Vector immunity is currently a major limiting factor in gene therapy. In the first place, patients with pre-existing immunity may either be ineligible for treatment or may require extremely high doses of vector to overcome it, especially where dosing needs to be systemic (this is a negligible factor where delivery is to immune-privileged sites such as the eye). This is highly pronounced for some of the AAV capsids and is typically a worse problem in older patients. When it comes to re-dosing patients with gene therapy, this is currently seen as an impossibility. The initial dose almost always induces a primary immune response to the vector and as a result, any future doses are destined to be neutralised upon administration. For this reason, gene therapy is viewed as a one-shot deal, a lifetime treatment.
Due to vector immunity, gene therapy developers live in the hope that the level of efficacy that the initial shot provides will be sufficient – there is no scope for a top up. For systemically administered treatments, it is hoped that dose levels are not unaffordably high from a COGS point of view. Moreover, it is hoped that the effect of the initial therapy has high durability and does not fade over time. We will have to wait to see how true this is, but there is a high degree of scepticism that current vector technologies can produce the magnitude of response that remains stable enough over many years, potentially decades, without the plethora of mechanisms that we already know about (e.g. gene silencing) undermining the long term outcome.
Commercial models need to assume durable, high levels of efficacy to justify pricing
In consequence, the business model for gene therapy is radically different from ‘standard’ pharmaceuticals. Developers have to assume curative or near-curative efficacy that is durable over the long time in order to justify very high, potentially multimillion dollar, prices. In turn, this puts pressure on payers who are unwilling to stump up the full price before the sustainability of the benefits is established, and this leads to payment-by-results and/or payment-by-instalment approaches being developed. These ‘annuity’ approaches are clearly feasible in a single payer system such as the UK’s NHS, but become rather complex in the USA where average residence time for a family with any particular health care plan is three to four years – will gene therapy patients have the ability to switch insurers, or will a new insurance company refuse to accept the liability incurred before the patient signed up and started paying premiums?
There may be a route to suspend vector immunity
The pre-existing immunity problem has stimulated a number of initiatives to develop unique capsids that are less affected in this respect. However, they do not address the re-dosing issue. There is a possible route that addresses both: a Swedish company, Hansa Biopharma, is developing imlifidase, a unique antibody-cleaving enzyme originating from Streptococcus pyogenes that specifically targets IgG and inhibits IgG-mediated immune response. According to Hansa’s website, it has a rapid onset of action, cleaving IgG-antibodies and inhibiting their reactivity within hours after administration. The initial indication for this therapy is slated to be kidney transplantation where highly sensitized patients have high levels of anti-HLA antibodies, which are likely to target and significantly compromise a transplanted organ. Desensitizing patients through a short course of imlifidase should result in an increase in the number of eligible organ recipients and potentially a higher transplantation success rate overall. Hansa has submitted the product to the EMA in February 2019.
In principle, the same product could be used to create a window for administration of a gene therapy to a patient with existing anti-vector immunity. Temporarily eliminating anti-vector IgG from the patient’s circulation may create a long enough interval for a gene therapy vector to be administered and reach its target site before new IgG is produced by the patient which closes the window. If this were to work, it would enable the use of practically any vector where pre-existing immunity is a problem, and should also allow re-dosing in the event that a higher dose of gene product is needed relative to the results of the initial dose or when effective levels of gene product decline over time below therapeutically effective levels.
Gene therapies become more like standard Rx products
Admittedly, there is a lot of development work that would be needed before we got to the stage of nirvana outlined above. But if imlifidase, or one of the other approaches to creating immunological ‘windows’ came to fruition, there would no longer be pressure to position gene therapies as single, lifelong treatments. Top-ups and redosing would be possible. As such, the market dynamics would become much closer to ‘standard’ pharmaceuticals, and, who knows, maybe so will the prices?