Gene transfer therapy approved for the treatment of ALL: part I

In August 2017, Novartis received FDA approval for its chimeric antigen receptor T (CAR-T) cell therapy, Kymriah, for the treatment of children and young adults with B-cell acute lymphoblastic leukaemia (ALL)

Kymriah is a novel immunocelluar therapy and a one-time treatment that uses a patient’s T cells to fight cancer. It is the first therapy based on gene transfer to be approved by the US Food and Drug Administration (FDA). Angharad Baldwin of Manufacturing Chemist spoke to Martin Lamb, VP at TrakCel, about his thoughts on the price tag, the tracking required in such a bespoke therapy and establishing a path to commercialisation.

Kymriah (tisagenlecleucel), formerly CTL019, an intravenous infusion suspension, is a CD19 directed genetically modified autologous T cell immunotherapy. Kymriah is a one-time treatment with a dose range based on patient weight. The treatment uses the 4-1 BB costimulatory domain in its chimeric antigen receptor (CAR) to enhance cellular expansion and persistence. Kymriah aims to meet the need for a novel treatment option and improve the outcome for patients with relapsed or refractory B-cell precursor ALL whose prognosis is poor. Patients in this group often undergo chemotherapy, radiation, targeted therapy or stem cell transplant, but less than 10% survive 5 years.

Acute lymphoblastic leukaemia (ALL) is a cancer of the white blood cells or lymphocytes. It occurs when normal blood cells start to divide uncontrollably; the cells start to crowd in the bone marrow and prevent the production of red blood cells, other white blood cells and platelets. Patients with ALL often need immediate treatment because of the acute nature of the disease.

Approximately 5970 cases of ALL are diagnosed annually in the US and 60% occur in patients younger than 20 years of age.1 Following initial treatment, 80–90% of adults will go into complete remission; however, 15–20% of children and 40–45% of adults relapse. The chance of survival in patients that relapse or do not go into remission is 16–30% for children and 5–8% for adults.

In 2012, Novartis and the University of Pennsylvania entered into a global collaboration to extend research, develop and commercialise CAR-T cell therapies for the investigational treatment of cancers, which included Kymriah. Its facility in Morris Plains, New Jersey, was the first manufacturing site approved by FDA for immunocellular therapy production in the US. The Children’s Hospital of Philadelphia (CHOP) was the first institute to lead a clinical trial to investigate Kymriah in the treatment of paediatric patients. The drug showed a 52/63 (83%) remission rate for patients who otherwise had limited treatment options and historically poor outcomes.

Price tag

The price tag of $475,000 according to Martin Lamb, at first glance appears high, but he reminds us it is not the first product with such a price tag. Strimvelis from GSK costs $700,000 and Glybera from Uniqure had a price tag of $1 million in Europe. Novartis has also offered a money back policy if the treatment is unsuccessful, meaning the income from successful treatments must cover the cost of unsuccessful ones. Lamb believes that there are a number of factors justifying the cost. First, Kymriah is restricted to patients who are up to 25 years of age and have a specific condition at a certain stage. Therefore, this restricts the market size of those requiring the product and development costs are recouped from a small number of patients.

Secondly, unlike standard pharmaceuticals and biologics, in which a batch of product can be utilised to treat thousands of patients, Kymriah is completely personalised and one batch equals one patient. This results in a high cost of goods and means economy of scale is incredibly difficult to achieve. Finally, because the therapy is a cell therapy, it is living, which means the supply chain must be tightly controlled — including manufacturing, collection, shipping, receipt and infusion. Otherwise, the integrity of the product is impacted. Implementing this type of control and standardisation throughout the supply chain is difficult and costly.

It is also pertinent to look at the value that a treatment such as Kymriah can deliver. In trials, a single treatment with Kymriah delivered a positive response in more than 80% of patients who had failed to respond to standard care. Time will tell whether the treatment is truly curative in the longer term; but, if it is, $475,000 would actually represent good value for money.

Regulatory approval

Currently, Kymriah is only manufactured in the US; however, if effective, it will likely soon expand into the EU and then globally. At the time of writing, Novartis was planning additional filings with the European Medicines Agency (EMA) at the end of 2017, and further filings beyond the US and EU are anticipated for 2018.

It is important to consider the different criteria for approval that exist between regulatory bodies such as FDA and EMA, said Lamb, stressing that although products are approved according to their efficacy and safety, it is the role of Health Technology Assessment (HTA) bodies, such as the National Institute for Health and Care Excellence (NICE) in the UK, to determine whether it is approved for reimbursement in a particular country.

He hopes that, between the pharmaceutical industry and HTAs, a model will be developed to support the use of products such as Kymriah in the EU. He says: “There have been discussions about potential reimbursement models in the UK, and I am sure similar debates are happening elsewhere in the EU. The industry expects future reimbursement to be based on long-term outcomes and Novartis has taken this into account with their “money back if the patient has not responded by the end of the first month following treatment” approach. I suspect some HTAs will look for longer-term outcomes, but this needs to be manageable.”

Importance of tracking

Track-and-trace systems are used to minimise mistakes. TrakCel is an example of one such system, but others are available — including in-house versions — although this can be challenging to monitor as therapies progress through development to commercialisation. Tracing a patient’s cells from collection, through to shipment, receipt, modification, shipment, receipt, handling and infusion is necessary to ensure the right cells go back to that patient.

At the start of the process, each patient or sample is assigned a unique ID that is stored in the system and used on tracking labels. This unique ID stays with the cells throughout the process. Even if a different label is applied post-manufacturing, the system links this back to the original unique ID.

This unique ID captures key data along the supply chain and triggers alerts to relevant parties, so the cells’ progress can be tracked remotely. The implementation of prescriptive workflows based on the product owner’s specific business processes and SOPs ensure that each processing step is consistently followed and the correct data captured in the right format.

Scheduling activities to ensure that upstream processes are planned for days or times when capacity for downstream activities are available is important. The integration of data from various sources provides a record that all activities were performed and the material’s environment was maintained, according to specifications, and identifies any sources of error if the product’s quality does not meet specification at any stage of the process. Whereas most couriers provide access to tracking information, this only covers part of the supply chain while the product is in transit. Other data will be captured at clinics, manufacturing sites and apheresis centres. This data can be collected from these sites, either from their system or manually to provide a full chain of custody report. However, information gathering from multiple sources is a labour-intensive task and can result in errors or information gaps.

Systems such as TrakCel, which users either input information directly into, or which integrates with third party IT systems, provides a full report of the material’s progress in the supply chain from collection to infusion (needle-to-needle reporting) from a single system.

Chain of custody

When asked to compare tracking capabilities in Europe to the US, Lamb stated that both EU and US regulations require a tracking system to be in place for cell therapy products. When therapies such as CAR-T are submitted to regulators for approval, it is necessary to confirm that such a system is in place.

When presenting Kymriah to the FDA, Novartis confirmed it had such a system in place: “Because tisagenlecleucel is an autologous product, each lot is produced for a single patient. For this reason, the applicant has implemented strictly controlled tracking and segregation procedures, from apheresis to infusion, to ensure a proper chain of identity so that the patient receives the tisagenlecleucel product made from his or her own cells.”

Novartis has developed an IT system to enable them to manage its complex supply cycle and ensure that the right therapy goes to the right patient. As a multinational pharma company, Novartis is likely to have multiple proven supply chain technologies already in place and Lamb believes that Novartis’ cell therapy solution will integrate with existing systems.

But whereas larger companies such as Novartis have developed their own solutions to measure the supply chain, not all cell therapies have the resources of Novartis nor the desire to invest in a non-core activity. This is when services such as those provided by TrakCel augment the core activities of cell therapy companies, to configure platforms to meet their track and trace requirements.

Lamb says: “Although the regulations do not specify that the tracking system needs to be an automated system, such as TrakCel, not surprisingly, companies who have taken an autologous therapy to market have invested in this technology. As the numbers of patients treated with these emerging therapies increases, it will be a massive challenge to manage these manually, hence the investment. By integrating with or being used by the above sources of supply chain data, users can perform base performance tracking and decision making, using a single-system view of the supply chain. And although tracking is a regulatory requirement in the US and EU, any system needs to be sufficiently flexible to be successful globally.”

Gene transfer therapy approved for the treatment of ALL: part II

Reference

  1. seer.cancer.gov/statfacts/html/alyl.html.

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