CAR-T is bringing true precision to the fight against cancer

pharmafile | November 1, 2017 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  CAR T, CAR-T, Gilead, Kymriah, Novartis, Yescarta 

Matt Fellows investigates how the first-ever CAR-T therapy approvals in the past months could mean the field of cancer treatment is changed forever

To this day, cancer still remains one of the greatest challenges for healthcare professionals around the world. In all of its forms, the disease is one of the leading causes of death globally, accounting for almost one in six deaths worldwide, claiming the lives of 8.8 million in 2015 alone, according to statistics published by the World Health Organization.

In recent years, the development of immunotherapies has proven to be one of the greatest boons in the fight against the disease. These treatments work by boosting the body’s natural defences to fight back against cancer cells, which are able to avoid detection by producing signals that suppress the immune system or mutate to become more resistant to attacks.

While there are a number of types of immunotherapies within the field of cancer and even beyond, the treatment among these which is creating waves in the industry for its vast medical potential is chimeric antigen receptor therapy, or CAR-T, a form of active cell transfer. On a basic level, the therapy involves the sampling of blood from the patients in order to extract their own specific T cells, a subtype of white blood cell and key element of the immune system. These T cells are then genetically engineered to produce chimeric antigen receptors on the cell surface, which then enables them to recognise and bind to specific antigens on tumour cells. These cells are then replicated and the tailored cells are then infused back into the patient, where they will continue to multiply and target the tumour cells by identifying the specific antigen they express, as they have been engineered to do.

The methodology is a true form of precision treatment, one which seeks to circumvent the all-too-often encountered problem that blanket immuno-oncology approaches can produce widely different results from patient to patient, with some responding very strongly and others failing to respond at all. Beyond this, the therapy provides avenues of treatment where previously there were none, or where options were severely limited.

In August, in a move that was termed as “historic” by the US regulator, the FDA approved the first-ever CAR-T therapy, Novartis’s Kymriah, for certain paediatric and young adult patients with acute lymphoblastic leukaemia (ALL) which was found not to respond to, or had returned following initial treatment. The decision came off the back of impressive trial results, where the treatment achieved complete remission within three months of infusion in 83% of patients.

 Pharmafocus reached out to Eric Althoff, Novartis’s Global Head of Media Relations, to learn more about the breakthrough approval.

“Kymriah represents a revolutionary treatment option for paediatric and young adult patients with relapsed or refractory B-cell ALL. It is the embodiment of personalised medicine,” he said. “Unlike traditional therapies, each dose is tailored individually to, and manufactured for, each patient using the patient’s own blood cells via pioneering technology and a sophisticated process. Kymriah is not a pill or traditional chemotherapy; it is a one-time treatment.

“Novartis was the first pharmaceutical company to invest in CAR-T, forging a first-of-its-kind collaboration with Dr Carl June, a pioneer in the CAR-T field, and his institution, the University of Pennsylvania. Novartis and Penn entered into a global collaboration to further research, develop and then commercialise CAR-Ts, including Kymriah, for the treatment of cancers.”

Dr June, who was instrumental in the development of the treatment which saved the life of Emily Whitehead, the first-ever child to be treated with CAR-T for ALL, has been vocal in the benefits of the therapy in recent months as Novartis’s landmark approval brought it into the spotlight.

“I have to keep pinching myself to see that this happened,” remarks Dr June, who serves as the Richard W Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine and Director of the Center for Cellular Immunotherapies at the Abramson Cancer Center. “It was so improbable that this would ever be a commercially approved therapy, and now it’s the first gene therapy approved in the US. It’s so different from all the pharmaceutical models. I think the cancer world is forever changed.

“This is a turning point in the fight against B-cell ALL that opens up opportunities for patients across the world who desperately need new options. We’re excited and proud to have moved this CAR therapy, in collaboration with Novartis and the Children’s Hospital of Philadelphia, through all phases of development and clinical trials, established its efficacy, and now extended its reach to children across the country under this FDA approval.”

And the downside?

While the ground-breaking treatment is a cause for great excitement, it is not without its challenges, which pose significant challenges on the path to greater adoption and successful treatment. The FDA’s approval statement carried an ominous and lengthy warning over the dangers of the therapy:

“Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.”

As if to sober the medical community following the great access breakthrough made by Novartis and Kymriah, just one week later saw the death of a 78-year old man who was treated with CAR-T therapy UCART123, Cellectis’ treatment for relapsed or refractory blastic plasmacytoid dendritic cell neoplasm. After experiencing a grade 2 CRS and grade 3 lung infection five days later, though the man was given tocilizumab and antibiotics which did cause his condition to improve, three days later he suffered a grade 5 CRS event and grade 4 capillary leak syndrome which did not respond to further treatment of tocilizumab or corticosteroids, resulting in his death a day later.

The timing of the sad news highlights the imperative need for available treatments to mitigate the potentially lethal side-effects of the treatment. Thankfully, this danger is fully understood, and the same day that the FDA approved Kymriah, the regulator also approved Genentech’s Actemra for the treatment of CRS after the drug stabilised the conditions of over 60% of sufferers within the first 14 days of the first dose of Actemra, in addition to corticosteroids.

The US regulator is assessing the risks of the treatment accordingly, noting: “Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use. The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognise and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS programme specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.”

A challenge in the making

Another perhaps unprecedented challenge lies in the manufacturing of the treatment because of its personalised nature – the therapy cannot be simply produced in bulk, as is the case with the majority of other drug treatments. Blood samples must be extracted from each and every individual patient in the clinic and sent to a specialised manufacturing facility where the engineering of the T cells within can be conducted. The newly-modified cells must then be delivered back to the clinic for infusion into the patient. The whole process presents a number of challenges to any drug manufacturer wishing to offer the therapy, especially on a large scale, necessitating specialised production lines, logistics and more.

The work put in by Novartis to successfully pull off Kymriah’s implementation, before and after its approval, has been vast and complex, as Althoff explains: “With this innovative new therapy came the need for Novartis to design an innovative manufacturing process specifically for cellular therapies. Novartis has leveraged our global research and development capability and manufacturing expertise to figure out how to take a cutting-edge, complicated individualised process from the clinic and industrialise it to bring it to patients around the world. We made significant investments, purchasing and upgrading the manufacturing facility in Morris Plains, New Jersey, and establishing a robust, reproducible and scalable manufacturing process and supply chain system to provide this personalised treatment approach on a global scale.

“The Morris Plains facility, which was utilised for global CAR-T clinical trials and has already manufactured Kymriah for more than 250 patients in 11 countries across various indications in the trials, is the manufacturing facility for Kymriah. Novartis has made significant investments and continues to invest in support of the anticipated demand to meet the needs of patients.

“Our manufacturing process uses cryopreserved leukapheresis, which enables patients to be apheresed early in their course of therapy, giving physicians the flexibility to schedule apheresis at a time that is in the best interest of their patients, including times far in advance of manufacturing. It also gives Novartis flexibility on when to start manufacturing Kymriah for the patient and allows for manufacturing and treatment of patients from around the world.

“Because of the sophisticated and individualised nature of Kymriah and our commitment to patient safety, Novartis is establishing a specific network of treatment centres to offer Kymriah upon commercialisation. We are planning to have a network of 32 fully certified treatment centres by the end of the year, with the possibility of extending further in the future.

“According to our REMS with the FDA, treatment centres must complete training and receive certification to administer Kymriah following FDA approval. Novartis is managing the onboarding and comprehensive training of the centres directly and only these centres will be able to collect cells for Kymriah manufacturing, and subsequently prescribe the product.”

The price of progress

Yet another topic of huge challenge and discussion is, like with many other treatments, the price tag for such a revolutionary therapy. Heated debate over pricing is nothing new in the industry, particularly in the US, and has been a constant presence in the headlines in recent years, but Novartis’s pricing of Kymriah has proven truly divisive, perhaps in part because its availability has no precedent. The company decided to price the drug at $475,000 per course of treatment – a move which actually surprised some analysts by undercutting their predictions, yet still many were quick to criticise the firm for such a seemingly insurmountable charge for the victims of cancers, even if it is hailed as ground-breaking.

Nonetheless, Novartis maintains that the decision was part of a deliberate process, as Althoff expounded upon: “We carefully considered the appropriate price for Kymriah. We looked at many factors, including the medical and clinical value, the value to patients, the healthcare system and society, both in the near-term and long-term,” he noted. “We also sought input from several renowned external health economic experts and took into consideration health technology appraisals by review bodies like NICE of the United Kingdom who determined a cost-effective price would be $600,000 to $750,000. And we looked at the current standards of care, such as the cost of allogenic stem cell transplants, which is between $540,000 and $800,000 for the first year in the US. These external assessments, as well as our own health economic analysis of the value of Kymriah, all indicated that a cost-effective price would be $600,000 to $750,000.

“Recognising our responsibility to bring this innovative treatment to patients, we have set the price for Kymriah below that level at $475,000 for this one-time, single administration treatment. We believe this will support sustainability of the healthcare system and patient access while allowing a return for Novartis on our investment.”

The reasoning appears sound, but certain vocal figures and patient advocates such as David Mitchell, Founder and President of Patients for Affordable Drugs, were not convinced. On the news of Kymriah’s approval, Mitchell commented: “While Novartis’ decision to set a price at $475,000 per treatment may be seen by some as restraint, we believe it is excessive. Novartis should not get credit for bringing a $475,000 drug to market and claiming they could have charged people a lot more.”

Althoff does nevertheless touch upon the crucial issue of reimbursement for the company. In order to make its offering of the treatment commercially viable, and therefore available to patients at all, drugmakers have to grapple with heavy expenditures, particularly in the areas of development and manufacture, both of which are in many ways incomparable to the standard set by the majority of other drugs on the market.

But Mitchell rebuts this in part, noting: “Let’s remember, American taxpayers invested over $200 million in CAR-T’s discovery. To date, Novartis has not acknowledged the significance of taxpayers’ investment, and the company declined to detail its own investment.

“The drug pricing system in America is completely broken,” he added. “Until policy in this country changes, the vicious cycle of patients struggling under high drug prices will continue.”

A challenger appears

Before Novartis could even finish celebrating, Gilead stepped into the ring with its own CAR-T therapy in mid-October – Yescarta (axicabtagene ciloleucel), approved by the FDA for the treatment of diffuse large B-cell lymphoma, a non-Hodgkin’s form of the disease. Gilead shelled out a massive $12 billion to acquire Kite Pharma and the rights to the therapy, and this was the price it had to pay to compete in the space.

It was deemed by analysts that Novartis had been particularly aggressive with its pricing and the offer that there would be no need to pay if the treatment was not measured efficacious a month after infusion, as a means of putting pressure on Gilead’s treatment. Due to the fact it targets a wider patient population and is less effective than Novartis’ treatment in its target population, the lower price point of Kymriah meant that Gilead had to enter the market at a cost perhaps lower than it would have liked.

However, Gilead took the move in its stride, and surprised the industry with the news that Yescarta would cost $373,000 per treatment, less costly than expected – a move that was widely approved as shares in the company immediately rose 4% on the announcement, and it is estimated that the company could rake in $250 million throughout 2018 on the back of the therapy.

How the market space will play out in light of this development, particularly as more contenders join the fray, will be something that patients and industry professionals alike will be fervently watching.

Even more to come

The latest exciting developments with CAR-T are still ringing in the ears of the industry and the good news is expected to keep coming. Novartis is far from done, with a slew of plans ready to unfold in the space, as Althoff outlined: “We are excited about the possibility of CAR-Ts to transform cancer care. Kymriah is just the first of Novartis’ CAR-T cell therapies. The company also plans to file Kymriah with the FDA in relapsed or refractory diffuse large B-cell lymphoma (DLBCL), as well as file applications with the European Medicines Agency for both B-cell ALL and DLBCL by the end of this year.

“As part of the company’ ongoing research and development collaboration with Penn, together we’ve generated CTL119 – a humanised anti-CD19 CAR – which is in initial clinical development for multiple B-cell malignancies,” he continued. “We’re also studying CART-BCMA, a novel, fully human CAR targeting BCMA, in multiple myeloma and CD123 CAR-T in myeloid leukaemia. Additionally we are studying a number of other CAR therapies in solid tumours, including a humanised anti-EGFRvIII CAR for Glioblastoma Multiforme, a lethal and common brain cancer, and a fully human anti-Mesothelin CAR (huCART-Meso) which recently began clinical testing.”

Gilead has also already announced its intentions to seek expanded indications of Yescarta, and rumblings in the industry indicate that there could be many more developments on the horizon, from Takeda’s partnership with Noile-Immune Biotech to develop its own “next-generation” CAR-T therapy in the treatment of solid tumours, to reports from the General Hospital of Massachusetts of the first-ever response of a nervous system tumour to such a treatment.

We are witnessing the blooming of the field, and the great news that has already given hope to suffering patients is sure to blossom into increasing treatment options and developments in areas where many are left behind, in spite of the many hurdles that are still to be tackled. As a professional who has been there since the beginning, Dr June is optimistic for the future: “We hope the momentum behind the technology builds as we continue to investigate the abilities of personalised cellular therapeutics in blood cancers and solid tumours to help patients with many other types of cancer.”

Matt Fellows