The landscape of immunology and inflammation therapeutics is on the brink of a thrilling transformation with the advent of trispecific biologics. In the realm of atopic dermatitis (AD), a chronic and often debilitating skin condition, Pfizer’s innovative trispecific candidates, PF-07275315 and PF-07264660, are poised to shake things up. Currently, in a Ph2 trial, these candidates targeting IL-4/13/33 (PF-07264660) and IL-4/13/TSLP (PF-07275315) together represent an unprecedented approach in AD treatment.
Traditional AD treatments have largely focused on IL-4 and IL-13, the dynamic duo in the Th2-driven inflammation pathway. But here’s where it gets interesting: PF-07264660 introduces IL-33 into the therapeutic equation, which is reported to be sevenfold higher in patients with AD vs. healthy population and is correlated with disease severity. While past attempts to target IL-33 alone (like Lilly’s torudokimab) didn’t pan out due to lack of efficacy, combining it with IL-4 and IL-13 inhibition could be a game-changer: while IL-4 and IL-13 drive the inflammation process, IL-33 acts as an upstream activator of the Th2 inflammatory response, amplifying the effects of IL-4 and IL-13. Combining IL-33 inhibition with IL-4 and IL-13 could, therefore, provide a more comprehensive suppression of the inflammatory pathways, potentially leading to greater efficacy and symptom relief, including the persistent itch that plagues so many patients.
Now, let’s talk about PF-07275315, a tri-specific antibody that expands this therapeutic strategy by incorporating anti-TSLP into its MoA. TSLP plays a crucial role in initiating and perpetuating the Th2 inflammatory cascade, leading to the production of downstream cytokines like IL-4 and IL-13, which are the key drivers of AD. By inhibiting TSLP, the inflammatory process can be disrupted at its inception, potentially preventing the cascade from escalating and providing early and broad suppression of the disease. Anti-TSLP has shown promise before, as in the case of tezepelumab, which showed sustained improvements in a Ph2b chronic spontaneous urticaria study even after 18-20 weeks of the last dose. Although it didn’t meet its week-16 primary endpoint, the longer-term sustenance of efficacy is indicative of the potential of anti-TSLP to provide a durable response in Th2-driven inflammatory diseases, which could be hugely beneficial for AD patients looking for long-term relief. The market for alternative AD therapies is significant, especially in the increasingly competitive environment targeting Dupixent failure patients. This competitive landscape is underscored by J&J’s acquisition of Proteologix’s portfolio featuring PX128, a bispecific antibody targeting IL-13 and TSLP that is gearing up for Ph1 development in AD. This move underscores the confidence in this combined approach strategy for tackling AD. While developing new therapies is inherently uncertain, addressing these unmet needs presents substantial rewards, making it a compelling pursuit.
Before we get too excited, it’s worth noting that the bi- and trispecific approach is still largely uncharted territory in immunology, especially in terms of ensuring safety, efficacy, and affordability. While bispecifics have made waves in oncology (recall epcoritamab, mosunetuzumab, and glofitamab in DLBCL), translating that success to inflammatory diseases is challenging. In oncology, bispecifics often have more severe safety profiles than CAR-Ts targeting the same antigen, highlighting the immense safety expectations for any novel treatment in chronic conditions like AD, where safety concerns, such as those associated with prevalent JAK inhibitors, remain prominent. Dermatologists may be hesitant to prescribe new therapies unless they match or exceed current safety standards.
Moreover, designing trispecific antibodies is complex and extends beyond PK/PD interplay to commercial manufacturing intricacies, potentially leading to a higher production cost. These factors combined could limit patient accessibility, as higher costs may translate to limited insurance coverage and affordability issues, indicating a smaller accessible patient pool. For Pfizer to push forward to Ph3, they will need to see robust safety and efficacy data in upcoming readouts to demonstrate a clear advantage over current therapies.
In conclusion, Pfizer’s trispecific biologics represent a bold leap into the future of AD treatment, targeting IL-4, -13, -33 and TSLP to address the unmet needs left by Dupixent, which revolutionized the AD landscape. Dermatologists treating severe or refractory cases will find these innovative therapies promising, given their potential for broader and more effective inflammatory suppression. However, to truly disrupt the market, these drugs must demonstrate superior safety and efficacy, overcoming the high bar set by the current standard of care. Addressing production costs and ensuring patient accessibility will also be critical. If Pfizer can achieve these benchmarks, its trispecific biologics could set new standards in immunology, making the future of AD treatment an exciting space to watch.