Barzolvolimab kills mast cells to eliminate chronic spontaneous urticaria disease activity
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Key takeaways:
- Barzolvolimab is an anti-KIT monoclonal antibody, and mast cells need KIT to survive.
- Weekly hive and itch scores fell with treatment.
- There were no serious adverse events related to the drug.
WASHINGTON — Urticaria activity symptom scores improved with barzolvolimab among patients with chronic spontaneous urticaria, according to a presentation at the American Academy of Allergy, Asthma & Immunology Annual Meeting.
Treatment also was tolerated well with a favorable safety profile, Marcus Maurer, MD, executive director of the Institute of Allergology at Charité – Universitätsmedizin Berlin, said during his presentation.
Death to mast cells
“It’s a horrible, horrific, life-destroying disease,” Maurer said. “It is a disease that severely impacts quality of life.”
Patients are devastated because of the extraordinary fear and anxiety that comes with the angioedema in the disease, he said, adding that chronic spontaneous urticaria (CSU) also keeps these patients from functioning.
CSU occurs when mast cells in the skin “go crazy,” Maurer said, as they release mediators, get aggregated and cause the signs and symptoms that patients suffer.
“Why don’t we kill mast cells? Why don’t we take them out of the game?” Maurer asked. “It’s radical, and it’s an approach that is needed for a disease that radically affects the lives of our patients.”
Barzolvolimab (Celldex Therapeutics) is an anti-KIT monoclonal antibody.
“Mast cells need KIT to survive. If we do not allow mast cells to use KIT to recognize [stem cell factor], they will go into programmed cell death and die. We’ve shown that proof of concept in chronic inducible urticaria,” Maurer said.
The patient population
The ongoing, double-blind, placebo-controlled phase 2 study comprised 208 patients with CSU who were refractory to antihistamines, including patients with previous experience with biologic treatment.
“It’s a fairly big group,” Maurer said. “These are our CSU patients as we see them in our regular practice.”
Treatment groups included patients who received 75 mg every 4 weeks (n = 53), 150 mg every 4 weeks (n = 52), 300 mg every 8 weeks (n = 51) or placebo (n = 51), all subcutaneously, for 16 weeks of placebo-controlled treatment followed by 36 weeks of active treatment and 24 more weeks of follow-up care.
The 75 mg group had a mean age of 42.2 years, with 40 (76%) women, nine patients (17%) who reported Black race and seven (13%) who reported Asian race. The other two treatment groups and the placebo group had similar percentages.
“We’re lucky to see a diverse patient population here,” Maurer said.
Mean baseline results for seven-question Urticaria Activity Scores (UAS7) included 30.3 for the 75 mg group, 30.75 for the 150 mg group, 31.33 for the 300 mg group and 30.09 for the placebo group.
Mean Urticaria Control Test Scores at baseline included 3.74 for the 75 mg group, 3.67 for the 150 mg group, 2.96 for the 300 mg group and 3.38 for the placebo group.
“This is urticaria hell,” Maurer said. “This is easily moderate, if not severely affecting for most patients.”
Study results
Least square mean changes in UAS7 from baseline compared with placebo (–10.47) at week 12 included –17.06 (difference, –6.6; P = .0017) for the 75 mg group, –23.02 (difference, –12.55; P < .0001) for the 150 mg group and –23.87 (difference, –13.41; P < .0001) for the 300 mg group.
“This is what barzolvolimab in a mast cell patient can do in chronic spontaneous urticaria,” Maurer said. “You start at 30 and you reduce that score by 24 points. That’s magnificent. That is a truly beneficial treatment response.”
All three treatment groups experienced responses, Maurer said, with the 300 mg group showing the greatest effects.
“A dose response, if you want,” Maurer said.
The researchers also called the symptom improvement rapid.
“Within the first week, the first 2 weeks of treatment, you have patients who experience significant benefit with all three doses, but most pronounced in the highest dose,” Maurer said.
Treatment was equally effective for hives and for itch, Maurer said.
“People with chronic urticaria itch because they have hives. If you reduce hives, by reducing the number of mast cells, you also reduce the itch,” he said.
Mean changes from baseline in Weekly Hives Severity Score included –8.25 (P = .002) for the 75 mg group, –11.19 (P < .0001) for the 150 mg group and –12.19 (P < .001) for the 300 mg group vs. –4.95 for the placebo group.
Similarly, mean changes from baseline in Weekly Itch Severity Score included –8.62 (P = .0061) for the 75 mg group, –11.68 (P < .0001) for the 150 mg group and –11.79 (P < .0001) for the 300 mg group vs. –5.47 for the placebo group.
“Now, maybe more important than the average reduction in disease activity to patients, is ‘what is my chance when I use this treatment of achieving the treatment goal?’” Maurer said.
“And what is that treatment goal? The treatment goal is to treat the disease until it is gone. That’s when we say we got it. Gone is gone. No more wheals. No more itch. No more angioedema,” he continued. “That’s what we want for our patients. That’s what they want from their treatment.”
Percentages of patients with UAS7 scores of 0 at 12 weeks, indicating complete response, included 22.9% (P = .0238) of the 75 mg group, 51.1% (P < .0001) of the 150 mg group and 37.5% (P = .0003) of the 300 mg group vs. 6.4% of the placebo group.
Percentages of patients with UAS7 scores of 6 or less, indicating well-controlled symptoms, included 41.7% (P = .0017) of the 75 mg group, 59.6% (P < .0001) of the 150 mg group and 62.5% (P < .0001) of the 300 mg group vs. 12.8% of the placebo group.
When the researchers stratified patients based on whether they had previously used omalizumab (Xolair, Genentech/Roche), Maurer said, the results were similar.
“They all respond,” he said.
Maurer also said treatment with barzolvolimab was more predictable than treatment with omalizumab.
“We can do an OK job in predicting who will benefit and who will not benefit from omalizumab,” he said.
But with barzolvolimab, he continued, the number of mast cells that get activated does not matter.
“You just take them out,” he said.
The pathways to mast cell activation that omalizumab or other targeted treatment would inhibit would not come into play, Maurer said.
“The responding cells are just not there,” he said.
Also, the researchers said, the drug-related toxicities were low grade. There were no serious adverse events related to the drug as well, although some patients experienced changes in hair color and neutropenia.
“This is not of clinical relevance,” Maurer said. “This may be considered a price to pay by patients, but it’s not something that puts patients at risk. It is a safe treatment.”
Maurer further noted the effects that treatment had on the patients’ outlook.
“These are happy patients,” he said. “There’s no nervous disorders that these people feel.”
Conclusions, next steps
Considering these findings, Maurer called the results of CSU treatment with barzolvolimab fast, sustainable, safe and tolerable.
“We’re very excited to see this program move forward,” he said. “We are certainly very happy for our patients that we can offer this to them.”
The benefits of treatment may extend beyond CSU too, Maurer explained, as researchers explore how barzolvolimab may apply to other mast cell diseases.
“I’m very happy we can kill mast cells now, because it will teach us about the role of mast cells,” he said. “We’ve already identified diseases that were generally held to be mast cell dependent, like prurigo.”
Indications may include diseases with mast cell signatures such as type 1 allergies, as well as diseases with increased numbers of mast cells, increases in mast cell activation status, and high levels of mast cell mediators linked with disease activity.
“It’s a good rationale to try and help these patients with mast cell activation,” he said.
Maurer expects barzolvolimab to require fewer doses than omalizumab and other treatments too.
“If you kill a mast cell, it takes quite some time for progenitors to come back into the skin. The mast cells that are damaged can take 8 weeks, 10 weeks, 12 weeks, maybe 16 weeks [to grow back],” he said. “This could be a treatment where you need to return every 12 weeks just to keep these mast cell populations down and gone.”
Maurer was not concerned about any negative impacts that such treatment would have on patients. Mast cell depletion may impair antibacterial responses and wound healing in mice, among other deficiencies, he said, but these effects are not seen in human beings.
“We looked very closely at all of the things that these mice have problems with, and humans do not have these problems,” he said.
Maurer suggested that these differences may be due to how experimental mice are born without mast cells, but human beings are born with fully developed mast cell systems that are depleted later.
The study included hundreds of human beings who have had depleted mast cells for months, not thousands of people with years of such history, Maurer added. Predicting what will happen to these people may be difficult, he said.
“Mast cell-depleted mice have a tremendous problem with venomous animals,” he said. “Mast cells in mice provide the antitoxin against these venoms.”
For example, none of the patients in the study have been bit by a cobra or stung by a scorpion, Mauer said.
“And we make sure that they stay away from these critters. But is that something that will eventually happen?” he said. “There may be situations, special situations, where mast cells come into play, and we’ll see what happens.”