On May 26, Tracy Atteberry, 57, arrived at the National Institutes of Health hospital in Bethesda, Md. He suffers from an extremely rare inherited disease that severely compromises his immune system, making him vulnerable to even the slightest infection. His visit was for a groundbreaking gene editing treatment, a potential cure never before tested in humans.
However, in a recurring narrative within gene therapy, Mr. Atteberry and a Canadian teenager might be the only two individuals ever to receive this specific treatment. Prime Medicine, the company behind it, has ceased its offering, a familiar outcome in the development of such therapies.
The core issue boils down to economics. While the scientific capability exists to cure Mr. Atteberry’s condition, a form of chronic granulomatous disease (CGD), the immense cost of developing and securing approval for such treatments often leads companies to abandon them, even after initial development.
This dilemma is largely driven by the extremely small patient population. Dr. Mohammed Asmal, Prime Medicine’s chief medical officer, notes that only around 200 individuals in the U.S. have Mr. Atteberry’s specific genetic disorder, and a mere 50 of those might qualify for gene editing.
Dr. Asmal further explained that the company had initially planned to treat six to twelve patients, with an estimated cost of $20 to $30 million, before funding for the study was exhausted.
The repeated pattern of gene therapies being developed and then abandoned results in shattered hopes for hundreds of millions globally who suffer from rare genetic diseases.
Joseph Hacia, a researcher in genetic treatments at the Keck School of Medicine of the University of Southern California, expressed frustration, stating, “It’s frustrating to see promising therapies stall after successful preclinical studies.” He was not part of the Prime trial.
He described these frequent cancellations as ‘gut wrenching’ and admitted they ‘keep him up at night.’
According to Dr. Asmal, the only path forward for Prime Medicine to offer the treatment more broadly is if the Food and Drug Administration (FDA) grants approval based on data from just two patients and a few months of observation.
Dr. Harry L. Malech, Mr. Atteberry’s physician at the NIH and head of genetic immunotherapy, characterized Prime’s hope for approval as ‘a Hail Mary move.’
Historically, other gene therapy trials for extremely rare conditions have involved more extensive patient data and longer observation periods. For instance, a gene therapy for spinal muscular atrophy received approval after two clinical trials that included 21 and 15 patients, respectively, with follow-ups exceeding six months. Similarly, a treatment for inherited retinal dystrophy was approved after observing 29 patients for a full year.
Despite these challenges, Dr. Asmal and his colleagues remain hopeful for approval. Dr. Martin Makary, the FDA commissioner, has hinted at a more flexible approval process for treatments targeting ultra-rare diseases.
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Mr. Atteberry, a software developer from Lincoln, Neb., recognizes the immense fortune of receiving a potential cure. He described life with CGD, a condition that cripples the immune system against common bacteria and fungi, as a constant battle against ‘another life-threatening infection.’
His daily routine involved many prophylactic pills and a strict list of prohibitions, such as avoiding soil and never raking leaves.
He was unable to have houseplants or a live Christmas tree. His life has been marked by frequent hospitalizations for pneumonia and infections that damaged his liver. Understanding his limited prognosis, he had already surpassed the average life expectancy for CGD patients, which is 40.
(Image: Dr. Harry Malech, Mr. Atteberry’s doctor at the NIH and chief of genetic immunotherapy. He described the effort to get Mr. Atteberry’s gene therapy approved by the FDA as ‘a Hail Mary move.’)
The experimental treatment Mr. Atteberry received was initially developed by Prime Medicine.
This therapy utilizes a novel gene editing technique, effectively performing a ‘find-and-replace’ operation on DNA. It can correct a gene with missing DNA letters, like Mr. Atteberry’s, into a functional one. Follow-ups in September showed that both Mr. Atteberry and the teenage patient had normal levels of the enzyme that their mutated gene previously failed to produce, suggesting the genetic defect was successfully corrected.
However, this promising cure is currently out of reach for other patients, as stated by David R. Liu, a Harvard researcher whose lab pioneered the gene editing technique used by Prime Medicine. No other individuals can access it at this time.
Dr. Liu, a co-founder of Prime Medicine with no operational involvement, expressed his core motivation: ‘I want to get this science out to people. It’s the whole purpose of my life.’
Dr. Asmal insists that Prime Medicine is not giving up and is actively discussing potential approval pathways with the FDA.
“We are leaning into the moment,” Dr. Asmal affirmed, “and trying to give it a shot.”
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Other experimental therapies often emerge from the relentless efforts of patient families who, driven by courage and hope, establish foundations and fundraise to support gene therapy development.
A prime example is Terry Pirovolakis from Toronto.
His son, Michael, suffers from spastic paraplegia 50 (SPG50), a condition with a bleak outlook.
“Paralysis from age 10, quadriplegic by age 20, microcephaly, seizures, never walk, never talk,” Mr. Pirovolakis recounted the devastating prognosis.
The diagnosis profoundly impacted him.
“I went home in a fog,” he recalled, “crying in the corner of the street.”
However, he soon rallied, establishing a charity that successfully raised $4.5 million over four years. This funding supported the development of a gene therapy by Steven Gray at the University of Texas Southwestern in Dallas.
Within three years, Dr. Gray successfully developed a treatment that uses a modified virus to deliver a functional gene into patients’ cells, replacing the faulty one.
Pirovolakis’s charity then contracted two companies: one for toxicology testing and another for manufacturing the treatment. Children’s Medical Center Dallas was designated as the treatment facility.
Michael received the gene therapy, and while his cognitive function improved, the prior damage was too extensive for a complete cure, his father explained.
Despite his efforts to make the gene therapy available, no biotechnology company was interested. The global patient population for SPG50 was simply too small, with only about 100 children affected, according to Mr. Pirovolakis.
Undeterred, he founded Elpida Therapeutics, a company dedicated to developing gene therapies for his son’s condition and other ultra-rare diseases. However, securing the necessary FDA approval required substantial additional funding for further testing.
“All the funding dried up. We were almost done,” he stated, but added resolutely, “I never give up.”
(Image: Tracy Atteberry described living with CGD as facing a constant threat of life-threatening infections. His daily regimen involves ten prophylactic pills and strict limitations, such as avoiding soil and even fallen leaves.)
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Academic researchers face comparable obstacles.
Dr. Donald B. Kohn, from the University of California, Los Angeles, has dedicated four decades to bringing gene therapy to patients with adenosine deaminase deficiency severe combined immunodeficiency disease (ADA-SCID), an inherited condition that severely impairs the immune system.
Dr. Kohn and his team successfully developed a specific gene therapy for ADA-SCID. This treatment has undergone rigorous testing, with a forthcoming publication in the New England Journal of Medicine confirming its effectiveness, according to Dr. Kohn.
When a biotechnology company declared it ‘could not find a path forward’ for the drug, Dr. Kohn and his colleagues launched Rarity, a public benefit company. Dr. Kohn explained that while such a company can be profitable, its primary goal is to ensure the drug’s availability. However, Rarity also requires investors.
Dr. Kohn continues to receive calls from anxious parents inquiring about the gene therapy for their children. He maintains a waiting list, holding onto the hope that he will eventually be able to offer them treatment.
Maria Thianthong, based in Los Angeles, shared that her daughter was added to this list as a newborn.
Now three years old, her daughter is still waiting, according to Ms. Thianthong.
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When asked for comment, a spokesperson for the Department of Health and Human Services did not detail any current shifts in the FDA’s gene therapy approval process for rare diseases. However, patients have found encouragement in the statements of FDA Commissioner Dr. Makary, who has signaled a willingness for the agency to adopt a more flexible stance.
During a June roundtable discussion where he engaged with scientists and patient advocates on this topic, Dr. Makary asserted, “We can learn from individual cases. That is the approach we need to take with cell and gene therapy.”
One proposal from Dr. Makary involves granting conditional approval for gene therapies for ultra-rare diseases. This would allow approval after trials with only a small number of patients, provided that rigorous safety and efficacy monitoring continues post-treatment.
However, such conditional approvals raise questions about insurance coverage for these potentially very expensive treatments.
Economists suggest that the focus shouldn’t solely be on the high cost of these drugs, but rather on how society values them.
Dr. Anupam B. Jena, a healthcare economist at Harvard Medical School, emphasized the significant societal value of therapies for the rarest diseases: “Treatment for a disease may be valuable to you even if you never use it. Just like insurance.”
Craig Garthwaite, an economist at Northwestern University’s Kellogg School of Management, shares this perspective, describing rare diseases as ‘a genetic lottery that people have lost.’ While the treatments can be ‘eye-watering’ in price, he argues that the total cost to the insurance system would not be overwhelming due to the extremely small number of patients for each condition.
Nevertheless, both economists acknowledge that with such limited patient numbers, definitively proving a drug’s effectiveness can be nearly impossible, suggesting that traditional regulatory expectations might not be suitable for these unique cases.
“If there is a technology with very limited data, we should be willing to try it if patients understand the risks and benefits,” Dr. Jena concluded.
For CGD patients unable to access the gene editing treatment, a shift in regulatory approach is urgently needed.
Laura Owens, 48, from Rincon, Ga., has endured numerous life-threatening infections and tissue damage due to CGD. The news of the Prime Medicine gene editing study brought her immense hope.
“Then I found out it was canceled,” she stated, disheartened.
“I wish the F.D.A. would listen to the doctors,” she pleaded. “Can you not help us?”