Can PROTAC Grab a slice of the $50 billion market for self-medicated drugs?

Sanofi announced positive results in a Phase I clinical trial of its $2.15 billion purchase of Kymera's IrAK4-degrading drug for autoimmune diseases, particularly after safety concerns were temporarily put to rest. The phase II clinical trial of KT-474 will be conducted next year.

This is a pivotal moment for Kymera and the field of protein degradation.

Kymera was founded six years ago to harness the huge potential of targeted protein degradation to bring more effective treatments to patients. Phase I clinical data from KT-474 demonstrate for the first time the clinical impact of the depressant KT-474 outside of oncology and in complex inflammatory diseases; It also demonstrated the clinical potential of IRAK4 inhibitors over small molecule inhibitors, and validated the platform of targeted protein degradation and the strategy of drug target selection.

But the market reaction was lukewarm. Why?

IRAK4 targets and related drugs in development

Interleukin-1 receptor (IL1R) -associated kinase 4 (IRAK4) is a central regulator of innate immune signaling. IRAK4 is a promising therapeutic target for diffuse large B-cell lymphoma driven by a MYD88 L265P mutant that acts as both a kinase and a scaffold protein for downstream signaling molecules. While previous efforts to regulate IRAK4 activity using kinase inhibitors alone have shown modest efficacy, protein degradation may provide a solution to block IRAK4 kinase activity and scaffold capability.

At present, the development of anti-inflammation and tumor drugs targeting IRAK4 mainly focuses on small molecule drugs that can inhibit IRAK4. In addition to single-target or multi-target inhibitors targeting IRAK4, PROTAC is also an important direction.

However, in 2018 GSK tried to develop a VHL-ligand-based IRAK4 protein suppressant, but pre-clinical trials were halted because they failed to resolve the druggability issue.

In August 2022, Pfizer announced the termination of development of the IRAK4 small molecule inhibitor PF-06650833 after an interim analysis based on the Phase III trial REALM-DCM indicated that the trial was unlikely to meet its primary clinical endpoint.

At the time, Kymera also broke the news that a 10-20 microsecond QTc extension had been observed in an ongoing Phase I clinical study. While the condition is not severe enough to be rated as an adverse event, there is a potential risk that continued dosing could exacerbate the condition. Excessive prolongation of QTc can lead to a potentially fatal ventricular arrhythmia called tip torsion ventricular tachycardia. The company extended the trial, increasing the dose from 14 to 28 days, and added clinical endpoints.

Fortunately, it looks like the all-clear has been lifted for now. This is because the Phase I clinical trial, after an extended observation period, found that KT-474 was generally safe and well tolerated, with no serious adverse events, no drug-related infections, and no dose interruption or discontinuation due to adverse events. In particular, slight QTc prolongation was observed on days 7 to 14 with continued dosing, QTc returned to baseline by day 28 and remained in the same normal range after dosing was discontinued. These phase I efficacy and safety data will support further development of oral KT-474.

In China, MY004 (MY004567), an IRAK4 inhibitor for the treatment of arthritis independently developed by Shanghai Meiyuei Biology, a subsidiary of Langlai Technology, was accepted by the National Medical Products Administration for clinical trials in March 2021, and is the first drug with the same target to be approved clinically in China.

The KT-474 shows its potential to challenge the autonomous sector

Kymera is a six-year-old startup developing targeted protein-degrading drugs. The company's name is derived from the Greek myth of Chimera, a monster with a lion's head and a snake's tail, which is a reference to PROTAC's drug mechanism.

In 2020, Sanofi received a license from Kymera to co-develop the protein-degrading drug KT-474 for a total amount of $2.15 billion, including a $150 million down payment and milestone payments.

According to the December 14 announcement, Kymera was tested on up to 132 healthy adults and a total of 21 patients with hidradenitis suppurative and atopic dermatitis (group C) in three clinical trials, and the results were in group C. Group A was a single dose escalation (SAD) study in 60 adults in healthy volunteers, and Group B was a multiple dose escalation (MAD) study in 72 healthy adults. Clinical trials evaluated the effect of KT-474 by improving EASI (eczema Area and Severity Index) and NRS (Numeric Rating Scale) in patients with atopic dermatitis.

Clinical indication: Atopic dermatitis (AD)

Clinical end points for AD collected in the trial included EASI score, peak itch NRS, and vIGA-AD. Peak itch NRS were used to derive the peak itch response rate of NRS. Results The vIGA-AD (Validated Investigator Global Assessment) was stable or improved in all patients, as shown in the table below.

Clinical indication: Hidradenitis suppurativa (HS)

The HS clinical endpoints collected in the trial included AN count, pain NRS, pruritus NRS, and HS-PGA. AN count and pain NRS were also used to derive 0/1/2, HiSCR, and pain NRS30 response rates. All patients were analyzed, including those with very severe (n = 12) and only moderate to severe disease (n = 10). Results As shown in the table below, HS-PGA was stable or improved in all patients.

Kymera evaluated the effects of KT-474 on clinical response to hidradenitis suppurativa (HiSCR50), peak pruritus Pain NRS (pruritus), Pain NRS30 (pain index), and the number of abscesses and inflammatory nodules (AN) in patients with hidradenitis suppurata. Based on these positive results, Sanofi and Kymera have decided to proceed to Phase II clinical trials of KT-474 next year.

In addition to the KT-474, Kymera company is against B cell carcinoma MYD88 mutations (B cell malignancies) degradation of STAT3 drug degradation and IRAK4 / IMiD "KT - 333" drug "KT - 413" issue for leukemia and solid cancer clinical trials. The KT-333 and it are scheduled to begin phase 1 clinical trials in blood and solid cancers early next year.

Can PROTAC break the $50 billion Auto-drug Market?

My mother suffered from autoimmune diseases, which are often difficult to diagnose, and even when they can be diagnosed accurately, there are currently limited treatment options, with few truly targeted drugs or radical therapies. It relies on immunosuppressive drugs to shut down the immune system in order to relieve symptoms. Even so, the remission rate of patients after treatment is not ideal, and the possibility of developing resistance remains high.

And because the immune system shuts down on a large scale, it often leads to a variety of serious side effects, mainly infections such as bacterial, fungal, parasitic and viral infections. It is even more painful in the context of COVID-19. Some immunosuppressive treatments can even increase the chance of developing cancer. As a result, autoimmune diseases are as difficult and painful to treat as cancer.

In this context, similar to the treatment of diseases such as cancer, how to reduce the side effects of drugs while improving the remission rate of diseases is the subject of the treatment of autoimmune diseases.

Currently, the most important treatment is to block the internal signaling pathways of the immune system using monoclonal antibodies or small molecule drugs that inhibit various cytokine signals. Well-known drugs include Adalimumab (TNF-α), Embo (TNF-α), Rituximab (CD20), Eutecumab (IL-12/IL-23), Dabital (IL-4α), Sukinumab (IL-17a), and Tolizumab (IL-6R). ), Tofacitinib (Jak1, Jak3), Omelizumab, Tyford, Fingormode, etc., It's used primarily for rheumatoid arthritis (RA), Psoriasis, Inflammatory bowel disease, Multiple sclerosis, and more. According to statistics, the market capacity of self-free drugs is more than 50 billion dollars.

IRAK4, which is targeted by Kymera's protein depressant, is the most important node where the two signaling pathways of the immune system, IL-1 family and TLR family, converge. Targeting IRAK4 could theoretically simultaneously block upstream signaling by oral administration, directly inhibiting the expression of key immune response signals such as TNFα and IL-6 in the first place.

Moreover, I have also noticed that there are some negative opinions on the results of KT-474 on social media. In related discussions, some investors expressed cautious optimism about the results of phase I experiment, after all, there are many failure cases of large companies in front of them.

Earlier this year, Pfizer halted Phase 3 trials of its IRAK4 inhibitor for hidradenitis suppurative, which dented the industry's confidence in the drug's target, but companies such as Gilead overseas and Landon Technologies are still advancing in the field. Notably, they focused on inhibitors rather than protein-degrading drugs (TPD) like Kymera.

From a macro perspective, the market for self-immunizing drugs for dozens of diseases, including rheumatoid arthritis, psoriasis, ankylosing spondylitis, Crohn's disease and lupus, is worth more than $50 billion. Currently, three autoimmune drugs are among the top 10 best-selling drugs in the world. Can a potentially best-in-class, cross-indication degradation drug emerge in the self-immunizing drug market? Let's wait and see.