On May 26, Tracy Atteberry, a 57-year-old battling an extremely rare inherited immune system disorder, arrived at the National Institutes of Health hospital in Bethesda, Md. For him, even the simplest germ could be deadly. He was about to embark on a groundbreaking journey: receiving a gene editing treatment, a potential cure never before tested in patients.
Yet, in a sadly familiar narrative for gene therapy experts, Mr. Atteberry and a Canadian teenager may be the sole beneficiaries of this innovative treatment. Time and again, promising gene therapies are developed only to be withdrawn, and this cure from Prime Medicine is no exception.
The core issue boils down to economics. While the scientific capability exists to cure conditions like Mr. Atteberry’s chronic granulomatous disease (CGD), the immense cost of developing and securing regulatory approval for such treatments frequently leads companies to abandon their efforts.
A major factor is the tiny patient population. According to Dr. Mohammed Asmal, Prime Medicine’s chief medical officer, only around 200 individuals in the U.S. have Mr. Atteberry’s specific genetic condition. Of those, merely 50 might be suitable candidates for gene editing.
Dr. Asmal noted that the company had initially planned to treat six to 12 patients, with estimated costs ranging from $20 to $30 million, before the study’s funding was exhausted.
This recurring cycle of gene therapy development and subsequent abandonment extinguishes hope for millions worldwide 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 his frustration: “It’s frustrating to see promising therapies stall after successful preclinical studies.” Hacia was not involved in Prime Medicine’s trial.
He described these outcomes as “gut wrenching” and admitted they often kept him awake at night.
Dr. Asmal believes the only remaining path for the company to offer this treatment more broadly is if the Food and Drug Administration (FDA) grants approval based on the limited data from just two patients and a few months of observation.
Dr. Harry L. Malech, Mr. Atteberry’s physician at the NIH and chief of genetic immunotherapy, called Prime’s hopes for approval “a Hail Mary move.”
Historically, gene therapy approvals for ultrarare diseases have required significantly more extensive data. For instance, a gene therapy for spinal muscular atrophy received approval after two clinical trials, involving 21 and 15 patients respectively, with observation periods exceeding six months. Similarly, a treatment for inherited retinal dystrophy was approved following a year-long study of 29 patients.
Despite the challenges, Dr. Asmal and his colleagues remain optimistic about gaining approval. Dr. Martin Makary, the head of the FDA, has even hinted at potentially streamlining the approval process for treatments targeting ultrarare diseases.
Mr. Atteberry, a software developer from Lincoln, Neb., understands the profound luck involved in his opportunity for a cure. His life with CGD, a condition that cripples the immune system against common bacteria and fungi, has been a constant battle against “another life-threatening infection.”
His daily routine included a regimen of prophylactic pills and a strict list of restrictions, such as avoiding soil and never raking leaves, to prevent infections.
Due to his condition, Mr. Atteberry couldn’t have houseplants or a live Christmas tree. He experienced frequent hospitalizations for pneumonia and liver-scarring infections, acutely aware of his limited time. At 57, he had already surpassed the average life expectancy of 40 years for individuals with CGD.
Prime Medicine was the company that pioneered the experimental treatment Mr. Atteberry received.
This innovative gene editing technique operates like a “find-and-replace” function for DNA. It successfully corrected Mr. Atteberry’s gene, which had two missing DNA letters, restoring it to a normal state. Follow-up appointments in September confirmed that both Mr. Atteberry and the Canadian teenager, who also received the treatment, showed normal levels of the enzyme that their mutated genes previously failed to produce, suggesting the genetic defect was fixed.
However, according to David R. Liu, a Harvard researcher whose lab developed the gene editing technique used by Prime Medicine, this potential cure is now out of reach for other patients. Nobody else can currently access it.
Dr. Liu, a co-founder of Prime Medicine with no current operational role, expressed his deep commitment: “I want to get this science out to people. It’s the whole purpose of my life.”
Dr. Asmal maintains that Prime Medicine has not abandoned its efforts and is actively engaging with the FDA to explore avenues for approval.
“We are leaning into the moment,” Dr. Asmal stated, “and trying to give it a shot.”
In other instances, the development of experimental therapies relies on the sheer determination and fundraising efforts of patient families, who, fueled by optimism, establish foundations to finance gene therapy research.
Terry Pirovolakis of Toronto exemplifies this dedication.
His son, Michael, suffers from spastic paraplegia 50 (SPG50), a condition with a bleak prognosis.
Mr. Pirovolakis recounted the devastating outlook: “Paralysis from age 10, quadriplegic by age 20, microcephaly, seizures, never walk, never talk.”
The diagnosis left him shattered and disoriented.
“I went home in a fog,” he recalled, “crying in the corner of the street.”
But he soon rallied, establishing a charity that, over four years, successfully raised $4.5 million. This funding was dedicated to a gene therapy developed by Steven Gray at the University of Texas Southwestern in Dallas.
Within three years, Dr. Gray’s team engineered a treatment involving a modified virus to deliver a functional gene into patients’ cells, effectively replacing the faulty one.
His charity then engaged two companies for development: one for toxicology testing and another for manufacturing. Children’s Medical Center Dallas was designated as the treatment facility.
Michael received the gene therapy, and while his cognitive function improved, his father noted that extensive prior damage meant he was not fully cured.
Mr. Pirovolakis attempted to offer the gene therapy to other companies, but no biotechnology firm expressed interest. The global patient population for SPG50 was simply too small, with only 100 affected children, he explained.
Undaunted, he founded Elpida Therapeutics, aiming to develop gene therapies for his son’s condition and other ultrarare diseases. However, securing the substantial additional funding needed for FDA-mandated testing proved challenging.
“All the funding dried up. We were almost done,” he lamented, adding defiantly, “I never give up.”
Academic researchers face comparable obstacles.
For four decades, Dr. Donald B. Kohn at the University of California, Los Angeles, has dedicated his efforts to bringing gene therapy to individuals suffering from adenosine deaminase deficiency severe combined immunodeficiency disease (ADA-SCID), a genetic disorder that severely compromises the immune system.
Dr. Kohn and his team developed a specific gene therapy for ADA-SCID, which, after extensive trials, has proven effective, as evidenced by a forthcoming publication in the New England Journal of Medicine.
When a biotechnology firm declared it “could not find a path forward” for the drug, Dr. Kohn and his colleagues established Rarity, a public benefit company. While a public benefit company can generate profit, its primary mission is to ensure drug availability, Dr. Kohn explained. However, Rarity also requires investor support to advance.
Dr. Kohn continues to receive calls from parents eager to know when their children can access the gene therapy. He meticulously maintains a waiting list, holding onto the hope of one day being able to welcome them for treatment.
Maria Thianthong from Los Angeles shared that her daughter was added to this list as a newborn.
Now three years old, her daughter is still patiently waiting, Ms. Thianthong confirmed.
While a spokesperson for the Department of Health and Human Services did not elaborate on any immediate changes to the FDA’s gene therapy approval process for rare diseases, patients have found encouragement in Commissioner Dr. Makary’s recent statements, which suggest a greater willingness for agency flexibility.
During a June roundtable discussion where he listened to scientists and patient advocates, Dr. Makary emphasized, “We can learn from individual cases. That is the approach we need to take with cell and gene therapy.”
One of his proposals includes granting conditional approval for gene therapies treating ultrarare diseases. This expedited pathway would allow approval after studies with a small number of patients, contingent on robust post-treatment safety and efficacy monitoring.
However, a key unanswered question remains: would insurers cover these potentially very expensive treatments under a conditional approval model?
Economists argue 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 health care economist at Harvard Medical School, highlights the significant “social 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,” he explained.
Craig Garthwaite, an economist at Northwestern University’s Kellogg School of Management, shares this perspective. He described rare diseases as a “genetic lottery that people have lost.” While the individual treatment costs might be “eye-watering,” he noted that the total financial impact on the insurance system would not be overwhelming due to the extremely small number of patients for each condition.
However, both economists acknowledged that with such limited patient numbers, definitively proving a drug’s efficacy can be nearly impossible, suggesting that traditional regulatory expectations might need re-evaluation.
“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 asserted.
For CGD patients who are currently unable to receive gene editing treatment, a shift in approach is urgently needed.
Laura Owens, a 48-year-old from Rincon, Ga., has endured countless life-threatening infections and tissue damage due to CGD. Upon learning about Prime Medicine’s gene editing study, she felt a surge of hope.
“Then I found out it was canceled,” she stated, her voice tinged with disappointment.
“I wish the FDA would listen to the doctors,” she pleaded. “Can you not help us?”