PP-CAG: Mechanism and Research Findings

PP-CAG is a long-acting amylin analog — a synthetic peptide designed to mimic amylin, a hormone involved in the regulation of blood glucose, hunger and satiety. Published research has examined it both on its own and in combination with PP-SM1, a GLP-1 (glucagon-like peptide-1) receptor agonist. Studies have investigated its activity at appetite-related signalling pathways in the brain and its effect on glucose regulation alongside insulin.

The summary below describes findings reported in the published literature. PP-CAG is supplied for laboratory research use only and is not approved for human or veterinary use. No conclusions can be drawn regarding safety or effects in humans.

Mechanism of Action of PP-CAG Peptide

Native amylin has a strong tendency to aggregate into fibrils and β-sheets, and this aggregation behaviour has been compared in the literature to intracellular processes implicated in neuronal damage. That aggregatory character was a central design constraint in developing a stable amylin analog, and several structural alterations were made to address it.

The 14E and 17R substitutions allow PP-CAG to form a salt bridge, which helps stabilise the central helix. The 25P, 28P and 29P substitutions reduce the tendency to form fibrils and β-sheets, and a C-terminal proline strengthens binding at the calcitonin receptor (CTR) channel. Reported potency is comparable to native amylin following these alterations.

A second design constraint was half-life. The first-generation amylin analog pramlintide has a short half-life. In the development of PP-SM1, half-life was extended by adding a fatty acid moiety that promotes covalent and non-covalent binding to albumin. The same albumin-binding approach was applied to PP-CAG through an N-terminal C20 fatty acid.

In clinical studies, the reported half-life of PP-CAG ranged from 159 to 195 hours across the exposure levels studied, with an elimination half-life of 7 to 8 days.

Research Evidence

A published trial comparing PP-CAG with liraglutide enrolled 706 participants aged 18 or over, without diabetes or metabolic disorder, with a body mass index of at least 30 kg/m², or at least 27 kg/m² with either hypertension or dyslipidemia. Participants were randomised 6:1 to PP-CAG, liraglutide, or a volume-matched placebo.

Five PP-CAG exposure levels were compared against liraglutide and a volume-matched placebo across six placebo groups. The study period ran 26 weeks, including a six-week escalation phase, followed by a six-week post-intervention follow-up. As part of the trial protocol, all participants received dietary and physical activity counselling targeting a 500 kcal/day deficit and 150 minutes of physical activity per week. The primary endpoint was percentage change in body weight from baseline to week 26.

At week 26, mean percentage weight change from baseline was greater across all PP-CAG exposure levels (6.0%–10.8%) than placebo (3.0%). The placebo group plateaued at week 18, while the change observed with PP-CAG continued across the full 26 weeks.

Body-weight changes were also greater with the highest PP-CAG exposure level than with liraglutide (10.8% versus 9.0%, P = 0.03). The trial reported greater change in body weight with both the highest PP-CAG exposure level and liraglutide than with lifestyle management alone. Reductions in triglycerides and very-low-density cholesterol at the two highest PP-CAG exposure levels were greater than pooled placebo and comparable to liraglutide.

Some weight was regained by week 32, following the end of the intervention at week 26. Mean change at week 32 ranged from -5.0% to -9.8% across the PP-CAG exposure levels, against -6.1% to -10.8% at week 26. The trial reported an exposure-dependent change in the body-weight endpoint over 26 weeks in participants with obesity or overweight.

Research Application

The PP-CAG and PP-SM1 combination is investigational and has been evaluated in trials measuring body weight and glycaemic endpoints. In one clinical trial, administration of the PP-CAG and PP-SM1 combination to participants with type 2 diabetes was associated with changes in glycemic control measures, including continuous glucose monitoring metrics. Mean change in HbA1c was greater with the PP-CAG and PP-SM1 combination than with PP-CAG alone, though not relative to PP-SM1. The authors noted the need for longer and larger phase 3 studies in this population.

Because PP-CAG and PP-SM1 act through different pathways, the combination has been studied for potential additive effects on glucose regulation and body weight endpoints. The PP-CAG and PP-SM1 combination remains under investigation in type 2 diabetes and obesity research.

Registered studies in this area have examined: the effect of the PP-CAG and PP-SM1 combination on markers of kidney damage in participants with type 2 diabetes, chronic kidney disease and obesity or overweight; the extent to which the combination affects blood glucose and body weight endpoints in participants with type 2 diabetes; and the combination compared with placebo in participants with painful diabetic peripheral neuropathy and type 2 diabetes.

A multicentre, randomised, double-blind, placebo-controlled and active-controlled phase 2 trial was conducted across 57 sites in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the United Kingdom and the United States) to compare several exposure levels. The intervention phase ran 26 weeks including an escalation phase of up to six weeks, followed by a six-week post-intervention period. Participants and investigators were masked to active intervention versus pooled placebo, but not between the different active interventions.

Cardiovascular endpoints have also been studied, including the effect of the PP-CAG and PP-SM1 combination on cardiovascular events in participants with type 2 diabetes and/or obesity. Trials in this area are generally randomised, double-blind and active-controlled, with change in body weight, cardiovascular events and HbA1c as common primary endpoints.

Future Application

The complementary mechanisms of amylin analogs and GLP-1 receptor agonists have made this combination an active area of metabolic research, and published phase 2 data have prompted further study. Ongoing clinical trials are examining the combination in participants with overweight or obesity. These findings support continued investigation of compounds with novel mechanisms of action in metabolic research.

Research use statement. PP-CAG and its combination with PP-SM1 are investigational compounds. The material supplied by Power Peptides is intended for laboratory research use only and is not approved by the U.S. Food and Drug Administration for human or veterinary use. It is not a drug, food or cosmetic, and must not be used in humans or animals.

References

1. https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c00565

2. https://journals.lww.com/cardiologyinreview/fulltext/2024/01000/PP-CAG__a_long_acting_amylin_analog_for_the.13.aspx

3. Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of PP-CAG with PP-SM1 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397:1736–1748.

4. Gadde KM, Martin CK, Berthoud HR, et al. Obesity: pathophysiology and management. J Am Coll Cardiol. 2018;71:69–84.

5. Efficacy and safety of co-administered once-weekly PP-CAG 2·4 mg with once-weekly PP-SM1 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial Frias, Juan P et al. The Lancet, Volume 402, Issue 10403, 720 - 730

6. Once-weekly PP-CAG for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial Lau, David C W et al. The Lancet, Volume 398, Issue 10317, 2160 - 2172