Three years ago, the U.S. FDA granted a landmark approval for luxturna to treat an inherited retinal disease (IRD) that can cause blindness. This is the first real gene therapy in the U.S. market, marking the official arrival of the era of gene therapy, but also ignited the heat of the gene therapy market.
Since then, the agency has approved another gene therapy for spinal muscular atrophy (SMA), zolgensma, and has given the green light to dozens of biotech and pharmaceutical companies to start clinical trials of other gene therapies. At present, gene therapy for a series of diseases, including hemophilia, sickle cell disease and several muscular dystrophy, has entered clinical trials, and new science is constantly stimulating research.
However, after a series of regulatory and clinical setbacks overshadowed optimism, the field of gene therapy is facing some major problems in 2021. Biopharma dive, a foreign biopharmaceutical website, recently published an article pointing out that this year, scientists, pharmaceutical manufacturers and investors will face five important problems.
1. Is the recent setback a warning sign for the field of gene therapy?
Last year, industry insiders generally expected the FDA to approve a high-profile gene therapy, roctavian, for hemophilia A, a more common blood disease. In August, however, the agency unexpectedly refused to approve roctavian and asked its developer, biomarin, to collect more data.
The day after that, audentes therapeutics reported on the death of a third clinical trial participant after receiving his gene therapy for a rare neuromuscular disease. The tragedy is reminiscent of the safety scares of gene therapy in the past, although gene therapy, which is currently in human clinical trials, seems to be generally safe.
In less than five months, the field of gene therapy encountered two setbacks. Uniqure is exploring whether a volunteer's liver cancer is caused by his gene therapy for hemophilia B. Sarepta, one of the industry's top developers, has also faced major questions about its gene therapy for Duchenne muscular dystrophy (DMD) after disclosing that a key study failed to meet one of its main goals.
In each case, the pharmaceutical companies involved give optimistic explanations and reasons. Biomarin still wants regulatory approval; audentes' clinical trial has now been approved by the FDA to resume testing; uniqure believes that cancer cases are unlikely to be treatment-related; Sarepta believes that its negative data is the reason for the study design.
But in conclusion, these advances strongly remind people that gene therapy still faces risks and uncertainties. The four incidents also highlight the lingering concerns about one-off gene therapy. For example, when it refused to approve roctavian, the FDA worried that the huge initial treatment benefits for hemophilia patients might diminish over time. At the same time, the deaths in the audentes study have once again raised a warning for ultra-high dose gene therapy. For a long time, researchers have been looking for evidence that replacing or changing genes may lead to cancer, especially in a gene therapy study in the early 21st century, four infants developed leukemia. Sarepta's negative results were surprising, as early signs of significant biological benefits did not seem to translate into significant functional improvements in all patients.
Experts still believe that gene therapy can fulfill its potential. But recent events suggest that it may take longer than some expected to get there.
2. Has FDA raised the standard?
Gene therapy is a complex treatment method with strict manufacturing standards. For example, most of Spark's 60000 page applications for luxturna approval involve what the industry calls "chemistry, manufacturing and control (CMC)".
In contrast, the basis of gene therapy is more clear for many rare single gene diseases targeted by developers. If a gene mutation causes disease, there should be great benefits in replacing or otherwise treating the gene.
In January 2020, the FDA released eight industry guidance documents on gene therapy, including CMC, indicating that the agency is paying close attention to the gene (and cell) therapy manufacturing industry. Sarepta, Voyager therapeutics, iovance biotherapeutics and Bluebird bio were forced to revise the development schedule of their gene therapy projects after being asked to provide new details of the production process. The FDA told the companies that standards must be raised.
In response, FDA officials said that a large number of data requests are the result of a sharp increase in the number of companies that have passed clinical tests.
3. Are gene editing stocks overheated?
Geulah livshits, an analyst at chardan, points out that while there have been many setbacks in the search for alternative gene therapies, 2020 will be a "transformative year" for therapies aimed at editing genes. CRISPR gene editing has been widely regarded as a scientific breakthrough. With two early pioneers, Jennifer doudna and Emmanuelle Charpentier, winning the Nobel Prize in chemistry, CRISPR gene editing has gained a higher reputation.
But the year also brought important advances for early adopters of biotechnology. For example, editas medicine and intellia therapeutics took the lead in using CRISPR editing technology in the human body. CRISPR therapeutics and its collaborator vertex demonstrated that gene therapy using CRISPR to edit stem cells was very effective in the top 10 patients with sickle cell disease or β - thalassemia treated in two early studies.
These data are the most concrete signs to date that CRISPR's clinical application can fulfill its laboratory promise. Although the treatment methods of these companies are still in the early stage, their progress has aroused great enthusiasm of investors.
CRISPR therapeutics, editas and intellia have a total market value of nearly $25 billion. Beam therapeutics is a nearly $6 billion startup that uses more accurate methods of gene editing.
"Gene therapy is bound to play an important role," said John Evans, chief executive of beam. But I do think that over the past year or so, there has been a growing awareness that you might rather edit genes than add extra ones, if possible. "
Clinical trials will prove that, but until then, as valuations get higher and higher, the sharp rise in gene editor's share price may not be sustainable. For example, some of the recent growth seems to have been driven by the liquidity of generalist investors through ETFs, rather than by investors with investment experience in preclinical or early stage companies.
Brad Loncar, chief executive of Loncar investments, a biomedical investment firm, predicted: "gene editing stocks should have been rationalized a long time ago. Many companies are targeting similar diseases, the most common of which are sickle cells and beta thalassemia. "
4. Can a new wave of startups develop better tools?
The task of scientists is to replace defective genes with functional genes. Most scientists have turned to two types of viruses to safely deliver gene instructions to cells. Adeno associated virus (AAV) is usually used for infusion therapy, while researchers who study extracting cells from patients usually choose lentivirus.
Each virus has advantages, but it also has obvious disadvantages. For example, AAV triggers pre-existing immune defenses in some people, making them ineligible or unfit for gene therapy. In contrast, lentiviruses can integrate DNA directly into the genome of their infected cells, which is useful in some ways but limited in others.
After decades of gene therapy research, scientists have found ways to adjust and modify these viral vectors to better meet their needs, but the basic tools are the same. Gene therapy pioneer Jim Wilson, who presided over the gene therapy research that led to the death of adolescent Jesse Gelsinger in 1999, told the participants at a stat conference last fall that he was "somewhat disappointed" at the slow progress of viral vector research.
With more and more gene therapy entering clinical trials, the limitations of viral vectors are becoming more and more obvious. However, the pace of research may be accelerating. Recently, a number of companies aimed at building better delivery tools have emerged, including Harvard University's start-ups dyno therapeutics and 4D molecular therapeutics, which recently raised $222 million in their initial public offerings.
A number of big companies are also interested. For example, Roche, Sarepta and Novartis have all entered into cooperation with dyno. At the same time, in gene editing, researchers are developing new ways to cut DNA, and beam and other companies are working together to promote different editing methods.
5. Will Big Pharma's bets bear fruit?
In the past few years, pharmaceutical companies have invested billions of dollars in gene therapy projects, and few large multinational pharmaceutical companies are absent in this field. In 2020, Bayer and Lilly signed a large-scale acquisition agreement, and Pfizer, Novartis, Johnson & Johnson, Bojian and ushibi also made a series of small-scale investments. CSL Behring, which is famous for its plasma products, paid US $450 million in advance to buy a phase III clinical gene therapy for hemophilia B, etranagene dezaparvovec, from uniqure.
Over the past three years, at least $30 billion has been spent on biotech deals in gene or cell therapy. Four of them accounted for the majority. All these transactions, though following promising and convincing science, are ultimately a gamble that one-time gene therapy can be expanded and commercialized to become a profitable business.
Many of the acquired companies are working on treating very rare diseases that affect hundreds or thousands of people. However, a few companies are targeting more common diseases, from relatively rare diseases such as hemophilia to diseases that affect millions of people such as Parkinson's disease. Brad Loncar pointed out that in order to meet our high expectations, gene therapy must jump out of these extremely rare diseases, not only for investors, but also for society.
On the commercial side, several therapies that have been marketed in the United States have mixed sales records. Luxturna is a niche product now owned by Roche. Zolgensma has a wider range of applications, earning Novartis a profit of about $1 billion in the year and a half since it went public. Meanwhile, two cell therapies from Novartis and Gilead are striving for commercial success.
The largest commercial test in the field of gene therapy is expected to take place this year, and biocorin's roctavian gene therapy for hemophilia A is expected to get regulatory approval to go public. The FDA's unexpected rejection could mean that the drug's launch in the U.S. market will be delayed by a year. However, there are still great challenges in the pricing, reimbursement and patient access of gene therapy.
Reference source: 5 questions facing gene therapy in 2021
