Pfizer Cuts Seven Pipeline Programs Including Bispecific Antibody PF-06671008

Compiled by Keke

On October 29, Pfizer updated its R&D pipeline portfolio, revealing seven newly discontinued investigational projects, primarily in the therapeutic areas of oncology and dermatology. Among these was PF-06671008, a bispecific antibody co-developed with MacroGenics. This solid tumor therapeutic was the first project developed based on MacroGenics’ bispecific platform, but it was terminated by Pfizer after only reaching Phase I clinical trials.

It is reported that this Phase 1 clinical study (NCT02659631) was initiated in January 2016 and terminated in May of this year. At the outset, Pfizer planned to enroll 110 patients with solid tumors in this dose-escalation study, with the primary endpoints being dose-limiting toxicities and objective response rate. In early 2018, Pfizer increased its enrollment target to 152 patients; however, recruitment was halted by late 2018, resulting in an actual enrollment of only 28 patients.

PF-06671008 is a half-life extended, bispecific, dual-affinity retargeting molecule with antibody-like properties that targets P-cadherin and CD3. Researchers have demonstrated the in vivo antitumor efficacy of this molecule in a human colorectal cancer/human peripheral blood mononuclear cell mixed xenograft mouse model. Preclinical study results indicate that P-cadherin is upregulated in various types of solid tumors and is associated with poor patient survival. Therefore, PF-06671008 is also considered a “promising” novel bispecific antibody drug for the treatment of patients with P-cadherin-expressing solid tumors. These findings have also attracted Novartis. Several years ago, Novartis tested a P-cadherin inhibitor in humans, but this has not yet translated into promising therapeutic progress.

PF-06671008 is derived from MacroGenics’ proprietary bispecific antibody platform based on its Dual-Affinity Re-Targeting (DART™) technology, in which a single recombinant molecule can target two distinct antigens. These DART proteins have multiple potential applications and may be used to redirect immune effector cells in vivo to destroy tumor cells. In October 2010, MacroGenics entered into a collaboration with Pfizer, granting Pfizer rights to candidate drugs from its bispecific antibody platform targeting two cancer antigens.

Bispecific antibodies have emerged as a hot research area in recent years. Compared with conventional antibodies, they demonstrate strong competitiveness in terms of tissue penetration, efficiency in killing tumor cells, off-target rates, and clinical indications. Major pharmaceutical companies such as Amgen, Roche, AstraZeneca, Sanofi, Johnson & Johnson, and Eli Lilly have all invested in this field. However, drug toxicity, design complexity, and stability remain significant challenges during development and clinical use. In February this year, Novartis halted the Phase 1 clinical trial of its CD123×CD3 bispecific antibody, XmAb14045, for leukemia after patient deaths occurred.

In its latest pipeline update, Pfizer removed four cancer-related drug research programs. Aside from the combination therapy study involving the marketed drug Ibrance, the other two projects were the pan-PI3K/mTOR inhibitor PF-05212384, which entered clinical trials only a decade ago, and the OX40 receptor agonist PF-04518600.

In addition, the pipeline changes also involve three dermatology drugs, including the oral TYK2/JAK1 inhibitor PF-06700841 (also known as brepocitinib), which has entered Phase 2 clinical trials for the treatment of psoriasis. Compared to competitors such as AbbVie and Gilead Sciences, who are developing single assets in many areas, Pfizer views the breadth of its kinase inhibitor portfolio as an advantage. Therefore, Pfizer stated that it will continue to study PF-06700841 as a topical treatment for psoriasis and explore its use as an oral formulation in other indications, including psoriatic arthritis, Crohn’s disease, and vitiligo.

The other two discontinued dermatology drugs are PF-06763809, a transcription factor inhibitor with promise for the treatment of psoriasis, and PF-06817024, a cytokine modulator for atopic dermatitis. Pfizer’s decision to abandon PF-06817024 came shortly after the completion of late-stage data analysis for its oral JAK1 inhibitor, abrocitinib. On October 14, at the 28th Congress of the European Academy of Dermatology and Venereology, Pfizer presented the results of the Phase III JADE MONO-1 clinical trial evaluating abrocitinib for the treatment of moderate-to-severe atopic dermatitis. Compared with placebo, the drug met all primary and secondary endpoints related to skin clearance and pruritus relief. Pfizer believes that, if approved, the drug will compete with Sanofi and Regeneron’s blockbuster drug Dupixent, as Dupixent and abrocitinib have different mechanisms of action. Dupixent’s net sales in the second quarter of this year amounted to $557 million, representing a 166% increase compared to the same period in 2018.

Reference Source:

[1] Pfizer kills off MacroGenics-partnered solid tumor bispecific

[2] Pfizer Announces Eczema Drug Abrocitinib Passed 2nd Phase III Trial

[3] https://clinicaltrials.gov [4] Company website, etc.