Image Source: Gilead
The medical field, particularly the biotech industry, is quite innovative, and advances in medicine can help a specific target population with the ultimate gift–the gift of a better life. We’re excited by the stunning advances in the CAR-T field for the treatment for various forms of cancer that have, in the past, come with an often-bleak prognosis. We expect a shift in the advances in immune-oncology as the CAR-T revolution is in its early stages.
Key Takeaways
CAR-T therapy holds the potential to revolutionize how hematological cancer is treated.
The biotech industry remains in the early stages of the revolution, but thus far the results have been promising.
We believe Gilead Sciences is best poised to exploit the promise of the therapy as its product continues to show the most durable response.
Until a competing therapy can enter the fray with a more efficacious product with a more benign side-effect profile, the market is Gilead’s to lose, in our view.
Novartis, Celgene, and bluebird bio are other key players in the area of this budding new therapy.
What is CAR-T therapy?
CAR-T therapy is short for Chimeric Antigen Receptor T-cell therapy a revolutionary treatment where an altered version of a patient’s immune system is used to identify and kill cancer cells. The process begins with the collection of blood from the patient’s arm, and the blood is filtered through an apheresis machine to separate out the white blood cells, which contain the T-cells—the key component of this therapy. The filtered blood is then returned to the patient with the white blood cells shipped off to a lab for modification. In the lab a gene is inserted into the T-cells called a Chimeric Antigen Receptor (CAR)—the Chimeric Antigen Receptor is the key player in this treatment as it allows the T-cell to bind to a certain protein found in the cancer cells. The modified T-cells are then grown in the lab with the end goal of re-infusion back into the patient.
Challenges of the Therapy
The intricate process to harvest, modify and reintroduce the altered T-cells is a painstakingly, delicate process that requires significant technical expertise as the process is highly patient selective. As the current time, the therapy is tailored to the individual patient with the relative lack of automation, which adds to the cost and ultimate speed of which therapy can begin. We have seen estimates ranging from 17-28 days for a complete course of therapy, which limits the sheer number of patients that can receive therapy at once. Due to the requirement of modification in the lab of each patient’s T-cells, highly trained individuals must complete the required step, which increases the overall cost of the therapy This can be problematic in the current time of highly-strained national healthcare budgets.
The greatest drawback to the therapy is the potential for Cytokine Release Syndrome (CRS), a release of cytokines from the host body in response to Car-T therapy. Cytokines are a form of immunity the body utilizes to fight off cells that the body recognizes as foreign. Granted the modified T-cells were once from the host, the additional of CAR may trigger an immune response. Signs of CRS include fever, sweat, chills similar to the symptoms seen in a patient who is fighting the flu. The drawback in the case of CAR-T therapy is that CRS has led to death for some of the patients involved in the clinical trials for this innovative treatment.
How Effective Is the Therapy?
The short answer to the question is revolutionary as witnessed by the overall response rates posted in clinical trials by the two products that have been granted marketing authority in the US and European Union. The companies that own the only two approved therapies on the market today are in our simulated newsletter portfolios with dividend growth stalwart Novartis (NVS) owning the rights to Kymriah and Best Ideas and Dividend Growth Newsletter portfolio idea Gilead Sciences (GILD) acquiring the rights to the nascent industry leader Yescarta via the Kite Pharma acquisition.
Both Kymriah and Yescarta gained approval for patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL), a particularly bleak form of hematological cancer with a poor prognosis via conventional treatment. The median survival rate of this patient population is 4 months with a complete response to therapy seen in 8% and partial response in 18%. Yescarta posted an astonishing overall response rate in 83% of the patients including a complete response in 58% of the patients based on data from the long-term Zuma-1 follow up which consisted of a median follow-up at 15.1 months. The data presented by Yescarta is far and away superior, in our view, than conventional therapies that, even with a 13% chance of grade 3 or higher Cytokine Release Syndrome, the rewards far outweigh the risks of the therapy, in our view.
The results for Kymriah are a marked improvement overall conventional therapy, but pale in comparison to the stellar results posted by Yescarta. On the basis of the data presented by the Juliet trial, Kymriah posted an overall survival rate of 37% at six months which consisted of 30% complete response and 7% partial response. The incidence of grade 3 or higher CRS is 23%, leaving the product at a competitive disadvantage compared to Yescarta, which underscores our bullish stance on Gilead Sciences as the company remains at the forefront of CAR-T therapy. The potential patient population for this treatment is estimated to be 29,000 patients in second line and 19,000 in third line therapy according to Novartis (a very robust patient population).
New Competition
The third entrant into the budding field is Celgene (CELG) via the recent acquisition of Juno Therapeutics for its novel CAR-T platform. Liso-cel (JCAR017) is actively being developed for the treatment of Relapsed or Refractory B-cell lymphoma similar to Kymriah and Yescarta. The results posted are in-line with the key takeaway of the side-effect profile, especially for CRS, but it seems more benign than what we have witnessed in Yescarta.
JCAR017 at the one-year mark showed 46 of the 102 test subjects revealing a response with 37 still showing a complete response. The incidence of grade 3 or higher cytokine release is 1%, which opens the product to lay a claim for a potential best-in-class safety profile. We view the results as excellent yet nowhere near as impressive as Yescarta, which in our view should dominate the field even with a higher incidence of CRS.
Our relative confidence in Yescarta revolves around the sheer cost and the “give me my best shot” concept. The sheer cost of the therapy will more-than-likely limit it to a once-a-lifetime event, hence the need for patients to choose what they believe will give them the best shot at survival. The 83% overall response rate for Yescarta will, in our view, likely cause the bulk of potential patients to choose this therapy as they may view it as their best shot at survival, even as they weigh the risk of CRS.
The most unique entrant into the field is bluebird bio (BLUE), with its anti-B-cell maturation antigen (BCMA) CAR-T cell therapy for the treatment of late-stage relapsed/refractory multiple myeloma an area of strength for its development partner Celgene. Thus far, the treatment has posted an overall response in 95.5% of the patient class at the >150 x 106 dose, but we must caution the sample size of 22 patients for this cohort is very small. 50% of the patient class displayed a complete response with a median follow-up at the 194-day mark. The incidence of CRS is 39% with no grade 3 or higher reported at the >150 x 106 whichbodes well thus far for tolerability. The trial results are phase one, but we view them as encouraging and worth Celgene and its partner bluebird bio’s capital to continue further development of this product.
Conclusion
The CAR-T revolution remains in its infancy with many biotech/pharma heavyweights jockeying for dominance. If we had to handicap the race in its current form, we feel Gilead Sciences is in the most enviable position, but the rate of CRS remains Yescarta’ Achilles heel. We will continue to follow the data closely as we feel the therapy has the potential to revolutionize the way we treat hematological cancers.
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Heathcare and biotech contributor Alexander J. Poulos is long Gilead Sciences (GILD). Some of the companies written about in this article may be included in Valuentum’s simulated newsletter portfolios. Contact Valuentum for more information about its editorial policies.