Using Zydis® ODT To Solve Delivery Challenges For Tolerogenic Vaccines

Originally published in Pharmaceutical Technology.

Respiratory allergic disease is one of the most widespread chronic health conditions in the world, yet despite this prevalence, delivery formats for these therapeutics are surprisingly limited. The Zydis® orally dissolving tablet (ODT) platform from Catalent is a freeze-dried (lyophilized) oral solid dosage form that disperses instantly in the mouth and provides unique delivery routes for allergy immunotherapies. For instance, the fast-dissolve technology platform offers the potential for pregastric or gastrointestinal delivery as well as local activity at the oral mucosa.

ALK, a Danish pharmaceutical company focused on allergy treatments, has leveraged Zydis ODT to create a patient-centric, commercially successful treatment option. Pharmaceutical Technology recently sat down with Simon Andrew Lawton, M.D., Vice President, Global Medical Affairs, ALK Abelló, to discuss the advantages of Catalent’s Zydis ODT technology platform, the various dose formats available for the delivery of allergy immunotherapies and the factors driving growth and acceptance of this unique delivery format.

How does a tolerogenic vaccine differ from an immunogenic vaccine?

LAWTON: With allergies, the body interprets an antigen as harmful when it is not. Thus, the goal of tolerogenic vaccines, such as allergy immunotherapy, is to normalize a patient’s immunological response to an antigen that is not pathogenic—essentially, trying to invoke tolerance to the allergen. Such vaccines are typically given to someone who has already developed the allergy. With respiratory allergies, there is evidence that if allergy immunotherapy is given for one allergy, it may even stop the progression of other allergies. An immunogenic vaccine (i.e., immunization) attempts to do the opposite by evoking an immune response upon contact with the pathogen. Immunization is largely a preventative measure given to someone who has not had the disease.

Can you describe the various dose formats of your allergy therapeutics?

LAWTON: Allergy immunotherapy generally has three main modalities: subcutaneous injections and sublingual formats as drops or ODTs. We use Zydis ODT for our sublingual immunotherapy tablets.

Subcutaneous injections have been in use for the better part of a century, while sublingual drops were developed in the 1980s. Many of these earlier products were initially made available as named patient products, although some have now received formal registration.

Conversely, the complete ALK sublingual tablet portfolio utilizes Zydis ODT and is fully registered. The level of documentation available for the ODT format is much higher than for the other modalities, both in terms of the products’ short- and long-term efficacy as well as the safety and tolerability profile.

The sublingual ODT dose form is also more convenient for the patient than subcutaneous injections, which are administered at the clinic. This includes maintenance therapy for as long as 3–5 years. With the tablets, the first dose is given under medical supervision. If this is tolerated, then the rest of the course of treatment, which is typically 3 years, can be given at home.

You mentioned named patient products. What exactly are those?

LAWTON: A named patient product is unregistered, and the physician takes responsibility for prescribing the preparation for the patient. Many of these products have primary and secondary packaging produced by the manufacturer, so they may appear very similar to any other pharmaceutical product; however, the product has not undergone a review by an independent regulatory body to get full marketing authorization.

How does the product differ when presented in the various dosage forms?

LAWTON: Zydis ODT is a lyophilized tablet format, which has many advantages over the other dosage forms available. Anyone who has worked with proteins knows that the freeze-dried format is a very nice environment for these large molecules because it maintains their chemical structure and offers high physical stability. Physical stability has to do with how the molecule fills conformational shape in a three-dimensional space. Maintaining their shape is important because the molecule must interact with certain complex receptors in the immune system. If there is a change in the molecule’s conformation, then the product may not interact with the immune system as intended.

Some of our molecules are proteases in the biological form, meaning they are obtained from different parts of the source material and then combined into the therapeutic extract. There is a risk that the proteases could degrade the other molecules, which is not conducive to high stability. The freeze-dried format inhibits this activity.

In contrast, the subcutaneous injectable and oral drop formats are in solution when prepared. Our products often are composed of multiple globular protein molecules that are quite soluble. They can go into a solution quite well, but the solution must then be housed in a container that often will contain hydrophobic surfaces (e.g., siliconized glass or a rubber stopper). Interacting with these materials can make the protein unstable and lead to aggregation. This does not occur with the freeze-dried ODT format.

Zydis ODT is advantageous not just from a theoretical perspective as we can see a real-world difference in terms of shelf life. For example, our subcutaneously injectable products normally have a shelf life of approximately two years and require refrigeration. Once the injectable product is opened and in use, that duration is reduced even further. Conversely, the ODT does not require any special storage conditions and has a shelf life of up to 5 years. From a formulation perspective, that is a big advantage for the freeze-dried tablet formulation.

How does your product influence an allergenic response without entering the circulatory system?

LAWTON: Typically, the sublingual route is targeted so that the molecule can enter the central vasculature, thereby avoiding the problem of first-pass hepatic metabolism. But interestingly, our Zydis ODT product does not target the vasculature at all. The effector cells we target (e.g., antigen-presenting cells) are in the oral mucosa itself. These specialized cells in the immune system recognize the antigen (or allergen, in this case), which results in a whole cascade of immunological responses within the lymphatic system. The target organ is the lymph nodes, and very little, if any, allergen enters the vasculature.

What is interesting about targeting the oral mucosa is that it is an evolutionarily important tolerance organ. We must ingest proteins because most of the food we eat contains proteins. If the oral mucosa recognized proteins as being antigens or potentially harmful substances, then we would not be able to tolerate food. So, the sublingual mucosa is set up to induce a tolerance. There are very few ways that the immune system will come in contact with an intact protein. The most common is through the oral route. That is basically the mechanism behind immunotherapy.

What types of allergies are you targeting with the sublingual method?

LAWTON: If we look at allergy immunotherapy overall, it is mostly used for aeroallergens, which typically include allergic rhinitis and allergic asthma. Allergy immunotherapy can also be used for allergy to the venom of stinging insects such as wasps and bees, and now is also approved for food allergies such as peanut-induced anaphylaxis. But when it comes to the sublingual route of administration specifically, it essentially is only to treat respiratory allergy caused by aeroallergens. That may change in the future. There is no reason why we would not be able to potentially use the sublingual route to induce tolerance for other atopic diseases. But that has not been tested yet. Perhaps in time, we will see development in that area.

What have your studies shown about the performance of your products in the Zydis ODT format compared with loosely compressed formats?

LAWTON: We have done numerous in vitro investigations. These have predominantly been run by our strategic partner in Japan, Torii Pharmaceutical Co. Ltd. The first of these studies looked at disintegration (i.e., how quickly the tablet breaks up after being put in solution) using a Japanese Pharmacopoeia method developed for this purpose. The disintegration time for the Zydis ODT in vitro was within 1 second. When the same method was used for loosely compressed tablets, disintegration took more than 30 seconds on average [1]. From our perspective, we want to limit the amount of time that a patient must keep the tablet under the tongue. Saliva washout can affect the uptake of the allergen, so rapid disintegration is an important consideration.

In addition, there is simply a limit to how long something can be held under the tongue without swallowing. That is particularly relevant in children. Getting a 5-year-old child to hold something under the tongue for more than a minute can be very difficult. If they swallow the product, it could potentially limit its effect, and it may also result in gastrointestinal adverse events from ingestion of the allergen extract. Again, rapid disintegration is an important component of our products that have pediatric indications.

We also want to ensure that the protein is fully released from its freeze-dried matrix at a molecular level. Torii Pharmaceutical Co. Ltd. performed an analysis in which they studied the kinetics of the released protein to see how long it took the allergens to be freed and therefore be able to interact immunologically. An immunoassay was used to confirm not only that the protein was released, but also that it was interacting with the target immunoreceptor appropriately (or, in this case, because it was in vitro, with a specific antibody). For the ODT format, we observed complete release within 15–30 seconds [1,2]. In contrast, antigen release from the loosely compressed format was not fully complete as of 10 minutes, the final time point in the assays. This was consistent across both grass pollen and house dust mite allergen formulations [1,2]. From our perspective, the timelines for the ODT product are in line with what we want to see to ensure fast allergen uptake and presentation to the patient’s immune system before saliva wash out and/or swallowing.

Our data are also very reproducible, with very consistent short disintegration times and rapid allergen release kinetics. We believe that has led to consistency across our clinical trial program. We have commercialized five sublingual ODT products to date. From first human dose to marketed product, our Zydis ODT portfolio has a 100% success rate, which is very high when compared with the standard among pharmaceutical products. We think much of this success can be attributed to the consistency and reproducibility of allergen release and uptake afforded by Zydis ODT technology.

What has been the patient response to the Zydis ODT formulation?

LAWTON: We have assessed both convenience and ease-of-use parameters, and Zydis ODT has scored very highly among healthcare professionals and patients.

What has been the commercial impact of the Zydis ODT formulation for you?

LAWTON: We launched the first Zydis ODT product in Germany in 2006. We were predominantly focused on subcutaneous injection at that stage, but we also had sublingual immunotherapy drops that were already successful. It initially took a little
bit of time for the company and our prescriber base to get used to the new ODT format. Plus, we only had one product, whereas now we have a range of products in our portfolio.

We have seen increasing success over the last five years, particularly in the last two years. We experienced over 40% growth in 2019 and 2020. The first quarter of 2021 is the first time that the sublingual immunotherapy tablet portfolio generated more revenue than the rest of our allergy immunotherapy portfolio combined.

We anticipate that our portfolio will continue to grow, and that growth is almost exclusively driven by the Zydis tablet segment. Like everything, change takes time. But now, acceptance and adoption of the tablet are fully established. We are seeing strong growth across an increasing prescriber base, which we attribute to our ODT portfolio utilizing Zydis tablet technology.

How has your relationship with Catalent contributed to this growth?

LAWTON: Our relationship with Catalent has been excellent. Without Catalent’s involvement in the production, ALK does not have a product. I believe the tablet portfolio is the only one within ALK’s offerings for which we have not had any back orders. Recently, the volume of tablets we require has been very high, and yet we have never had a supply issue. A major factor leading to this achievement has been due to working closely with Catalent and their assistance in helping us meet the high volume demands of our customers.

REFERENCES

1. Lund K., Kito H., Skydtsgaard M.B., Nakazawa H., Ohashi- Doi K., Lawton S. The Importance of Tablet Formulation on Allergen Release Kinetics and Efficiency: Comparison of Freeze-dried and Compressed Grass Pollen Sublingual Allergy Immunotherapy Tablet Formulations. Clinical Therapeutics. (2019) 41:742.
2. Ohashi-Doi K., Kito H., Du W., Nakazawa H., Ipsen H., Gudmann P., Lund K. Bioavailability of House Dust Mite Allergens in Sublingual Allergy Tablets Is Highly Dependent on the Formulation. International Archives of Allergy and Immunology. (2017) 174:26.