TiGenix

TiGenix NV
Public (euronext: TIG)
Industry Biotechnology
Founded 2000
Headquarters Leuven, Belgium
Key people
 Eduardo Bravo, CEO
Products ChondroCelect
Number of employees
 50
Website http://www.tigenix.com

TiGenix is an advanced biopharmaceutical company focused on developing and commercialising novel therapeutics from its validated, proprietary platform of allogeneic, expanded, adipose-derived stem cells, or eASCs, in inflammatory and autoimmune diseases. TiGenix was founded in 2000 by Prof. Dr. Frank P. Luyten and Gil Beyen as a spin-off from the Katholieke Universiteit Leuven and the Universiteit Gent. In 2007, the Company was listed on the Euronext exchange in Brussels, Belgium. The Spanish stem cell company, Cellerix SA, was acquired in 2011. Corporate headquarters are in Leuven, Belgium, and it has operations in Madrid, Spain.[1]

TiGenix aims to become a fully integrated biopharmaceutical company with research and development, manufacturing, and sales and marketing capabilities to commercialise its products in Europe. License and distribution partners are being sought to develop and commercialise its products in the United States and other regions.

Cell Therapy and Tigenix

After small molecules and large molecules (‘biologicals’), cell and gene therapy are the next wave of medicinal therapy development. Cell therapy is distinctive and promising for addressing unmet medical needs because it can be regenerative, that is it repairs and replaces tissue and organs which are damaged; and it can be immune-modulatory, that is it controls inflammation and can help the body to return to homeostasis (stable equilibrium). Tigenix is at the forefront of this new wave, with a marketed product and a pipeline of late stage assets. The pipeline is developed from the eASC platform, an allogeneic cell therapy model whose products are scalable and ready for use.

Mechanism of action of stem cells

Adult mesenchymal stem cells have an inherent ability for self-renewal and differentiation potential, exert immune-modulatory and anti-inflammatory properties, are considered immune-privileged, and are easily accessible.

Two main biological mechanisms underlie the efficacy of stem cells in disease treatment: their anti-inflammatory properties, and their secretion of repair and growth promoting molecules. For the treatment of inflammatory and autoimmune diseases, the former property is thought to play the most fundamental role.

Certain stem cell populations act as immune-modulatory agents by interacting with cells of the immune system. TiGenix’s scientists have been able to confirm that activation of eASCs by interferon-gamma (IFN-γ) and the subsequent expression of tryptophan metabolising enzyme, indoleamine 2,3 dioxygenase (IDO), are at the heart of the immune-modulatory properties of eASCs. During the inflammatory process, IFN-γ is secreted by the patient’s lymphocytes. When eASCs are injected into the inflamed site, they are activated by the IFN-γ, resulting in the expression of the enzyme IDO. The enzymatic activity of IDO suppresses the proliferation of activated lymphocytes, shutting down chronic inflammation, and thereby supports a natural healing of the inflamed tissue.

The second property of the eASCs, secretion of repair and growth promoting molecules, is playing a role after the initial control of inflammation, as in fistula healing.

Allogeneic eASCs (Cx601) have shown promising results in pre-clinical and clinical studies after local administration for the treatment of anal fistula, most likely due to modulation of the inflammatory cascade, stimulation of the tissue healing process, and a favourable safety profile.

Expanded adipose tissue as an active ingredient

TiGenix has developed its platform using expanded adipose stem cells (eASC) extracted from human adipose tissue. By sourcing cells from adult adipose (fat) tissue, the company is able to capitalise on the benefits associated with this type of cell compared with other cell types (such as stem cells sourced from bone marrow). The most important advantages of this approach are: the ease and amount of supply (cells are collected through a routine liposuction); a rich supply of stem cells (stem cells can represent 2% of the total cells of the Stromal Vascular Fraction (“SVF”) of the fat tissue; a potential yield of 100 to 1,000 times higher than other possible sources of stem cells; robust phenotype (eASCs do not require overly elaborate growth conditions and can be grown continuously without the loss of their primary characteristics); and a good safety profile.

Allogeneic approach

An allogeneic (derived from donor cells) treatment has a number of advantages when compared with autologous (derived from the patient’s own cells) products:
Efficient production of large lots (batches) of cells

Cells are always available

No patient biopsy/tissue procurement needed

Commercial product attractiveness

Different routes of administration of eASCs

The choice of injecting the eASCs through different routes depends on a combination of the type of disease and targeting the immune system in the most optimal way. For local diseases or tissue damage, depositing the cells as close as possible to the affected tissue or organ is expected to optimise the effect of the cells. Indeed, locally administered cells will not be diluted, and thus will achieve the highest concentration of cells at the site of action. Moreover, the cells will immediately encounter the inflamed environment leading to direct activation of the eASCs and their immune-modulatory actions. Therefore, diseases like fistulas and inflammatory bowel disease (IBD) are targeted by local administration of the cells.

For systemic diseases like rheumatoid arthritis (RA), where the cells need to act at several places in the body, systemic administration of the cells is the route of choice. Indeed, systemic administration, either through the blood or lymphatic circulation, will allow the cells to be distributed throughout the body and to reach the affected tissues. The capacity of eASCs to sense inflammation and to migrate to the site of inflammation is expected to result in an efficient mechanism of action at the site of inflammation.

Finally, the intralymphatic route is attractive because the systemic effect of the cells is expected to be seen in the secondary lymphoid organs: the draining lymph nodes and spleen. Recent preclinical and clinical experience with vaccines and antitumour agents has demonstrated the feasibility and practical use of this administration route.

Cx601

Crohn's disease

Crohn’s disease is a chronic inflammatory disease of the intestine. A complication of the disease is complex perianal fistulas. A perianal fistula is an abnormal connection between the perianal space and outside skin surface which causes a significant negative impact on quality of life. A fistula is considered to be complex when its treatment involves a high risk of causing loss of anal continence, the fistulous tract crosses more than 30% of external sphincter, several tracts are found, it is recurrent, or when the patient has incontinence, local irritation, or Crohn’s disease. Current treatment for complex fistula in patients with Crohn’s disease is marked by poor efficacy and high costs. Patients with complex fistula but no inflammatory disease require surgery, with its attendant risk of faecal incontinence.

Cx601

Cx601 is a suspension of allogeneic expanded adipose-derived stem cells (eASCs) delivered locally through intra-lesional injection. In a Phase II clinical trial, Cx601 showed efficacy at 24 weeks in 56% of treated fistula tracts, which is more than two times higher than the current standard of care (TNF inhibitors). Efficacy was measured as the complete closure and re-epithelisation of the fistula being treated with an absence of drainage. Additionally, 69.2% of patients demonstrated a reduction in the number of initially draining tracts. The trial also confirmed the safety of the use of allogeneic stem cells for the treatment of perianal fistula. Based on these results, TiGenix sought scientific advice from the European Medicines Agency (EMA) on the future development path of Cx601. TiGenix then initiated a randomised, double-blind, placebo-controlled Phase III trial in Europe and Israel, codenamed ADMIRE, designed to comply with the requirements laid down by the EMA. This pivotal study is intended to enable filing for marketing authorisation in Europe and to serve as a key supportive study in filing for approval in other territories, including the US. The study’s primary endpoint is closure of all treated external openings draining at baseline despite gentle finger compression confirmed by MRI (no collections > 2 cm). The trial has a first complete analysis of results at 24 weeks, with a follow-up analysis to be performed at 52 weeks post-treatment. Recruitment of the whole sample of patients was completed in the fourth quarter of 2014. The first clinical report is expected to be available in the third quarter of 2015. With positive results, TiGenix intends to submit a request for marketing authorisation with the EMA early in 2016.

TiGenix is also preparing to develop Cx601 for the US market. The company has filed for a Special Protocol Assessment (SPA) by the Food and Drug Administration (FDA) to ensure that the design of a new Phase III study to be conducted in the US is aligned with the FDA’s requirements for the future approval of Cx601. The company has appointed Lonza as its contract manufacturing organisation (CMO) for the clinical development of Cx601 in the US. Following the transfer of manufacturing technology to Lonza expected in the first half of 2016, and the confirmation by the FDA of the US Phase III trial design, the Company will be ready to begin the Phase III trial in the US. Tigenix is currently evaluating partner organisations with whom to develop and commercialise Cx601 in the US.

Orphan drug

Based on the relatively rare occurrence, severe nature and lack of effective treatments of the therapeutic indication, Cx601 obtained Orphan Drug designation from the European Medicines Agency (EMA) in 2009. Orphan drug designation provides a number of benefits for a manufacturer, including research grants and subsidies, detailed feedback and assistance from the EMA in developing clinical trials, a streamlined process for obtaining the relevant regulatory approvals in Europe as well as up to 10 years European market exclusivity from the date of the product’s launch. Based on the Phase II clinical trial report, the Committee for Medicinal Products for Human Use (CHMP) of the EMA stated that it considered the presented preclinical and clinical data package sufficient for the submission of a Market Authorisation Application (MAA). The CHMP also indicated that a single Phase III study would be sufficient to support an MAA in terms of efficacy.

Market

With an incidence of more than 50,000 Crohn’s disease patients with complex perianal fistuals each year in both Europe and the United States, TiGenix estimates a market opportunity in excess of EUR 2 billion in Europe and the US combined. TiGenix is currently evaluating partnering options for the programme. Soft loan to support development of Cx601.

In October 2011, TiGenix, through its wholly owned subsidiary Cellerix SA, obtained a EUR 4.95 million soft loan from the “Madrid Network” to finance the Cx601 Phase III study. The soft loan covers a substantial part of the development costs of Cx601. ‘Madrid Network’ is an organisation within the Autonomous Region of Madrid which helps companies to grow through high-technology innovation. The programme is funded by The Secretary of State for Research, Development and Innovation (Ministry of Economy and Competitiveness) within the framework of the INNTEGRA plan.

Cx611

Cx611 is an intravenous injection of allogeneic expanded adipose-derived stem cells (eASC’s) in development for the treatment of early rheumatoid arthritis and for severe sepsis.

Early rheumatoid arthritis

Rheumatoid arthritis is a chronic polyarticular inflammatory joint disease, typically involving the small joints of the hands and feet, that affects between 0.5 and 1% of adults in the developed world. Between 5 and 50 per 100,000 people develop the condition each year. After initial treatment with methotrexate and non-steroidal anti-inflammatory drugs (NSAIDs), and/or corticosteroids, disease activity in a number of patients is insufficiently controlled and typically leads to treatment with a group of drugs known as ‘biologicals’, such as the TNF-alpha inhibitors. The lack of an adequate response in a significant portion of patients treated with ‘biologicals’, safety concerns, and declining efficacy over time requiring a substantial number of patients to periodically change drugs, indicate the need for additional therapeutic approaches. Specifically, there is a need for a treatment with an alternative mechanism of action that could increase the proportion of patients brought into remission, and reduce the need to progress to chronic, sequential and expensive biological therapies.

In animal models, expanded adipose-derived stem cells (eASCs) have been shown to down-regulate pro-inflammatory cytokines and up-regulate regulatory T cells which modulate the immune system. In a Phase IIa study of Cx611 in refractory rheumatoid arthritis patients, completed and presented in 2013, (see below), the safety of the product was confirmed and encouraging signs of efficacy were seen. Some patients treated with Cx611 entered remission after years of treatment with conventional and biological drugs.

Assisted by a Steering Committee consisting of Professor Mark Genovese (Professor Immunology and Rheumatology, Stanford University, US), Professor Paul Emery (Professor of Rheumatology, University of Leeds, UK) and Professor José María Alvaro-Gracia (Head of the Biological Therapies Unit at the Hospital Universitario de La Princesa, Madrid, Spain), the principal investigator in the earlier Phase IIa study of Cx611 in refractory rheumatoid arthritis, TiGenix is working with a group of leading clinical experts, including Professor Luyten, (Professor and Chairman of Rheumatology, University Hospital of Leuven, Belgium), to complete the protocol for a randomised, double-blind, comparative Phase II study to test the efficacy of Cx611 in rheumatoid arthritis patients exhibiting substantial disease activity despite treatment with methotrexate and corticosteroids, but unexposed to a biological drug. Recruitment for the proposed study is expected to start in the fourth quarter of 2015, enabling final results to be available in the second half of 2017.

Phase IIa clinical trial in refractory rheumatoid arthritis

In April 2013, TiGenix reported positive 6-month safety data of its Phase IIa study of Cx611 in refractory rheumatoid arthritis (RA), as well as a first indication of therapeutic activity on standard outcome measures and biologic markers of inflammation for at least three months after dosing. The multicentre, randomised, double blind, placebo-controlled Phase IIa trial enrolled 53 patients with active refractory rheumatoid arthritis (mean time since diagnosis 15 years), who failed to respond to at least two biologics (mean previous treatment with 3 or more disease-modifying antirheumatic drugs and 3 or more biologics). The study design was based on a three-cohort dose-escalating protocol. For both the low and medium dose regimens, 20 patients received active treatment versus 3 patients on placebo; for the high dose regimen, 6 patients received active treatment versus 1 on placebo. Patients were dosed on Days 1, 8, and 15 and were followed up monthly over a six-month period. Follow-up consisted of a detailed monthly workup of all patients measuring all pre-defined parameters. The aim was to evaluate the safety, tolerability and optimal dosing over the full 6 months of the trial, as well as exploring therapeutic activity. Only one patient suffered serious adverse events that led to discontinuation of the treatment. All other side effects were mild and transient. Importantly, the first results show no signs of haematological side effects or thrombosis.

Measured clinical activity scores were ACR20, ACR50, ACR701, EULAR2 response rates, and the disease activity score, DAS283. To gain a first insight into therapeutic activity, these parameters were evaluated every month for six months. Patients receiving Cx611 had higher ACR scores, better EULAR response, and higher DAS28 scores than patients receiving placebo. The number of patients with high scores and responses remained steady over the months following treatment, suggesting a long-lasting therapeutic effect.

These results are remarkable, as they constitute a clear signal of sustained clinical activity of a cell therapy in RA. Moreover, this was achieved in a very refractory RA patient population. At the same time, the outcome of the study provides unique clinical and laboratory insights to set the stage for further exploration of TiGenix's eASC platform in RA, and in other autoimmune and inflammatory diseases with high unmet medical needs, such as severe sepsis.

1 ACR 20 means a 20% improvement in tender or swollen joint counts as well as 20% improvement in at least three of the following five criteria: patient assessment, physician assessment, erythrocyte sedimentation rate, pain scale and functional questionnaire. The ACR50 and ACR70 categories adhere to the same criteria, but for 50% and 70% improvement, respectively.
 2 EULAR, European League Against Rheumatism
 3 DAS28, Disease Activity Score 28 joint count'

Severe sepsis

Sepsis is a potentially life-threatening complication of infection. Sepsis occurs when inflammatory molecules released into the bloodstream to fight the infection trigger systemic inflammation. This inflammation can trigger a cascade of detrimental changes that damage multiple organ systems, causing them to fail. If sepsis progresses to septic shock, blood pressure drops dramatically, which may lead to death. Patients with severe sepsis require close monitoring and treatment in a hospital intensive care unit. Drug therapy is likely to include broad-spectrum antibiotics, corticosteroids, vasopressor drugs to increase blood pressure, as well as oxygen and large amounts of intravenous fluids. Supportive therapy may be needed to stabilise breathing and heart function and to replace kidney function. Patients with severe sepsis have a low survival rate so there is a critical need to improve the effectiveness of current therapy. Only a small number of new molecular entities are currently in development for severe sepsis.

In animal models, eASCs have been shown both to decrease pro-inflammatory mediators and to increase anti-inflammatory mediators, and to have anti-microbial effects. As a result of this mechanism of action, Cx611 has demonstrated efficacy in significantly reducing mortality in two animal models of sepsis. TiGenix therefore believes that Cx611 has a potentially important role when combined with current standards of care in patients with severe sepsis.

The company has produced a development plan for Cx611 in this indication with an Advisory Board of Professor Pierre-François Laterre (Professor of Medicine and Head of Intensive Care, Saint Luc University Hospital, Brussels, Belgium), Dr. Bruno François (Service de Réanimation Polyvalente, Centre Hospitalier Universitaire, Limoges, France), Professor Sébastien Gibot (Service de Réanimation Médicale, Centre Hospitalier Universitaire, Nancy, France) and Professor Tom van der Poll (Department of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands).

In December 2014, the first subject entered a Phase I proof of principle study designed to demonstrate the efficacy of Cx611 in healthy volunteers challenged with a bacterial endotoxin (lipopolysaccharide) which elicits an inflammatory response inducing sepsis-like clinical symptoms. The trial is a placebo-controlled dose-ranging study (3 doses of eASC’s) in which 32 healthy male volunteers will be randomised to receive Cx611 or placebo in a ratio of 3:1. Primary endpoints will be vital signs and symptoms, laboratory measures and functional assays of innate immunity. All 32 volunteer subjects were recruited and dosed by March 2015. TiGenix expects to complete the trial in the second quarter of 2015, and then to follow up with a Phase II trial of Cx611 as an add-on therapy to the standard of care in patients with severe sepsis.

Cx621

Cx621 is an allogeneic expanded adipose-derived stem cell (eASC) product candidate for the treatment of autoimmune diseases via a proprietary technique of intralymphatic administration. The promise of the intralymphatic route is that the systemic effect of the eASC’s occurs at the secondary lymphoid organs: draining lymph nodes and spleen.

Recent preclinical and clinical experience with vaccines and antitumour agents indicates that intralymphatic administration is feasible and safe. Indeed, the subcutaneous lymph nodes are readily visible by ultrasound, as their paracortical area is hypoechoic. Injection of a superficial lymph node in the groin area can be performed very quickly, within minutes, even by doctors who have little experience with ultrasound. Furthermore, intralymphatic injection is relatively painless as lymph nodes are poorly innervated.

Phase I clinical trial

After obtaining positive results from toxicology, biodistribution and efficacy models in mice using human eASCs via the intralymphatic route, TiGenix conducted a Phase I clinical study in 10 healthy volunteers, which was concluded in July 2012. The results of the Phase I study confirmed the safety, tolerance and the feasibility of injection into the inguinal ganglia. The confirmation of the safety of intra-lymphatic administration of expanded adipose-derived stem cells (eASCs) has potentially important clinical and commercial implications. It opens up the possibility of achieving efficacy at lower dosages which would further increase the safety profile of TiGenix’s eASCs, while also reducing the cost and improving margins. An additional benefit is that subcutaneous lymph nodes are superficial and readily visible by ultrasound, thus allowing for a rapid and easy injection.

Current status

The development of Cx621 is currently on hold while TiGenix focuses its resources on the development of Cx601 and Cx611.

ChondroCelect

ChondroCelect, indicated for cartilage repair in the knee, was the first cell-based product approved in Europe that successfully completed the entire development track from research through clinical development to European approval and received European Marketing Authorisation in October 2009 as the first Advanced Therapy Medicinal Product. It was approved for reimbursement in Belgium in February 2011, in the Netherlands in June 2012 (retroactively to January 2011) and in Spain in March 2013. Effective 1 June 2014, the company has entered into a distribution agreement with Sobi (Swedish Orphan Biovitrum AB) for the exclusive marketing and distribution rights with respect to ChondroCelect in Europe (excluding Finland, where TiGenix has a pre-existing distribution agreement with Finnish Red Cross Blood Services), the Middle East and North Africa.

ChondroCelect is a cell-based medicinal product for use in autologous chondrocyte implantation in which cells are taken from the patient’s own knee, multiplied to reach a large quantity, and then re-implanted at the site of the defect. ChondroCelect is indicated for the repair of single symptomatic cartilage defects of the femoral condyle of the knee (International Cartilage Repair Society grades III or IV) in adults.

Treatment with ChondroCelect comprises a two-step surgical procedure. In the first step, a cartilage biopsy is obtained arthroscopically from healthy articular cartilage from a lesser-weight bearing area of the patient’s knee. Chondrocytes, the cells that produce and maintain the cartilage matrix, are isolated from the biopsy, expanded in vitro through a process based on cell characterisation, and delivered as a suspension for implantation in the same patient. ChondroCelect can be delivered nine weeks from the day of biopsy.

Management

Board of Directors

See also

References

  1. ↑ FlandersBio | http://flandersbio.be/life-sciences-database/tigenix/

External links

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