Virus World

A quarter patients with high-risk, BCG-unresponsive disease were recurrence free at 3 years.

WASHINGTON -- The gene therapy nadofaragene firadenovec (Adstiladrin) continued to demonstrate clinical activity in patients with high-risk bladder cancer, researchers reported.

The long-term follow-up data came from a phase III study of patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. The data showed that of 55 patients who had achieved a complete response (CR) to the therapy at 3 months, 14 (25.5%) were still high-grade recurrence free at 3 years, according to Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues, at the Society of Urologic Oncologyopens in a new tab or window (SUO) annual meeting. The findings emphasize the importance of obtaining long-term data from novel therapies in order to set treatment expectations, he said. Primary trialopens in a new tab or window results, reported at the 2019 SUOopens in a new tab or window meeting, demonstrated that the 55 patients who achieved a CR at 3 months represented 53.4% of 103 patients eligible for analysis. Here, Boorjian and colleagues reported that the long-term high-grade recurrence free results were:

• 40.8% (n=42 patients) at 6 months
• 35.0% (n=36) at 9 months
• 24.3% (n=25) at 1 year
• 19.4% (n=20) at 2 years
• 13.6% (n=14) at 3 years

In addition to the 3-year results, of those 55 patients who achieved a CR, the percentage who maintained that response was:

• 76.4% (n=42) at 6 months
• 65.5% (n=36) at 9 months
• 45.5% (n=25) at 12 months
• 36.4% (n=20) at 24 months

The median duration of CR was 9.7 months, and the probability of duration of CR for at least 36 months was 34.2%. The cystectomy-free survival rate at 36 months was 53.8% (95% CI 43.3-63.1), and the 3-year overall survival rate was 90.4% (95% CI 82.3-94.9).

Nadofaragene firadenovecopens in a new tab or window is an adenoviral vector-based product that the FDA approvedopens in a new tab or window in 2022 as the first gene therapy for the treatment of high-risk BCG-unresponsive NMIBC for adult patients with CIS, with or without papillary tumors. The single-arm, open-label, multicenter trialopens in a new tab or window enrolled 107 patients, 103 of whom met the protocol definition of BCG-unresponsive NMIBC and were included in an efficacy analysis. Patients received nadofaragene 75 mL intravesical instillation (3 x 1011 viral particles/mL) once every 3 months for up to 12 months (4 doses) or until unacceptable toxicity or recurrent high-grade NMIBC. Per protocol, a five-site biopsy of the bladder was performed at 12 months, and patients who were high-grade recurrence free were offered continued treatment. The trial is ongoing with a planned 5-year treatment and monitoring phase. The median age of the entire cohort of 107 patients was 72, 89% were male, and 99% had received at least two BCG courses before enrolling in the study. Boorjian and colleagues reported that 3.9% (n=4) of patients experienced progression to muscle-invasive disease as documented by transurethral resection of bladder tumor at the time of high-grade recurrence. Two patients discontinued treatment due to adverse events (AE), including a grade 3 bladder spasm and a grade 2 instillation site discharge. Neither event was considered a serious AE.

The lone volunteer in a gene-editing study targeting a rare form of Duchenne muscular dystrophy likely died after having a reaction to the virus that delivered the therapy in his body, researchers concluded in an early study. The lone volunteer in a gene-editing study targeting a rare form of Duchenne muscular dystrophy likely died after having a reaction to the virus that delivered the therapy in his body, researchers concluded in an early study. Terry Horgan, 27, of Montour Falls, New York, died last year during one of the first tests of a gene-editing treatment designed for one person. Some scientists wondered if the gene-editing tool CRISPR played a part in his death. The tool has transformed genetic research, sparked the development of dozens of experimental drugs, and won its inventors the Nobel Prize in 2020. But researchers said the virus—one used to carry treatment into the body because it doesn't usually make people sick—combined with his condition, triggered the problems that ultimately killed him. Horgan appears to have had a more severe immune reaction "than others receiving similar or slightly higher doses" of the virus, the authors wrote in the study, which has not yet been peer-reviewed. Horgan was enrolled in an early-stage safety trial approved by the Food and Drug Administration. It was sponsored by Cure Rare Disease, a Connecticut-based nonprofit founded by his brother, Rich, to try and save him from the muscle-wasting disease caused by a mutation in the gene needed to produce a protein called dystrophin.

In a statement, Rich Horgan thanked the research team led by the University of Massachusetts Chan Medical School and Yale University for a "thorough, comprehensive" investigation that provided valuable insights. He added, "On a personal note, this study is another important step toward honoring Terry's legacy and his commitment, as well as our entire family's, to the rare disease community." The therapy Horgan got aimed to use CRISPR to increase a form of the dystrophin protein. The process began with suppressing Horgan's immune system to prepare his body for the therapy, which was delivered by IV with "a high dose" of what's known as an adeno-associated viral vector, or AAV, according to Cure Rare Disease. But Horgan soon began experiencing problems, went into cardiac arrest six days after the treatment and died two days later from organ failure and brain damage. Because of the timing of symptoms, and the fact researchers could find little of a gene-editing enzyme in his body, they concluded that the therapy hadn't been activated yet. This isn't the first time viral vectors have been implicated in a gene therapy trial death. In a major setback for the field, 18-year-old Jesse Gelsinger died in 1999 during a study aimed at combatting his rare metabolic disease. Scientists later learned that his immune system overreacted to the virus used to carry the treatment. The virus used in Horgan's trial is considered safer but it is not without problems. "People have been trying to make safer vectors … but they still remain challenging," said Arthur Caplan, a medical ethicist at New York University who was not involved in the study but has followed the case closely. "We don't really understand why some people run into trouble and others don't. We don't know whether it's their underlying disease, some co-morbidity, or some strange immunology." Rich Horgan said they plan to submit the study to a peer-reviewed journal. Meanwhile, Cure Rare Disease said it will use alternative viruses for the other treatments it is trying to develop. Dr. Terence Flotte, dean of the UMass medical school and senior author of the study, said he hopes it leads "to further research into how to identify subsets of patients who might be prone to severe, unexpected reactions like this."

Cited research available in  medRxiv (May 30, 2023):

 https://doi.org/10.1101/2023.05.16.23289881 

At age 45, Dr. Lakiea Bailey said, she was the oldest person with sickle cell anemia that she knew. The executive director of the nonprofit patient advocacy group the Sickle Cell Consortium was diagnosed with sickle cell disease at age 3. Because of it, she’s had heart problems, had her hips replaced, and experienced serious pain all her life. Bailey told the US Food and Drug Administration’s independent advisory committee Tuesday that she believes a cutting-edge therapy that is currently under review offers the sickle cell community something many haven’t ever had before: hope. “Hope is on the horizon, and we are looking toward this hope for a change of the lives that we are living of excruciating pain,” Bailey told the FDA committee on Tuesday. The independent committee is helping the FDA think through how it should evaluate a treatment called exa-cel that could potentially cure people of sickle cell disease, a painful and deadly disease with no universally successful treatment. This was an ongoing discussion with no vote or decision about the therapy, but the discussion likely moves the US one step closer to approving a groundbreaking new treatment that uses gene editing. If approved, exa-cel, made by Boston-based Vertex Pharmaceuticals and the Swiss company CRISPR Therapeutics, would be the first FDA-approved treatment that uses genetic modification called CRISPR. CRISPR, or clustered regularly interspaced short palindromic repeats, is a technology researchers use to selectively modify DNA, the carrier of genetic information that the body uses to function and develop. The FDA said treatment for severe sickle cell is an “unmet medical need.” When someone has sickle cell disease their red blood cells don’t function the way they should. Red blood cells are the helper cells that carry oxygen from the lungs to the body’s tissues, which use this oxygen to produce energy. The process also generates waste in the form of carbon dioxide that the red blood cells take to the lungs to be exhaled out.

With sickle cell disease — also called sickle cell anemia — red blood cells take on a folded or sickle shape that can clog tiny blood vessels and cause progressive organ damage and pain, and can lead to organ failure. The sickle cells also die earlier than they should, which means the person is constantly short red blood cells. One person with sickle cell who testified said she had been hospitalized 100 times just last year. Median life expectancy is only 45 years. Sickle cell is rare, and it disproportionately impacts African Americans. About 100,000 people in the US are diagnosed with sickle cell and, of those, 20,000 have what’s considered severe disease. Up until now, the only real treatment has been a stem cell or bone marrow transplant. For stem cells, fewer than 20% of patients have an appropriately matched donor, the FDA said, and the transplants are risky and may not work. Sometimes a transplant can kill the patient. The new exa-cel treatment under FDA consideration can use the patient’s own stem cells. Doctors would alter them with CRISPR to fix the genetic problems that cause sickle cell, and then the altered stem cells are given back to the patient in a one-time infusion. In company studies, the treatment was considered safe, and it had a “highly positive benefit-risk for patients with severe sickle cell disease,” Dr. Stephanie Krogmeier, vice president for global regulatory affairs with Vertex Pharmaceuticals Incorporated, told the panel. Thirty-nine of the 40 people tested with the treatment did not have a single vaso-occlusive crisis, which means the misshapen red blood cells block normal circulation and can cause moderate to severe pain. It’s the top reason patients with sickle cell go to the emergency room or are hospitalized. Before the treatment, patients experienced about four of these painful crises a year, resulting in about two weeks in the hospital. The FDA sought the independent panel’s advice, in part, because this would be the first time the FDA would approve a treatment that uses CRISPR technology, but Dr. Fyodor Urnov, a professor in the Department of Molecular and Cell Biology at the University of California, Berkeley, reminded the committee CRISPR has been around for 30 years and, in that time, scientists have learned a lot about how to use it safely. “The technology is, in fact, ready for primetime,” Urnov said. With this kind of genetic editing, scientists could inadvertently make a change to a patient’s DNA that is off-target, and the therapy could harm the patient. The FDA wanted the experts’ advice so it could understand what criteria it should use to evaluate the treatment and determine how to evaluate long-term safety issues.

An FDA presentation to the panel suggested the agency may have some questions about the data. It called a lack of confirmatory testing “concerning.” It also noted the study’s small size. In a discussion of the company’s methodology, several panel experts said that they believed the data the companies have submitted for FDA approval were reasonable. Committee member Dr. Gil Wolfe, a distinguished professor in the department of neurology at University at Buffalo Jacobs School of Medicine and Biomedical Sciences, said he liked that the company promised to monitor patients for 15 years to see if there were any problems down the road. He said, generally, it was “exciting” to see how many patients have been treated and how positive the results have been so far. As far as any concern for what’s called “off-target effects,” meaning the potential unwanted or adverse alterations to the genome that could accidentally happen in this process and cause cancer or other problems down the road, Dr. Daniel Bauer, principal investigator and staff physician at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston Children’s Hospital, told the panel the risk is “relatively small.” Wolfe thought the depth of analysis the companies used should be good enough to detect any potential problems down the road. “We want to be careful to not let the perfect be the enemy of the good,” Wolfe said. “At some point, you have to just try things out.” “I think, in this case, that there’s a huge unmet need for individuals with sickle cell disease, and it’s important we think about how we can advance therapies that could potentially help them, and I certainly think this is one of them,” Wolfe added. Asked by the committee how he would advise patients how to evaluate the risks with this treatment, Bauer said he would be honest that there is some uncertainty, but most of the human genome is non-coding, meaning it doesn’t provide instructions to the cells to act a certain way. “It might be that many places in the human genome can tolerate an off-target edit and not have a functional consequence,” Bauer told the committee. In other words, if they made an editing error, it might not matter, and may not harm the patient. “My guess is it’s a relatively small risk in the scheme of this risk benefit. But it’s new, it’s unknown,” Bauer said. “We need to be humble and open to learning from these brave patients participating.” The FDA is expected to make an approval decision by December 8.