...I/O Update – Despite KITE, Serious Risks for Immunotherapy Exist & That Is Why We Like ZIOP - also CELG me ntion
The FDA stopped five blood cancer trials testing AstraZeneca Plc’s immunotherapy drug Imfinzi in combination with Celgene medicines from accepting new patients and halted another study entirely. This is due to safety concerns seen in similar trials of Merck’s Keytruda medicine in combination with the widely-used multiple myeloma drugs Celgene sells. The news comes on the heels of the FDA had placing similar partial clinical holds on three BMY trials of Opdivo immunotherapy in combination with multiple myeloma treatments. The FDA placed a hold on three Merck multiple myeloma combination trials in July after safety monitors reported more deaths among patients who received Keytruda than those in the control group.
Keytruda, Opdivo and Imfinzi are all PD-1 or PD-L1 inhibitors that work by blocking a mechanism tumors used to hide from the immune system. They have received numerous approvals for other cancers, such as lung cancer and melanoma. Several companies are testing similar drugs against a wide variety of cancers. Further clinical hold announcements are possible if they are being tested against blood cancers as the FDA works “to better understand the true cause of the safety concerns,” it said last week. The FDA said it still believed the benefits of Keytruda and rival medicines in the class outweigh risks when taken for their approved uses.
Under the partial clinical holds placed on the Bristol-Myers and the AstraZeneca-Celgene studies, patients who were experiencing clinical benefits can continue treatment, but no new patients will be enrolled. Patients in the study under full clinical hold will no longer receive the treatment. Most of the affected combination studies were for multiple myeloma. One of the trials under partial hold was testing Imfinzi in patients with lymphoma CLL. CELG has not identified an imbalance in the risk/benefit profile in its trials, suggesting that the safety issue reported in the Keytruda studies had not cropped up in its trials with the AZN drug.
As more trials and combinations of the sexy new immunotherapies are tried, the more likely we will hear of possible side events and serious adverse events. Early I/O trials led to CRS – or cytokine release syndrome where the pathogenesis is that the antigens bind to the T cell receptor, activating the T cells before they are destroyed. The cytokines released by the activated T cells produce a type of systemic inflammatory response similar to that found in severe infection characterized by hypotension, pyrexia, and rigors. The patient feels very unwell, as if in a high fever – indeed, the cytokine release syndrome is effectively a type of non-infective fever. Once the immune system goes haywire, it is difficult to stop and can lead to multi-organ failure and sadly, sometimes death.
It is this reason that the CAR-T makers are scrambling to develop ways to turn the cytokine storm off when things go wrong. It is also
why our choice in the CAR-T immunotherapy race is and has been ZIOP. Their RheoSwitch IL-12 technology is, in our view, the best “turn-off” valve in the race. Not only can Rheoswitch turn off a drug when CRS sets in, it can also titer the drug allowing for much more precise dosing and a physician can use is repeatedly on the same patient if necessary. It is this flexibility of RheoSwitch that makes ZIOP so attractive. Companies like BLCM have their switch, although one may not be able to utilize it more than once in any individual patient. CRS may also be the reason that a) the market for CAR-T therapies may be limited; b) KITE sold out early to GILD (albeit the crazy price Gilead is paying). Nonetheless, the race is on and now more fast and furious than ever after GILD pulled the $11.8 billion trigger. We just want subscribers to understand that not all immuno-oncology/CAR-T players are created equal. As the new therapies come to market (e.g., NVS last month, KITE/GILD soon) and more combinations are attempted (especially by rogue oncologists), we are also likely to hear about more serious A/Es, FDA clinical holds and fatalities as well