Two deaths in a clinical trial of a drug for acute myeloid leukemia have prompted the Food and Drug Administration to impose a partial clinical hold on the study.
Monrovia, California-based Xencor said Wednesday that the FDA placed the partial hold on its Phase I study of XmAb14045 in relapsed or refractory AML. The drug is being developed as part of a $2.6 billion collaboration between Xencor and Swiss drugmaker Novartis that the two formed in 2016 around XmAb14045 and another drug, XmAb13676.
Under the partial clinical hold, patients who are currently taking the AML drug can continue treatment, but the study will not enroll any new patients until the hold is lifted. According to ClinicalTrials.gov, the trial is designed to enroll 105 patients and reach completion by July, having started in August 2016.
Shares of Xencor fell more than 7 percent on the Nasdaq Wednesday morning following the news.
XmAb14045 is a bispecific antibody that targets CD123, an antigen commonly expressed in AML, and CD3, on the surface of T cells. Bispecific antibodies are designed to act as a “bridge” that allows T cells to target and destroy cancer cells. The only bispecific antibody currently on the market is Amgen’s Blincyto (blinatumomab), which targets CD19 and CD3 and is approved for acute lymphoblastic leukemia.
One of the patients who died in the Phase I XmAb14045 study experienced cytokine release syndrome, a toxicity also known to occur with Blincyto, for which that drug’s label carries a boxed warning. The other developed acute pulmonary edema. Both were deemed at least possibly related to the drug.
The company had presented early data from the study at the American Society of Hematology’s 2018 annual meeting on Dec. 3. According to the data, 66 patients had received the drug, and five of the 18 who were evaluable for efficacy showed a complete remission with complete or incomplete hematological recovery, producing a CR/CRi rate of 28 percent. Patients in the study had a median age of 61 and were heavily pretreated, with a median of three prior therapies. At the time, a maximum tolerated dose had not been reached in the trial.
But last month, Novartis returned rights to the other compound the two were developing, XmAb13676, as part of a shakeup of its pipeline. That drug is a bispecific antibody targeting CD20 and CD3 and in Phase I development for B-cell malignancies. Its target is the same as that of Roche’s Rituxan (rituximab), a commonly used drug for B-cell non-Hodgkin’s lymphomas and chronic lymphocytic leukemia.
In late December, the FDA approved the first anti-CD123 therapy, Stemline Therapeutics’ Elzonris (tagraxofusp), a cytotoxin designed to target the antigen. It was also the first approved treatment for blastic plasmacytoid dendritic cell neoplasm, or BPDCN, a rare blood cancer that causes skin lesions and is often mistaken for various other blood cancers – including AML – with similar symptoms. The drug is also in three clinical trials – one Phase I study and two Phase I/II studies – that are recruiting patients with AML.
However, Elzonris has in the past encountered safety issues of its own. In February 2017, Stemline reported a patient death from capillary leak syndrome, a known and potentially fatal side effect of the drug, in its pivotal Phase II study of the drug. Updated data from the trial presented at the ASH conference showed that CLS occurred in about 17 percent of 202 patients and was fatal in three of them. Elzonris’s label includes a boxed warning for CLS.
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