A drug must undergo clinical trials for safety and efficacy before it can be approved for patients and the results might not be encouraging. In what is being considered a rather sad news, Juno Therapeutics, USA, a biotech company, has recently announced halting phase II clinical trials of a new drug for acute lymphocytic leukemia (ALL), known as JCAR015, for the second time this year. The announcement came amid the demise of two more patients.
Juno Therapeutics released these details on 25 November, 2016 in bmj.
Acute lymphocytic leukemia is a complicated type of cancer, in which the body produces cancerous and immature white blood cells. Estimates by The American Cancer Society show 6,590 new cases of ALL causing 1,430 deaths in 2016 alone.
Most cases of ALL occur in children younger than 5 years of age and the risks slowly declines as the child ages. The risks increase again rise after the person has crossed the age of 50 years.
The drug being in question is an immunological treatment for acute lymphocytic leukemia and two more patients died due to excessive fluids causing brain swellings, i.e., cerebral edema. Their symptoms were identical to the first three patients who died in a previous trial.
Previously, trials of the same leukemia drug were halted by the US Food and Drug Administration (FDA) after three patients died, according to a report on 14 July, 2016.
Clinical trials go through three main phases, and a few sub-phases, after which they are determined safe for consumer use.
In preclinical trials, the drug being developed is tested on animals for toxicity levels and to gather data about pharmacokinetics, meaning how the drug works. The drug is first tested on animals because there is some risk that the drug will react improperly and cause deaths.
Phase 0 is the earliest trial in humans. The purpose of the trial is to test toxicity parameters, pharmacokinetics and to calculate half-life of the drug.
Phase I, II and III are the testing of the drug on healthy volunteers. Each successful trial indicates the viability of the drug while phase IV is the post-market surveillance.
The new treatment for ALL, being halted in phase II, involves taking T cells from a patient so they can be identified for certain antigens on the surface of the tumor cells. The T cells are then genetically engineered, grown in a laboratory and are re-introduced in the patient to attack and destroy the cancer cells.
These modified T cells are called CART and have chimeric antigen receptors (CAR) on their surface which attacks tumor cells.
The development of this new treatment is being carried out not only by Juno Therapeutics but also by two rivals, Kite Pharma and Novartis. In the 14 June report, Juno says that the three deaths, one of them caused in May, were caused by a combination of the drug, JCAR015, and a chemotherapy agent, fludarabine. The role of the chemotherapy was to destroy the existing T cells to give chance for the new T cells to grow.
Juno Therapuetics is a biotech company that was formed in 2013 by leading US cancer centers. It started with $120 million in funding, $300 million from private investors and $265 million by a public placing. In June 2015 it entered in a 10-year partnership with Cellgene, which markets any products of Juno’s that are licensed.
A Juno spokesperson said that all three deaths were caused by brain swelling and fewer than 10 patients had been administered fludarabine. The FDA stopped the trials after two additional deaths.
Strangely enough, the FDA allowed the trials to be resumed just after three days, surprising professional critics, because the process usually takes months.
The lift on regulations by the FDA was seen as a vote of confidence for Juno to keep development of the cancer immunotherapy in phase.
Juno was slightly ahead in the development of the JCAR015 treatment than its two rivals and the approval from FDA was seen as “attractive in light of improved efficacies shown from data in multiple trials,” according to Hans Bishop, chief executive officer of Juno Therapeutics.
Other trials in phase by Juno are the JCAR14 for advanced B cell malignancies and JCAR17 for pediatric acute lymphoblastic leukemia.
Juno also pointed out that fludarabine, a chemotherapy drug, was to blame, due to its increased incidence of neurotoxicity. The combination of fludarabine and JCAR015 led to massive proliferation of the modified T cells, causing brain inflammation.
Fludarabine was then removed from the treatment protocol as a prerequisite to resume the trials. At that time, FDA did not give any reasons for uplifting the hold but the lack of other available treatment options was seen as a key motive which played in the decision.
Instead of fludarabine, Juno then started using cyclophosphamide, but it did not eliminate the risk. On 23 November, two patients died under similar conditions; the inflammation of the brain due to excessive fluids.
Hans Bishop refuses to acknowledge that the study is terminated. Options include continuing the study with different protocols, starting a new study or terminating the development. Juno has several other CART treatments under development while Kite Pharma and Novartis are also involved in the same development, although the latter closed down its cell and gene therapy division.