Through a pair of recent clinical milestones, Kymera Therapeutics continues to cash in on its up-to-$2 billion collaboration with Sanofi to develop first-in-class targeted protein degradation (TPD) therapies for patients with immune-inflammatory diseases.

Kymera this month said it dosed the first patient in the Phase II ADVANTA trial (NCT06058156), designed to assess the company’s lead pipeline candidate KT-474—which Sanofi calls SAR444656—in atopic dermatitis (AD).

The milestone touched off a $15 million payment from Sanofi to Kymera, two months after it received a $40 million milestone payment from the pharma giant for dosing the first patient in another Phase II trial, ZEN (NCT06028230), evaluating KT-474/SAR444656 in another chronic skin condition, hidradenitis suppurativa (HS).

KT-474/SAR444656 is an oral small molecule degrader of interleukin 1 receptor associated kinase 4 (IRAK4), a key protein involved in inflammation mediated by the activation of toll-like receptors (TLRs) and interleukin -1 receptors (IL-1Rs).

Nello Mainolfi, PhD, Kymera Therapeutics founder, President and CEO

“The reason why we selected this target is because it’s one of the very few key nodes in innate immunity that is responsible for driving a plethora of inflammatory signals. We look at this particular target as a key node of broad autoimmunity,” Kymera’s founder, president and CEO Nello Mainolfi, PhD, told GEN Edge. “While you can target it with a small molecule inhibitor, you only actually can fully block the pathway signaling with a degrader. So by removing the target, you can actually fully elaborate the biology of this pathway.”

IRAK4 is a key protein of the myddosome complex that mediates signaling through IL-1 and TLRs. Eliminating IRAK4 completely through degradation impacts both the kinase and scaffolding functions, thus potentially achieving a broad, well-tolerated, anti-inflammatory effect that offers a novel therapeutic approach for immune-inflammatory diseases.

IRAK4, Kymera reasoned, was superior to individual IL-1, IL-18, and IL-36 cytokine blockers because IRAK4 penetrates into the cell, while the cytokines have to signal through the same intracellular node.

“By us blocking that node, we block basically all those cytokines, together with a single molecule. And in addition to being potentially more effective, it’s also more convenient being an oral drug versus an injectable,” Mainolfi said. “Why we believe this target was unique is because it allowed us to build on the existing validation of the pathway, but having an oral small molecule that would be superior to the single cytokine blockers that have been developed.”

Beyond AD and HS

KT-474/SAR444656 is designed to treat AD, HS, and potentially other IL-1R/toll-like receptor (TLR)-driven complex inflammatory diseases where Kymera perceives an opportunity to significantly advance the standard of care.

The diseases are varied enough to include psoriasis, generalized pustular psoriasis, inflammatory bowel disease (IBD), asthma, chronic obstructive pulmonary disease (COPD), systemic sclerosis (SSc), interstitial lung disease (ILD), rheumatoid arthritis (RA), psoriatic arthritis (PSA), systemic lupus erythematosus (SLE), osteoarthritis (OA), progressive systemic sclerosis (PSS), multiple sclerosis (MS), and age-related macular degeneration (AMD).

Sanofi is sponsoring both Phase II trials of KT-474/SAR444656. ADVANTA is a multinational, multicenter, double-blind, placebo-controlled, parallel-group three-arm study in adults with moderate to severe AD who are inadequately controlled with topical therapies or for whom such topical therapies are inadvisable and who are candidates for systemic therapy.

ADVANTA is expected to enroll about 115 participants. They will be randomized to receive any of two doses of KT-474/SAR444656 or matching placebo during the trial. The study’s primary endpoint is the percent change from baseline in the Eczema Area and Severity Index (EASI) at Week 16 following treatment.

ZEN is a parallel, two-arm trial designed to evaluate the efficacy, safety, pharmacokinetics (PK), and biological effects of KT-474/SAR444656 compared with placebo in adults with moderate to severe HS aged ≥18 to 70 years. The primary endpoint of the roughly 100-participant study is the percent change from baseline in total abscess and inflammatory nodule (AN) count.

Both ZEN and ADVANTA are 24-week trials whose estimated primary completion time frames are both in the first quarter of 2025.

“Based on that, we estimate enrollment to go through 2024, and then for those studies to read out in the first quarter of 2025,” Jared Gollob, MD, Kymera’s chief medical officer, told GEN Edge.

Jared Gollob, MD, Chief Medical Officer

In July 2020, Kymera and Sanofi inked their collaboration, through which they agreed to develop and commercialize first-in-class protein degrader therapies targeting IRAK4 in patients with immune-inflammatory diseases. Sanofi paid Kymera $150 million upfront, and up to $2 billion-plus in payments tied to achieving development, regulatory, and sales milestones, as well as double-digit tiered royalties outside the U.S.

Under the collaboration, Kymera oversaw development through Phase I trials, at which point Sanofi assumed clinical development and commercialization responsibilities. The companies have agreed to split profits 50/50 in the U.S.

“There are plenty of other indications where we can also go with this drug depending on what we see in these initial Phase II studies in HS and AD,” Gollob said. “After Phase II, we (Kymera) then have the option of being able to opt back in to co-develop and co-commercialize KT-474 in the U.S. with Sanofi for Phase III.”

Clinical studies of KT-474/SAR444656 began more than two years ago.

Initial proof of concept

Last month, researchers from Kymera and research partners published in Nature Medicine results from a Phase I trial (NCT04772885) showing KT-474/SAR444656 had achieved initial proof of concept in both HS and AD—what researchers called the first, to their knowledge, published clinical trial using a heterobifunctional degrader.

According to the study, researchers observed degradation of IRAK4 in the blood of healthy volunteers, with mean reductions of ≥93% after a single dose of 600 mg to 1,600 mg, and ≥95% after 14 daily doses of the drug at 50–200 mg. Similar IRAK4 degradation was achieved in the blood of patients with the disorders. A total of 105 healthy volunteers were enrolled in the trial’s placebo-controlled single and multiple ascending dose escalation cohorts (SAD and MAD), while 21 HS and AD patients were enrolled into an open-label patient cohort.

“The preliminary clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD is encouraging and supports moving forward with confirmatory, placebo-controlled [P]hase [II] trials,” the researchers concluded in their abstract.

Researchers also found reductions of disease-relevant inflammatory biomarkers in the blood and skin of HS and AD patients, results that were associated with improvement in skin lesions and symptoms.

“I think the study very much exceeded our expectations, because this was our first study in humans. It was very important for us to see what we call fidelity of translation from our preclinical species or in vitro work to humans. And we saw very nice fidelity of translation, meaning the PK/PD relationship that we saw in animals, we saw the same sort of relationship in humans,” Gollob said.

The dose exposures that led to 80–90% degradation of the target in blood and skin was very close to what researchers predicted.

“This was a critical study. This was really Kymera’s first first-in-human study, the first time we were in the clinic with a heterogeneous degrader of ours, the first time a heterogeneous bifunctional degree was used in healthy volunteers, and the first time it was also used in patients with non-oncology conditions—in this case, HS and AD,” Gollob said. “First for the field, and obviously important, first for us as a company.”

“What especially exceeded our expectations was the clinical activity, the fact that these patients with moderate-to-severe disease, HS and AD, after just four weeks of treatment, we were able to knock the target down, very hard in the skin and blood, and see an anti-inflammatory effect,” Gollob added. “We were surprised that after only 4 weeks we saw what would appear to be such a clear impact on the clinical endpoints, on skin lesion burden, on pain, on itching. That was pleasantly surprising to us.”

KT-474/SAR444656 is one of Kymera’s three clinical phase programs. The other two are Phase I programs designed to treat various cancers.

One is KT-333, a highly selective degrader of STAT3 being developed to treat multiple STAT3-dependent disorders including hematological malignancies and solid tumors. KT-333 has potential indications that include large granular lymphoma leukemia (LGL-L), peripheral T-cell lymphomas (PTCL), primary cutaneous T-cell lymphomas (CTCL), and solid tumors.

Earlier this month at the American Society of Hematology (ASH) 65th Annual Meeting and Exposition in San Diego, Kymera researchers presented early data from an ongoing Phase I trial (NCT05225584) linking KT-333 with early signs of antitumor activity at doses that were generally well-tolerated and associated with substantial STAT3 knockdown in blood and tumor.

The researchers reported seeing a partial response (PR) in one patient with Hodgkin’s lymphoma, and two PRs and one stable disease were reported among the five CTCL patients treated. Stable disease was seen in four patients with advanced solid tumors, including two head and neck cancer patients as well as patients with cholangiocarcinoma and renal cell cancer.

The other clinical oncology program is KT-253, which targets MDM2, a key regulator of p53, the most common tumor suppressor. Because p53 remains wild type in about 50% of cancers, it retains its ability to modulate cancer cell growth.

Alex Philippidis is senior business editor of GEN.

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