Gelezen op Seeking Alpha. Volgens mij heeft Molmed ook een suicide switch. Alleen weten de Amerikanen nog niet.
Bellicum Is The Most Undervalued CAR-T Stock
Nov. 28, 2016 12:43 PM ET|11 comments | About: Bellicum Pharmaceuticals (BLCM), Includes: CLLS, JUNO, KITE, NVS, XON, ZIOP
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Summary
BLCM has a technology that makes its CAR-T safer than its competitors.
However, BLCM is valued at less than one-fifth of these competitors.
Upcoming ASH presentations represent buying opportunity.
Two things distinguish Bellicum (NASDAQ:BLCM) from the rest of the companies in the CAR-T space. One is its proprietary self-destructing switch technology developed as a consequence of research done at the Baylor College of Medicine, and the other is the huge valuation gap between BLCM and the likes of Juno Therapeutics (NASDAQ:JUNO) and Kite Pharma (NASDAQ:KITE).
Bellicum's edge: suicide switch
Bellicum's principal claim to fame in CAR-T is that in a space saturated by big names like Juno and Kite, it is developing a simple technology that can switch off CAR-T treatment if it threatens healthy cells.
This pioneering technology is triggered by rimiducid, a small molecule originally developed to control gene therapy. In Bellicum's approach, CAR-T cells are genetically programmed to self-destruct in the presence of rimiducid.
Source: Investor Presentation
BLCM's principal contribution to CAR-T technology is its proprietary CID technology, which stands for Chemical Induction of Dimerization. This CID technology handles programmed cell death of apoptosis, Bellicum's approach to the safety issue surrounding CAR-T. BLCM's CAR-T cells come with a type of signaling proteins which are triggered by rimiducid. According to BLCM, rimiducid has no other effect on the body apart from this protein to protein signaling. This leads to a programmed and cascading death in the targeted immune cells. This is its trump card, where Juno's trials have seen up to 30% of patients undergoing severe cytokine release syndrome, including at least a few reported treatment-induced fatalities. BLCM's trial, although much smaller, has not seen any such death. Juno is developing its own suicide switch using cetuximab, which has its own side effects and is not as good as BLCM's.
This is important because 33% of all patients who have undergone CAR-T therapy have developed severe, sometimes life threatening fevers and inflammation, including the so-called cytokine storm and cytokine release syndrome. In fact, deaths have been reported in some CART trials. That is always a problem with any kind of immune-mediated therapy; the genetically modified immune cells kill cancer cells so quickly that they cause inflammation. More importantly, especially when solid tumors are targeted, these cells could also attack nearby healthy cells which express the targeted receptor proteins. Hence the need for a so-called suicide switch that can make the immune cells self-destruct if their killing spree goes out of hand. Bellicum is the first of the CAR-T companies to have developed a suicide switch for BPX-401, a CAR-T cell for leukemias and lymphomas. BPX-401 targets CD19, a receptor protein found on the surface of blood cancer cells, and comes with the CaspaCIDe self-destruct safety switch.
Comparison with competitor switches and methods
Building a suicide switch has become an essential part of any CAR-T program, especially after the Memorial Sloan deaths in the Juno trial. In fact, there's a perception that without some way to control the CAR-T mechanism, the FDA will not approve a CAR-T product.
Among the most well-known switch developers is Cellectis (NASDAQ:CLLS), which uses Rituxan, a chemo drug, for the activator of a cell surface protein, RQR8. However, compared to rimiducid, Rituxan is a strong and also expensive drug, and it can have serious side effects. Moreover, Cellectis's overall program is behind BLCM.
After safety problems in its CAR-T trials, Juno built a switch technology to be used in at least two of its trials, including JCAR014 for advanced leukemia. The trick, however, is to build switches for solid tumors. Juno's armored CAR-T technology is yet to be field tested. It is based on a truncated EGF receptor and the activator erbutix.
Both Juno and Cellectis suffer from the same problem - since both their switches kill via antibody - dependent cell-mediated cytotoxicity, they cause inflammation, as opposed to BLCM's cleaner method. BLCM's method has also been successful in earlier human studies using stem cells at Baylor. In fact, BLCM's switch has been discussed as a possible buyout target of Juno because of its relative success.
ZIOPHARM Oncology (NASDAQ:ZIOP), another small company, has a suicide switch meant to work like a rheostat, which can theoretically control the activity of the CAR-T cells in a much better manner than BLCM's, making it accelerate or decelerate as desired. Veledimex, a drug that is used as an immune system stimulant, and developed by Intrexon (NYSE:XON), is the control drug here.
Kite does not have a switch at present. Another two CAR-T players, bluebird bio (NASDAQ:BLUE) and Novartis (NYSE:NVS) have not disclosed their plans.
Trial results
BPX-401 reported excellent preliminary results from the phase I/II trial in September. This is the BP-004 trial on children with leukemias, lymphomas, and genetic blood diseases undergoing T-depleted, haploidentical hematopoietic stem cell transplantation (HSCT). "Interim data from 18 subjects in a Phase 1/2 clinical trial assessing BPX-501 in pediatric patients with primary immune deficiencies show all continue to be disease-free at a median of 13 months of follow-up with no treatment-related mortality after a T-depleted haploidentical hematopoietic stem cell transplant (HSCT) and infusion of BPX-501." 16 (n=17) high-risk pediatric patients with acute leukemia were disease-free. 24 pediatric patients with non-malignant genetic diseases were also disease-free, and there were no treatment-related deaths.