Gene Therapy 2002: Setting the Standards

Current standards of care may shape future expectations for hemophilia gene therapy

by Kevin C. Kelley
The Parent Exchange Newsletter - February 2002
© LA Kelley Communications Inc., 2002

The young generation of hemophilia patients in the U.S. can aspire to active, full lives.

But for most of the world, care is sporadic or nonexistent, with traumatic bleeds, crippling joint damage and premature death all too common.

United States Remains Focused on Safety

Researchers and companies in the U.S. hoping to develop gene therapy as a treatment or cure for hemophilia face numerous scientific obstacles. They also face stringent regulatory and marketing requirements to develop a product with exceptional safety and efficacy. Because infusion therapy (treatment with recombinant or plasma-derived factor) has proven so effective and, for the past fifteen years at least, extraordinarily safe, the bar is raised for anyone hoping to replace either on-demand or prophylactic factor treatment with gene therapy.

As human trials of several different gene therapy methods proceed (see table), a number of positive signs have emerged that offer continued hope that gene therapy will eventually work as a cure for hemophilia. Yet much attention has focused on setbacks in each of the trials. Fortunately, no severe side effects or deaths have occurred in the hemophilia trials, but no trial has proceeded without interruption. Each of the five trials initiated has been halted for a time, to address safety or regulatory concerns. Both of the trials begun within the past year were halted after unexpected findings in the first patient treated in each trial. This scrutiny of ongoing trials clearly demonstrates that safety standards for the trials are very high, but also indicates that many unresolved issues remain.

Advocacy groups, most notably the National Hemophilia Foundation (NHF), are closely monitoring the ongoing trials, as are government agencies like the Food and Drug Administration (FDA) and the Recombinant Advisory Committee (RAC) of the National Institute of Health (NIH). Additionally, each institution conducting trials has its own internal Institutional Biosafety Committee (IBC) overseeing each trial. The NHF’s dual objective is to aggressively support and encourage research toward a cure, while taking steps to ensure that all safety risks are adequately addressed. This is not always a simple task; it is often difficult to determine which risks are reasonable and unavoidable, and which risks are excessive or better addressed by additional laboratory experimentation. Some risks can’t even be anticipated until they occur, and the decision becomes whether to terminate a trial or allow it to proceed. In an effort to minimize risks in future trials, the NHF’s Medical and Scientific Advisory Committee (MASAC) has issued guidelines for conducting human gene therapy trials.¹ The NHF has also expanded efforts to educate consumers, especially prospective trial participants, on the risks and benefits of human trials.²

The focus on safety in gene therapy trials was emphasized in September 1999, when Jesse Gelsinger, a teenage patient in a non-hemophilia trial, died as a result of the gene therapy procedure.

Yet for hemophilia, the commitment to safety probably owes more to the impact of HIV and hepatitis within our community. Devastated by products that were once thought to represent the safest and most advanced treatment available, our community is now committed to ensuring that another iatrogenic (treatment-related) disaster does not occur. In recent years, for example, the NHF has consistently advocated for limiting the release of factor products that may, even theoretically, have been contaminated with Creutzfeldt-Jakob Disease (CJD).

While recognizing that such restrictions might reduce the availability of donors and, eventually, factor itself, the NHF has argued that this risk is not worth taking until safety is proven—essentially establishing a “zero tolerance” policy regarding risk of contamination in factor. At an April 2000 WFH conference in Montreal, NHF President Mark Skinner explained, “The essential elements of our current effort can be captured in three concepts: safety, availability and affordability... It is imperative that safety is always the first and foremost consideration in our decision-making process. Until persuaded otherwise, we will not accept risk, even at a theoretical level. We simply have no other choice.”⁴

While these comments were directed specifically at factor concentrates, most hemophilia advocates in the U.S. are similarly convinced that safety must play a primary role in gene therapy. However, some researchers worry that we may become too restrictive, arguing that gene therapy trials should be called clinical “research” rather than “trials,” to emphasize the experimental nature of the work. NHF President-elect Glenn Pierce, MD, Ph.D., explains, “We may need to accept a significant level of risk if we ever hope to achieve the ultimate goal of curing hemophilia.” According to Pierce, gene therapy “clinical research” differs from the clinical trials for factor products in which many community members participated: the nature of the clinical trials offered limited risk and almost guaranteed efficacy. “Entering a clinical trial to test a new recombinant factor VIII,” says Pierce, “patients fully expect it will work and cause no side effects. In contrast, gene therapy is a novel technology for which the only way to identify and quantify some risks is through human experimentation.”

To Pierce and others, the key is to conduct appropriate testing in animals before treating humans, whenever possible. More important, it is essential that all trial participants give “informed consent.” We will never be able to eliminate all risk in gene therapy trials, but as long as the risks are identified as clearly as possible to patient participants, believes Pierce, “the ultimate burden of choice rests with the individuals in the trial and their physicians. If we put too much emphasis on trying to guarantee safety, we may impose restrictions that can never be met, effectively derailing gene therapy or, perhaps, discouraging researchers from choosing hemophilia as the disorder to study. That would significantly delay scientific breakthroughs that will benefit those of us with bleeding disorders.”

Philosophical arguments aside, specific issues raised by the human trials have required regulators to make concrete decisions about when to allow gene therapy clinical research to begin, or continue. Some issues appear minor, even trivial. Others raise important questions about what level of risk we, as a community and a society, are willing to accept as part of our progress toward attaining gene therapy’s promise. With the potential benefit so high—perhaps the cure for hemophilia and a multitude of disorders—our willingness to accept some risk seems appropriate. The question, theoretically and practically, is how much risk? And should the level of risk we accept depend on the likelihood and degree of benefit?

The first interruption in a hemophilia gene therapy trial occurred in the hemophilia A trial sponsored by Transkaryotic Therapies, Inc., conducted at Beth Israel/Deaconess Hospital in Boston. This “hold” came in early 2000, after the death of Jesse Gelsinger in late 1999 focused a spotlight on gene therapy trials around the country, including another unrelated trial at the Beth Israel/Deaconess in which regulatory irregularities were uncovered. Perhaps in response to negative publicity, and apparently hoping to demonstrate their commitment to patient safety, the authorities at BI/Deaconess announced the suspension of the hemophilia trial to review its safety profile. Ironically, this hold only cast further suspicion on the entire gene therapy field. In fact, the BI/Deaconess hemophilia trial was proceeding with no safety incidents, and with small but significant efficacy findings. Ironically, the suspension of the TKT trial was imposed at a time when no new patients were being recruited, so the announced suspension had no real impact on how the trial was proceeding. Fortunately, hospital administration moved quickly to lift the hold, and the trial was allowed to proceed as planned. The suspension was a front page story in The Boston Globe; the trial’s subsequent resumption, a footnote buried deep inside the same newspaper. While it appears that no real safety issue was ever involved, suspicion was cast on a trial that could instead have been used as an example of the proper way to conduct a gene therapy trial.

The second hold of a hemophilia gene therapy trial occurred in the summer of 2000. A routine test of a semen sample from a patient in the Chiron trial showed traces of the viral vector used in the procedure to transfer the factor IX gene. In pre-clinical animal studies, this vector had never been found in the semen of treated animals, so the result led the FDA to request a temporary halt of the trial. The presence of vector in semen raises the possibility that the vector could infect sperm cells, and eventually be passed through the germline (eggs or sperm) to future offspring. So far, no one knows exactly what effect this might have, but to date the scientific community and regulatory authorities have never allowed a trial to take place involving intentional germline transfer. The possibility of unintentional transfer is still seen by most as an unacceptable risk.

Fortunately, investigators for the Chiron trial reported that additional testing of the sample in question produced negative results, as did subsequent sampling from the same patient. It was concluded that the initial test result was probably an error, or “false positive.” Chiron received FDA permission to resume the trial, but stopped it soon after, for what Chiron called “business reasons.”

The third trial to be put on hold was Avigen’s trial for hemophilia B, involving intramuscular injections of adeno-associated viral vectors. In this trial, as with the TKT trial, the suspension was not directly related to a specific side effect in any of the patients. In Avigen’s case, reports from other adeno-associated viral studies in mice had yielded some initial evidence that the mice being studied were more likely to develop tumors after being treated with the vector. However, a review by the FDA and RAC concluded that these results were unlikely to be relevant to the Avigen trial, and this hold, like the others, was also lifted.

It’s apparent from these examples that putting a trial on hold doesn’t mean that any patients are actually at risk—but there is enough cause for concern to pause and resolve uncertainties before moving ahead. Caution remains the guiding principle in all trials. The interruption of a trial is often a business or logistical setback, rather than a real scientific problem. However, in the two most recent holds, both of which occurred in 2001, actual side effects were observed that truly warranted the suspension of the trials, at least temporarily. Regulatory authorities now had much more complex decisions to make about allowing the trials to proceed.

The issue of positive semen samples, first occurring in the Chiron trial, has reappeared in the second Avigen trial for hemophilia B. Like the first Avigen trial, this trial utilizes an adeno-associated viral vector; but in this case, the vector is infused into the hepatic (liver) artery, targeting the liver, rather than injected into muscle. In general, infused vectors (like the retroviral vector used in the Chiron trial) are more likely to travel through the bloodstream to remote sites in the body, and get into various tissues and organs. This is usually considered insignificant, since the amount of vector that ends up in various tissues is small, and normally persists only briefly before it is “cleared.”

It is hoped that little harm will be done by this roving vector. However, several sequential semen samples from the first patient treated in the liver-directed Avigen trial were positive for vector. Once again, the remote possibility was raised of vector getting into a patient’s sperm, and being passed on to sexual partners or offspring. Once again, the FDA requested the trial be put on hold. But since the samples were truly positive this time, decisions had to be made: Was the presence of vector in the semen reason enough to permanently halt the trial? Still determined to minimize the risk of germline transfer, investigators continued testing—until several sequential samples showed that the vector did indeed clear from the semen. They also tested for signs of the vector in actual sperm cells, and found no detectable traces of vector in the patient’s sperm.

After reviewing the data, the FDA decided to allow the trial to resume, but with some alterations: additional steps to monitor patients’ semen and sperm would be incorporated into the trial; and participants would be advised to avoid unprotected sex until it was demonstrated that their semen was free of vector. It is likely that this trial will proceed more slowly than originally planned, but if no further problems arise, it should proceed to completion. If additional persistent traces of vector are detected in semen samples, or if traces of the virus are found within future patients’ sperm, the trial may be subjected to additional holds.

The final trial to consider is the hemophilia A trial conducted by GenStar Corporation. This trial raises the most serious questions to date. Utilizing a modified adenoviral vector, the trial was initiated in June 2001, after numerous animal studies were conducted to evaluate its potential safety. Some of the tests (particularly a series of experiments studying non-human primates) were designed to look specifically at the effects of the vector in animals whose immune responses were most likely to resemble what might be seen in humans. The GenStar trial, just like Jesse Gelsinger’s trial, uses an infused adenoviral vector targeting the liver. Some scientists and hemophilia advocates were concerned that the issues raised by Gelsinger’s death could be relevant, particularly since the exact cause of death has never been pinpointed. However, it is important to note that Gelsinger had a genetic defect that affected his liver; this may have made him particularly susceptible to toxic effects of infections. Studies conducted by GenStar indicated that even at a dosage of vector 100 times greater than the first patients in the trial would receive, the primates showed no significant side effects. Based on this information and other extensive pre-clinical data, GenStar received FDA approval to initiate its trial.

Unfortunately, the first patient treated with the GenStar protocol quickly developed unexpected side effects, including a drop in platelets and factor VII levels, and increases in several liver enzyme levels. These effects were transient, and the patient’s levels soon returned to normal. But the results raised enough concern that GenStar, in consultation with the FDA, placed the trial on hold. GenStar noted that, even at this very low dosage, a measurable rise (up to 3%) in circulating factor VIII levels was observed in a patient whose factor levels were previously undetectable. The levels have apparently been sustained at about 1% over several months. GenStar stressed that all the side effects were transient, and while the deviations in blood chemistries were real, they were never severe enough to cause a health threat to the patient. Also, the patient had a high, pre-existing antibody response to the adenoviral vector, raising the possibility that patients with lower antibody levels might respond differently. After reviewing the protocol and the patient’s lab results, the FDA agreed to allow the trial to resume with modifications. GenStar agreed to lower the starting dosage ten-fold, to minimize the chance of repeating the first patient’s side effects. To date, no new patients have been enrolled or treated, and the NHF and GenStar continue to discuss the best way to move forward with this research.

Unquestionably, the envelope has been pushed. The debate over what level of risk is acceptable has intensified. Not all experts agree with the FDA ruling allowing the GenStar trial to continue. Some feel that until the immune response to adenoviral vectors is better understood, it is too risky to use them for anything other than life-threatening disorders. Some consider it premature to use these vectors for hemophilia, in relatively healthy patients who have viable alternatives in existing therapy. On the other hand, many proponents of gene therapy clinical research point to the overall safety of gene therapy, believing that we must accept some level of risk if we hope to achieve true progress.

It is unknown whether the immune response seen in the GenStar patient is related to that seen in Jesse Gelsinger. It is also unknown whether future patients face a real risk of repeating either the effects seen in the first GenStar patient, or those seen in Gelsinger. What is beyond question is that the decision to conduct trials, and the decision to enroll in them, has become more complex, requiring greater consideration by all involved—regulatory authorities, trial sponsors, doctors conducting the trials, advocacy groups like NHF and, perhaps most important, the patients themselves.

Identifying, quantifying, and accepting risk is an inherent part of the discovery process in medicine. As it does in all new areas of medical research, the debate over risk will continue, not just in the hemophilia trials, but across the field of gene therapy. Additional risk factors will emerge, or shift from theoretical risk to real risk. So it’s possible that the closer we get to seeing the fruits of gene therapy and realizing its benefits, the more difficult the decisions will become. As we wind through this process, our guiding principle must be to ensure that we not take excessive, unnecessary risks during the trials, and that we understand any process thoroughly before allowing it be used on a broad commercial basis.

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Risk-Benefit Considerations Far Different in the Developing World

Most adults with hemophilia in the U.S. are living with HIV or hepatitis. Teenagers, for the most part, live active, nearly normal lives, largely unaware of how fortunate they are to have escaped the HIV ‘holocaust’ of the early 1980s. Younger children with hemophilia are often treated prophylactically—many have never been treated with plasma-derived factor concentrates, and have no concept of the physical and emotional trauma that older people with hemophilia have endured. But what unites these groups, their families and caregivers, is the conviction that they will never again accept any compromise in the safety and efficacy of the treatment they receive.

The proactive U.S. hemophilia community has demanded, and received, products with ever-improving safety profiles: extensive screening of plasma donors; plasma quarantining; monoclonal purification; viral inactivation (even double viral inactivation of some plasma-derived concentrates); recombinant factor concentrates; and now, even recombinant products free of all human albumin and/or animal proteins. Considering our history, if gene therapy is to succeed in the U.S. it will need to achieve extraordinary levels of safety, and prove more effective than current treatment. Why would we settle for a therapy that is less safe or less effective than what we already have?

But not everyone can afford to insist on such high standards of safety or efficacy. Not everyone has safe and effective treatment readily available. In fact, the World Federation of Hemophilia (WFH) estimates that worldwide, three out of every four people with hemophilia receive no care or sporadic care. And the chance is slim that most of these people will ever gain access to meaningful care in the form of factor concentrates. For approximately 200,000 of the world’s 270,000 with hemophilia, treatment consists of little more than ice and rest—assuming that ice is available, and rest is a possibility.

Not surprisingly, many patients in developing countries view gene therapy differently than we do in the U.S. For them, gene therapy is not just one more step forward in the search for a cure; it is the last, best hope for meaningful treatment in the foreseeable future. Yet because most of the gene therapy programs are being developed in the U.S., they are designed in accordance with the regulatory standards and economic realities of the U.S. market. As a result, any processes developed may remain inaccessible to most patients in developing countries, long after the scientific obstacles to successful gene therapy have been overcome.

Medicine is not the only arena in which accepted standards vary from country to country. What is unusual is the degree to which medical standards of the most highly developed countries, like the U.S., dictate what care is, or isn’t, available to the rest of the world. When it comes to housing or general public health issues like water quality or food inspection, developing countries clearly cannot be held to the same restrictive standards that are justified in industrialized countries. Most Americans support the “watchdog” efforts of domestic agencies like the Environmental Protection Agency, the Food and Drug Administration, and the Centers for Disease Control. Yet no one would suggest that villages in Ethiopia or Cambodia should be required to conform to the same housing or public health standards expected in the U.S. In most policy areas, local communities or individual countries determine which regulations, if any, are warranted, weighing the economic, cultural and technical factors affecting each community. Unfortunately, when it comes to medical care, the choice for developing countries is often all-or-nothing: conforming to the standards of highly industrialized countries, or providing no care at all. Except for regional herbal medicines and a few locally manufactured pharmaceuticals, the developing world is almost entirely dependent on the developed world for producing the drugs and medical devices it needs. Frequently the options are limited: either pay dearly for these expensive treatments, or choose not to treat at all.

Clearly, millions of patients around the world have benefited from vaccines, antibiotics, and other drugs that have saved countless lives. But as advanced technologies, including recombinant drugs, are developed, they are often targeted for consumers in highly developed countries—consumers who can afford expensive treatments. Part of the problem is that U.S. drug companies prefer to focus on lucrative products like PROPECIA® (to treat hair loss), VIAGRA® (to treat sexual dysfunction), and a host of obesity drugs, all targeted American men facing cosmetic or lifestyle changes—rather than conduct research on vaccines and drugs that could ease the many infectious and parasitic diseases that go untreated in developing countries. Even without considering economic motivation, the very structure of the pharmaceutical industry and the design of drug development programs in the U.S. make it unlikely that the end products—factor concentrates or gene therapy—will readily reach the hands of the patients who need them most.

Many factors affect the availability of drugs and other medical products in developing countries. Two of these, high cost and stringent safety requirements, are particularly relevant to hemophilia products—existing factor concentrates or, potentially, future gene therapy products. In the U.S. and other highly developed countries, cost is a concern, but not usually a critical factor in a consumer’s decision process. Most consumers are covered by either private insurance plans or government health programs. Healthcare cost containment is an important topic of political debate in the U.S., but at present few patients actually are denied access to high purity concentrates due to cost alone. This is not the case in the developing world, where people are rarely able to obtain product on their own, and where government expenditures needed to secure factor for patients are impractical. According to the WFH, the per patient cost to provide factor for patients in developing countries would be a minimum of $9,000 per year—a completely unrealistic figure in many countries.

Will gene therapy cost as much or more than factor concentrates? The final cost is unknown, but gene therapy is unlikely to be inexpensive. A novel technology that has required years of research and development to reach its current status, gene therapy will probably require years more before becoming commercially available. The methods currently being studied don’t appear to be simple to manufacture on a large scale, and some of the programs will be difficult to distribute or administer globally, without incurring extraordinary expense. Right now, greater emphasis is on safety and efficacy than on the eventual affordability of a gene therapy process.

The emphasis on safety in the U.S. and other industrialized countries is understandable. Devastated by viral contaminants like HIV and hepatitis in factor concentrates, the U.S. hemophilia community is united in the conviction that safety must be a dominant consideration for all products, including gene therapy. The depth of this feeling was conveyed by Mark Skinner, President of the National Hemophilia Foundation, at a WFH Forum in April 2000.¹ Referring to the theoretical risk of CJD in factor concentrates, Skinner said, “Safety is always the first and foremost consideration in our decision-making process,” noting, “Our community has made too great a sacrifice to allow history to repeat itself.”

Although these comments were directly aimed at factor concentrates, a comparable sentiment exists in the U.S. community regarding gene therapy. Even in initial human clinical studies, where risk is unavoidable, great effort is made to minimize risks and respond quickly to any perceived risk factors that emerge. It is unlikely that, on a commercial scale, any gene therapy process will ever be widely accepted if it carries even a minimal risk of transmitting harmful viruses, or increased risk of inhibitor formation. Expectations in the U.S. are great, and the bar is raised high for researchers hoping to introduce new treatment methods.

By comparison, the majority of the world suffers from conditions that most Americans can barely imagine—untreated bleeds; severe arthropathy and crippling joint damage; frequent internal bleeds leading to brain injury or damage to other organs; infections from bleeds leading to amputation; even premature death from bleeds easily treated in more highly developed countries. Under these circumstances, the emphasis on safety that seems so appropriate in the U.S. is untenable. According to Mark Skinner, “Until persuaded otherwise, we will not accept risk even at a theoretical level.” Yet Ashok Verma of India, another presenter at the WFH Forum, used similar words to express a very different view: “In developing countries, there is usually no choice. When faced with an acute complication because of hemophilia, and with no access to safe concentrates, any form of replacement therapy has to do.”

Neither side is wrong. Each simply deals with differing realities in differing communities. However, we must keep in mind that the decisions made in the U.S. and other developed countries have a great impact on lesser developed countries. Our decisions about which products to develop or sell can directly determine whether care is—or is not—available to the rest of the world. If we require, directly or indirectly, all nations to adhere to the standards we demand in developed countries, we may effectively eliminate the chance for developing countries to access treatment of any kind. “If the developing world accepts the safety standards applied in the developed world,” notes Ashok Verma, “there would not be any therapeutic material available, and 80% of people with hemophilia in the world would be condemned to permanent crippling and premature death.”

So far, it is too early to predict which gene therapy methods will work, and whether they will be globally accessible. But it is not too early to begin examining how global access to gene therapy might be made more feasible. For gene therapy to ever be considered a real success, it must reach the tens of thousands of patients who need it the most—patients in developing countries who have little hope of ever gaining access to meaningful care in any other way. We must expand our current dialogue on issues that might affect global access, and search for ways to make global access to hemophilia gene therapy a viable goal. It is too soon to hope for clear answers, but not too soon to begin asking questions.

Hemophilia Gene Therapy Clinical Trials

Kevin C. Kelley is DNA Products Manager at New England Biolabs in Beverly, MA, and father of a fourteen-year-old with hemophilia. He has published articles on blood safety and recombinant factor products previously in PEN. You can reach him with comments or questions at (800) 249-7977 or info@kelleycom.com