All medical progress brings risks. The hunger for their children’s survival drives the demand by parents; the hunger for profits motivates pharma - along with justifying years of effort; and there’s yet another yen: the hunger of doctors and researchers to score “a success.” The FDA and various ethical protocols are supposed to provide oversight. These include vetting proposed clinical trials by supposedly independent ethics boards, such as Institutional Review Boards (IRB), to provide another layer of supervision. But sometimes, permission is given to test what might be considered unreasonably dangerous therapies.
Lorenzo’s Oil
One such disease is cerebral Adrenoleukodystrophy [CALD]. And the story of the desperation of parents like Augusto and Michaela Odone to find a cure for their son, Lorenzo, who was suffering from this rare, debilitating neurological disease, is better known as “Lorenzo’s Oil.”
“In CALD, very-long-chain fatty acids (VLCFAs) build up in the brain and can destroy the protective myelin sheath around the nerve cells that control our muscles, interfering with their ability to communicate within the brain. Untreated, CALD progresses rapidly and can cause permanent cognitive and motor disabilities and death…”
Boys are typically diagnosed with the disease between 5 and 10 years old, gradually becoming mute, deaf, blind, and paralyzed before dying, typically within two to ten years.
Lorenzo’s oil, a fatty mixture developed by Lorenzo’s father, seemed to work, but clinical trials haven’t verified the effectiveness and is still considered experimental by the FDA. A newer experimental gene therapy treatment carried out by Boston Children’s Hospital (costing $3 million) is available in the form of a viral-vector gene therapy. Last week, carcinogenic effects of that therapy were reported in 10% of the study’s recipients.
According to the NEJM, the researchers describe the risk of the gene therapy, “eli-cell,” to cause cancer, oncogenesis, as “unclear.” Quite the contrary. The risk turned out to be very clear, as STAT reports:
“Seven of the 67 children who received Bluebird Bio’s gene therapy Skysona … developed blood cancer. [N]ew research shows — and one patient has died from complications stemming from the cancer treatment.” The adverse events developed 14 to 92 months after treatment.
Early phase 2 and 3 clinical studies reflect that the treatment has produced very good results. One study in the New England Journal of Medicine reported that 26 of 32 boys studied improved significantly.
The real question is, did the benefits outweigh the cancer risks?
Risks
The risks are disclosed in the study protocol, although exactly what was disclosed is unclear. A prior version of the therapy noted that there were 5 out of 20 serious adverse events, although therapy improvements were projected to minimize – but not eliminate – risks.
A spokesperson for the manufacturer, Bluebeard Bio, noted that “the cancer cases were previously known to a safety monitoring board, FDA, and patient advocates, and are reflected in a warning label for the product.”
But, researchers are expecting more children to develop cancer in the coming years.
“All of us who are in this space would give anything for there not to be [more cases]/ But I think that is not a practical likelihood.”
- Dr. Christine Duncan, Researcher, Boston Children’s Hospital
That means that the remaining 60 trial participants now must worry about cancer, the likelihood of which increases as time marches on. However, given the horrors of the disease, perhaps this might be an acceptable risk parents wish to take. [1]
Evaluating Research on Human Subjects
As Dr. Miller and I wrote, international protocols exist to assure the protection of volunteer subjects in medical experimentation. The crucible for this paradigm is the Nurenberg Code, developed in 1947, establishing “the prime directive,” which states that no research may be conducted without the subject's informed consent. That “the voluntary consent of the human subject is absolutely essential” is folded into the Declaration of Helsinki, the standard utilized in the protocol for testing the CALD therapy.
The Legacy of Jesse Gelsinger
Viral gene vector therapy, of which this therapy is an example, has a notoriously bad history. The technology first received widespread prominence in 1999 after its use to treat a genetic metabolic disorder, ornithine transcarbamylase deficiency (OTC), suffered by an 18-year-old named Jesse Gelsinger, which impacted his body’s ability to break down ammonia. Jesse’s OTC was supposedly controlled by diet and medication, and ostensibly, he entered into the study conducted at the University of Pennsylvania with “a humanitarian objective,” i.e., believing the (viral vector) treatment posed little risk to him and would help those born with OTC in the future. A few days after being administered the treatment, Jesse died. The cause of death: multiple organ failure triggered by the viral vector. Coupled with an inaccurate benefit analysis was a lack of disclosure of the risks, resulting in a lack of fully informed consent.
Confounding the decision to administer the therapy were alleged financial conflicts of interest between the researcher and the physicians. Jesse’s father sued the University of Pennsylvania and persons involved with the research, including prominent bioethicist Dr. Art Caplan, director of Penn’s Center for Bioethics, who sat on the gene therapy team. [2] While noting the problems incident to clinical trials, Caplan recounts a different version of events. As reported by the British Medical Journal, Caplan said Jesse had to take 40 pills a day to control his metabolic disorder and had four life-threatening crises a year and that no one with his disorder had lived past 27. The facts make a difference, but so does the lack of clear guidelines for ethicists approving trials. Worse, perhaps, is that case set viral vector research back at least a decade. [3]
“The area is rife with hypocrisy… "The system is broken. It's been broken for a long time. It took gene therapy to make it evident. Monitoring is non-existent. Adverse event reporting is a joke."
- Dr. Art Caplan, bioethicist
The Gelsinger case is surely distinguishable from the CALD study. In the CALD study, we have children who are unquestionably suffering from a serious and fatal disease who would benefit from successful treatment; informed consent is full and fair, and even knowing of the risk of cancer, the parents might have consented.
“This is a severe adverse event, [but] we should never lose sight of the fact that so many patients … have been helped. [These findings] could help scientists and researchers design safer and better vectors for the future.”
- Dr. Punam Malik, hematologist, Cincinnati Children’s Hospital
But there are other concerns: While there is no hint of financial conflict of interest driving this specific research, in many cases, the university or medical institution conducting the trial (who often also supplies the IRB) stands to benefit financially and promotionally via publication.
Even as promises are being made to continue this research, other ostensibly safer means of treating CALD are either available or under development:
In 20% of cases, the treatment of choice is a matched-sibling bone marrow transplant, although it is not fool-proof; deaths from presumed graft-versus-host disease have been occasionally reported. And there is competition from a CRISPR gene-editing treatment that is nearly $1 million cheaper and portends to be safer. That doesn’t help Bluebird Bio, which has invested years in developing this therapy. But when those involved in the work have reservations, perhaps it’s time to take a step back:
“There’s some biology that we need to understand better.”
- Dr. David Williams. Chief, Division of Hematology/Oncology, Boston Children's Hospital
[1] The recipients are underage, and while their “assent” is important, the ultimate decision-making, the consent, vests with the parents, a factor that carries ethical concerns of its own.
[2] The case was eventually settled, and Caplan was released as a defendant
[3] Ricki Lewis, The Forever Fix, Gene Therapy and the Boy Who Saved It
