JAK inhibitors: Are they a good option for treating inflammatory diseases and cancer?

Janus Kinase (JAK) inhibitors are a popular class of drugs in the biopharma industry. Several have been approved to treat inflammatory diseases and cancer, and regularly bring in billions of dollars in yearly revenue for pharma giants like Pfizer and AbbVie. They work by inhibiting the activity of one or more of the JAK family of enzymes, which includes JAK1, JAK2, JAK3, TYK2. These all play a key role in cytokine signaling and are linked to both inflammatory diseases and cancer, which means that, by blocking the action of these enzymes, JAK inhibitors help reduce the inflammation and other symptoms of these disorders.

The role of JAK inhibitors in treating I&I diseases 

JAK inhibitors have gained particular attention in the inflammation and immunology (I&I) space, an area that has brought in a wave of investment in recent times. Pharma giants such as Pfizer and AbbVie have received a number of approvals for their JAK drugs in indications such as atopic dermatitis, ulcerative colitis, and rheumatoid arthritis. 

Hannah Kopelman, a dermatologist at Kopelman Aesthetic Surgery, commented: “As a dermatologist who treats patients with JAK inhibitors, I’ve seen the remarkable benefits these medications can offer, particularly for individuals struggling with autoimmune and inflammatory skin conditions like psoriasis, atopic dermatitis, and alopecia areata.”

JAK inhibitors for psoriasis

Kopelman said that this class of drugs is particularly valuable for patients with psoriasis, a condition that is characterized by red, scaly patches on the skin and affects a staggering 125 million individuals worldwide, representing 2 to 3% of the global population. 

“Psoriasis is driven by an overactive immune response, and JAK inhibitors help to calm this response, leading to significant improvements in skin appearance and a reduction in the severity of flare-ups,” explained Kopelman. “For many patients with psoriasis, JAK inhibitors offer a new level of control over their condition, particularly for those who haven’t responded well to other treatments.”

JAK inhibitors for alopecia

In recent years, JAK inhibitors have also been approved to treat alopecia areata, where the immune system attacks hair follicles, causing sudden, patchy hair loss. The indication was highlighted in 2022 as an unmet need by professionals in the space. Soon after, Eli Lilly’s Olumiant (baricitinib) received U.S. Food and Drug Administration (FDA) approval, making it the first approved JAK inhibitor to treat the condition. Before this, patients would seek local corticosteroid injections as off-label treatments. The most recent approval for the indication came in July when Sun Pharma’s JAK inhibitor Leqselvi (deuruxolitinib) was given the green light to treat severe alopecia areata.

Kopelman said that these JAK inhibitors have shown impressive results in promoting hair regrowth, “giving patients back not just their hair but also their confidence.”

“As a dermatologist, it’s incredibly rewarding to have a tool like JAK inhibitors at my disposal, especially for patients who have struggled with limited treatment options in the past. The potential for these medications is vast, and I’m looking forward to seeing how their use continues to evolve,” stressed Kopelman. 

Improving the function of JAK inhibitors for cancer 

Although the majority of approved JAK inhibitors are for I&I diseases, these types of drugs can also be used to treat cancer, particularly myelofibrosis, a rare type of bone marrow blood cancer. In fact, the first-ever FDA-approved JAK inhibitor, Incyte’s Jakafi (ruxolitinib), was given the nod for the treatment of myelofibrosis, and, since then, several other JAK drugs have been approved to treat this type of cancer. 

Looking at the current clinical landscape, it would appear that certain companies are now also searching for ways to make JAK inhibitors more effective at treating cancer – whether that entails creating a newer type of JAK inhibitor or using them in combination with other therapies to improve overall efficacy.

Ajax Therapeutics’ AJ1-11095

Ajax Therapeutics is one of the companies trying to create a new form of JAK inhibitor. With the help of computational drug specialist Schrodinger and research that originated at Memorial Sloan Kettering Cancer Center, the company has designed a JAK drug that works differently, with the potential to be far more precise and potent than those that have come before it. In fact, the chief executive officer (CEO) of Ajax told Biopharma Dive: “Nobody’s taking the same approach that we’re taking to target JAK [enzymes].”

The approach in question involves how Ajax’s drug, known as AJ1-11095, binds to its target. Being developed to treat myelofibrosis, it targets JAK2 while the enzyme is in an “inactive” state rather than an “active” state. Or, to be more technical, Ajax’s drug selectively binds the type II conformation of the JAK2 kinase instead of type I. 

According to the company, this should allow AJ1-11095 to overcome resistance mechanisms that limit the effectiveness of more traditional JAK inhibitors like Jafaki. This has already been demonstrated in preclinical studies, as the drug has been shown to reverse marrow fibrosis, reduce mutant allele burden, and maintain efficacy against myeloproliferative neoplasms (MPN) – meaning cancers that start in the bone marrow – cells that become resistant to chronic type I JAK2 inhibition.

Ajax’s next-generation JAK inhibitor is attracting interest. In May, the company raised $95 million in series C financing and received clearance for its Investigational New Drug (IND) application from the FDA to initiate a phase 1 study for AJ1-11095, which is expected to commence later this year. 

Combination of JAK inhibitors with immune checkpoint inhibitors

Another interesting development in the JAK inhibitor field is testing these drugs in combination with immune checkpoint inhibitors (ICIs) to improve cancer treatment. Although ICIs have substantially improved the treatment of some types of cancers, not all patients respond to them, and cancer patients often have chronic inflammation and immunosuppression, which can limit ICI treatment response. Incyte has recently been leading the charge in this area, as two of its JAK inhibitors, one of which is Jafaki, have been shown in clinical studies to improve cancer immunotherapy response in patients.

In one study, ruxolitinib (Jafaki), which targets JAK1 and JAK2, was tested in combination with Bristol Myers Squibb (BMS)’s anti-PD-1 drug nivolumab in patients with relapsing-refractory Hodgkin lymphoma who had previously received ICI therapy and were either unresponsive or showed a mixed response. The results of the phase 1/2 trial showed that administration of ruxolitinib eight days before the start of nivolumab resulted in improved clinical efficacy in patients who had previously failed ICI immunotherapy. Among the 19 patients who participated, overall survival was 87% at two years compared to previous reports of 23.8% treated with only ICI.

Meanwhile, in the other study, the JAK1 inhibitor itacitinib – currently in clinical studies in patients with acute and chronic graft-versus-host disease (GVHD) – was tested along with Merck’s anti-PD-1 ICI pembrolizumab as a first-line treatment for metastatic non-small cell lung cancer (NSCLC). This phase 2 trial, which included 21 patients with treatment-naive NSCLC, found that delayed administration of itacitinib following treatment of pembrolizumab improved the response of immunotherapy – median progression-free survival was nearly two years, compared to the 6.5 to 10.3 months reported in other trials with only ICI.

The findings of these two trials are significant, as they could potentially pave the way for new first-line treatment options for certain cancer types. 

Safety concerns surrounding JAK inhibitors

JAK inhibitors are certainly not faultless. There have been some major concerns in the last few years linked to their safety; when used to treat inflammatory diseases, these drugs work by blocking immune-regulating proteins, which means that they can also impair how the body defends itself against harmful microbes or cancer.

In 2021, the FDA put restrictions in place on three JAK drugs – Pfizer’s Xeljanz, Eli Lilly’s Olumiant, and AbbVie’s Rinvoq – that meant they could only be given to patients who cannot take or do not respond to a TNF inhibitor. The decision came after an FDA review of a large randomized safety clinical trial, from which the organization concluded that there is an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with the arthritis and ulcerative colitis medicines Xeljanz and Xeljanz XR. 

The European Medicines Agency (EMA) followed suit in 2022, recommending that Xeljanz, Pfizer’s other drug Cibinqo, Olumiant, Rinvoq, and Galapagos’ Jyseleca be restricted in patients who are at least 65 years old, at increased risk of major heart disease or cancer, or are active or long-time smokers. 

Two other popular JAK inhibitors, Jakafi and Bristol Myers Squibb’s Irebic were excluded from these restrictions because they are used for blood disorders as opposed to inflammatory conditions, and, therefore, need different updates to their prescribing information, according to the FDA. 

JAK inhibitor market set to surge

Not that these safety concerns are putting drugmakers off JAK inhibitors. The JAK inhibitor market is actually set to surge in the coming years. It already grew from $14.61 billion in 2022 to $17.29 billion in 2023, and is expected to reach $33.38 billion in 2027, maintaining a robust compound annual growth rate (CAGR) of 17.9%. The potential driver behind this forecasted market increase is the escalating prevalence of autoimmune diseases. 

With many big pharmas currently developing JAK inhibitors, and with the potential for more companies like Ajax to emerge in an attempt to develop more effective JAK drugs, the field is set for continued growth. Plus, their ability to be used to such good effect in combination with ICIs could open up a whole new avenue for cancer treatment. But will companies also be able to address concerns around their safety? We will have to wait and see.

New technologies related to JAK inhibitors

• Gastrointestinal (GI) Locally-Activating JAK Inhibitor for Treatment of Ulcerative Colitis – University of Michigan
• JAK1 Inhibitors in the Treatment of Interstitial Cystitis – Mount Sinai Health System