Enzyme replacement therapies promise improvement or even a second chance at life for patients with ultra-rare diseases. At a quarter to a half million dollars a year, these therapies require careful patient management.
Abstract
On the highest end of the drug-cost spectrum, enzyme replacement therapies are beneficial to only a few thousand patients at most. But to give those with life-long struggles a chance at a ‘normal existence,’ can insurers and employers put a price on hope? The field is booming, making the question more important with each passing day.
Leslie Fish, PharmD, has seen the data on enzyme replacement therapies (ERTs). As head of pharmacy services for Fallon Community Health Plan, in Worcester, Mass., Fish dedicates staff to monitor those rare times when a member needs these therapies. Like all medications, sometimes ERTs are very effective and sometimes they are not. For many patients, they are very much needed, and in others they may not be. Many times, these medications are given even if a patient does not get better.
“We call that ‘paying for hope,’” says Fish. “It’s really hard to do that with a medication that costs half a million dollars a year.”
One injectable pharmacy specialist at Fallon tracks patients requiring these infusion drugs, along with other injectable ERTs. She also follows a patient to make sure that he or she is getting the right dose, and tracks each case to see if it’s having the desired effect.
ERTs are on the highest end of the cost chart for drugs. In a field perhaps first brought to public awareness with a treatment for severe combined immunodeficiency disease, or Bubble Boy disease, in 1990, a growing number of ERTs are entering the market. Several cost between $200,000 to $300,000 a year for conditions that typically affect only a few hundred to a few thousand people in the United States. In extreme cases, says Fish, she has seen a patient’s cost rise to close to $1 million. That puts a severe strain on a health plan.
Shire HGT’s pipeline includes therapies for what President David Pendergast, PhD, calls “ultra-orphan diseases.” A therapy for Gaucher disease is nearing phase 3 trials, and preclinical trials are being explored for MPS III.
PHOTOGRAPH BY CHRIS FITZGERALD
“Enzyme replacement fits into a very large discussion of how we are going to maintain what we are doing and give everyone what they need at the current rate,” says Fish. “Some of these are great products, but there’s going to be a point when even those who have the deepest pockets will look back and say, ‘How did this happen and how are we going to continue to pay for it?’”
Since the passage of the Orphan Drug Act in 1983, dozens of biotech companies have sprung up to advance new research into neglected fields, including enzyme deficiency. Hunter syndrome is one example of an enzyme deficiency. Others include Gaucher disease, Pompe disease, Fabry disease, and Niemann-Pick disease. Several new FDA approvals this year will provide a further test of third-party payers’ tolerance for the cost of the products.
Some relief may be on the horizon. A few new ERTs and other products based on competitive technologies are in the pipeline and are being positioned as lower-cost alternatives. Eventually, they may offer the field’s first taste of price competition.
COST OF A NORMAL LIFE
Hunter syndrome, or Muco-polysaccharidosis II (MPS II), attacks early, punishes its victims, and cannot be prevented. It begins to become apparent — at least to the most observant physicians — when children are anywhere from 1 to 3 years old. Those afflicted are not producing iduronate sulfatase, an enzyme needed to break down complex sugars. The cell damage that results causes growth delay and the development of abnormal facial features. In the worst cases, there are breathing problems, cardiovascular complications, and enlargement of the liver and spleen, resulting in early mortality.
But last summer, patients gained a new therapy to turn to.
Shire’s Human Genetics Therapies (Shire HGT) division — the U.S. subsidiary of the United Kingdom-based company created when Shire purchased Transkaryotic Therapies last year — developed idursulfase (Elaprase), the only treatment option for patients diagnosed with Hunter syndrome. Idursulfase gained FDA approval in July as an orphan product that is now on the market for a patient population of about 500, a number that wouldn’t even amount to a rounding figure for most blockbuster therapies.
The therapy is a recombinantly prepared enzyme, grown in a human cell line and given intravenously. “It’s literally a replacement for the deficient or missing enzyme in Hunter patients,” says Shire HGT President David Pendergast, PhD.
For the 96 patients with Hunter syndrome who enrolled in Shire’s late-stage clinical trial, it is also a key to a better life. On average, patients receiving weekly infusions were able to walk 38 yards farther in a 6-minute test after 12 months of therapy than the control group. The degree of liver and spleen enlargement also improved.
But Pendergast also is quick to note that neither idursulfase nor any other ERT is a cure. Like insulin, treatment with ERT must continue for the benefits to remain, and over the years, researchers will track their experiences to determine the real long-term effects. To that end, Shire HGT tracks health data among individuals affected by Hunter syndrome as part of the company’s long-term Hunter Outcome Survey (HOS). HOS is designed to support the gathering, analysis, reporting, and sharing of Hunter syndrome data from around the world.
They’re working with a group of patients for whom the drug is a lifeline.
“This is an extremely motivated patient population,” says Pendergast, who remembers a lunch with the parents of a boy who suffered for years from a malady that puzzled most of the physicians he saw.
Pendergast relates how the parents painfully recalled watching their child go through every terrifying step of development: the failure to progress, respiratory problems, difficulties with everyday activities, and the struggle to “be a normal kid.”
Now, all of a sudden, there’s a therapy available. There’s reason for hope.
“There’s the theoretical potential for having a normal life if you’re diagnosed early,” says Pendergast. “Some of the impact of the disease is reversible. One of the things that happens with this disease is that substrates build up, causing large livers and spleens. Those effects, for the most part, seem reversible until organs become scarred and can’t shrink.”
New screening techniques for newborns could offer quicker diagnosis and the opportunity to arrest the disease before it can create permanent damage, though that’s still years away from reality.
Shire does have a marketing advantage: seven years of market exclusivity as the country’s officially sanctioned therapy for Hunter syndrome.
“One of the difficult things about these ultra-orphan drugs,” he adds, “is that you have to go through the same development process as drugs that treat a much larger population. The development costs are very similar.”
He recites the steps. There’s the creation of an initial cell line, animal model testing to gauge the correct dosing and regimen, the entire clinical development stage with toxicology studies, and formulation work right through to the building of a factory.
Add it all up, says Pendergast, and the bill comes to around $150 million just to bring idursulfase to market.
HERCULEAN DEVELOPMENT EFFORT
Drug developers, while aware of the impact these costs can have on a health plan, also are mindful of the development model at work for medications that have such a tiny patient population.
Take the newly approved alglucosidase alfa (Myozyme), which won FDA approval in April as a therapy for Pompe disease.
Thus far, Cambridge, Mass.-based Genzyme has spent more than $500 million on the drug, according to company spokesman Dan Quinn, and there are plenty of additional costs ahead for postmarketing safety and efficacy studies and the disease registry, which are all requirements for gaining approval.
Selected emerging and recently approved enzyme replacement therapies and competing technology products
| Name | Manufacturer | Treatment for | U.S. stage of development |
|---|---|---|---|
| Alglucosidase alfa (Myozyme) | Genzyme | Pompe disease | Approved April 28, 2006 |
| ALTU-135 | Altus Pharmaceuticals | Pancreatic insufficiency | Phase 2 completed |
| AT2101* | Amicus Therapeutics | Gaucher disease | Phase 1 |
| AT2220* | Amicus Therapeutics | Pompe disease | Preclinical |
| GA-GCB | Shire | Gaucher disease | Phase 3 |
| Glucocerebrosidase | Protalix Biotherapeutics | Gaucher disease | Phase 1 completed |
| Idursulfase (Elaprase) | Shire Human Genetics Therapies | Hunter syndrome | Approved July 24, 2006 |
| Migalastat hydrochloride (Amigal) | Amicus Therapeutics | Fabry disease | Phase 2 |
| Sapropterin dihydrohchloride (Phenoptin)† | BioMarin | Phenylketonuria | Phase 3 |
Pharmacological chaperone technology.
Enzyme cofactor therapy.
SOURCE: BIOTECHNOLOGY HEALTHCARE ANALYSIS
“Myozyme represents some of the greatest technical challenges we’ve been able to overcome,” says A.J. Joshi, MD, medical director at Genzyme. “The amount of enzymes needed is enormous, and the technical challenges to make enough of the drug available are phenomenal.”
To gather even the small number of patients needed for an ERT trial, companies typically have to look throughout the world. “That effort is Herculean,” says Joshi. Physicians’ costs — infusing the drugs, updating patient assessments, and performing MRIs, to name a few — are huge, up to $100,000 per patient in a recent trial for Fabry disease.
To evaluate alglucosidase in 18-month-old children, the company’s researchers had to identify and enroll 18 infants younger than 6 months who have this extraordinarily rare ailment that is frequently overlooked. This process required searching for participants in the Middle East, Asia, and the United States, and, in some cases, bringing the families to its research site in Durham, N.C.
These children face a lifetime of affliction from a disease characterized by severe muscle damage that makes it difficult to walk or breathe, to the point that the respiratory complications can kill them. In recognition of their research and development breakthrough, Genzyme won the 2006 U.K. Prix Galien Gold Medal, a prestigious international award that recognizes outstanding innovation.
The science behind it also gained Genzyme orphan status for the therapy, and the company is wasting none of the seven-year window of exclusivity that comes with it.
For Genzyme to retrieve its development costs, fund new research, and make a profit on a product that is used by only a few hundred patients six months after market approval, patients and third-party payers share the burden of the price.
As an established developer of ERTs, Genzyme’s sales operations kicked an international campaign into high gear to gain reimbursements for the new product. Its sales of alglucosidase in the third quarter hit $20.4 million, gaining honorable mention for its place on the company’s roster of ERTs.
“ERT will require longitudinal data. We need a decade to a decade and a half of experience to answer questions about quality of life, and to assess morbidity and the long-term impact of these therapies.”
— Sharon Levine, MD Permanente Medical Group
“Myozyme is off to a strong start,’” Genzyme CEO Henri Termeer told analysts during a recent quarterly roundup of its numbers. “It will be a significant driver.”
PRICE ADVANTAGES
Years after the expiration of orphan drug status for its Gaucher disease therapy, imiglucerase for injection (Cerezyme), Genzyme still enjoys market exclusivity and high returns. Genzyme’s revenue for imiglucerase — approved 10 years ago — was still climbing even as alglucosidase was hitting the market. But that may eventually change. Some of the ERTs in the pipeline offer the first potential competition to pioneers like imiglucerase, along with the possibility that prices will start to come down.
To make imiglucerase, Genzyme modifies mammalian cells to create the sophisticated sugar structure the protein needs to work as a drug. Israel-based Protalix Biotherapeutics hopes to substitute the mammalian cells with plant cells that don’t require the same expensive laboratory process involved in trimming sugars.
“This is a big advantage,” says Protalix President and CEO David Aviezer, PhD. “The sugar pattern is not identical. Overall, the three-dimensional structure is very similar, but subtle differences in sugar composition seem to be beneficial on the biochemical and pharmacological level.”
A phase 1 safety study of its potential competing product, prGCD (plant cell recombinant human glucocerebrosidase), has wrapped up with positive results. Under typical circumstances, that would still leave most developers years away from filing for FDA approval. But Aviezer has mapped out a shorter path to market.
Protalix hopes that it can prove to the FDA that it’s ready to proceed right into a phase 3 trial. Provided that the trial delivers the data the FDA and European regulators need, Protalix wants to be able to review new data in 2008 and hit the market with a therapy priced less than imiglucerase.
Small patient populations can be a cost advantage, keeping sales and marketing costs down. So says Matt Patterson of Amicus Therapeutics, which is using pharmacological chaperone technology to develop therapies that would compete with ERT.
PHOTOGRAPH BY CAROL SEITZ
“Because our manufacturing process requires fewer steps needed to process the glycosomal residue on the protein,” says Aviezer, “we think we would have some price advantage.” But Aviezer isn’t willing — at least at this point — to get more specific on what that advantage could be.
Amicus Therapeutics, located in Cranbury, N.J., is developing products to treat several lysosomal disorders, based on a new approach called pharmacological chaperone technology, which is fundamentally different from ERT. Each of the lysosomal disorders, such as Fabry disease and Gaucher disease, are caused by a genetic mutation that results in the body’s inability to generate normal levels of a specific enzyme. In many cases, patients have a type of mutation that allows the cell to make the required enzyme, but, due to the genetic mistake, it is unstable and often “misfolded,” notes Chief Operating Officer Matt Patterson.
As opposed to the ERT approach of replacing what is deficient through infusion, Amicus’ small-molecule drugs are designed to “fix the problem at its source” by getting to all cells and binding to the unstable protein — and by doing so, helping it to perform its normal function in the cell, he says.
Patients who respond to this approach could account for 75 percent of those who have these conditions, says Patterson. On top of that, by developing a small-molecule drug that is taken by oral capsule, the company wants to do away with the large-molecule technology that mandates expensive infusion programs. In addition, pharmacological chaperone technology may have applications in more common diseases known to be caused by a mutation to a specific protein, such as Parkinson’s, cystic fibrosis, or even certain cancers.
Amicus has had its share of successes. Researchers exploring the experimental drug migalastat hydrochloride (Amigal) are enrolling patients in a phase 2 trial for Fabry disease. In addition, Amicus has an experimental therapy for Gaucher disease (AT2101) in phase 1 trials and a drug for Pompe disease (AT2220) that is currently in preclinical development.
Clinical trials will be less expensive without the need for a hospital-based infusion program, helping to bring down overall development costs. The key differentiator could be a different, and less expensive, manufacturing program.
And those $200,000 to $300,000 in annual ERT costs?
“We hope to offer a new treatment option that is priced well below ERT,” says Patterson.
If all goes according to plan, says Patterson, Amicus will go to the FDA for approval of its treatment for Fabry disease “in a few years.”
If there are any in-house qualms about potential new competitors hitting the market, Genzyme isn’t putting them on public display. The more businesses focus on ERTs, says the company, the better off patients will be.
At Genzyme, “Generally, our feeling is the more attention to these diseases, the better,” says Quinn. “Even though Cerezyme has been in market as long as it has, understanding and awareness of the disease is still pretty low.”
For some developers, the education effort starts with the insurers.
In situations like this, says Shire’s Pendergast, “We have to make the payer aware of the therapy and its impact on the disease. In the cases of those patients who might be eligible for Medicaid, we need to provide individual assistance to each patient in each state. You have to work through all the prior authorizations. Physicians may have to write letters. It’s unique to almost every patient.”
In the United States, private payers have the largest role to play. Shire has a program through which it works through the process with patients and their families.
THE CHOICE AHEAD
For the researchers, there’s good reason to believe that the number of ERTs available will grow for some time to come.
Theoretically, says Pendergast, 42 lysosomal storage diseases can be treated with ERTs. While some have populations that are too small or targets too inaccessible for current development strategies to reach, there’s still room for growth.
“I think this is an area that will expand for the next several decades,” he says.
For now, some integrated systems, such as Kaiser Permanente, are gathering their own data to evaluate therapies.
With most ERTs new to healthcare, says Sharon Levine, MD, associate executive director of the Permanente Medical Group, an insurer can play an important role in gathering data on how these therapies work in the long run. Most of the markers for patient improvement are biological, she says, and show that the deficiency has been reversed.
“We have an obligation to provide access to innovative therapies that make a difference, as well as an obligation to make certain that the investment is delivering a real health improvement,” says Levine. “ERTs will require longitudinal data. We need a decade to a decade and a half of experience to answer questions about quality of life, and to assess morbidity and the long-term impact of these therapies,” says Levine.
For payers, though, there’s very little leverage that can be used to gain a price concession.
“These are monopoly products,” says Levine. “There’s no opportunity for price concessions. Price concessions exist where the opportunity to say ‘No’ exists. You can’t say no, so you’re a price taker.”
Ultimately, she says, the best long-term hope that payers have for serious price breaks is whether Congress will mandate a regulatory procedure for approving follow-on biologic products.
Others in the insurance field are also pondering the long-term effect of such sky-high therapies. “We have to consider a lot of things,” says Fish, at Fallon. Although she cautions that “We’re not there yet,” more and more physicians are going to have to use a higher standard to evaluate ERTs and other equally expensive biologics.
ERTs can save lives, notes Fish, but there also needs to be long-term evidence that the drugs are doing what they are designed to do. Without that, she says, “There’s a choice that has to be made.”