Evidence Grade C — Moderate human evidence. 40748 published studies, 24972 human. 9 registered clinical trials.
Medically reviewed by a licensed medical professional
P21 is a synthetic peptide designed to mimic the effects of a brain growth factor (CNTF), with a modified amino acid to improve oral stability. It has been studied in mouse models of Alzheimer's disease by a single research group. No human clinical trials have been conducted. It is important to note that results in Alzheimer's mouse models have historically translated to human benefit extremely poorly.
P21 is also known by these brand and alternate names:
40,748 published studies: 24972 human, 8535 animal, 9989 in-vitro, 1589 reviews
P21 has no marketing authorisation. No human clinical trials have been conducted. The evidence base consists entirely of studies in transgenic Alzheimer's disease mouse models, conducted primarily by a single research group.
Animal studies reported behavioural and biochemical changes in AD mouse models following chronic oral administration. The translation of results from transgenic mouse models of Alzheimer's disease to human disease has historically been extremely poor — the vast majority of compounds showing efficacy in such models have failed in human trials. Products available through unregulated channels lack pharmaceutical quality assurance.
Research in transgenic mouse models of Alzheimer's disease suggests P21 may interact with neurotrophic factor signalling pathways, potentially influencing neurogenesis and BDNF expression. These observations are from animal studies using genetically modified disease models, and their relevance to human neurodegenerative disease has not been established.
Research in transgenic Alzheimer's mouse models suggests P21 may influence neuronal growth and brain-derived neurotrophic factor expression, with consistent findings across multiple disease models and treatment durations up to 18 months. However, nearly all data comes from one research group, and an independent replication attempt in a different disease model (CDKL5) failed. No human data of any kind exist — no pharmacokinetics, no safety assessments, no efficacy data. The track record of Alzheimer's mouse model findings translating to human benefit is exceptionally poor across the pharmaceutical industry. Products from unregulated channels lack pharmaceutical quality assurance.
PeptideTrace tracks 9 registered clinical trials for P21 sourced from ClinicalTrials.gov.
KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia
Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
Senescence and the Early Ageing Phenotype After Chemotherapy for Testicular Cancer: the SEA-CAT Study
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
Molecular Pathways Related to Short-term Fasting Response
P21 (also called P021; code GLXC-21260) is a small CNTF-derived peptide mimetic with the sequence Ac-DGGLAG-NH2 (acetyl-Asp-Gly-Gly-Leu-Adamantylglycine-amide), where the C-terminal residue is an adamantylated glycine, a glycine bearing a tricyclic adamantane moiety that increases lipophilicity and blood-brain barrier penetrance. Molecular weight is 578.3 g/mol (C27H42N6O8). The core tetrapeptide DGGL corresponds to amino acid residues 148-151 of human CNTF, identified via epitope mapping using neutralizing antibodies. Developed by Khalid Iqbal at the New York State Institute for Basic Research in Developmental Disabilities. Plasma half-life exceeds 3 hours (versus approximately 2.9 minutes for recombinant CNTF). The compound shows approximately 90% gastric stability and >95% intestinal stability, enabling oral administration in animal feed at 60 nmol/g. Currently under development by Phanes Biotech.
Research suggests P21 operates through a dual mechanism: competitive inhibition of leukemia inhibitory factor (LIF) signaling (promoting neural progenitor cell formation from stem cells) and upregulation of BDNF expression (promoting survival and maturation of newborn neurons). The downstream cascade involves BDNF to TrkB to PI3K/Akt to inhibitory phosphorylation of GSK-3beta at Ser9, leading to reduced tau hyperphosphorylation (at AT8, PHF1, 12E8 sites). GSK-3beta inhibition also reduces amyloidogenic APP processing. Animal studies indicate P21 normalizes phosphorylated CREB/total CREB ratios and increases synaptic markers including MAP2, PSD-95, synaptophysin, synapsin I, GluA1, and GluN1. The compound was designed to capture CNTF's neurotrophic activity while avoiding the severe adverse effects of full-length CNTF (anorexia, cramps, weight loss).
The landmark Kazim et al. (2014, Neurobiol Dis) study in 3xTg-AD mice showed that oral P21 (60 nmol/g feed for 6-12 months) produced performance comparable to wild-type in Morris water maze, significantly reduced phosphorylated tau at multiple epitopes, significantly increased BDNF, and rescued Ki-67+ and DCX+ cells in the dentate gyrus to wild-type levels. Baazaoui and Iqbal (2017) demonstrated that preventive treatment from age 3 months for 18 months increased DCX+ and Ki-67+ cells approximately 4-fold versus vehicle and showed no tumors, weight loss, or adverse effects. Kazim et al. (2017) showed efficacy in the Ts65Dn Down syndrome mouse model. However, Bhattacharyya et al. (2024) studying CDKL5 deficiency disorder failed to replicate BDNF increases in vivo and showed limited behavioral benefit. No clinical trials are registered.
The information on this page is provided for educational and research reference purposes only. This is not medical advice. Always consult a qualified healthcare professional before making any health-related decisions.
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Trofinetide is marketed as Daybue (Acadia Pharmaceuticals, approved March 2023). It is the first FDA-approved treatment for Rett syndrome, a condition that affects an estimated 15,000–20,000 individuals in the US. Previously, treatment was limited to managing individual symptoms. In the LAVENDER trial, trofinetide showed significant improvement on both a clinician-assessed severity scale and a caregiver-assessed behaviour questionnaire compared to placebo. The most common side effects are diarrhoea (approximately 80%) and vomiting. While the improvements are meaningful to patients and families, trofinetide does not cure Rett syndrome — it is a symptom management treatment that requires ongoing daily dosing.
This content is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making decisions about your health.
