Amgen has agreed to co-develop and co-commercialize with Kyowa Kirin its Phase III-bound KHK4083, a potentially first-in-class treatment for atopic dermatitis, through a collaboration that could generate more than $1.2 billion for the Japanese pharma—and expand its development into other autoimmune diseases.

“Plans will be reviewed with global regulatory agencies later this year, with the hope of initiating global Phase III studies in H1 2022 to demonstrate the value of KHK4083 for moderate to severe atopic dermatitis patients,” Andrew J. McKnight, PhD, Kyowa Kirin’s chief research officer and head of open innovation, told GEN.

The collaboration, announced Tuesday, positions Amgen and Kyowa Kirin among companies working to challenge the top-selling drug for atopic dermatitis, the most common type of eczema, Dupixent® (dupilumab) co-marketed by Sanofi and Regeneron Pharmaceuticals. The companies equally split profits and losses from U.S. sales of the blockbuster drug, while sharing profits outside the United States on a sliding scale, with Regeneron last year reporting $4.045 billion, and Sanofi, €3.534 billion ($4.317 billion).

Through its Kymab subsidiary, which it acquired for up to $1.45 billion (of which $1.1 billion was upfront) in a deal completed April 9, Sanofi now holds full global rights to another atopic dermatitis drug that last year generated positive Phase IIa results, KY1005.

KY1005 is a monoclonal antibody designed to work by binding with OX40-Ligand, a ligand of the OX40 costimulatory receptor. OX40 itself is targeted by KHK4083 as well as by another atopic dermatitis candidate, Ichnos Sciences’ ISB830 (telazorlimab), now in Phase IIb.

Kyowa Kirin and Amgen say KHK4083 offers a more involved mechanism of action that should ultimately prove more effective than competing drugs.

“It not only blocks OX40 signaling, which plays an important role in the pathogenesis of atopic dermatitis, but also efficiently eliminates OX40-expressing activated T cells and memory T cells. As a result, KHK4083 is expected to have a sustained effect that may help to differentiate it from other treatments,” McKnight said. “Our KHK4083 mAb has the potential to be differentiated on the basis of its mechanism of action, potency against activated T cells, and durability—pending results from Phase III trials.”

With global revenues set to leap five-fold over 2018, to nearly $25 billion by 2028, according to a Decision Resources Group estimate shared by Kyowa Kirin, the market for new atopic dermatitis treatments is sizeable. So too is the potential global patient population, estimated at 30 million prevalent cases—14 million of them diagnosed—in the United States, Japan, and the five largest European nations or “EU5” (France, Germany, Italy, Spain, and the United Kingdom). The United States is the largest market with 5.1 million estimated drug-treated cases, compared with 3.6 million for EU5 and 700,000 in Japan.

A 2019 study estimated the number of U.S. adults diagnosed with atopic dermatitis at 16.5 million, of which 6.6 million meet criteria for moderate to severe disease. Studies published between 2011 and 2014 have found approximately 9.6 million U.S. children under age 18 have the disease.

Positive Phase II data

The collaboration comes more than three months after Kyowa Kirin trumpeted what it said was positive data from a 274-participant Phase II trial (NCT03703102) assessing KHK4083 in patients with moderate-to-severe atopic dermatitis. The company said KHK4083 had achieved statistically significant superiority to placebo cohort for the primary endpoint of “percent change from baseline in Eczema Area and Severity Index (EASI) at 16 weeks.”

However, Kyowa Kirin has not released detailed data. McKnight said yesterday that detailed results will be presented this fall at the European Academy of Dermatology and Venereology (EADV) 30th Congress 2021, a virtual event to be held September 29–October 2.

“Until that time, what we can highlight is all KHK4083 cohorts in a Phase II study of 274 patients, achieved superiority to placebo cohort for the primary endpoint of “percent change from baseline in Eczema Area and Severity Index (EASI) 7 at 16 weeks” with statistical significance,” McKnight said.

In addition, there was a significant difference in “the percentage of patients achieving an EASI-75 (EASI score of 75% or greater improvement from baseline) at 16 weeks” and “the percentage of patients achieving the Investigator’s Global Assessment (IGA) of 0 or 1 with an improvement of 2 points or more at 16 weeks,” McKnight added. “Further improvement in efficacy of KHK4083 was observed after week 16, indicating potential long-term effects.”

He said common treatment-emergent adverse events for KHK4083 cohorts were pyrexia, nasopharyngitis, worsening of atopic dermatitis, and chills during the first 16 weeks: “No deaths were observed in the study.”

Amgen and Kyowa Kirin also agreed to explore developing KHK4083 in indications beyond atopic dermatitis—citing what they said was potential in other autoimmune diseases—by applying data generated by Amgen’s deCODE Genetics subsidiary.

“The companies are not pursuing eye disease indications,” McKnight declared.

OX40 plays a central role in controlling T-cell function in a number of autoimmune disorders. Because of the importance of this pathway, Amgen will leverage the human genetics capabilities of its deCODE subsidiary to inform the potential use of KHK4083 in indications beyond atopic dermatitis.

deCODE already has genetics information on 1.5 million volunteers and is in the process of adding information on one million more individuals from around the world, McKnight said.

“KHK4083 is an important asset in our global pipeline,” Masashi Miyamoto, PhD, president and CEO at Kyowa Kirin, said in a statement. “We know Amgen well, and this alliance will build on the past success and trust we have, bringing additional resources and therapeutic expertise to KHK4083’s development and commercialization, to meet the needs of patients living with atopic dermatitis who seek alternative treatment options.”

Inflammatory disease focus

The partnership with Kyowa Kirin to develop KHK4083 follows Amgen’s focus on developing a portfolio of inflammatory disease treatments. These include the marketed drugs Otezla® (apremilast); Enbrel® (etanercept); Amgevita®, a biosimilar to AbbVie’s multi-indication blockbuster drug Humira® (adalimumab); and Avsola®, a biosimilar to Janssen Biotech (Johnson & Johnson)’s Remicade® (infliximab).

Amgen’s inflammatory disease pipeline also includes tezepelumab, a thymic stromal lymphopoietin (TSLP) inhibitor human monoclonal antibody for which the company filed last month for FDA approval as a potential first-in-class treatment for severe asthma; and ABP 654, a biosimilar to Janssen’s Stelara® (ustekinumab); and several Phase IIb candidates for systemic lupus erythematosus and celiac disease.

The collaboration will revive a partnership that led to a joint venture between Amgen and Kyowa Kirin’s corporate parent Kirin Holdings. The companies’ joint venture lasted more than three decades before ending in 2017, when it became a wholly-owned Amgen subsidiary, with Kyowa Kirin in-licensing some Amgen drugs in the Asia-Pacific region.

The joint venture was formed in 1984 to develop and commercialize EPOGEN® (sold in Japan as ESPO®), which in 1989, became the first Amgen drug approved in the United States, and a year later became the first Kyowa Kirin treatment approved in Japan. Over time, the joint venture expanded to include the development and commercialization of several other medicines, including Neupogen® (GRAN® in Japan), Neulasta® (G-Lasta® in Japan), Aranesp® (NESP® in Japan), and Nplate® (Romiplate® in Japan).

“We are excited to renew our relationship with Amgen, with a focus on opportunities in inflammation. However terms of the agreement are distinct from the previous Amgen-Kirin 50–50 JV,” McKnight said.

For KHK4083, Amgen agreed to lead development, manufacturing, and commercialization in all markets globally except Japan, where Kyowa Kirin will retain all rights. Amgen will also consolidate sales for KHK4083 in all markets globally, except for Japan.

In return, Amgen agreed to pay Kyowa Kirin $400 million upfront and up to $850 million in payments tied to achieving milestones, plus “significant” royalty payments on future global sales, the companies said.

Kyowa Kirin and Amgen agreed to share global development costs, except in Japan, and U.S. commercialization costs. Kyowa Kirin also agreed to co-promote KHK4083 with Amgen in the United States and have opt-in rights to co-promote KHK4083 in some other markets outside the United States, including in Europe and Asia.

“Kyowa Kirin was one of Amgen’s very first collaborators and we are delighted to be joining forces with them once again to advance this promising late-stage asset to treat atopic dermatitis,” added Amgen chairman and CEO Robert A. Bradway.  “We will take advantage of our two decades of experience in inflammatory disease, as well as our industry-leading human genetics capabilities, to help realize the full potential of KHK4083 as quickly as possible.”

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