Baby KJ's Story - a remarkable success of the customized CRISPR gene editing treatment

This morning, FDA conducted a roundtable discussion on cell and gene therapies. The roundtable invited 23 panel members from the academic and industry and was attended by FDA commissionner Dr Marty Makary and FDA CBER director Dr. Vinay Prasad. At the second half of the roundtable discussion, HHS secretary, RF Kennedy Jr, NIH director, Dr Jay Bhattacharya, and CMS Administrator, Dr Mehmet Oz all gave commentary speeches. The overall tone of the roundtable is very positive and the government agencies are very supportive to the cell and gene therapy (including xenotransplantation) development. The panel suggests various ways to support the cell & gene therapies. Renewing the pediatric priority review voucher program, Reduction of CMC requirements, continued support of flexible trial design and accelerated approval, and more reliance on post approval requirements and real-world evidence (RWE) were highlighted as key tools for the agency to reduce the number of programs caught in the

clinical “valley of death”. See the articles reported by FierceBiotech "'Not a horse and pony show': at FDA cell and gene roundtable, officials look for ways to cut red tape". and by BioSpace "RFK Jr. Joins Deputies in Voicing Support for Regulatory Flexibility for Cell and Gene Therapies".

During the roundtable discussions, the baby KJ's case was mentioned multiple times. It is worth discussing the baby KJ's story.

KJ Muldoon is a 10-month-old infant who became the first person in the world to receive a personalized CRISPR-based gene-editing therapy, marking a significant milestone in the treatment of rare genetic diseases.

Diagnosis and Condition

Shortly after birth, KJ was diagnosed with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a rare and life-threatening genetic disorder that impairs the body's ability to eliminate ammonia. This condition can lead to toxic ammonia buildup, causing severe neurological damage or death in infancy. 

Development of Personalized Therapy

With conventional treatments offering limited hope, a multidisciplinary team from the Children's Hospital of Philadelphia (CHOP) and Penn Medicine embarked on an unprecedented effort to develop a customized gene-editing therapy tailored specifically to KJ's unique genetic mutations. Within six months, researchers identified two truncating variants in the CPS1 gene and designed a bespoke CRISPR-based therapy using base editing technology. This approach allowed precise correction of the faulty DNA without cutting the genetic code. 

Treatment and Outcome

KJ received multiple infusions of the experimental therapy, delivered directly to his liver using lipid nanoparticles carrying the gene-editing components. The treatment aimed to correct the genetic defect responsible for his condition. Following the therapy, KJ showed significant improvement, including better tolerance to dietary protein and reduced dependence on supportive medications. After spending over 300 days in the hospital, he was discharged and returned home with his family.

Significance and Future Implications

KJ's case represents a groundbreaking advancement in personalized medicine and gene-editing therapies. It demonstrates the potential of customized CRISPR treatments to address ultra-rare genetic disorders by rapidly developing individualized therapies. While long-term outcomes and scalability remain areas for further research, this success story offers hope for treating other rare diseases through similar personalized approaches. 

For more detailed information, you can watch the FDA roundtable discussion on cell and gene therapies where KJ's case was mentioned: FDA Roundtable Discussion.

Impact of Baby's KJ's Case on Clinical Trial Design of Gene Therapies

Baby KJ's story was extensively discussed in a follow-up podcast "FDA Direct Ep. 7: This Week at the FDA!" by FDA commissioner Dr Makary and CBER director Dr Prasad. Their discussion of Baby KJ's story extended to the clinical trial designs for gene therapy studies and ultra rare diseases. 

The FDA's approach to clinical trial designs for gene therapy studies emphasizes flexibility and a nuanced understanding of the specific condition and therapy. Here are the key points:

• Flexible Trial Designs: The FDA acknowledges that a "one-size-fits-all" approach is not suitable. They adapt trial designs based on the specific condition, its frequency, severity, and the uniqueness of the therapy.
• "N of 1" Trials for Rare Diseases: For extremely rare and dire conditions, a single-patient ("N of 1") trial can be sufficient for approval, especially when there is a plausible mechanism of action and clear biological markers demonstrating effectiveness. An example highlighted is the rapid approval of a custom-tailored gene editing treatment for Baby KJ's rare condition.
• Plausible Mechanism Pathway: A strong, scientifically sound mechanism of action can support approval, even without extensive large-scale trials, if it suggests safety and effectiveness through extrapolated data.
• Challenges with Slowly Deteriorating Conditions: For conditions with slow and variable deterioration, relying on anecdotal evidence from "N of 1" studies without clear biological correlates is more difficult, as it's harder to distinguish treatment effects from the natural disease progression.
• Surrogate Endpoints: The FDA accepts the use of surrogate endpoints, such as tumor shrinkage in cancer, as indicators of a drug's activity.
• Industry Desire for Predictability: The industry seeks greater predictability regarding FDA expectations for endpoints, control arms, and when randomization is necessary. Improved communication and transparency are suggested to address this.
• Concerns with International Trial Data: There are concerns about relying solely on clinical trial data from certain countries, particularly if the majority of participants are from a single foreign country, for U.S. regulatory decisions.
• Re-evaluation of Trial Requirements: The FDA is open to re-evaluating requirements, such as the need for two clinical trials versus one for new drug approvals, to potentially streamline the process.

The overarching theme from recent FDA discussions is a shift towards a more flexible, common-sense, and scientifically driven approach to gene therapy regulation, prioritizing patient needs and scientific plausibility, especially for rare and life-threatening conditions.

References:

• World's first patient treated with CRISPR gene editing therapy at CHOP returns home
• First Personalized CRISPR Gene Editing Therapy Patient Baby KJ Discharged 
• Gene editing helped a desperately ill baby thrive. Scientists say it could someday treat millions

• A Baby Receives the First Customized CRISPR Treatment
• A Gene-Editing Breakthrough Saves Infant With Rare Disease