ARVN - Kymera: Data Derisks Platform But I Will Wait For More

Summary

• Kymera Therapeutics, Inc.'s KT-474 HS/AD data de-risked the IRAK4 protein degradation platform, as did Sanofi's partnering.
• However, more differentiating data seems to be needed in these indications and with IRAK4 inhibitors.
• I also wish to see more data from self-owned products.

I covered Kymera Therapeutics, Inc. ( KYMR ) in November, when it was on the verge of publishing critical proof of concept phase 1 trial data from its protein degrader platform, the particular molecule being called KT-474. This is, according to the company , “a potent, highly selective, orally bioavailable IRAK4 degrader, for the treatment of IL-1R/TLR-driven conditions and diseases with high unmet medical need.”

In that article, I discussed the protein degrader platform, where Arvinas ( ARVN ) is the leader, and IRAK4 antagonism, either through degradation or inhibition, where Pfizer ( PFE ) produced poor data, bringing down the entire space. Kymera’s December 14 data is an effort to differentiate IRAK4 degraders from the failing or failed IRAK4 inhibitors.

I also discussed Sanofi’s ( SNY ) collaboration with Kymera for this molecule, where I said:

The Sanofi partnership started in 2020 with $150mn in upfront payment. The deal is valued at $2bn in potential milestone payments plus tiered royalties. The focus is on IRAK4 in immuno-inflammatory diseases. Kymera just has to advance the molecule through phase 1, and once the POM is handy, Sanofi takes over. KYMR retains U.S. co-dev and co-co opt-in rights, and rights to IRAK4 in oncology. Pretty good deal for an early stage company, thoroughly derisking their phase 1 program.

A month later, Kymera published this data and it was good enough for Sanofi to take over development. This was data from Part C of the Phase 1 clinical trial for KT-474 in patients with hidradenitis suppurativa ((HS)) or atopic dermatitis ((AD)). This section of the trial was designed to check whether the PK/PD seen in healthy volunteers translates to patients with HS/AD. Baseline IRAK4 levels in skin lesions of these patients were twice as much as what was seen in healthy volunteers. However, presence of KT-474 in plasma PK after dosing was shown to be equal to what was seen in healthy volunteers in the MAD3 dosing, or the third dosing of the multiple ascending dose that was given to them. About this dose , here is the data:

Patients received 75 mg of KT-474 once daily in the fed state. That dose was selected to achieve similar exposures to healthy volunteers in the multiple ascending dose ((MAD)) portion of the Phase 1 clinical trial who received 100 mg in the fasted state (MAD3).

KT-474 was able to knockdown IRAK4 up to 90% in both HS and AD patients at the same level as was seen in healthy volunteers given MAD3. The drug demonstrated activity against known biomarkers of inflammation (the company provides a list of these biomarkers), and inhibition of up to 84% in HS and up to 98% in AD were observed.

In AD, clinical activity was shown through pruritus reduction of 63% in 7 days, and eczema reduction of 37%. Although it is hard to compare trials, these results compare well with a dupixent trial in AD which saw a peak pruritus reduction in the second week of dosing of 51% patients. To take a random sample from another trial, here abrocitinib, KT-474 peak pruritus reduction again compares well with this specific endpoint, 63% versus 55.3%.

This JAKi molecule is owned by Pfizer. Dupixent, an IL-4/IL-13 inhibitor, is owned by Kymera’s partner Sanofi, and is approved for various allergic inflammatory diseases. Both drugs are approved for atopic dermatitis. There are a number of other approved drugs, however the market is large for AD, with US+EU size being about $10bn, and the global market is estimated to be $22bn by 2031.

The HS market is much smaller, pegged at just north of $1bn. Humira is the only drug approved by the FDA to treat HS. Here, too, there were impressive mean reductions observed across multiple endpoints like AN Count (46%), Pain NRS (49%), Peak Pruritus NRS (62%). AN count is abscess and inflammatory nodule count, and here, in Humira’s trial , the data is as follows:

This data is difficult to compare (for me) with KT-474 data. A cross trial comparison from Evaluate shows the following data for another important score, HiSCR:

Here, KT-474 had a score as follows:

For all patients (n=12) and moderate-to-severe patients (N=10):

The data seems highly competitive.

KT-474 remained safe and well-tolerated. As a result of this data, Sanofi decided to continue into a phase 2 trial, to be started in 2023.

There was some QTc prolongation in this trial, however, it resolved back quickly without needing intervention.

Two other degraders in oncology, KT-333 and KT-413, also produced similar human translational data. KT-333 showed an average of 66% STAT3 knockdown, with maximum STAT3 knockdown of up to 86%. It is being evaluated in a phase 1 trial in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors. KT-413 also showed strong degradation of its target molecules. A third asset, KT-253, will start a similar proof of mechanism trial.

Financials

KYMR has a market cap of $1.89bn and a cash balance of $596mn after raising $150mn through a private placement in September. Research and development expenses were $43.9 million for the third quarter of 2022 while general and administrative expenses were $10.6 million. That gives them a cash runway of 8-10 quarters.

Bottom Line

Kymera Therapeutics, Inc. seems to be an emerging company in the protein degrader space, with good data validated by the Sanofi partnership. There are no major near-term catalysts, however, and Kymera Therapeutics, Inc. stock is up a lot from its May 2022 lows. I would like to buy, but lack of major near-term catalysts coupled with the price gives me pause about Kymera Therapeutics, Inc. Maybe I will wait for a better price point, and further de-risking in terms of catalysts for self-owned assets.

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