The itching starts without an obvious trigger. An outbreak of hives covers a person’s body in hundreds of red, bumpy wheals, which last for hours. Then, mercifully, it’s over — until it starts again the next day.
“This is even worse than having 100 mosquito bites every day for not only days, not only weeks, but for months. And sometimes years,” said Martin Metz, a dermatologist at Charité – University Hospital of Berlin.
Many people with this autoimmune condition, known as chronic spontaneous urticaria (CSU), currently have no option but to suffer through the bouts of hives and the deeper swelling that can sometimes accompany them. Although the FDA approved an antibody drug a decade ago, the precise nature of the condition varies from person to person, meaning that the medication does not work for everyone.
But a new small molecule drug may offer some desperately needed relief. Novartis’ Rhapsido (remibrutinib) blocks the activity of Bruton’s tyrosine kinase (BTK), which plays a central role in the development of the immune system’s target-identifying B cells. Based on the strength of a recent clinical trial that demonstrated the oral drug’s safety, effectiveness, and fast-action, the FDA has approved it as a treatment for CSU.
“It’s rare in drug development that you see a small molecule that is so well tolerated,” said Angelika Jahreis, Global Head, Development, Immunology at Novartis. “I am, as you can tell, super excited.”
Novartis' Angelika Jahreis emphasizes the focus on “unmet needs” and “maximizing the asset” with Rhapsido, which is now approved for CSU.
Credit: Angelika Jahreis
Jahreis is excited to see Rhapsido help people suffering from CSU, but she’s also eager to see what other indications the drug can treat. Ultimately, her company envisions Rhapsido as a medication that medical providers can prescribe for a range of autoimmune conditions.
“That’s the approach to immunology here at Novartis,” said Jahreis. “A real focus on unmet needs … and then a real focus on maximizing the asset and bringing it to as many patients as we can.”
While Novartis is not the first company to develop a BTK inhibitor, they are the first to offer one for a disease like CSU, which is not immediately life threatening.
From cancer to autoimmune disease
Scientists have known about the BTK gene since 1993, when multiple research groups showed that mutations in this DNA sequence cause X-linked agammaglobulinemia — a disorder that leaves people without mature B cells or antibodies to fight infections.
Subsequent studies showed that BTK also plays a major role in the activation of mast cells, which are a distinct group of immune cells that contain the histamines responsible for carrying out allergic reactions.
Realizing that BTK’s importance to B cells in particular could make it an ideal target for treating blood cancers and autoimmune disorders, scientists at Pharmacyclics, which is now a subsidiary of AbbVie, decided to develop a small molecule they had acquired in 2006. Seven years later, the FDA approved their drug Imbruvica, which doctors still prescribe for certain blood cancers.
But even though Imbruvica disrupts a target very closely associated with B cells, the medication itself is not very selective. It can interact with other kinase enzymes and cause severe side effects. While someone who would otherwise die from lymphoma may be willing to tolerate joint pain and gastrointestinal issues, it’s a different story for people with CSU and other diseases that are not life threatening.
“You have to have a really safe drug,” said Metz. “Otherwise, it will never be used in dermatology and immunology.”
Luckily, people with lymphoma and leukemia did not have to wait long for more selective medications. Since 2017, the FDA has approved three additional BTK inhibitors for different types of blood cancer. These second-generation drugs cause fewer side effects and remain the standard of care for several cancers linked to B cells.
Finding an autoimmune disease to treat
As their BTK inhibitors became more selective, developers started testing the drugs on autoimmune disorders as well. But success proved elusive.
Garth Ringheim, a pharmacologist who currently works as an independent consultant, developed a BTK inhibitor while he worked at Celgene in the mid-2010s. He explained that animal studies conducted around that time indicated that BTK inhibitors might treat rheumatoid arthritis as effectively as TNF (tumor necrosis factor), which many people now take to manage that disease.
“Everybody went into the arthritis field,” Ringheim said. “And they [the drugs] almost all failed.”
He clarified that the drugs failed to achieve the goals of clinical trials that he and his colleagues designed. But he also pointed out that these trials generally only lasted a month because that’s how long it takes for TNF inhibitors to work.
The issue is that TNF and BTK play different roles in the immune response. Whereas TNF is released right away by certain white blood cells to trigger immediate inflammation, BTK is involved earlier in the process, helping B cells grow and mature so that they can travel through the body and, later on, cause inflammation in response to a threat.
By using a drug that targets BTK, “you’ll get the inflammation response in the end,” Ringheim said. “But you won’t see it in four weeks.”
It’s rare in drug development that you see a small molecule that is so well-tolerated.
– Angelika Jahreis, Novartis
Scientists have also determined that rheumatoid arthritis can have multiple, distinct underlying causes. Malfunctioning B cells are at the root of only some of these cases. Other cases are more strongly associated with dysfunctions in macrophages, the white blood cells responsible for engulfing and digesting infectious agents. And BTK does not appear to be all that important for those cells.
So, even if companies went back and did the longer trials that Ringheim believes would produce better results, the researchers running the trials would need to be selective with their participants and understand the limitations of BTK inhibitors in the context of arthritis.
“That’s not exactly low-hanging fruit for a pharmaceutical company,” Ringheim said.
Ringheim thinks that BTK inhibitors could still be a useful part of a treatment strategy for arthritis. But to get these drugs on the market for autoimmune diseases, he and his colleagues realized that they would need to start with a more obvious choice. They would need a disease driven primarily by the antibodies produced by B cells and, ideally, by histamine-releasing mast cells as well.
As it turned out, CSU fit the bill.
A disease in need of a drug
Although CSU can cause major disruptions in a person’s life, Metz said that, historically, the disease has not received enough attention. Part of the issue is that the hives are temporary, and people often go to the doctor’s office without any present.
“As dermatologists, we are very visual people,” Metz said. “The tendency is not to take it as seriously as maybe a psoriasis.”
Martin Metz, a dermatologist at Charité – University Hospital of Berlin, stresses the need for “a really safe drug” for CSU, noting Rhapsido’s high tolerability as key for use in dermatology.
Credit: Martin Metz
Before 2014, doctors typically prescribed antihistamines, but those do not work for many of the people with CSU who try them. Then, regulatory bodies approved Xolair, an antibody medication that targets IgE (immunoglobulin E) which is an antibody released by B cells that plays a role in recognizing parasitic worms, but is best known for its involvement in allergic reactions. When IgE binds to harmless allergens, it triggers the release of histamines — an overactive immune response that many allergy medications are designed to block.
But even though IgE antibodies are involved in most cases of CSU, IgG antibodies — produced by a different type of B cell that targets bacteria and viruses — also contribute to many cases. Metz explained that this complexity means that Xolair cannot completely eliminate symptoms for many people with CSU.
“If you imagine you have 100 itchy wheals per day, you get a 50 percent reduction: well, you have 50 itchy wheals per day. That doesn’t help much,” Metz said.
There was a treatment gap, and some of the drug developers who were trying to figure out what to do with their BTK inhibitors saw an ideal indication in CSU. After all, BTK inhibitors arrest the development of all types of B cells and prevent mast cells from responding to any IgE antibodies that remain.
Enter Rhapsido
Novartis was neither the first company to develop a BTK inhibitor to treat autoimmune diseases nor the first to explore using one to treat CSU. In fact, Metz and his colleagues first learned about the drugs from developers at Roche, who were looking for CSU experts to help them test their BTK inhibitor, fenebrutinib. Although fenebrutinib proved effective, it caused undesirable side effects in the liver.
“Other BTK inhibitors were all developed earlier, but we have really taken the learnings from these and have developed a pretty unique molecule,” Jahreis said.
Rhapsido (remibrutinib) works by blocking BTK-mediated mast-cell activation and histamine release.
Credit: Martin Metz
In particular, their drug, Rhapsido, is highly selective for BTK. Metz explained that Rhapsido only affects one other tyrosine kinase. “That made it a much more likely tolerable drug,” he said.
Novartis reached out to Metz and his colleagues after reaching out to Roche and set up their own trials. Earlier this year, they concluded that Rhapsido could treat CSU both safely and effectively. Now it is the first BTK inhibitor to receive regulatory approval to treat the disorder.
Ultimately, he expects that dermatologists will use it as another treatment option, in addition to existing therapies like Xolair. Not only could Rhapsido be effective in cases of CSU that involve IgG antibodies, but it is also an oral medication. For people who do not like needles, it could be a more attractive option than Xolair, which must be injected.
“It offers new possibilities, and it offers an overall much higher rate of patients that, in the end, get an effective treatment,” he said.
In the meantime, Novartis is continuing to develop Rhapsido as a treatment for other autoimmune diseases that evidence has linked to B cells. The company is testing the drug on chronic inducible urticaria, in which a person’s wheals have a specific trigger, as well as food allergies and hidradenitis suppurativa, which causes painful lumps under the skin. The company’s neuroscience division is also currently running trials to see if Rhapsido can be used to treat myasthenia gravis and multiple sclerosis, conditions that arise when B cells target nerve cells.
“So, a really broad development program for this molecule,” Jahreis said. But for people with CSU in particular, “I think this will be a really impactful therapy for patients with a significant unmet need.”
