vaccine development. These vaccines are not a tetanus shot.”
Among the chief contenders for FDA approval, just under half are personalized vaccines. These may be the quickest way to prove in principle that vaccines work, Lyerly says. Over the long term, though, he thinks something so technologically challenging and expensive will not be widely applicable.
That again raises the question suggested at the outset of this article: Are these vaccines for prevention or treatment? The answer is not trivial because of the insurance coverage implications.
“Let’s say you have a precancerous condition of the breast, ductal carcinoma in situ, and then you immunize and you prevent that from progressing. That’s not really preventing and that’s not a therapeutic vaccine, because you don’t have breast cancer yet, Lyerly says. “But if you look at the genome of DCIS, it’s very close to invasive cancer. That’s where I start wondering, ‘What is really therapeutic?’ For example, suppose you want to prevent recurrences. Is that really a therapeutic or a preventive vaccine?”
“An interesting question,” replies Farino, at PWC. “Our existing payer model doesn’t really address prevention. I don’t know what the ultimate answer will be, but certainly from an economic standpoint, it is in the best interest of payers and patients to deal with prevention.
PWC’s report puts Farino’s comment in perspective by comparing Gardasil to the normal course of therapy for multiple sclerosis. “The two aren’t related,” Farino says, “but it was a way of juxtaposing a disease-altering, or preventive, vaccine for $400 per course of therapy with another that is north of $20,000 for palliative care. Part of the issue is that markets have become accustomed to paying very, very low prices on vaccines, which is one reason that the vaccine business went the direction it went.”
That may now all change.
Farino believes that products that demonstrate value should be rewarded. Moreover, he stresses, if they drive an outcome that can be demonstrated to prevent disease and avoid cost, payers are going to have to look at that and say, “That’s the right answer.” The healthcare system has long been criticized for having a model “that looks back to front,” meaning it tends to pay for treatments for acute and chronic illness. “To underwrite a model that says ‘I’m going to prevent disease in someone who isn’t likely to be a member of my plan in years to come’ is something else.”
A shift in the emphasis of healthcare to prevention is something the fathers of managed care envisioned in Jackson Hole 30 years ago. These new technologies have the potential to force the issue — and as they do, biopharmaceutical companies and payers will have to work through some difficult legal, regulatory, and coverage issues, even as they face new business opportunities.
As Sullivan, at Specialty Pharmacy Solutions, likes to say: “In change, opportunity. In crisis, the greatest opportunity.”