BrainTrust #3: Gene Therapy Whispers Hope, Reshaping the Therapeutic Landscape
Eleven years of silence were broken for a young boy at the Children's Hospital of Philadelphia (CHOP) in October 2023. Diagnosed with OTOF-mediated hearing loss, a hereditary condition that has been robbing him of sound since birth, he became the first patient in the U.S. to receive and benefit from gene therapy. Through a minimally invasive procedure, Akouos, Inc., a division of Eli Lilly, sponsored this therapy, which delivered a healthy copy of the missing otoferlin gene directly to his inner ear. OTOF stands for otoferlin, the gene responsible for proper hearing function in the inner ear.? Just four months later, the results were remarkable: his profound deafness had been reduced to mild-to-moderate hearing loss, allowing him to hear spoken words, environmental noises, and even music.
Efficacy and Safety Verified, Impact Widening: This success establishes a proof-of-concept for gene therapy's potential to address various forms of genetic hearing loss, affecting 1 in 500 newborns worldwide. While OTOF mutations represent a smaller segment (2% of all genetic hearing loss), the focus is shifting towards the more prevalent GJB2 mutation, responsible for nearly 50% of genetic hearing loss cases.
Competitive Acceleration: This space has a number of organizations like Akouos, Decibel Therapeutics, Sensorion, and others engaged in various stages of clinical trials (see table). This underscores the imminent entry of gene therapy into the market, likely marked by rapid scale-up and diversification as different players contribute their expertise.
Bigger Picture:?Taking a step back, gene therapy, once fiction, is continuing to offer a glimpse into a future where genetic disorders are not merely managed but potentially cured. The recent success at CHOP exemplifies this shift, allowing treatment to shift from cochlear implants, which provide sound perception, to directly addressing the root cause of the deafness and bypassing the need for lifelong symptom management.? The table below summarizes the major approvals of gene therapies and their manufacturers.
Beyond Hearing: A Universe of Possibilities Unfolds
While a successful patient's cure for hearing marks a milestone, it's an initial act in a larger play. Gene therapy's potential extends beyond the potential for cures for cystic fibrosis and muscular dystrophy to Alzheimer's and certain cancers. The ability to target and correct faulty genes at their source offers hope for a multitude of conditions.? Notably, the field is evolving beyond its initial focus on rare, life-threatening childhood diseases (like Novartis’ Zolgema) to address chronic conditions affecting individuals with longer lifespans. While dated, the below Wells Fargo landscape shows the depth and breadth of the pipeline in gene therapy over the near to medium term.? As these therapies scale, it magnifies the need to address issues such as delivery complexity, access, long-term effects, and scalable patient support, which are discussed below.
Moving from Rare Diseases to the Mainstream:
Moving from groundbreaking clinical results to mainstream adoption requires acknowledging and addressing the human barriers as well.
Delivery Dilemmas: Delivering modified genes precisely to targeted cells and tissues, especially within intricate organs like the inner ear, remains a complex endeavor. Researchers are actively exploring innovative delivery vectors, such as viral vectors and nanoparticles, along with minimally invasive surgery techniques or delivery systems to overcome this hurdle and ensure the therapy reaches its intended destination.
Cost: These therapies run at more than $2 million per patient, which leads to the question of equitable access. Developing cost-effective strategies and broadening insurance coverage are crucial for ensuring that this life-changing therapy isn't reserved for the privileged few. Collaborative efforts between researchers, governments, and manufacturers are vital to addressing access.? Manufacturers have been offering value-based contracts that provide rebates if durability thresholds are not met.
Long-term effects: While initial results are promising, there is a delicate balance between benefit depending on the disease state and the medical risk that the patient sees.? Long-term safety data and side effects necessitate ongoing investigation and monitoring, which will be part of the post-approval clinical requirements.
Patient Support: Supporting patients throughout their gene therapy journey is a critical hurdle in itself, given the complexity.
Ethics: The rapid advancement of gene therapy will require a larger discussion, particularly around germline editing, which alters genes passed on to future generations, especially as these patients have the opportunity to have children of their own.
Ripple Effects: Reshaping the Healthcare Landscape
The implications of this paradigm shift extend far beyond the realm of individual patients. While this might take decades to fully materialize, the medical device landscape itself stands to be reshaped.? Medical device manufacturers may need to consider how their products can complement or integrate with gene-based solutions. There are many potential examples, such as cochlear implants for hearing loss, deep brain stimulators (DBS) for movement disorders, corneal implants for vision impairments like keratoconus, drug delivery for severe spasticity, continuous glucose monitors (CGMs) and insulin pumps for diabetics, and pacemakers for rhythm disorders.? From a revenue projection standpoint, many players have a good sense of procedure volume based on prevalence and incidence numbers, with a number having business models based on recurring revenue or periodic replacement. Assuming appropriate pricing, curative therapies would dramatically change these dynamics.
Investor Observations and Outlook
Despite diverse assessments, all major sources anticipate a remarkable expansion for the gene therapy market. By 2032, market size estimations range from a substantial $23.9 billion (MarketsandMarkets) to a staggering $91.85 billion (Expert Market Research), reflecting an anticipated CAGR of 13.9% to 32.6%.
Optimism and Caution: While these projections and recent success in treating hearing loss with gene therapy indicate optimism, investors should acknowledge the bumpy road the field has navigated over the past 24-36 months.
Nearly all players have experienced significant market capitalization declines. While some are explainable (e.g., major correction in the mRNA/sRNA space due to revised COVID vaccine forecasts), even companies with primarily pre-clinical and clinical pipelines have seen dramatic stock declines.
Recovery and Stabilization: In vivo therapies, including the approach used in the hearing loss treatment, and gene editing approaches are exhibiting a gradual return and stabilizing trend.
Ex-vivo Challenges: However, ex-vivo approaches, in which gene editing takes place outside the body and is then reinfused, haven't recovered as quickly as their peers.
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Future Focus: Although uncertainties around regulatory perspectives, high manufacturing costs, and market access persist, our 2024 focus will remain centered on monitoring key clinical milestones.
What are your thoughts?
As we observe the ever-changing landscape of healthcare, this reflects Netra Health's (Puneet Gupta and Manan Atit's) current understanding of the topic. We believe in fostering ongoing dialogue and welcome insights to refine our perspective in light of emerging scientific developments.
#genetherapy #healthcare #innovation #futureofmedicine #hearingloss #NetraHealth #Lilly #Akouos #CHOP #Sensorion
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The promise of gene therapy is a powerful reminder of Margaret Mead's words, "Never doubt that a small group of thoughtful, committed citizens can change the world." This advancement not only opens doors for countless individuals but paves the way for monumental shifts in healthcare. Speaking of monumental, there is an opportunity to be part of a Guinness World Record for Tree Planting, which mirrors the ambitious spirit of medical innovation. Explore here: https://bit.ly/TreeGuinnessWorldRecord ????? #FutureIsBright #InnovationForChange
?? "The future belongs to those who believe in the beauty of their dreams." - Eleanor Roosevelt. The promising strides in gene therapy highlighted in #NetraHealth's insightful article indeed kindle hope for not just managing but curing genetic disorders. ??? By continuously pushing the boundaries of medicine, we're stepping closer to a world where limitations are seen as challenges to overcome, not just live with. #genetherapy #healthcareinnovation #ManyMangoesSupportsScience