Breaking Barriers: TECELRA Becomes the First Engineered T-Cell Therapy for Solid Tumors
Developed and manufactured by Adaptimmune, TECELRA is a personalised therapy for treating synovial sarcoma, a rare and aggressive cancer that primarily affects younger individuals. This is great news for patients as no new therapies had been approved for this disease in over 10 years. (1)
There is a lot to learn from how Adaptimmune has developed and launched TECELRA, in particular how it has navigated the challenges of launching the company's first personalised cell therapy in a rare disease. In this article we will explore what steps Adaptimmune took as well as their plans for commercialization. We will wrap up with some key questions for drug developers in these areas.
Synovial Sarcoma
Synovial sarcoma is a type of soft tissue sarcoma that typically arises near the joints of the arm, neck, or leg. This cancer is notorious for its aggressive nature and poor prognosis. Symptoms often include a palpable mass, pain, and limited range of motion in the affected area. The disease is particularly prevalent among adolescents and young adults, with a median age of diagnosis around 30 years. The prognosis for synovial sarcoma is generally poor, with a five-year survival rate of around 36% and 20% for metastatic cases. Standard of care has been to treat patients with radiation, surgery and chemotherapy. (1)
TECELRA: Pioneering T-cell Therapy for Solid Tumors
Mechanism of Action
TECELRA is a genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating lentivirus to express a T-Cell Receptor (TCR) specific for human MAGE-A4 on the cell surface. The TCR recognizes a specific MAGE-A4 peptide, an antigen expressed in synovial sarcoma. Antigen-specific activation of TECELRA results in T cell proliferation, cytokine secretion, and killing of MAGE-A4/HLA-A*02 expressing synovial sarcoma cells. (3)
Companion Diagnostic Requirements
TECELRA is a personalized therapy and requires biomarker tests for HLA type and MAGE-A4 tumor expression before treating patients. These tests must be determined by FDA-approved or cleared companion diagnostic devices.
Preparation and Administration
The process of preparing and administering TECELRA is intricate and patient-specific, reflecting the complex supply chains commonly associated with engineered cell therapies. It begins with leukapheresis, where T-cells are collected from the patient's blood. These cells are then genetically engineered in a specialized laboratory to express the MAGE-A4 receptor. After the modification, the cells are expanded to sufficient numbers and infused back into the patient in a single infusion. Prior to the infusion, patients will undergo lymphodepletion, a chemotherapy that commences 7 days before the infusion.
This entire process requires coordination between the testing and treating centers as well as the manufacturing facility to ensure timely and precise delivery. It is possible that this may be one of the reasons why Adaptimmune have decided to undertake all the manufacturing themselves.
Pivotal Trial
The Accelerated Approval of TECELRA was based on the results of an open-label, single-arm Phase 2 trial (SPEARHEAD-1), based on the data from the first of three cohorts of patients (N=44).
The primary end point was the Overall Response Rate (ORR) reaching 43%, with a median time to response of 4.9 weeks. Median Duration of Response (DOR) was 6 months with 39% having a DOR of 12 months or greater. Serious adverse events were observed in 52% of patients, with 9% comprising Cytokine Release Syndrome (CRS). As a result, TECELRA carries a black box warning for CRS. (3)
From Accelerated Approval to Full Approval
Having received Accelerated Approval from FDA, TECELRA will still need to present further results to obtain the full FDA approval. Adaptimmune is planning to submit data from the 2nd and 3rd patient cohorts from SPEARHEAD-1 to FDA next year, which will shed light on Duration of Response at 15 months on a large patient pool. (2)
Additional Expedited Regulatory Schemes
In addition to securing accelerated approval, Adaptimmune also obtained Orphan Drug Designation (ODD) and Regenerative Medicine Advanced Therapy (RMAT) status. Both schemes allow for greater interactions with FDA and opportunities for the shortened approval times, and of course extended market exclusivity (ODD). For therapies as novel as TECELRA these schemes are of immense value, not only in accelerating the drug to market but also reducing the risk of clinical development.
Commercialization, Pricing and Patient Reach
Adaptimmune are launching TECELRA themselves and will manage the commercial field teams as well as the manufacturing. It will launch with a list price of $727,000, which Adaptimmune says reflects the clinical value of treating the rare tumour, the improvement in clinical efficacy, and the level of innovation in an area that has seen no new approval in over a decade. Peak sales are expected to reach $400M which suggests a total of approximately 500 patients. Adaptimmune plan to grow the the number of patients through a line extension to the paediatric population as well as geographic expansion.
As mentioned earlier, in order for patients to be eligible for treatment, they will need to test positive with the associated companion diagnostic test. In addition to being a requirement in the drug label, Payers are certain to include this in prior authorization criteria to access the therapy. Therefore the development and widespread availability of the companion diagnostic, in addition to the therapy, are key success factors for the uptake of TECELRA. (2)
Post Approval Infrastructure
Adaptimmune is in the process of establishing up to 30 authorized treatment centers across the U.S., many of which if not all, participated in the pivotal trial. It is expected patients will have testing in local centers, but be referred to these Authorized Treatment Centers for treatment. These centers will be equipped with the expertise and facilities needed to administer TECELRA. They are also experienced in treating patients with advanced cell therapies and have experience in managing adverse events such as CRS.
Additionally, patient support programs are being set up to assist with logistics, insurance navigation, and other aspects of the treatment journey. (2)
Geographic Expansion
At this moment in time, Adaptimmune has not yet filed for approval outside of the US, saying that the company’s focus for the time being is on the US. It's possible this is a result of Adaptimmune needing to quickly deliver the return on investment as well as further support for its ongoing pipeline. This is a difficult transition for any company, least of all a company selling a product with a complex supply chain for a life-threatening disease. This certainly merits the strong focus on getting this right for patients from the start.
It is also possible that lower prices for some advanced therapies in Europe have reduced rates of return for companies such as Adaptimmune, as highlighted by BluebirdBio’s decision to withdraw from Europe in 2021, following challenging negotiations with Health Technology Assessment bodies. It is likely that Adaptimmune will seek to enter other geographies once more data becomes available and the US launch starts to consolidate. (4)
Questions for Life Science Companies
The experience of Adaptimmune in the development and launch of TECELRA is packed with important considerations for other innovative drug and advanced therapy programs:
- What is the optimal accelerated pathway for getting our therapy to patients? Have we explored all possible regulatory pathways?
- How can we design our studies to ensure regulators and other key stakeholders have the evidence they need without delaying access unnecessarily to patients?
- How do we communicate the value of the therapy we are launching and how do we justify our price?
- How do we manage complex supply chain risks?
- What is the right pace for geographic and therapeutic expansion?
- Have we brought all stakeholders along with us in the journey for our therapy? Patient associations, payers, specialist treatment centers, investigator sites, companion diagnostic partners, regulators
Conclusion
The FDA approval of TECELRA marks a significant advancement in the treatment of synovial sarcoma and solid tumors. As the first engineered T-cell therapy for solid tumors, TECELRA offers new hope for patients who have long awaited effective treatment options. Furthermore, the experience of Adaptimmune is a rich case study for other developers working in similar areas.
Contact
If you are interested in discussing any of the issues above for your company/drug development program, please contact me through my email address dniven@nivenbiopharma.com. Feel free to also visit my website at www.nivenbiopharma.com for more information.
I have no conflicts of interest in the production of this article.
Sources
- Adaptimmune Receives U.S. FDA Accelerated Approval of TECELRA® (afamitresgene autoleucel), the First Approved Engineered Cell Therapy, Adaptimmune Press Release, 01 Aug 24
- Adaptimmune Conference call, 02 Aug 24
- FDA TECELRA Label (FDA website)
- With the pricing situation 'untenable' in Europe, bluebird will wind down its operations in the 'broken' market, FiercePharma, 09 Aug 21
