CJC-1295 Without DAC: Discovery and Research History

Introduction

CJC-1295 without DAC (Modified GRF 1-29, tetrasubstituted GRF(1-29)) occupies a position within a scientific lineage extending back to the isolation of hypothalamic growth hormone-releasing hormone (GHRH) in 1982. Understanding the compound's history requires tracing several parallel research threads: the biochemical characterization of endogenous GHRH, the development of shortened and stabilized synthetic analogs, the elucidation of plasma degradation mechanisms, and the eventual synthesis of the tetrasubstituted scaffold that defines this compound class. This article traces that history based on published primary literature and regulatory documents.

Discovery Period: Isolation of GHRH (1982)

For most of the twentieth century, the identity of the hypothalamic factor responsible for stimulating pituitary GH secretion remained unknown. The isolation of somatostatin (GH-inhibiting factor) by Guillemin's group in 1973 provided half of the hypothalamic GH regulatory circuit, but the corresponding releasing factor proved elusive.

Resolution came in 1982 through an unanticipated experimental source: ectopic GHRH-secreting tumors in patients with acromegaly — a condition of GH excess resulting from tumor-driven pituitary overstimulation. Guillemin, Brazeau, and colleagues at the Salk Institute isolated and characterized a 44-amino acid peptide with GH-releasing activity from the pancreatic tumor of an acromegalic patient, reporting its structure and in vitro and in vivo biological activity in Science [1]. The same year, Rivier, Spiess, Thorner, and Vale characterized an equivalent peptide with 40 residues from the pancreatic tumor of a second acromegalic patient, published in Nature [2]. Both groups demonstrated that their respective peptides stimulated pituitary GH secretion specifically and potently, establishing that the hypothalamic GH-releasing factor had been identified. These independent simultaneous discoveries are regarded as landmark events in neuroendocrinology.

Subsequent work confirmed that endogenous GHRH exists primarily as a 44-residue form (GHRH(1-44)-NH2) and a 40-residue form (GHRH(1-40)-OH), and that the primary amino acid sequence was shared between the tumor-derived and hypothalamic forms.

Early Research: The Bioactive N-Terminal Fragment and the Analog Design Program

Following GHRH isolation, research groups characterized which portions of the full-length peptide were required for GH-releasing activity. Studies established that the N-terminal 29 amino acids — specifically hGRF(1-29)-NH2 — retained full biological potency at the pituitary GHRH receptor, with the C-terminal residues beyond position 29 dispensable for receptor engagement. This insight drove the development of sermorelin, the synthetic 29-amino acid N-terminal fragment, as a more tractable research and clinical tool.

A fundamental pharmacological challenge became apparent early in this research. Frohman and colleagues (1989) rigorously characterized the enzymatic degradation of GHRH in human plasma, identifying dipeptidyl peptidase-4 (DPP-4) as the dominant inactivating protease [3]. DPP-4 cleaved the Tyr¹-Ala² N-terminal bond with high efficiency, generating the biologically inactive fragment GRF(3-29). Secondary cleavage by trypsin-like plasma enzymes further inactivated the molecule. These findings catalyzed a multi-decade program of analog design — precisely the program that produced CJC-1295 without DAC. A parallel analog development trajectory in the GHRH field produced tesamorelin, a full-length GHRH analog that received FDA approval in 2010, illustrating the broader clinical relevance of the enzymatic-stabilization research program.

Early analog studies through the 1980s and 1990s explored single-residue substitutions at the DPP-4 cleavage site, demonstrating that replacing L-Ala at position 2 with D-Ala substantially reduced DPP-4 susceptibility. Systematic evaluation of receptor tolerance for conservative amino acid substitutions at multiple positions throughout the GRF(1-29) sequence built a structure-activity relationship map that guided later multi-substitution analog design — ultimately producing the tetrasubstituted scaffold that defines CJC-1295 without DAC.

Regulatory Milestones: Sermorelin and the GRF(1-29) Scaffold

The unmodified hGRF(1-29)-NH2, sermorelin acetate, was developed as a therapeutic and diagnostic agent and received FDA approval in 1997 under the brand name Geref (Serono Laboratories). The approved indications were treatment of idiopathic GH deficiency in children with growth failure and diagnostic assessment of pituitary GH reserve [4]. Sermorelin's approval represented the first regulatory recognition of a GHRH analog as a therapeutic agent in the United States, validating the GRF(1-29) scaffold's clinical relevance and tolerability.

The commercial Geref product was voluntarily withdrawn from the US market in 2008. The FDA confirmed, in a 2013 Federal Register notice, that this withdrawal was not for reasons of safety or effectiveness [4] — a significant regulatory distinction establishing that the underlying compound's history does not carry a safety-based disqualification. The GRF(1-29) pharmacological scaffold thus retains a regulatory record of clinical use, establishing the safety context within which subsequent analogs including CJC-1295 without DAC are evaluated.

Development of the Tetrasubstituted GRF(1-29) Scaffold

The synthesis of the tetrasubstituted GRF(1-29) compound — incorporating D-Ala², Gln⁸, Ala¹⁵, and Nle²⁷ substitutions simultaneously — emerged from the converging findings of the structure-activity relationship literature. The specific combination of four positions was selected to address the multiple degradation pathways identified by Frohman and others: D-Ala² for DPP-4 resistance at the N-terminus, Gln⁸ and Ala¹⁵ for stability against secondary protease recognition sequences, and Nle²⁷ to eliminate the methionine oxidation site.

The ConjuChem Inc. research program, based in Montreal, Canada, extended this framework by attaching a Drug Affinity Complex (DAC) — a lysine-linked maleimidopropionamide derivative — to the C-terminus of the tetrasubstituted scaffold. This moiety was designed to react in vivo with the free thiol of albumin Cys34, creating a covalent albumin conjugate with a plasma half-life measured in days rather than minutes. The resulting compound — CJC-1295 with DAC — was formally characterized in the Jetté et al. 2005 Endocrinology paper that documented its preclinical pharmacology [5].

CJC-1295 without DAC — the same tetrasubstituted scaffold without the albumin-binding appendage — emerged as a distinct research entity in parallel. In the secondary and commercial literature, the without-DAC form is frequently identified under the alternative designator "Modified GRF 1-29" or "Mod GRF 1-29," distinguishing it from the DAC-bearing CJC-1295 that is the subject of the formal peer-reviewed clinical literature.

2006 Clinical Research on CJC-1295 with DAC

The published peer-reviewed clinical evidence for the CJC-1295 compound class derives from a productive burst of research published in 2006, all examining CJC-1295 with DAC. Teichman and colleagues published results of two randomized placebo-controlled trials in the Journal of Clinical Endocrinology & Metabolism, reporting dose-dependent GH and IGF-1 secretory responses with a favorable tolerability profile in healthy adults [6]. Ionescu and Frohman, also publishing in 2006 in the same journal, reported the preservation of pulsatile GH secretion during sustained GHRH-R agonism by CJC-1295 with DAC in healthy men — a mechanistically significant finding demonstrating that pharmacological GHRH-R stimulation does not abolish the physiological pulsatile architecture of GH secretion [7]. Alba and colleagues published concurrent preclinical data demonstrating growth normalization in GHRH knockout mice receiving the tetrasubstituted CJC-1295 core [8].

These three publications collectively established the scientific foundation for the CJC-1295 compound class in the peer-reviewed literature. Though none specifically examined CJC-1295 without DAC as an isolated agent, they provided the pharmacological framework within which the without-DAC variant is scientifically understood and generated substantial interest in this compound class.

Current Research Landscape

CJC-1295 without DAC continues to be studied as a research-use material, with the question of whether the shorter pharmacodynamic pulse profile of the without-DAC variant has distinct experimental implications — compared to the sustained tonic GHRH-R stimulation of the DAC variant — representing an area of active scientific discussion. Details on the synthesis, purity verification, and storage standards applied to CJC-1295 without DAC supplied for research are covered in the CJC-1295 without DAC sourcing and quality article. Research-grade CJC-1295 without DAC from SpartaLabs is available with third-party verified batch Certificates of Analysis. Research interest in GHRH analogs as a class has continued in the academic literature, with a 2025 publication in Reviews in Endocrine and Metabolic Disorders extending characterization of GHRH-R signaling at molecular and splice-variant levels [9].

In December 2024, the FDA's Pharmacy Compounding Advisory Committee (PCAC) evaluated CJC-1295 (both DAC and without-DAC formulations) as candidate bulk drug substances for potential inclusion on the 503A compounding Bulk Drug Substances list — reflecting continued regulatory engagement with this compound class. The committee's evaluation and any resulting determination by the FDA were ongoing at the time of publication of this article.

References

1. Guillemin R, Brazeau P, Böhlen P, Esch F, Ling N, Wehrenberg WB. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218(4572):585-587. PMID: 6812220. DOI: 10.1126/science.6812220

2. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982;300(5892):276-278. PMID: 6292724. DOI: 10.1038/300276a0

3. Frohman LA, Downs TR, Heimer EP, Felix AM. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma. J Clin Invest. 1989;83(5):1533-1540. PMID: 2651468. DOI: 10.1172/JCI114049. PMC: PMC303858

4. US Food and Drug Administration. Federal Register: Determination that GEREF (Sermorelin Acetate) Injection was not withdrawn from sale for reasons of safety or effectiveness. Fed Regist. 2013;78(43):14201. Available at: https://www.federalregister.gov/documents/2013/03/04/2013-04827/determination-that-geref-sermorelin-acetate-injection

5. Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, et al. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005;146(7):3052-3058. PMID: 15817669. DOI: 10.1210/en.2004-1286

6. Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006;91(3):799-805. PMID: 16352683. DOI: 10.1210/jc.2005-1536

7. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006;91(12):4792-4797. PMID: 17018654. DOI: 10.1210/jc.2006-1702

8. Alba M, Fintini D, Sagazio A, Lawrence B, Castaigne JP, Frohman LA, et al. Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. Am J Physiol Endocrinol Metab. 2006;291(6):E1290-E1294. PMID: 16822960. DOI: 10.1152/ajpendo.00201.2006

9. Szalai M, Kandrács Á, Vass RA, et al. Growth hormone-releasing hormone receptor (GHRH-R) and its signaling. Rev Endocr Metab Disord. 2025;26:343-352. DOI: 10.1007/s11154-025-09952-x. PMC: PMC12137518