TYK2 Inhibitors: A New Frontier in Drug Development
In January 2019, a difficult choice lay before Bristol-Myers Squibb.
At that time, Bristol-Myers Squibb announced the acquisition of Celgene, and a "deal of the century" worth $74 billion slowly began to unfold.
However, the curtain got stuck halfway up, with the United States Federal Trade Commission playing the spoiler. In the view of the Federal Trade Commission, this merger involved monopoly issues:
Celgene possessed an approved psoriasis oral drug, Otezla, and Bristol-Myers Squibb's pipeline also included a psoriasis oral drug—the TYK2 inhibitor Sotyktu.
Based on antitrust requirements, Bristol-Myers Squibb faced a "choose one out of two" dilemma. It was a tough decision. Otezla was an approved blockbuster with annual sales exceeding one billion dollars; Sotyktu, though in the clinical stage, could become a star of hope.
In the end, after weighing the pros and cons, Bristol-Myers Squibb chose to keep Sotyktu and sell Otezla. In hindsight, Bristol-Myers Squibb made the right bet. In September 2022, Sotyktu was approved for market launch, becoming the only JAK inhibitor without a black box warning and successfully igniting the TYK2 inhibitor track.
Advertisement
However, Bristol-Myers Squibb may have underestimated the ruthlessness of the autoimmune track.
Since its approval, Sotyktu's sales volume has not met expectations, and it is about to face its strongest competitor in the psoriasis field—Johnson & Johnson's Icotrokinra. This also means that the situation Sotyktu faces will become more complex.
The autoimmune market is a pie, but a single misstep could lead to a trap.
/ 01 / The Hopeful Contender
The boom of TYK2 inhibitors is not surprising. After all, the prospects of the JAK inhibitor market have been fully proven, with only safety issues needing improvement.
So far, four members of the JAK family have been discovered:
JAK1: mainly associated with acute lymphocytic leukemia, acute myeloid leukemia, and solid organ malignant tumors;
JAK2: mainly associated with polycythemia vera, myelofibrosis, primary thrombocythemia, and other diseases;
JAK3: mainly associated with acute megakaryoblastic 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 lack selectivity and inhibit other JAK family members, they can produce various side effects.
This also leads to JAK inhibitors being unable to shake off the FDA's black box warning. The emergence of Sotyktu, however, broke this stalemate.
Sotyktu employs a differentiated structural design, binding to the pseudokinase domain JH2 of TYK2, rendering TYK2 in an inactive conformation.
Unlike the JH1 domain, the JH2 structures of different JAK family members are not the same, so by inhibiting this domain, it can only block the signal transduction of IL-23, IL-12, and type I interferons dominated by TYK2, without inhibiting other JAK pathways.
This also brings safety advantages. In September 2022, the FDA approved Sotyktu for the treatment of psoriasis, without adding a black box warning as with other JAK drugs.
Given Sotyktu's performance, Bristol-Myers Squibb boldly predicted that its peak sales would reach $4 billion. Consequently, after Sotyktu was approved for market launch, it completely made TYK2 inhibitors a new "hotspot".
/ 02 / Sotyktu's Unfavorable Start
The key to whether the "hotspot" of TYK2 inhibitors can continue lies in Sotyktu's sales performance. Unfortunately, Bristol-Myers Squibb's current performance does not truly support this.
Specifically, Sotyktu's sales in 2023 were $170 million; in 2024, the ramp-up was not fast, with Q1, Q2, and Q3 sales revenues of $44 million, $53 million, and $66 million, respectively. In the third quarter, Sotyktu's year-over-year growth rate had already reached zero.
Whether in terms of total sales or ramp-up cycle, Sotyktu's current performance is significantly lower than market expectations. After all, Sotyktu's first indication, psoriasis, is a super market.
Psoriasis is a common chronic, systemic immune-mediated disease affecting nearly 7.5 million people in the United States; psoriasis is known as the "incurable cancer," with patients often requiring lifelong medication until the drug can no longer control the condition.
These two factors lead to a considerable market size for psoriasis. In 2019, the market size had already exceeded 20 billion US dollars, and the success of the old drug king adalimumab is inseparable from the contribution of the psoriasis indication.
Moreover, Sotyktu also has the advantage of being oral. Compared to mainstream drugs that require injection, Sotyktu is one of the only two oral drugs on the market, the other being Otezla, which Bristol-Myers Squibb had previously sold. It seems that Sotyktu's strength is even stronger than Otezla's.
The FDA's approval of Sotyktu's market launch was based on the results of phase III clinical trials named POETYK PSO-1 and POETYK PSO-2.
These two clinical trials proved that among 1,684 patients aged 18 and over with moderate to severe plaque psoriasis, Sotyktu taken once daily was more effective than placebo and Otezla taken twice daily.
However, under such circumstances, Sotyktu has not been able to break through after more than two years on the market.
/ 03 / The Ruthless Autoimmune Track
Sotyktu's poor sales highlight the ruthlessness of the autoimmune market.
Over the past year, Sotyktu's sales issues have been a focus of concern for analysts, and Bristol-Myers Squibb has repeatedly apologized and explained for the subpar volume.
Currently, the subpar performance of Sotyktu is mainly due to the following two points:
First, the competition in the psoriasis market is indeed too fierce, which the management may not have realized in the past, and future execution needs to be further improved;
Second, the difficulty of market access is greater than imagined. The barriers of competitors are not only the prescribing rights of doctors but also include channel advantages.
Products in the immunology field are strictly controlled and managed by large pharmacy benefit management companies (PBMs). Due to entrenched contract relationships, it took Bristol-Myers Squibb a long time to enter the preferred position, achieving about 65% coverage as of the end of June this year. Moreover, it paid a higher price; according to the third-quarter conference call, Bristol-Myers Squibb stated that it increased the rebate ratio, meaning it made a larger-scale concession.
It is precisely because of this that Sotyktu has been slow to accelerate its volume. For Bristol-Myers Squibb, while dealing with existing competitors, it also needs to be vigilant against newcomers.
On November 18, an official announcement from Johnson & Johnson meant that the field had entered a new level. On that day, Johnson & Johnson announced that the ICONIC-LEAD clinical trial had obtained top-line results, meaning that the world's first selective oral peptide Icotrokinra targeting the IL-23 receptor was about to hit the market.
If Icotrokinra is approved, it will inevitably put pressure on Sotyktu.
In terms of efficacy, the proportion of Sotyktu's PASI 90 at week 16 is around 27-36%, and the PASI 90 proportion at 24 weeks is only between 32%-42%.
Icotrokinra, at week 16 of treatment, compared to the placebo group, the treatment group reached a PASI 90 proportion of 49.6%, while the placebo group was only 4.4%; the proportion achieving IGA 0/1 was also higher, reaching 64.7%, compared to 8.3% in the placebo group.
The patient response rate increases with the duration of medication. At week 24, 64.9% and 74.1% of patients in the Icotrokinra group achieved PASI 90 and IGA 0/1, respectively.
Of course, Sotyktu has a first-mover advantage and may use channel advantages to suppress Icotrokinra. But regardless, the increased competition is a visible fact.
It can be said that in the broad market prospects, Sotyktu has hit a steel plate.
/ 04 / Conclusion
The "low opening" of the first indication does not mean that Sotyktu has lost its appeal, nor does it mean that TYK2 inhibitors will fall out of favor. After all, the potential indications for TYK2 inhibitors are not limited to psoriasis.
But regardless, Sotyktu's performance has served as a reminder to many participants. While maintaining high expectations, it is also necessary to be fully prepared for a tough battle.
Because the autoimmune market is not all smooth sailing.