Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience

• Published in: Diabetes care Vol. 15; no. 5; pp. 666 - 692
• Main Authors: GALLOWAY, J. A, HOOPER, S. A, SPRADLIN, C. T, HOWEY, D. C, FRANK, B. H, BOWSHER, R. R, ANDERSON, J. H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-05-1992
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Diabetes Mellitus, Type 1 - drug therapy; Hormones. Endocrine system; Humans; Insulin - therapeutic use; Medical sciences; Molecular Sequence Data; Pharmacology. Drug treatments; Proinsulin - chemistry; Proinsulin - metabolism; Proinsulin - pharmacology; Proinsulin - therapeutic use; Protein Conformation; Receptor, Insulin - metabolism; Endocrinopathy; Human; Human origin; Proinsulin; Immunopathology; Chemotherapy; Pancreatic hormone; Treatment; Insulin dependent diabetes; Review
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/diacare.15.5.666

Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies,
and clinical trial experience.
J A Galloway ,
S A Hooper ,
C T Spradlin ,
D C Howey ,
B H Frank ,
R R Bowsher and
J H Anderson
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Abstract
OBJECTIVE--To describe the rationale for the preclinical and clinical developmental course of human proinsulin (HPI), the
second product after human insulin for the treatment of diabetes mellitus to be manufactured by DNA technology. RESEARCH DESIGN
AND METHODS--The relevant and available published and unpublished preclinical and clinical information generated on pork proinsulin
and human proinsulin has been integrated to demonstrate how certain clinically attractive features of pork proinsulin (a soluble
intermediate-acting and possibly hepatospecific insulin agonist) led to the development of HPI. RESULTS--Clinical pharmacology
studies demonstrated that HPI was definitely, although marginally, hepatospecific. More striking was the finding that the
intrasubject/patient coefficient of variation of response to HPI was significantly less than that observed with NPH insulin.
However, the fact that unique efficacy in controlled multicenter studies was not demonstrated suggested that these pharmacological
features were not translated into clinical benefit. In one multicenter new patient study there were six myocardial infarctions,
including two deaths, in patients treated for greater than or equal to 1 yr with HPI and none in the control group. CONCLUSIONS--To
obtain an independent review of the risks and benefits of HPI, in February 1988, Lilly convened a consultant group that examined
all relevant information on HPI available. These experts shared our concerns about the safety of HPI in light of the failure
to demonstrate unique efficacy. Accordingly, clinical trials with HPI were suspended in February 1988. Experience with HPI
demonstrates the challenge associated with the development of new drugs in general and insulin agonists in particular.