BTK inhibitors: promising therapies for cancer and autoimmunity

Bruton tyrosine kinase (BTK) inhibitors are a class of drugs that were initially developed to control the spread of cancer. It was first approved over a decade ago to treat a rare blood cancer. Now, they are in the running to treat a host of autoimmune diseases.

One of the drugs shooting for the crown is Sanofi’s rilzabrutinib. The therapy, which was acquired by the French multinational in a $3.7 billion buyout of Principia Biopharma, has reaped promising results in a phase 3 trial for immune thrombocytopenia (ITP). ITP is a blood disorder in which the number of platelets – cells that prevent bleeding – in the blood is lower than normal. The disease causes bruising and internal bleeding in people.

The study met its primary endpoint of durable platelet response. The patients who enrolled in the study had been failed by other existing ITP therapies, and had a platelet count of 15,000/μL. The normal platelet count ranges from 150,000-450,000/μL. While Sanofi is yet to put out more data about the drug’s efficacy, it looks to file for approval in the U.S. and Europe by the end of the year.

Sanofi’s Rilzabrutinib: a potential game-changer BTK inhibitor for inflammatory and autoimmune diseases

Apart from ITP, rilzabrutinib is a contender for inflammatory and autoimmune conditions like asthma, prurigo nodularis, warm autoimmune hemolytic anemia, and chronic spontaneous urticaria (CSU), as well.

CSU is a skin condition that can result in painful hives. Despite antihistamines to relieve allergy symptoms, the symptoms persist in many patients. Rilzabrutinib reduced itching within the first week of treatment. Set to begin phase 3 soon, rilzabrutinib could give competition to Swiss multinationals Novartis and Roche’s monoclonal antibody Xolair, which is also given to patients with CSU.

Moreover, the readout of the phase 2 asthma study will be later this year. And, rilzabrutinib’s performance in patients with IgG 4-related disease – an inflammatory condition that causes organ dysfunction – and autoimmune hemolytic anemia will be revealed by the end of this year.

The latter is a rare blood disorder that occurs when antibodies produced by the body’s immune system cause the red blood cells to burst leading to a low number of blood cells, and affects one to three people per 100,000 every year. While steroids and immunosuppressants are typically prescribed to curb inflammation, BTK inhibitors like rilzabrutinib could offer hope to patients that don’t respond to these treatments.

How do BTK inhibitors work for autoimmune diseases?

But how exactly do these drugs that were meant to treat cancer, target inflammatory and autoimmune conditions?

These drugs disrupt the B-cell receptor signaling pathway. In the case of cancer, when this pathway becomes disordered, B cells grow at an uncontrolled rate, giving rise to cancer cells. This growth loop is aided by the enzyme Bruton tyrosine kinase. BTK inhibitors put a stop to this abnormal growth of cells by inhibiting the enzyme.

The BTK enzyme expressed in B cells and other immune cells plays a critical role in inflammatory pathways as well. For example, in multiple sclerosis (MS), B cells produce autoantibodies that attack the myelin sheath, which protects the nerves from damage. So, silencing BTK expressed in these cells can target the root cause of the condition.

BTK inhibitors cause side effects

However, while this class of drugs seems likely to treat MS in theory, many biotechs have struggled to get past clinical holds on their BTK drugs. Sanofi’s tolebrutinib, Chinese company InnoCare Pharma’s orelabrutinib – a collaboration Biogen bowed out of – pharma giants Merck’s evobrutinib – now dropped from the pipeline – and Roche’s fenebrutinib have all come under regulatory scrutiny. This was following reports of patients experiencing liver injury when treated with these BTK inhibitors.

Moreover, American company Gossamer Bio’s GB5121 was binned after a phase 2 trial witnessed two deaths that included a fatal case of bleeding in the brain and adverse events like atrial fibrillation – a condition that causes the heart to beat abnormally fast – according to a Securities And Exchange Commission filing.

Amid this spate of clinical pauses, American biotech Oncternal Therapeutics also bailed on clinical trials involving its monoclonal antibody zilovertamab along with multinationals Johnson & Johnson and AbbVie’s Imbruvica (ibrutinib) – the first BTK inhibitor to receive approval – for mantle cell lymphoma (MCL), a rare blood disorder, citing that the growing market of BTK inhibitors made the pairing an “an unviable commercial opportunity.”

Recently approved BTK inhibitors

Lilly’s Jaypirca

Oncternal was referring to the several BTK inhibitors that have hit the market in recent times. Lilly’s Jaypirca is one of them. First approved for patients with MCL who have either relapsed or not responded to prior treatment, back in January last year, the drug has since raked in $3 billion in sales for Lilly, eating up 60% of the blood cancer-BTK inhibitors market.

Jaypirca, which was first developed by American biotech Loxo Oncology before Lilly’s $8 billion buyout, is designed to bind to both, the normal BTK gene as well as the BTK gene with C481 mutations in order to halt the activity of the BTK enzyme. The drug was cleared after a successful phase 1/2 trial where half of the patients achieved the overall response rate (ORR) – the percentage of patients in a trial whose tumor has either been destroyed or shrunk by a drug – with 13% of them having a complete response.

In December, the drug was also green lit for chronic lymphocytic leukemia (CLL) in cases where patients have received at least two lines of therapy previously, including another BTK inhibitor. CLL is a type of cancer where the bone marrow makes too many white blood cells (WBCs). As more than 62,000 people are diagnosed with the disease every year in the U.S., patients who have been failed by currently-available medicines are left with barely any treatment options. Drugs like Jaypirca could change this. The only other BTK inhibitor authorized for CLL is pharma giant AstraZeneca’s Calquence, which is gaining ground in addressing MCL.

BeiGene’s Brukinsa

Like Jaypirca and Imbruvica, multinational pharmaceutical BeiGene’s Brukinsa bagged U.S. approval for MCL back in 2019. Recently, it received the go-ahead to treat follicular lymphoma, a blood cancer formed by the cluster of WBCs that go on to form lumps in organs. This was based on a phase 2 trial in combination with monoclonal antibody obinutuzumab where 69% of the patients experienced tumor shrinkage. A further 69% of the patients continued to show little to no signs of the disease after 18 months. This approval came after Imbruvica failed a phase 3 follicular lymphoma trial.

BTK inhibitors in the clinic: Novartis and Biogen candidates show promise

At present, Novartis’ remibrutinib seems to be making progress with hidradenitis suppurativa, an inflammatory skin condition that causes lesions and scarring on the body. A phase 2b study found that the drug met the primary endpoint, and patients had a 50% reduction in abscess – painful pus-filled lumps. The response rate was higher with the 25 mg dose compared to the 100 mg dose. However, patients did report adverse events like acute pancreatitis, a condition in which the pancreas becomes inflamed for a short while.

Although a small trial consisting of 66 patients, the drug’s approval could expand treatment options, which tend to be centered around antibiotics at the moment. The drug is waiting for approval for CSU as well, after a phase 3 trial met primary endpoints. Also in line for approval is American multinational Biogen’s BTK inhibitor BIIB091, which is currently in phase 2 trials for MS.

As the autoimmune and blood cancer spaces seem to be brimming with BTK inhibitors, it explains why Oncternal backed out of its program. But questions about the safety of these drugs still remain, as clinical holds can only be lifted once the adverse side effects are addressed and dealt with.