In the first of a two-part series on the case for personalised gene therapy, pharmaceutical medical professional and patient advocate Dr Laura Issa discusses the challenges of ensuring access to these rapidly emerging bespoke treatments. Dr Issa would like to acknowledge Nicholette (Nicky) Conway, the chair of Genetic Alliance Australia for providing an expert review of the series.
Imagine a world where a single treatment could cure lifelong, debilitating genetic diseases. No daily medications, no repeated hospital visits - just one shot to fix the problem at its source. It sounds like science fiction, but it’s happening now.
It’s called 'gene therapy' and it’s a Pandora's box full of hope.
Put simply, gene therapy involves replacing, removing or correcting a gene defect or adding back the missing gene product (the protein), either throughout the body or in the diseased organ, tissue or cell type. Gene therapy has been mostly studied in cancer and common heritable genetic diseases but is now showing great promise for rare and ultra-rare conditions. The basic components of a gene therapy are the vehicles (or vectors) used to deliver the therapy via injection, the cargo comprising the genetic material and other proteins that help with processing the gene inside the cell.
Twenty-twenty-four was a bumper year for gene therapy with seven marketing approvals by the FDA; bringing the total to 43 overall. Included is Vertex Pharmaceutical’s first CRISPR-based gene editing therapy to treat severe sickle cell disease, a blood disorder where the protein (haemoglobin) that carries iron (and oxygen) in red blood cells is missing. Also noteworthy is the first-ever therapy for children with metachromatic leukodystrophy (MLD) by Orchard Therapeutics. Infantile MLD is a life-threatening fat storage disease that destroys nerves and the brain, with a life expectancy of around 5 years.
The horizon is also looking bright. According to the American Society for Gene & Cell Therapy (ASGTC) April 2024 report, 476 non-oncology rare disease gene therapies are in the pipeline (at preclinical to clinical stage). Of these, 34 treat Amyotrophic Lateral Sclerosis (ALS) and 25 treat Duchenne’s Muscular Dystrophy (DMD). This level of innovation speaks to the growing interest of biopharma and investors in the commercial opportunity of gene therapy as a therapeutic modality.
The transformational potential of a one-shot gene therapy to reduce disease burden and mortality is undeniably huge. However, there are several emerging challenges.
Firstly, the longevity of therapeutic effect can vary significantly between patients and with different technology platforms, anywhere from zero to 10 or more years. Several factors can influence durability of effect. How efficiently the viral vector gets into cells to deliver the gene (transduction efficiency) is a big factor. Cell turnover over time can be different for different organs and cell types. Sometimes, the cellular machinery shuts down (or silences) the gene (this is called epigenetic processing). In some cases, a person’s immunological response to the viral vector can impact duration of response, safety and efficacy. Another more complex consideration is the patient’s stage of disease, more specifically, the pathological state of the affected tissues and cells to be targeted by gene therapy.
Secondly, gene therapies that use recombinant (engineered) adeno-associated viral (rAAV) vectors are not suitable for everyone. These viruses are ancient human viruses that have hung around forever; most of us have been exposed to certain variants. Individuals who have developed neutralising antibodies to rAAV due to environmental exposures (“seropositive”) are unlikely to respond to certain variants.
Significantly, the costs associated with development and access of these therapies represent a barrier to uptake. For example, a once-in-a-lifetime shot of a gene therapy for sickle cell anaemia costs around US$2.2 million. Investment in clinical development, advanced manufacturing, patient support programs and post marketing safety monitoring means this type of gene therapy is not a sustainable solution for large patient populations. Major economies, including Australia, the US, the UK, the EU, and Japan, might afford them, with restrictive pay-for-performance arrangements. What about the rest of the world? In fact, in the past decade, Australia has reimbursed only two viral-based gene therapies for a rare genetic disease: one for inherited retinal dystrophy and the other for children with spinal muscular atrophy (SMA). A one-shot of SMA gene therapy costs the government AU$2.5 million.
The reality is a patient get one shot on goal. Patients who receive a gene therapy are ineligible for redosing or treatment with another similar gene therapy because of potential immune response (or immune memory). The risk-benefit trade-off is a tough choice for patients with a life-long or life-threatening illness.
Ensuring patient safety whilst balancing access to experimental, potentially transformative therapies through clinical research is challenging. The unfortunate death of Jesse Gelsinger, one of the first people to receive a rAAV, has forced a closer inspection of their use. We made major strides with improving safety in the quarter century since Jesse’s loss. Yet the stakes remain high. After the sudden death in 2024 of a boy in a DMD trial, Pfizer halted then shelved the program. In another study, a 27-year-old DMD patient treated with rAAV died of acute respiratory distress syndrome (ARDS) and cardiac arrest. The high dose of rAAV9 required to transduce whole-of-body muscle tissues is thought to have caused a severe innate immune reaction, triggering ARDS. This is disappointing for the DMD community and a step back for the field of gene therapy.
Notwithstanding, it’s clear that a personalised approach to pre-screening patients to confirm suitability and likelihood of response, together with customised therapeutic design is imperative to getting gene therapy right for every patient, the first time.
Despite the transformational potential of gene therapy, commercial success is not guaranteed. High cost of development, long lead times, high risk, competition and low willingness to pay by insurers makes it especially challenging. For large addressable patient populations with big budget impacts, payers may preference a once monthly biologic over a high-priced, one-shot solution. For example, with haemophilia A and B it is possible to replace the missing gene with a weekly or monthly injection of recombinant protein (biologic).
So how affordable are gene therapies for society? Although the US is an early adopter of gene therapies, access is impossible for the average patient or family without health insurance. A moral conundrum exists if the patients who need therapy the most are least able to afford it. A case in point is adoption of sickle cell anaemia gene therapy in the US, which predominantly affects populations where cultural and societal factors impact uptake and affordability. The potential to create healthcare and reproductive inequities within society and globally based on affordability is concerning.
Will gene therapy be economically viable for payers and innovators in the long term?
Does Pfizer’s exit from gene therapy for DMD and haemophilia B signal a shift in industry perspective on the commercial viability of this modality? Considering that the big pharma commercial model favours scalable commodities, like lipid-lowering drugs and vaccines, is big pharma best placed to commercialise personalised gene therapy?
Bluebird Bio is another case in point. Bluebird has three gene therapies in-market (for sickle cell disease, beta-thalassemia, and cerebral adrenoleukodystrophy (ALD). After having treated only 57 patients, Bluebird is being delisted and rescued by private equity for a tiny fraction of its stock value at peak.
Can we expect more companies to reduce investments in gene therapy R&D in view of these challenges?
Scaling a high cost, advanced therapy is a considerable investment. What happens if the organisations that have the resources and capabilities to do the R&D decide it is no longer commercially and economically viable? When innovators invest in conditions and technologies only where there is a high probability that payers will pay, we create what economists call a “moral hazard”.
In such an event, what is the future opportunity for gene therapy in rare diseases?
How can we collectively work towards designing and building an economically sustainable model that enables equitable access to life-changing, high-value therapies for patients who need them the most?
All signals point to the conclusion that we ought to reserve advanced, high-cost therapies for serious, life-threatening or debilitating, genetic conditions where there is no alternative pharmacotherapy and where there is paucity of innovation. Rare and ultra rare (orphan) genetic conditions certainly qualify.
A disease is considered rare if it affects ≤ 5 in 10,000 people. Ultra-rare disease affects fewer than 1 in 50,000 people. There are at least 7,000 known rare diseases, with more being discovered as population genomic sequencing increases. Of these, 80 per cent are genetic in origin, and almost 70 per cent present in childhood. In a population of 27 million, it is estimated that around 8 per cent or approximately 2 million Australians are living with a rare condition. Sadly, the average time for an accurate diagnosis is 4.8 years; and about 30 per cent of children with a rare disease die before age 5 years. In Australia, the undiagnosed rate is woefully low at approximately 50 per cent. Depending on the data source, between 5 to 10 per cent of rare diseases are addressable by existing pharmaceuticals and many more could be treated with drug repurposing.
Collectively rare diseases make up a big population, but individually, they could be a few as N=1. Creating a medicine for a single person is no easy feat; it's costly with a negative ROI. Making it extremely difficult for innovators to convince investors to pull out their chequebooks.
So, who’s going to pick up the bill?
In the current environment, families of children with rare diseases, who have the means and literacy, are setting up foundations and GoFundMe pages to pursue personalised gene therapy for an N=1 clinical trial.
Canadian couple Terry and Georgia set out to prove that passionate parents make N=1 trials possible. Their son Michael was diagnosed with an ultra-rare genetic condition called SPG50, a form of hereditary spastic paraplegia (HSP). Incredibly, in under three years, Terry and Georgia established a scientific network of academic experts, and partnerships with contract research organisations (CROs) and manufacturers to get regulatory approval for a trial for Michael. Remarkably, 12-month follow-up data published in Nature Medicine show promising efficacy outcomes with good safety. The CureSPG50 Foundation estimated that the total cost of the project for preclinical development was Canadian $3.5 million. The cost of the clinical trial was approximately $250,000 plus expenses related to concomitant medicines, whilst in-kind contributions were not estimated.
Closer to home, Tallulah’s parents created Moon’s Mission to CureSPG56, after she was diagnosed with HSP. They gave up their day jobs and sold their home to cover the costs of designing and testing a gene therapy for Tallulah. They are currently raising funds to manufacture product for a clinical trial.
Should parents have to fund-raise, sell their homes and do the heavy lifting to get access to personalised gene therapy?
