Bringing gene therapy manufacture in-house avoids ‘imbalanced’ CMO relationship

By Ben Hargreaves contact

- Last updated on GMT

(Image: Getty/Johnathan Dwyer)
(Image: Getty/Johnathan Dwyer)

Related tags: Orchard Therapeutics, Krystal Biotech, Ge healthcare

The explosion of the gene therapy industry is leading to supply issues, which has led one company to view producing its own clinical materials as its best option.
Krish Krishnan
Krish Krishnan, CEO of Krystal biotech

For the cell and gene industry, supply is a major topic of conversation. With the rapid growth of the industry and a pipeline of potential treatments​ continuing to expand, the pressure on contract manufacturing organisations (CMOs) to supply the necessary materials is intensifying.

At a recent industry event​, Phil Vanek, general manager of cell & gene therapy at GE Healthcare, stated that the rapid explosion of interest in the area has led to the industry “building the plane as we’re flying it.”

He noted that it is time intensive to react to the demands of industry, particularly when treatments are often patient-specific.

As a result, governments and companies are now investing in supporting the speed of innovation by building out manufacturing capabilities.

The UK is investing heavily in manufacturing capabilities​ to back growth in the sector, which has seen a 60% expansion in good manufacturing practice (GMP) licensed facilities.

While some of the early innovators in the space, such as Orchard Therapeutics​, are building out their own facilities to either supplement or replace a reliance on CMOs to meet clinical and commercial material demand.

When BioPharma-Reporter (BPR​) spoke to Krish Krishnan (KK​), CEO of Krystal Biotech, he emphasised that the completion of the construction of the company’s own GMP facility​ resulted from lessons learnt from the larger and more established companies in the space.

BPR: Why have you chosen to keep your gene therapy manufacturing in-house?

KK:​ There are two reasons: one is the supply and demand issue, which a lot of companies face in the gene therapy space. There are so many gene therapy players and so few manufacturers – which causes a choke point, in terms of time and cost. We began to break ground on our facility long before the clinical data came out.

Setting up a GMP facility is a lot of work and a lot of expertise – it's like building a house 100 times over. The other side of it is that there are a lot of trade secrets when it comes to process development and manufacturing. For instance, in how you pick a virus, how you pick the right clone, how you get to the right purity and how you scale up whilst keeping costs down. Almost like a fine restaurant, the recipe is out there but you have to learn how to make the dish that bit better. That IP is kept in-house.

When you go to a third party, you're more or less educating them and all they give you in return is a cleanroom. It's an imbalance and so we thought we should just set it up ourselves. A lot of the classic gene therapy companies, they always get to the same point: bring it in-house. 

BPR: What is Krystal Biotech currently working on?

KK:​ We are working on rare diseases caused by a single gene that is either missing or mutated. The idea behind modifying the virus is to essentially provide a delivery vehicle to supply the missing gene to the patient and treat the disease. There are a handful of such monogenic diseases. We are in the middle of a Phase I/II clinical trial with respect to the lead indication of KB103, dystrophic epidermolysis bullosa (DEB), and we aim to start a pivotal Phase III trial sometime in the second half of 2019, which would run for six to eight months.

The reason we built our GMP facility is to provide the clinical trials material for these trials and also to be the singular, dedicated source commercial material for our lead product, KB103. The design and development was strategic because we wanted something to be very focused and applicable before moving onto a second, larger GMP facility that would take care of our pipeline products.

BPR: What is in the pipeline?

KK:​ We have five other candidates, which are approaches for monogenic skin diseases and are six months or so behind our lead candidate.

BPR: How will these gene therapies be delivered?

KK:​ We are delivering these as a topical cream, meaning it is formulated into a gel-type application and applied locally onto a patient. This is quite unique within the gene therapy area because, traditionally, when you think of gene therapy, you think of a tailored approach where the patient is invited to a specialised centre and sometimes cells are removed from them.

In contrast, with KB103, we are talking about an off-the-shelf approach, where it would be the same product for all patients. It could be applied by a local caregiver and potentially, in the future, by adults at home – that's a unique concept. Every other discussion about gene therapy revolves around the 'one and done' approach, about how expensive they are or about how difficult managing the supply chain of the therapies is – whereas we are in a different situation for all three of these conversations. 

Our therapies are for chronic application, they are shipped like any other small molecule medicine, and can be delivered by a local caregiver. This is why our story is so different.

BPR: What are the logistical requirements of the therapies?

KK:​ We use a reverse thermal gel, which is a liquid in frozen conditions so it's shipped like a vial. When it comes into contact with the skin, it solidifies at room temperature and spreads like a gel. We have started by suggesting that the treatment is used on three wounds at a time, as a measured approach, and treatment will be maintained on those wounds until safety is established. After this, treatment could get incrementally more aggressive.

BPR: Why will the application be continuous and not 'one and done', as with other gene therapy treatments?

KK:​ In this particular disease, DEB, and what is also true for other skin disease, skin cells have a half-life of about two to four weeks so the concept of 'one and done' is impossible. The particular diseases we are going after are not possible to treat in such a way.

BPR: More broadly, what barriers are gene therapies facing?

KK:​ Safety is still a big issue. There are two types, one is a virus that integrates into your DNA and, when it's a 'one and done therapy', the anxiety is that you've fundamentally changed the DNA across a lot of a patient's cells. It's a bit unknown what the long-term consequences could be. Ours is an episomal virus, it does not integrate with the DNA and so from a safety perspective, we haven't touched your DNA. We have just used a carrier to supply a missing gene and the carrier is eliminated with cell dilution.

Krish Krishnan is CEO of Krystal Biotech, who was specifically involved in two successful IPOs of New River Pharmaceuticals and Intrexon Corporation, as well as approval of the blockbuster drug, Vyvanse (lisdexamfetamine dimesylate), with the former company. He was also involved in the sale of New River to Shire for $2.6bn.

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