Unproven Therapies Are 'Muddying' Cell and Gene Advances

Liam Davenport

February 25, 2019

HOUSTON — The revolutionary impact of novel cell and gene-based therapies that have recently been approved, many in oncology and hematology, is in danger of being muddied by a huge number of unproven therapies, which could ruin the field's reputation, warn two leading experts.

The world of cell and gene therapy is at a "crossroads," commented John Rasko, MD, PhD, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, speaking here at the Transplantation and Cellular Therapy (TCT) 2019.

So far, 44 such products have been approved worldwide. Of these, five have been approved in the United States. All of these products have followed the phased-development, empirical route to approval and are backed by clear evidence.

However, at the same time, there has been an explosion in the number of unregulated clinics offering stem cell therapy and other cell and gene-based therapies, which claim to treat a huge range of conditions. None of these therapies are supported by any data.

The proliferation of these unregulated clinics can confuse patients about what constitutes real cell and gene therapy and could ruin the reputation of the entire field, Rasko warned. There is also the risk that resources will be diverted from proven therapies to unproven ones.

Rasko said that, essentially, "there's an opportunity cost with everything.

"What breaks my heart is that people who are hardworking are doing crowdfunding, asking their neighbors, their families and friends for money to go down to the mall, to clinics where stem cells are advertised in the newspaper, and get their osteoarthritis treated, or indeed their migraines, or their kid's autism, or cerebral palsy, or all the things that ail you," he said.

"They're treated at $5000, $10,000, $20,000 a pop. That's hard-earned money for individuals," he continued.

"Now expand that to the whole industry and...the fixed medical budget approved by each government and jurisdiction each year, and you're looking at an opportunity cost," he said.

"If you're spending it on futile therapeutics that have never been proven, then you ain't spending it on things that I would suggest are going to do better," he concluded.

The day after the meeting, Medscape Medical News spoke with John F. DiPersio, MD, PhD, president of the American Society for Blood and Marrow Transplantation (formerly, the American Society for Transplantation and Cellular Therapy).

DiPersio pointed out that currently, there are 700 unproven therapies, as described by Rasko. He added: "Must I say more!"

DiPersio noted that none of the stem cell treatments that are offered at unregulated clinics have been studied in any kind of clinical trial.

"They are marketing products which are either ineffective or not proven to be effective," he pointed out. "I can't say they're deleterious, but we're allowing lots of things to happen without much in the way of regulation.

You can't just start injecting knees...and say you're curing people. Dr John DiPersio

"You can't just start injecting knees, and injecting spinal cords, and injecting everything else, and say you're curing people," DiPersio emphasized. Nor can you inject stem cells and claim to be regenerating the heart or liver.

"There has to be some kind of real, rigorous, preclinical and clinical development of these products," he said.

"Then you can sit up on a stage like this," he said, referring to the presidential symposium that he was chairing at the meeting, "and show your results, and then, maybe, regenerative medicines can be proven.

"I'm not saying you shouldn't test whether a stem cell can enhance heart recovery after a heart attack. You should, but none of that's been proven yet," he emphasized.

"And I'm not saying you can't test a stem cell or a targeted therapy to regenerate a liver, but I think these false claims are muddying the waters, and they tear down the brand recognition of real gene therapy and cell therapy," he said.

The presidential symposium that was held during the meeting highlighted research in cellular and gene therapy that has led to approved products. "It takes 20 years of hard work by many people" to develop a drug to the point of being approved, he said. It is also "very expensive and very tough," he commented.

He joked about the people who run the unapproved stem cell clinics: "If they knew it would take 20 years and all that effort to get a drug approved, they probably would have shot into some other discipline."

More Approved Products Coming Soon

In his talk at the meeting, Rasko predicted that more innovative cell, tissue, and gene therapies will appear soon. Approvals of these types of products are expected to increase by up to 900% by 2025.

This reflects the steady growth in approvals worldwide since the turn of the 21st century. The majority of approvals are in the United States, South Korea, and the European Union.

He said a total of 44 cell and gene therapy products have received marketing approval across the globe. Of these, 37 are cell therapies and seven are gene therapies.

He said 24 autologous products have been approved, of which 17 are allogeneic and three are gene vectors.

The indications for the therapies are increasing: 16 target oncologic and hematologic conditions; nine target skin, mucosal, or soft-tissue disease; eight treat skeletal diseases; and six are approved for immunologic conditions, including graft-vs-host disease.

The road to market approval for these therapies has been a long one, he commented.

He noted, for example, that the first report on the use of bone marrow transplant as a treatment for cancer was published in the late 1950s.

However, it was not until 1980 that the first successful transplant of hematopoietic stem and progenitor cells was performed, and it wasn't until the 1990s that the number of approved products began to increase.

Cell and Gene Therapies in the US

Rasko noted that in the United States, five cell and gene therapy products have been approved by the US Food and Drug Administration (FDA):

  • Talimogene laherparepvec (Imlygic, BioVex, part of Amgen), a biopharmaceutical to treat inoperable melanoma lesions

  • Voretigene neparvovec (Luxturna, Spark Therapeutics), a gene therapy for the treatment of Leber congenital amaurosis

  • Sipuleucel-T (Provenge, Dendreon Pharmaceuticals), a cell-based immunotherapy for metastatic hormone-refractory prostate cancer

  • Tisagenlecleucel (Kymriah, Novartis), a chimeric antigen receptor (CAR) T-cell treatment for acute lymphoblastic leukemia and relapsed or refractory diffuse large B-cell lymphoma

  • Axicabtagene ciloleucel (Yescarta, Kite Pharma), a CAR T-cell therapy for the second-line treatment of large B-cell lymphoma

These revolutionary treatments followed the orthodox path to approval via phased development, he noted.

Unapproved Cell Therapies

Rasko said that, in contrast, during the past couple of decades, there has been an "explosion" in the number of businesses that take advantage of loopholes in the regulations to sell unapproved cell therapies.

They often are known as same-day surgical procedures or minimally manipulated cell treatments. Even in well-regulated countries, businesses are able to "subvert" the rules, and they do so "with great alacrity, enthusiasm, and to enormous profit," Rasko commented.

He emphasized that regulatory frameworks are designed to protect the integrity of healthcare markets and provide a "level playing field" on the basis of rigorous, independently validated evidence.

The regulation of cell therapies has evolved differently in different countries and territories. The European Union, for example, standardized its requirements and strictly limited access to recognized centers.

In the United States, the picture is more complicated.

Rasko said that the FDA has defined "homologous use" and "minimal manipulation" so as to close some of the loopholes that companies have been exploiting.

The FDA has also created breakthrough therapy designations, "which have accelerated approvals of many different therapeutics," Rasko said.

"However, the Right to Try Act and the REGROW Act have caused enormous consternation not just in America but worldwide," Rasko noted.

He said that the Right to Try Act, which was passed in May 2018, is particularly concerning because it subverts the traditional compassionate use rules that are used by almost all countries to allow access to experimental therapeutics.

It requires only that phase 1 preliminary toxicity studies be performed. Moreover, it protects companies from litigation, avoids FDA oversight, and removes the limit on what manufacturers can charge patients.

Rasko said that such legislation reinforces the "market-driven philosophy that says we don't really need clinical trials or empirical evidence to decide the efficacy of drugs."

He continued: "Sounds bizarre? What's the alternative?

"The alternative is a brain that none of us individually have here, but it's a brain that surrounds the earth and it's called The Market, and The Market is a means by which all decisions, apparently, can be made," he said.

He explained: "If a drug is sold and it makes money and it continues to make money for the company that sells it, it must be okay, eh?

"If it doesn't make money and the company folds or somehow it's not very, very successful in the market, then it can't be good, and therefore you don't need to worry about it."

He contended that the result is that alongside the traditional "good" and "bad" treatments, there is a growing number of what he termed "futile" therapies, which have no provable efficacy.

Rasko said that "rogue" clinics that offer these futile treatments claim that they are "champions of patient autonomy and free markets" and are "concerned primarily with patient care."

They also say they are "offering a counterpoint to cold, scientific facts and statistics" and are "fighting back against a corrupt big pharma system," he continued.

This is not a small problem — there are hundreds of these rogue clinics.

Although they are found all over the developed world, by far the highest concentration is in the United States. California and Florida have the most such clinics, although few states are untouched by them, he said.

The FDA is beginning to fight back against companies that market dangerous and unapproved stem cell products, Rasko commented, but he emphasized that these unregulated clinics are something that the entire healthcare system has to tackle.

Clinical Evidence Continuum

To help patients and clinicians alike, he proposed a clinical evidence continuum, from unproven to proven therapies.

The unproven side is characterized by therapeutics that have no biological rationale or that rely on case reports and that have been used to treat few patients or none at all.

On this side of the spectrum lie stem cell creams, nutraceuticals, and the other "snake oils," he said.

Therapeutics in the middle of the continuum require proof of principle and either randomized controlled trials or post hoc or prospective registries and an increasing number of patients, toward the hundreds.

This in-between area includes products such as animal fetal cells, cord blood cells for autism, and hematopoietic stem cell transplants for multiple sclerosis.

The proven end of the spectrum includes therapeutics in clinical practice. These treatments are supported by postmarketing phase 4 studies involving thousands of patients and, eventually, meta-analyses.

It is here that hematopoietic stem cell transplants for blood cancers and the use of stem cells for burns can be found, Rasko noted.

No one will know what is a futile or an efficacious so-called therapeutic. Dr John Rasko

"If we don't adopt this kind of scheme, then we reach the point where no one will know what is a futile or an efficacious so-called therapeutic," he warned.

"Without that distinction, all estimates of value, reimbursement, cost to the community melt away, because no one will actually know what the value is," he said.

He consequently believes that "we are at a crossroads.

"There are those who would argue that a market-driven approach to medicinals is one that should dominate," Rasko said.

On the other side, "there are those who...believe that the way that we have developed medicines now for a long, long time, based on empiricism, is the fundamentally more important basis by which we should use our judgment to adopt new therapeutics."

Rasko reports receiving honoraria, speaker's fees, and clinical trials from GSK, Takeda, Gilead, Cynata, Pfizer, Spark, Novartis, Celgene, Bluebird Bio, AvroBio; having the role of director of pathology and being a stockholder in Genea; having a consultant role for Rarecyte (with stock in lieu) and Imago; and being chair of the Gene Technology Technical Advisory for the Australian government.

Transplantation and Cellular Therapy (TCT) 2019: A Global Perspective of Gene and Cell Therapy. Presented February 21, 2019.


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