BioPharma, Pharma

Takeda Details the Clinical Data That Led to a $4B Deal for an Autoimmune Drug

Takeda Pharmaceutical drug TAK-279 achieved the main goal of a mid-stage clinical trial in plaque psoriasis, setting the stage for Phase 3. The Japanese pharmaceutical giant sees the small molecule as complementary to its top-selling product, the blockbuster inflammatory bowel disorder drug Entyvio, and competitive against Bristol Myers Squibb’s Sotyktu.

Takeda Pharmaceutical struck one of the biggest life science deals of 2022, acquiring a clinical-stage Nimbus Therapeutics drug addressing a promising new target for autoimmune disorders. Other than saying mid-stage trial results in plaque psoriasis were significant and positioned the drug to be best in its emerging class, the companies disclosed no data specifics. Some details are out now and they indicate why Takeda paid $4 billion up front to acquire the small molecule.

In a Phase 2 clinical trial enrolling patients with moderate-to-severe plaque psoriasis, Takeda drug TAK-279 handily beat a placebo at achieving skin clearance, showing statistically significant results for three of the four doses tested. At the highest dose, a significant number of patients achieved near-total or total loss of the lesions characteristic of the autoimmune disorder, which manifests as itchy red patches on the skin.

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The data, presented Saturday during the annual meeting of the American Academy of Dermatology in New Orleans, suggest Takeda’s drug could be competitive against Bristol Myers Squibb’s Sotyktu—the only approved product that addresses a target called tyrosine kinase 2, or TYK2. TAK-279 still needs to show that the results of its TYK2-targeting drug can hold up in a larger Phase 3 study. With the mid-stage data in hand, Takeda now plans to meet with regulators to discuss the design of that pivotal study. The Japanese pharmaceutical giant is also proceeding with a broad plan to evaluate the drug in several other autoimmune disorders, which it sees as complementing Entyvio, the blockbuster ulcerative colitis and Crohn’s disease drug that is Takeda’s top-selling product.

“We’ve been, for the past eight years, looking for a molecule that we think would be a molecule that we’d want to have next to Entyvio in our GI [gastrointestinal] and inflammation portfolio,” Andy Plump, Takeda’s president of R&D said, speaking during a Saturday conference call. “This is the first one that we made the decision to go after.”

TYK2 is an enzyme that’s involved in signaling pathways associated with many immune-mediated disorders, such as plaque psoriasis. It’s part of a protein family called Janus kinases (JAKs). Drug hunters pursuing TYK2 are trying to achieve selectivity—the ability to target the TYK2 enzyme without also hitting the other JAK proteins and triggering toxic effects. The challenge is that TYK2 and JAKs have structurally similar target sites.

TAK-279 came from the labs of Nimbus, a biotech company that places computational methods at the heart of its drug discovery approach. Cambridge, Massachusetts-based Nimbus designed the molecule, which it called NDI-034858, to selectively bind to one particular domain of TYK2 without hitting closely related JAK proteins.

The Phase 2b clinical trial evaluated 259 patients with moderate-to-severe plaque psoriasis. The main goal was to measure how many patients treated with the once-daily pill achieved 75% improvement at 12 weeks, measured according to a scale used to assess the severity and extent of psoriasis. For the two highest doses, 15 mg and 30 mg, 68% and 67% of patients respectively met the study goal. For the 5 mg dose group, 44% of patients met the goal. In the placebo group, just 6% of patients achieved that mark. At the 30 mg dose, 32.7% of patients achieved scores showing 100% skin clearance.

The frequency of adverse events ranged from 53% to 62%; it was 44% in the placebo arm. The most frequent adverse event was Covid-19, reflecting that the study was conducted at the height of the pandemic, said Graham Heap, Takeda’s vice president global program leader, R&D. Other side effects reported included acne and diarrhea.

Cross-trial comparisons are tricky because trial designs, study populations, and doses are different. However, the main goal of achieving 75% improvement according to the psoriasis scale was the same, and on this measure, Takeda posted better skin clearance scores than Sotyktu in Phase 3. But William Blair analyst Matt Phipps wrote in a Monday research note that the more appropriate comparison is Sotyktu’s Phase 2 data. On this comparison, both drugs showed similar results.

Takeda’s drug could more clearly distinguish itself from Sotyktu at 30 mg, the highest of the four doses tested, Phipps said. This dose has the potential for higher rates of patients achieving 100% skin clearance. Incidentally, BMS did not take its highest dose of Sotyktu into Phase 3 testing due to what it said was plateauing results at 75% skin clearance. Phipps said the decision was likely also due in part to concerns that a higher dose could introduce safety risks. The company likely wanted to avoid a black box warning on what last September became the first FDA-approved TYK2-targeting drug.

“Whether or not a 12 mg per day dose of Sotyktu would have driven higher efficacy in Phase 3 trials will likely remain a mystery, but based on preclinical data Takeda likely has a larger window to push the dose higher before any potential JAK1 inhibition would have been observed,” Phipps said.

Takeda isn’t saying which dose of TAK-279 it plans to advance to Phase 3, but Plump noted that the clear separation on the 100% clearance measure at 30 mg has the company looking closely at that dose. Uthra Sundaram, Takeda’s executive vice president & head of global product & launch strategy, added that the potential to achieve 100% clearance is important because clear skin or near-clear skin is becoming the plaque psoriasis standard for both physicians and patients.

The field of companies trying to selectively target TYK2 is growing. Ventyx Biosciences has reached early clinical development with its TYK2 inhibitor. Preclinical biotech Sudo Biosciences emerged from stealth last fall, raising $37 million to advance the development of its TYK2-selective drug. Meanwhile, BMS is looking to expand Sotyktu beyond plaque psoriasis. Separate Phase 3 studies are underway testing Sotyktu in psoriatic arthritis and lupus. Mid-stage tests of the drug are ongoing in alopecia areata, Crohn’s disease, ulcerative colitis (at a higher dose following a 2021 Phase 2 trial failure), and discoid lupus erythematosus.

The terms of the TAK-279 acquisition put Nimbus in line for two $1 billion milestones payments from Takeda. The first is triggered when the molecule achieves $4 billion in annual net sales; the second one is tied to the achievement of $5 billion in annual net sales. In the near term, Takeda is focused on quickly generating the data to support regulatory submissions. Additional data readouts for TAK-279 could further distinguish the Takeda drug from Sotyktu and others in the drug class. Takeda expects a Phase 2b study in psoriatic arthritis will yield data later this year. The company also plans to start Phase 2 tests in inflammatory bowel disease and lupus.

“We’re ready to push this program forward,” Plump said. “It’s our top program in R&D right now.”

Photo: Scott Eisen/Bloomberg, via Getty Images