Gilead Sciences’ $4.9 billion investment to acquire a biotech company developing a new form of cancer immunotherapy drug bore some of its first fruit Friday as data for its lead asset showed most patients in an early-stage study of two rare blood cancers achieving responses to therapy.
The Foster City, California-based company announced the presentation of data from its Phase Ib study combining magrolimab with Bristol-Myers Squibb’s Vidaza (azacitidine) in 68 patients with untreated higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The data are being presented in an oral session of the American Society of Clinical Oncology’s annual meeting, which is taking place online due to the Covid-19 pandemic.
Gilead took control of the drug in March when it acquired its developer, Forty Seven. Forty Seven’s name alludes to magrolimab’s target, the antigen CD47, sometimes called the “don’t eat me” signal. While expressed in normal cells, CD47 is over-expressed in cancer cells, enabling them to evade immune system detection. The drug works through the CD47/SIRPa axis, targeting CD47 on cancerous cells and enabling myeloid cells to detect and kill them through their corresponding receptor, SIRPa. Thus, it is an immunotherapy, albeit distinct from the approved PD-1 and PD-L1 checkpoint inhibitors like Merck’s Keytruda (pembrolizumab) and AstraZeneca’s Imfinzi (durvalumab).
The ASCO presentation provides data on 39 patients with higher-risk MDS and 29 patients with AML. The population included 12 AML patients with TP53 mutations, who are considered to have a particularly poor prognosis. In a phone interview, Mark Chao, a co-founder of Forty Seven and its head of clinical development, added that the study also added a subset of four MDS patients with TP53 mutations who achieved a high response rate.
Patients with TP53 mutations constitute a lower proportion in the higher-risk MDS population overall as compared with AML, but they tend to show up at academic cancer centers more frequently, as doctors refer them due to their poorer-risk cytogenetics, Dr. David Sallman, a leukemia and MDS specialist at the Moffitt Cancer Center in Tampa, Florida, who presented the study results at ASCO, said in a phone interview. In the general higher-risk population, they account for about 8% of patients, but they account for about 20% of those in clinical trials and at Moffitt, he added.
“On a population basis, it’s much smaller, but it’s actually a big issue from an academic and clinical trial perspective,” Sallman said.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
AML and higher-risk MDS are similar cancers, though the latter has a lower percentage of circulating blasts, the malformed myeloid white blood cells that characterize both diseases.
“I think this drug is a very promising combination therapy, based on early results, compared with what’s approved,” said investigator Dr. Monzr Al Malki, an assistant clinical professor and hematologist at City of Hope, in Duarte, California, in a phone interview.
Al Malki pointed to the efficacy data, noting that it was favorable compared with what is observed with Vidaza alone.
According to the presented data, 91% of the 33 MDS patients evaluable for efficacy responded to therapy, including 42% who achieved a complete response (CR). After at least six months of follow-up, the complete response rate had deepened to 56%. In the AML population, 25 patients were evaluable for efficacy, of whom 64% responded, including 56% who achieved a CR with or without a complete recovery of blood counts, known as the CR/CRi rate. In particular, 75% of the 12 patients with TP53-mutant AML achieved a CR/CRi. Median durations of responses in MDS, AML and TP53-mutant AML had not yet been reached. Patients in the study received a priming dose of 1mg per kilogram of body weight, followed by a maintenance dose of 30mg/kg once per week or biweekly, with the biweekly dosing selected for patient convenience.
The responses in the TP53-mutant population elicited particular excitement.
“It was very exciting to see that CR/CRi rate in this population,” Al Malki said.
Given a general dearth of new treatment options, the data for MDS has also attracted interest.
“It’s a good place to look because there’s not much going on there,” said Dr. Gary Schiller, an investigator in the upcoming Phase III ENHANCE study of magrolimab at the University of California Los Angeles, in a phone interview. ENHANCE is testing the drug plus Vidaza against Vidaza and placebo in untreated MDS. The 180-patient trial is expected to start in June, according to ClinicalTrials.gov and company guidance.
“This design is intended to potentially receive not just U.S. but ex-U.S. approval,” Chao said.
While ENHANCE is designed for global registration, Chao added that the company may also seek accelerated approval in the U.S. based on the Phase Ib study and is in discussions with the Food and Drug Administration. “In this population of MDS, there have been no approved drugs in 13 years,” he said.
In terms of safety, only one patient dropped out of the Phase Ib study due to an adverse event. Treatment-related adverse events occurring at any grade of severity included anemia, occurring in 38% of patients, fatigue in 21%, as well as neutropenia, thrombocytopenia and infusion reactions.
“It has a challenging toxicity profile that needs to be elucidated a little bit more,” Schiller said. In particular, he pointed to infusion reactions, which occurred in 16% of patients, questioning what that specifically refers to.
Chao explained that the reactions occurred within the first two doses, mild to moderate and included chills, rigors, fevers and some cases of fatigue and headache.
For AML, Al Malki suggested the company appeared to be working on a possible registrational path for TP53-mutant disease, though Chao said the strategy for AML was still the subject of internal discussions.
Sallman also noted that plans are in the works for registration studies in TP53-mutated AML, noting that one of his presentation’s slides mentioned them.
“A nice feature of magrolimab is that it’s not a targeted therapy and not limited to TP53 mutations,” Chao said.
Photo: Tomsmith585, Getty Images
