In some cases, regulatory agencies have even withdrawn approval as a direct result of the pricing such as the case of Skysona in EU, withdrawn at the request of the manufacturer for commercial reasons, or Zynteglo, which had to be pulled out of Germany due to the government officials refusing to pay the listed price^(1,2).

If we compare the cost per dose of these approved drugs with a lifetime of treatment, the cost is usually justified. In a recent article, the example of the recent Hemgenix^® approval was taken.

The $3.5 million single-dose treatment would replace a lifetime treatment up to $20 million for Hemophilia B patients⁽³⁾.

However, in the healthcare system we live in, these single-dose prices are not compatible with giving the wider population access to all these potentially curative therapies within a few short years⁽⁴⁾.

This is even more true when we think of ultra-rare diseases, as the amount of research and development necessary is usually comparable, but the smaller patient population leads to a much lower drive for return. Something has to change. Hopefully, in the last years many countries have kicked off initiatives tackling part of these problems and are setting up best practices for others to follow. Some countries have, for example, developed early access programs, allowing access at a certain discounted price, which can be followed by negotiations depending on the real therapeutic value of the drug and then reconciled.

France is a good example of managing this. Many EU countries have developed innovative pay-for-performance (P4P) models, where the payment is linked to the outcome of the patient drug administration, helping to minimize financial risk and to generate further clinical evidence. Experimental P4P models vary a lot; Italy and Germany are among the countries leading these initiatives⁽⁵⁾.

However, innovative payment and reimbursement models will not be sufficient to address all the issues.

This is just one part of the potential solution. There are many other angles from which we could tackle this. Manufacturers could be pressured to decrease the prices. But why would they do that? Of course, these drugs are the fruits of years of R&D, and the investment in R&D is clearly a large part of the cost, as it includes accounting for the risks associated with developing a drug that will take a lot of effort to reach the market and might not get approved in the end. A study published in 2021 estimated that “R&D costs per new medicine (accounting for the cost of failure) ranged from $944m to $2,826m (adjusted to 2019 prices)”⁽⁶⁾. The current cost of manufacture is far harder to define. Even if the manufacturing platforms were identical, just differences in the dose required could mean more than a 1000-fold difference. While this cost is smaller than the R&D costs, it still has an impact and is a part of the cost that we, as industrialists, can help to reduce. If successful this will help manufacturers lower costs, while still being profitable.

When we look at that last part, the high cost of manufacturing and the direct cost of a dose is a combination of many factors, but I believe there are two main ones. The first one is the actual quantity of product that is going into the patient compared to the total quantity of material produced. Indeed, some case studies outline that for a phase 3 clinical trial, only 2% of the product that is manufactured actually goes into the patient⁽⁷⁾. This percentage might increase slightly once the product moves into routine production, but there is still a large part of the manufactured product that is used for analytical testing, comparability studies, assay controls, stability testing, device losses… the list of points where losses occur goes on.

Optimizing the methods around analytics, stability testing, and material requirements overall will help increase the quantity of product produced and that can be administered to the patient. This ultimately decreases cost per dose.

“How do we go from a 3X improvement to something that is closer to a 100X increase in yield?”

The second one is that we are manufacturing these therapies, these viral vectors, with technologies that have mostly been developed for the mAb and recombinant protein industry. They are ok and have enabled more and more approved products to reach the market. But they could be better if specially developed for viral vectors. There is a major lack of process maturity and adapted technologies. This is an area where solution providers will have a major role to play.

Let’s keep focus on that last point. Solution and technology providers are constantly looking to drive innovation in the way we manufacture products, and drug developers are constantly seeking higher performing processes. Closing the gap on the technologies for viral vector production can only be achieved through close collaboration between drug manufacturers and technology providers. This is the only way we can maximize the chances of developing the right product that the industry needs, in the shortest time. By using more adapted technologies specially developed for these specific products, we will be able to increase the total productivities and recovery, ultimately leading to a decrease in the manufacturing cost per dose. Keeping close contact with regulatory experts through this process will also help make sure the improved technologies will not raise more concerns than they bring solutions.

When we look at the manufacturing process for a viral vector (e.g. adeno-associated virus or AAV, lentivirus or LV) the process can usually be broken into two parts: the upstream process (USP) and the downstream process (DSP). USP productivity can be optimized through bioprocess development/optimization, cell line optimization, plasmids and transfection reagent optimization, and in some cases the use of stable cell lines. To increase the DSP yield, the main levers are process optimization and better recovery at every step of the process. In the case of AAV manufacturing, for example, DSP recovery is often around 25% to 30%, with a few processes achieving up to 50%.

Therefore, in a worst-case scenario (25% yield), even with all the improvements we could think of, such as better affinity ligands and innovative solutions to better purify these viral vectors, we can perhaps expect to improve the yield to 80% delivering a 3X yield improvement and a probable decrease in cost per dose between 1.5X and 2X.

Most experts in this area align on the fact that we need to improve the yields a factor between 10X and 100X in order to decrease the cost of these therapies significantly to facilitate their access and make them economically viable.

So, the question is: How do we go from a 3X improvement to something that is closer to a 100X increase in yield? To do this we need to work on the USP. This includes the use of better plasmids and transfection reagents, stable producer cell lines, USP intensification (e.g. engineering cell lines to excrete AAV for example to make processing easier), improving the AAV full:empty ratio out of the cell and the infectious titer, among others. USP optimization is the real cost lever that will help make these therapies more accessible.