FDA's clinical warning analysis on Oncopeptides peptide conjugate Pepaxto

On February 26, 2021, the FDA accelerated the approval of PEPAXTO ® (melphalan flufenamide) in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma.
These patients have received at least four-line treatment and have at least Adult patients with relapsed or refractory MM who have failed to treat a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody
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This is also the first anti-tumor peptide-drug conjugate to be marketed.
As an additional condition for the accelerated listing process, Oncopeptides is required to perform post-marketing Phase III clinical trials (OCEAN)
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On July 28, 2021, the FDA issued a clinical warning stating that based on the results of a confirmatory trial required by the FDA, Pepaxto (melphalan flufenamide) may increase the risk of death in patients with myeloma.
The FDA has suspended all Pepaxto clinical trials.
Patient registration, Oncopeptides stock fell 18.
78% that day
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Figure 1 FDA warning letter Figure 2 Structural formulas of Pepaxto and Melphalan Due to high lipophilicity, Pepaxto can be rapidly absorbed by myeloma cells
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Once inside the cell, the conjugated peptide of Pepaxto is immediately cleaved by aminopeptidase, releasing the hydrophilic alkylating agent to effectively load the melphalan, and is trapped in the cell
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On September 2, 2021, the FDA announced that it will hold a meeting of the Oncology Drug Advisory Committee (ODAC) on October 28, 2021 to discuss the safety results of Pepaxto, including the overall survival of the OCEAN study
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On September 11, 2021, Oncopeptides presented the OCEAN research data at the 18th International Myeloma Symposium (IMW).
Oncopeptides CEO Marty J Duvall said: “We have full confidence in the OCEAN data and are working closely with the FDA.
Solving the Pepaxto ® problem"
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Experts comment on the founding partner and CTO of Zhipeptide, Dr.
Changfa Chen.
Dr.
Changfa Chen: Founding partner and CTO of Zhipeptide
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Dr.
Chen Changfa used to be the head of the research and development of the new drug group and the project leader of the Shanghai Pharmaceutical Industry Research Institute
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Since 2021, he has been the CTO of Zhipeptide Bio, a global technology platform company focusing on chemical coupling research; the company's R&D pipeline involves nuclide conjugates, small molecule conjugates, peptides and antibody conjugates, etc.
Research and development; company goal: to discover and create clinical value
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Zhipeptide Bio was established in August 2021 and registered in Shanghai Zhangjiang Science City
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Pepaxto is not currently a commonly defined PDC, and its core part is a dipeptide
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Table 1 PDC and Pepaxto transport modes and differences in body distribution Figure 3 PDC and Pepaxto transport mechanism 1, according to Table 1 and Figure 3, PDC and Pepaxto transport modes are different Actively targeted drugs with transmembrane proteins as targets, and their entry into tumor cells is an active transport that consumes energy
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2) Pepaxto is due to the high lipophilicity of the drug to enter the cell through passive transport, so it is not an active targeting drug that relies on transmembrane proteins as the target
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Second, the distribution of PDC and Pepaxto in the body is different 1) PDC can accurately target tumor cells with high expression of target targets
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2) Pepaxto can enter tumor cells and normal cells due to its high lipophilicity; in view of the FDA warning letter about its phase III clinical OS decline may be related to this
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PDC global research projects are shown in Table 2.
Preclinical and clinical Phase I/II preliminary results show that PDC has broad clinical prospects
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Table 2 Global PDC research projects* As of September 2021, PDC drugs have the characteristics of strong tumor penetration, non-immunogenicity, and low production cost
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Compared with other conjugated drugs, PDC drugs have a broader industrial foundation and clinical value! Reference 1.
https:// F, et al.
Cancers (Basel).
2019;12(1).
pii: E15; 2.
Wickström M, et al.
Oncotarget 2017;8(39):66641-66655.
4.
Demeule M et al.
AACR 2020, Abstract #4335.
; Makawita S, Meric-Bernstam F.
Am Soc Clin Oncol Educ Book.
2020; 40:1-10.
5.
PEPAXTO® (melphalan flufenamide) for injection, for intravenous use .
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