JAK inhibitor, the successor to Hummero?

To AbbVie and others, JAK inhibitors are angels. Sales of AbbVie's Rinvoq, a key product in the field of autoimmune diseases, rose 59.3% to $695 million in the third quarter.

Against this backdrop, AbbVie has high hopes for Rinvoq as one of Humira's successors.

But AbbVie's optimism comes as the European Medicines Agency's safety committee issued a recommendation limiting the use of JAK inhibitors in four high-risk groups. The restricted category also includes AbbVie's Rinvoq.

Side effects have always been the wild card with JAK inhibitors. The European Medicines Agency follows the FDA's move last year to push JAK inhibitors off the list for a wider range of people.

Both the pros and cons stand out, making the future of JAK inhibitors uncertain. So will JAK inhibitors become angels after all?

01     A "jack-of-all-trades" in immunization

Abbvie could be forgiven for looking at Rinvoq as one of Humira's successors. In a way, they're very similar.

Humira is the drug king for two reasons:

First, it applies to a wide range of people. When Humira topped the list in 2012, it was approved for nine indications. Now there are more than 10.

Second, the particularity of autoimmune diseases leads to a relatively long drug cycle. For example, in areas like psoriasis, patients need to take the drug for life until the disease is no longer under control.

Because of these two characteristics, Humira's popularity and sales continued to rise until the patent expired.

Perhaps Rinvoq is also a possibility.

The JAK kinase targeted by JAK inhibitors is at the core of the entire JAK-STAT signaling pathway. JAK-STAT signaling pathway is one of the few proven immune regulatory pathways.

Many diseases, such as rheumatoid arthritis, psoriasis, and hematological disorders, have been shown to require the transmission of JAK-STAT signaling.

This means that, like Humira, Rinvoq has the potential to expand.

Indeed, just a short time ago, the FDA approved a new indication for Rinvoq for end-line treatment in adult patients with nonradiological axial spongearthritis (patients who have failed multiple lines of therapy or are not suitable for tumor necrosis factor inhibitors such as Humira).

This is the sixth indication approved for Rinvoq. According to the current clinical development strategy of AbbVie for Rinvoq, the indications for Rinvoq are likely to be expanded in the future.

At the same time, the indications for Rinvoq are also concentrated in the field of self-exemption, which has the characteristics of long drug cycle and high frequency, and the potential ceiling is also not low.

This, also can peep through its sales performance. In the third quarter of 2022, Rinvoq's sales reached $695 million, up 59.3% year over year. And it's not hard to see why AbbVie has high hopes for Rinvoq.

02      Regulation that keeps "cracking down"

But JAK inhibitors have not only AbbVie's optimism, but also regulatory warnings and pressure.

On 28 October 2022, the European Medicines Agency's Safety Committee (PRAC) issued the following recommendations:

The use of currently approved JAK inhibitors is limited to individual populations because of serious side effects, including cardiovascular disease, blood clots, cancer, and severe infections.

PS: Restricted JAK inhibitors, including AbbVie's Rinvoq, Pfizer's Cibinqo and Xeljanz, Eli Lilly's Olumiant, Gilead's Jyseleca and others.

People who are not eligible for JAK inhibitors, according to the committee's recommendations, include those older than 65 years of age, those at higher cardiovascular and cerebrovascular risk, and those with higher risk factors for cancer, such as smoking.

In addition, the committee recommended dose reduction, although not restriction, for patients with higher risk factors for thrombosis.

So why did the committee restrict the use of JAK inhibitors?

The reason is that according to clinical results of Pfizer's Xeljanz and Incyte/ Eli Lilly, JAK inhibitors can cause side effects such as cardiovascular and cerebrovascular diseases, blood clots, and severe infections.

Based ON THIS, THE COMMITTEE CONSIDERS THESE POTENTIAL RISKS TO BE PRESENT IN ALL GROUPS OF USERS FOR APPROVED INDICATIONS, AND THEREFORE PROPOSES RESTRICTIONS ON USE.

In fact, prior to the European Medicines Agency's action, the U.S. FDA had also restricted most JAK inhibitors based on safety concerns about Xeljanz:

The use of JAK inhibitors in the United States has been limited to patients who have at least tried and failed treatment with TNF inhibitors.

In other words, the FDA pushed back the JAK inhibitors; At the same time, the FDA added a black box warning to the drug.

Compared with the European Medicines Agency's policy, the FDA's policy applies to all patients, and the impact will be more far-reaching.

Pfizer's Xeljanz sales plummeted because of the FDA's policies:

Xeljanz sales plunged 29% in the first half of 2022. Xeljanz's sales have fallen because demand in the US has fallen sharply.

Although the safety concerns so far stem mainly from Xeljanz, there are signs that JAK inhibitors, including Rinvoq, ceiling, may also be affected.

03      There are risks as well as opportunities

JAK inhibitors how the ceiling, the domestic drug companies must be concerned about the problem.

As a kind of innovative medicine with high market heat, domestic pharmaceutical companies are indispensable. On Oct 16, 2022, Zegem Pharmaceutical's application for the marketing of Jacotinib was accepted by the China Food and Drug Administration (FDA) for the treatment of intermediate and high risk myeloid fibrosis.

If jackatinib is successfully approved for marketing, it is expected to become the first domestic JAK inhibitor. At the same time, including the JAK inhibitor SHR0302 developed by Hengrui Medicine, are also close to the market.

To some extent, some domestic JAK inhibitors may also have the risk of side effects of overseas products, which is determined by its mechanism.

Some JAK inhibitors currently approved for the market, the reason why there are greater side effects is that the selectivity is not high.

Four members of the JAK family have been discovered:

JAK1: Mainly associated with acute lymphoblastic leukemia, acute myeloid leukemia, solid organ malignancies;

JAK2: Mainly associated with polycythemia vera, myelofibrosis, essential thrombocythemia and other diseases;

JAK3 is mainly associated with acute megaloblastic leukemia, T-cell leukemia and lymphoma.

TYK2: Mainly associated with cutaneous lymphoproliferative diseases and T-cell leukemia.

Each member of the JAK family plays multiple roles, so when JAK drugs inhibit other JAK family members, there are multiple side effects.

According to the mechanism, the selectivity of some domestic JAK inhibitors is also not high. For example, Zgem's had significant inhibitory effects on JAK1, JAK2, JAK3 and TYK2. That means it may also suffer.

Of course, not all JAK inhibitors face this problem. According to the research and development process of overseas pharmaceutical companies, differentiated structure design can obtain selective JAK inhibitors, thus opening the ceiling.

For example, Bristol-Myers Squibb finally got a successful TYK2 inhibitor after a series of modifications and optimization. No adverse signals associated with JAK1, JAK2 and JAK3 were found in patients treated with this drug.

A race for TYK2 inhibitors has begun, and domestic drug companies have not fallen behind. At present, pharmaceutical companies including Gaoguang Pharmaceutical, Jiayue Pharmaceutical, Qiyuan Biological, Nuocheng Jianhua, Hisco, Beigene and so on are all carrying out the research and development of TYK2 target drugs.

For a product like JAK inhibitor, which has both advantages and disadvantages, there are risks and opportunities. Whoever can solve the corresponding problem with technology will be rewarded handsomely.