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Clinical development of TA-101 for the treatment of rheumatoid arthritis

Final Report Summary - TA101-GOCLIN (Clinical development of TA-101 for the treatment of rheumatoid arthritis)

Executive Summary:
The aim of TA101GOCLIN Project was to take TA101 into the clinical stage of development for rheumatoid arthritis and prepare the product for a novel mode of administration in the market of biologic therapeutics.
TA101 is a small domain antibody that is being developed for the treatment of rheumatoid arthritis and has passed through preclinical efficacy studies with much success. TA101GOCLIN project is within the scope of the clinical development of TA101 and was aimed at providing safety data in humans through a clinical trial of Phase Ia and Ib. However upscaling of TA101 was not accomplished with success as expression sytems tested did not allow for optimization of the solubility of this antibody.
Concomitantly, TA101GOCLIN developed with success a novel mode of administration for small domain antibodies to be used after project end. This will provide a major competitive advantage for this class of molecules and other proteins that can be incorporated as new administration.
The innovative administration uses microneedle patches, a new method that allows the autonomous administration of the drug through the skin without the pain of conventional injections.
To achieve the above mentioned objectives, TA101GOCLIN gathered three competitive SMEs from Portugal, Belgium and The Netherlands. TechnoPhage, Q-Biologicals and Amspar, respectively, were responsible for developing the clinical data of Phase I for TA101, develop an upscale method for production of the drug, and develop the microneedle device for administration of TA101. Overall, TA101GOCLIN holds the promise that an innovative product for drug administration was developed, with the confidence that the technologies that are at its base will create a new solution for the patients, with the major benefits of efficacy, safety, convenience and affordability.
This project’s workplan was designed in order to effectively pursue several key objectives, namely:
1) Generate an efficient method for the production of TA101 for clinical studies;
2) Perform clinical studies of Phase I (safety studies in healthy volunteers);
3) A Proof-of-Principle for the delivery of TA101 by microneedle-patch formulation in an appropriate model.

The number of people aged 65 and over in Europe will almost double over the next 50 years, from 85 million in 2008 to 151 million in 2060. Reumathoid arthritis (RA) is a significant aging-related disease with high costs for patients and society. Furthermore, it is one of the great unmet medical needs of industrialized nations, causing severe pain and discomfort, often preventing patients from working when in its advanced stage. According to the 2009 Report on RA prepared for the European Federation of Pharmaceutical Industry Associations the average cost per patient with RA in Europe is estimated to be 12.900€,. The total cost of the disease was estimated at 25.1 billion €.
The new product will have a strong economic impact and revenue potential, not only through the traditional ageing markets, but also in favourable emerging markets such as China, Korea, India and Brazil, which appear as very interesting potential buyers for this project’s innovative technology, conferring it a very strong and promising economic impact for the entire participant SMEs. As a result, through the TA101GOCLIN project, participants will significantly improve their competitiveness and reach new markets.
The RA market is a well-established but growing market of about USD 16 billion globally at present.
A new microneedle device will reach the market for the benefit of EU patients. Also, the production process capabilities for biologic therapeutics will be improved after QB experience with small domain antibodies. Overall, the EU will be a pioneer in developing a truly innovative device for RA patients who will not have to go to the hospital anymore to be administered their biologic.

Partners proposed the use of micro-needle patches as a method of autonomous administration of the drug through the skin without the pain of conventional injections. In addition, drug administration could be performed from their home without the need for hospitalization. The project brings under its umbrella three small- and medium-sized enterprises to devise clinical drug production techniques, produce the micro-needle device and perform the clinical trial.
During the first part of the study, researchers tried to optimize the expression parameters for the drug (plasmid and host) as well as the fermentation conditions and purification method. Significant progress was made with respect to the design and manufacture of the micro-needle device and this can be used in the companies as well as sold to other entities for the delivery of small domain antibodies and other sort of proteins. This was an important accomplishment of the project.

Project Context and Objectives:
The TA101-GOCLIN project intended to research and develop (from pre-clinical to phase I clinical trials) an innovative safe, painless and effective therapy for rheumatoid arthritis (RA) - TA 101 - that is administered in an easier and more efficient manner than current competing products and would be produced using a high yield manufacturing process, thus reducing the overall cost of treatment. The RA therapeutics market is a well-established but growing market of about USD 16 billion globally at present. Half of the market is dominated by Tumor Necrosis Factor Alpha (TNF-α) blockers which are predicted to remain dominant market players. In view of this, the project coordinator, TechnoPhage, S.A. (TP), developied an innovative biological therapeutics, within the TNF- α product category, which should provide important developments considering the current state of the art, namely differentiation benefits and cost advantages. This new compound has already been subject to preclinical testing comprising animal in vivo research and was approaching the clinical development stage. This new therapeutics appeared as a competent alternative to existing products on the market and would bring along an improvement of competitiveness of the SMEs involved . Moreover, the project would have a major contribution in the context of the development of TA101 at TechnoPhage, because the company was preparing its development up to Phase IIa, also known as Proof-of-Concept, at which the economic return on investment is optimal for biotechnology companies like TechnoPhage. For Phase I of the clinical development of the new therapeutics for RA a consortium with complementary expertise provided by three SMEs which were involved in this project.
• TP provided a small domain antibody [for the clinical studies (TA101), through it's subcontractors SGS the clinical development would be performed. Plastopharma another of Technophage's subcontractor was responsible for the development of a patch after testing the passage of the TA101 in the MNA, in different systems using caffeine as a control for release.
• Q-Biologicals (QB) was responsible for the optimization of the vector-host combination via its preferred subcontractor Artes GmbH, for development and upscaling the production process of TA101, for analytical method development and for the documentation needed to ensure a smooth transfer of the process and technology to the manufacturer of the cGMP product. Q-Biologicals would also take care of the development of a suitable formulation process.
• Amspar (AMS) was in charge of developing the more adequate device for the delivery of TA101, based on intelligent skin patches which incorporate microneedles. This was done by subcontracting Microcreate.The use of injections as a mode of administration, even under the modern pen systems, always carries a psychological burden for the patient. The new mode of administration of TA101 will allow the patient to have her treatment in a totally autonomous, painless and discrete manner, thus adding much value to the growing RA patient population. Possible self-administration by the patient in the case of such intelligent skin patch leads to considerably lower treatment costs compared to syringe administration usually done by medically trained personnel. It is well known that clinicians struggle with patient compliance for treatments. Therefore, this new product was expected to reach 2-4% of the markets when it became available in the first two years.

WP1 – Process Development of TA101 for Phase I clinical trials
1. Select best vector-host expression system for production of TA101 (QB and subcontractor ART).
2. Optimize fermentation process for TA101.
3. Optimize purification process for TA101.
4. Study stability profile of TA101 upon process development.
5. Provide analytical methods accessory to the production process
6. Provide all documentation related to the production process to support the transfer to the manufacturer of the clinical materials
WP2 – Clinical research of Phase I of TA101
Start month: 14
WP3 – Development of a medical device for the optimal administration of TA101
1. To optimize a medical device capable of providing efficient administration of TA101 to patients.
2. To select the best possible array design for clinical application of TA101 tailoring the dimensions of the Microneedle array, e.g. needle length and width, number of needles per array, and positioning on the array)
3. To select the best conditions (a.o. solvent) to load the single domain antibody (TA101) on the arrays
4. Provide npMNA devices loaded with TA101 for POC in animals.
5. Develop a prototype of the integrated array-patch device with appropriate loading capacity
6. Test the physico-chemical properties of the loaded array patch devices
WP4 – Dissemination and training
1. Provide dissemination of the project results in industry conferences and also to the public
2. RTD providers give to TA101-GOCLIN scientists timely updates and information of project results to assure continuous follow up of project achievement among partner SMEs.
WP5 – Intellectual Property
1. To assure that valuable information arising from the project results is protected in terms of Intellectual Property.
WP6 – Project Management
1. To obtain a base of structured practices to keep streamlined activities within the Consortium.
2.To give to all partners timely updates and information of project results and assure timely follow-up of project deliverables and milestones.

Project Results:
The TA101-GOCLIN project aimed to develop a new safe, painless and effective therapy for RA, which allows patient controlled administration and will be produced through a high yielding manufacturing process, thereby reducing the overall cost of treatment. The project intended to rapidly demonstrate the feasibility of a long half-life sdAb to treat TNF-α mediated inflammatory disease and had identified a lead candidate. The new patch was developed with success. However the TA101 was not possible to upscale as it demonstrated aggregation issues in all the different expression systems tested. This led to a non accomplishment of the aims proposed as with no upscaling proccess Phase I was not possible.

This project aimed to carry out Phase I of the clinical development of a therapeutic agent currently being developed for the treatment of RA using proprietary technology. It is a biologic molecule engineered specifically to target TNF-α in patients afflicted with RA which can be administered less frequently (once a month), in combination with existing medicines, and that is more cost-effective and thus, accessible to more patients suffering from RA.The product under development included linking the polypeptide to an albumin-binding domain. The aims were:
• Develop a production process that optimizes the yield and yet generates a pure and cost effective product (TA101).- this result as related in the deliverables an interim report failed, which led to the impossibility of performing the Phase I trial.
• Develop an intelligent skin patch integrating and microneedles that represents an innovative mode of administration for TA101 that carries a competitive advantage in a fiercely competitive market of RA therapeutics- this task was performed with success. The MNA was developed and tests were made as described in the deliverables that prove that TA101 can be delivered with success. For the companies involved (Amspar and Microcreate) this is a proof of concept that there technology can be used for delivery of antibodies and proteins of smaller size, which opens the perspective of new markets. Also for Technophage this was an important accomplishment for although TA101 will not be delivered due to upscaling problems, a new drug delivery possibility opens also a new market for these small domain antibodies. The development of an optimized medical device, ready for demonstrating based on pre-clinical POC of ceramic nanoporous microneedle arrays and its integration into an easy-to-administer intelligent skin patch, was a success.
• Optimization of the expression construct and expression host to improve the expression yield of TA101, the development of a scalable fermentation and purification protocol and the manufacturing of TA101 using conditions that can easily be transferred to the manufacturer of cGMP-grade material. This was executed by QB and its preferred subcontractor ART (WP1)- This work package and the related tasks were all done but the TA101 had solubility issues that were not solved by alteration of the systems tested.

• Phase I clinical trial design and set up (covered by SGS);
• High-yield npMNA microfabrication allowing for flexible design selection and directly enhanced loading capacity. These activities will be performed by MC (RTD 8);
• Assembly of semi-finished npMNA components into a skin patch device allowing for fine-tuning the dose of TA101 to appropriate dose levels and providing such medical device prototypes for POC of TA101 skin patch administration in animals. This intelligent skin patch technology will be developed at Plasto (RTD 7).
• Selection of the best expression method through the Fast Screening technology described below (performed by ART - RTD 8)

In this sense, the current project will contribute to strengthen the innovation capacity of the SMEs involved, to foster collaboration and to leverage research efforts in such a way as to allow the development of a new technology-based product which will enable access to a high growth market.

To this end, TA101-GOCLIN will set the ground for small domain antibodies to become the next generation of therapeutics with efficient production, and an improved mode of administration.
Global objectives:
• Improve the current yield production from 2 mg/mL up to 10 mg/mL, a 5 fold increase that allows administration to humans under a clinical study (described in WP1);
• Define the safety profile for human administration of TA101 small domain antibody (described in WP2);
• Develop an innovative mode of administration for TA101 that distinguishes it from competitors (described in WP3), a prototype of an intelligent, ready-to-use npMNA skin patch device for the delivery of appropriate amounts of antibody for treatment of RA;
• Proof of Concept in animals for the transdermal delivery of a small domain antibody by using an intelligent npMNA skin patch device (efficacy testing in comparison to subcutaneous injection).

Scientific Objectives:
• Select best expression system, fermentation conditions and purification method for production of TA101, including the development of accessory analytical methods (WP1).
• Study stability profile of TA101 at 4ºC and -20ºC upon process development (WP1).
• Determine the safety profile of TA101 for therapeutic use in humans, including PK/PD data (WP2).
• Determine the safe dose of administration of TA101 to be used in Phase II clinical studies after the end of TA101-GOCLIN project (WP2).
• Show that the innovative microneedle patch has the ability to deliver TA101 in a rat model of RA and improve the disease in a similar fashion to preclinical studies already performed by TechnoPhage (WP3).
• Investigate of advanced drug storage and delivery properties for MLT’s npMNA platform technology for transdermal adminstration of antibodies
• Characterization of release profiles of the npMNA-integrated skin patch device reaching clinically relevant TA101 serum levels

Technological Objectives:
• Optimize and upscale of the fermentation protocol (WP 1);
• Develop accessory analytical methods;
• Optimize purification protocol for TA101 to reduce aggregate formation (WP1);
• Adapt the microneedle arrays developed by MLT to patches able to deliver small domain antibodies to patients (WP3 );
• Apply the Fastscreen® technology to obtain the best vector-host combination for expression of TA101(WP );
• Produce TA101 under cGMP conditions (WP );
• Gain insight in production yield limiting parameters, overall dimensions and required properties for npMNA platform technology in skin patch assembly (WP3);
• Gain insight into technological solution for combining a microfluidic system of microneedle arrays and an additional reservoir (e.g.Hill Top Chamber or similar).

Potential Impact:
Currently, the project is still far from reaching the market and, thus, expected societal impacts will not occur during the duration of the project. However, the success of the project’s implementation will be crucial for these social gains to be obtained and generalized to patients.

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