Discover the Essentials: What to Know Before You Buy RAD 140 

RAD 140 Mechanism of Action & Pharmacokinetics 

RAD140 attaches to and activates androgen receptors in various tissues with a high degree of selectivity. Once connected to the androgen receptors, RAD140 produces tissue-specific effects that promote lean muscle and bone growth, while minimally stimulating the prostate and seminal vesicles.

RAD 140 & Neuroprotection 

RAD140 displayed neuroprotective properties in vivo using a rat model with kainate-induced lesions. Showing ability to protect nerve cells (neuroprotective effects) depends on a specific cellular communication pathway called MAPK signaling (Mitogen-Activated Protein Kinase, a crucial cell signaling mechanism in living organisms). 

Evidence supporting this includes the observation that ERK, a protein involved in the MAPK pathway, becomes more phosphorylated (a process that activates or modifies proteins) when RAD140 is present. 

These innovative findings showcase the initial preclinical success of RAD 140 in providing neuroprotective actions pertinent to Alzheimer’s disease and associated neurodegenerative disorders. 

Bioavailability of RAD 140 

RAD 140 exhibited a high affinity for the androgen receptor due to its structure, molecular weight, and half life. 

Various characteristics of chemical bonds affect the bioavailability (which plays a huge role in a compound half life ) of a specific compound. One such factor is the measure of molecular flexibility, known as the rotatable bond count (rotatable bond count).

The total number of hydrogen bonds, including both donors and acceptors, contributes to the binding of ligands, which is essential for the proper functioning of androgen receptors. 

Although specific details regarding the bioavailability of RAD140 may vary, its administration generally suggests that it is designed for efficient absorption and utilization in test subjects.

Significance of Preclinical Data

Efficacy of RAD140 in Cynomolgus Monkeys For its Effects on Lean Tissue, Fat, and Liver Health 

A study using RAD140 in young male cynomolgus monkeys took place to determine effective administration amounts for a preclinical species that investigators deemed more relevant in their clinical research.

The study was relatively straightforward and non-terminal, allowing researchers to evaluate the effect on muscle mass, lipid levels, mean weight gain and other clinical chemistry parameters. To assess activity, initially, researchers examined overall body weight, which is known to be a sensitive indicator of anabolic androgen action in young primates.

The body weight of primates was measured from day -21 through 28 days of RAD140 administration (0.01, 0.1, and 1 mg/kg, orally) and 21 days after stopping the administration. Each group subject to testing had three monkeys.

The change in body weight from day -1 to day 29 was statistically significant only for the 0.1 mg/kg (p < 0.01) and 1.0 mg/kg (p < 0.05) groups.

The difference in body weight at day 29 between the 0.1 mg/kg group and the 0.01 mg/kg group was statistically significant (p < 0.05), while the difference between the 1.0 mg/kg and the 0.01 mg/kg group was not statistically significant (p < 0.1).

An average weight increase of over 10% was accomplished in merely 28 days at an administration of 0.1 mg/kg, and a similar outcome was observed for the group receiving 1.0 mg/kg of RAD 140.

Additionally, to evaluate the impact of RAD140 on muscle tissue and fat, dual-energy X-ray absorptiometry (DEXA) scans were conducted on all monkeys two days before the study started and one day after the last dose (on day -2 and day 29).

No consistent impact on absolute fat mass was observed, while muscle exhibited a qualitative trend of increasing with the administration of RAD 140. Despite the majority of the mass increase appears to be due to an increase in lean muscle tissue, none of the tissue weight increases were statistically significant (p > 0.05).

Even though there were significant increases in body weight and muscle mass over a short period, there was no rise in liver enzyme transaminase levels more than two times the baseline value in any animal. In other words, the substantial weight gain did not lead to a concerning increase in liver enzyme levels, which might have indicated liver damage or stress.

These measurements taken in the study showed that RAD140 exhibits a highly favorable preclinical profile within laboratory research. 

Effects of RAD 140 In Preclinical Laboratory Research 

RAD 140 functions as an antagonist, with a suitable half life. It obstructs AR activation and AR-driven cell growth, which could potentially inhibit prostate enlargement in males and impede AR-dependent breast cancer cell proliferation. 

In this preclinical study, researchers examined the effectiveness and action of the orally administered selective AR modulator RAD140 in both in vivo and in vitro models of AR/ER+ breast cancer. 

A range of in vitro tests were employed to assess RAD140’s affinity for four nuclear receptors and examine its tissue-specific AR activity. The effectiveness and pharmacodynamics of RAD140, both as a standalone and in combination with palbociclib were analyzed. 

RAD140 demonstrated a strong and specific binding affinity to AR in breast cancer cells, but not in prostate cancer cells. When administered orally, RAD140 significantly reduced the growth of AR/ER+ breast cancer subject-derived xenografts.  

In simpler terms, RAD140 effectively targeted and activated AR in breast cancer cells, and its oral administration considerably slowed down the growth of AR/ER+ breast cancer in laboratory models. 

Upon administration with RAD140, AR activation and inhibition of the ER pathway, including the ESR1 gene, were observed. We discuss these terms below.   

The ER pathway, or estrogen receptor pathway, is a biological signaling pathway that involves the estrogen hormone and its interaction with estrogen receptors, primarily ERα and ERβ. These receptors are proteins, transcription factors that function as regulators, controlling the expression of particular genes they are targeting when bound to estrogen.   

The ER pathway can be involved in the progression of the disease, as estrogen binding to its receptors can stimulate the growth and division of cancer cells.    

The ESR1 gene, also known as the Estrogen Receptor 1 gene, is a gene that encodes the estrogen receptor alpha (ERα) protein. This protein functions as a nuclear hormone receptor for estrogen.   

The ERα protein plays a significant role in the growth and progression of some types of breast cancer, as it can promote the division and growth of cancer cells when bound to estrogen.   

Data appeared so that by combining RAD140 and palbociclib demonstrated amplified effectiveness in the AR/ER+ subject-derived xenograft models. 

RAD140 led to the suppression of a group of AR-repressed genes related to DNA replication. This effect seemed to increase when palbociclib was administered simultaneously. 

This means RAD140 successfully suppressed a specific group of genes that are normally repressed by the androgen receptor (AR) and are involved in DNA replication. 

Furthermore, when palbociclib was administered alongside RAD140, this suppression effect appeared to be even stronger. The suppression of these genes is considered a positive outcome, as it aligns with the intended effectiveness of the RAD 140 in this study, likely in the context of inhibiting cancer cell growth or progression. 

Conclusively, RAD140 exhibits itself as a powerful AR activator in breast cancer cells, possessing a unique mode of action that involves the AR-driven suppression of ESR1. It effectively hinders the growth of various AR/ER+ breast cancer subject-derived xenograft models, and also when used in conjunction with palbociclib.

The preclinical findings showcased in this context advocate for continued clinical exploration of RAD140 in the reception of AR/ER+ breast cancer. 

A First: Phase 1 Trial of SARM RAD 140 for ER+/HER2- Advanced Breast Cancer

For context purposes, ER+/HER2- advanced breast cancer is a specific subtype that has spread beyond the breast tissue and lymph nodes to different areas within the body (also known as metastatic or advanced breast cancer).

This initial trial, a Phase 1 study, sought to evaluate the safety, tolerability, highest amount that can be administered without causing severe adverse outcomes, pharmacokinetic (PK) properties, and anti-cancer effectiveness of RAD140.

This study involved gradually increasing the measure of RAD 140, using a 3 + 3 design and an additional group to examine pharmacokinetic (PK) properties. It included postmenopausal subjects diagnosed with ER+/HER2- advanced breast cancer.

Serum sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were employed as substitute indicators to measure the interaction between RAD140 and the androgen receptor.

These two markers (SHBG & PSA) were chosen because they are known to be influenced by the activity of the AR. By measuring changes in their levels, researchers can estimate the extent of AR engagement by RAD140, helping them understand the effectiveness and its impact on the targeted cancer cells. 

A total of 22 patients (21 with AR+ status) who had previously undergone extensive remedies were included in the study.

Meaning that among the 22 subjects included in the study, 21 of them had cancer cells that were positive for the androgen receptor (AR+). In other words, these 21 subjects had cancer cells with androgen receptors present on their surface, making them ample candidates for this study. 

They were administered either 50 mg (for 6 subjects), 100 mg (for 13 subjects), or 150 mg (for 3 subjects), dispensed once daily.

The most common adverse outcomes were experienced by more than 10% of the subjects during the study. A significant number of them had increased liver enzymes (AST at 59.1% and ALT at 45.5%) including higher bilirubin levels in their blood, which are indicators of liver function. As well as total blood bilirubin (27.3%), vomiting, dehydration, and reduced appetite and weight (each occurring in 27.3% of subjects).

Severe adverse outcomes, classified as Grade 3/4, were observed in 16 subjects (72.7%), which consisted of elevated AST/ALT levels and low phosphate levels in the blood (each affecting 22.7% of subjects).

During the study, 17 out of the 22 test subjects (77.3%) experienced adverse events (TEAEs) that were considered to be related to the RAD 140 being administered.

Among them, 7 test subjects (31.8%) experienced severe (Grade 3) adverse impacts. However, none of the subjects encountered very severe or threatening (Grade 4) outcomes.

The clinical satisfaction rate at 24 weeks was observed to be 18.2%, and the median duration of progression-free survival was 2.3 months.

All 18 subjects who were evaluated experienced a decrease in sex hormone-binding globulin (SHBG), while 16 out of 20 subjects had an increase in prostate-specific antigen (PSA) levels. The analysis of tumor biopsies taken before and during the administration of RAD 140 showed evidence of androgen receptor (AR) involvement.

In conclusion, RAD140, a novel oral AR-targeted agent, has shown an acceptable safety profile along with initial signs of target engagement and antitumor activity in subjects with AR+/ER+/HER2- metastatic breast cancer (mBC).

Clinical Conclusion of RAD 140 

The overall preclinical properties of RAD-140 appeared to be quite promising. This compound has successfully completed preclinical toxicology assessments in both rat and monkey models, demonstrating its potential for further research.

Researchers investigated the efficacy and mechanism of RAD140, an orally administered selective AR modulator, in both living organisms and laboratory-based models of AR/ER+ breast cancer. The preclinical results presented in this study support the ongoing clinical investigation of RAD140.

A Phase 1 study aimed to assess the safety, tolerability, maximum tolerable administration, pharmacokinetic (PK) characteristics, and anti-cancer efficacy of RAD140.

RAD140 has a suitable safety profile as well as initial indications of target interaction and cancer-fighting effects in test subjects with AR+/ER+/HER2- metastatic breast cancer (mBC) revealing favorable properties to be further investigated.

How Does Data on RAD 140 Compare to Other Clinically Tested SARMs? 

There are a wide range of SARMs that have been evaluated in clinical settings before including RAD 140, Ostarine (MK-2866), MK-677, and LGD-4033.

Arguably, Ostarine is the most studied and clinically evaluated SARM and RAD 140 vs Ostarine is the most frequently studied SARMs comparison.

Ostarine has undergone extensive evaluation of its effectiveness and safety through a series of preclinical investigations and clinical trials in phases 1, 2, and 3. While RAD 140 has only gone through one Phase 1 trial that was much smaller than that of Ostarine. The clinical outcomes of Ostarine indicate its potential for subjects suffering from muscle mass wasting disorders and cancer. 

How Do the Safety Profiles Of Ostarine and RAD 140 Compare?

Once again, RAD 140 has only been subject to one phase l trial (where the compound administered is studied for its basic level of safety and efficacy) while Ostarine has undergone many. This includes a phase lll trial (comparing currently administered compounds and tested compounds to one another for specific outcomes on a disease in a clinical setting). 

The key difference between the trials including Ostarine and RAD 140 were their tasks at hand. Ostarine, being tested amongst subjects with NSCLC (Non-Small Cell Lung Cancer) for its ability to impact lean muscle mass and bone in a tissue selective manner, and RAD 140 tested amongst the examinee for its ability to block AR-driven cell growth and activation, in regard to ER+/HER2- Advanced Breast Cancer. 

The ratio of adverse outcomes and their severity are what determine the safety and efficacy of any specifically tested compound. 

Ostarine’s clinical phase lll trial included over 300 test subjects. Half were administered Ostarine while the other half were administered placebo. The phase l trial with RAD 140 included a total number of 22 test subjects (far less than Ostarine). 

56 out of 160 subjects (35%) administered Ostarine appeared to have serious adverse outcomes. While the primary outcome measures of that study were still promising in the aid of deadly symptoms in test subjects. 

Throughout the research including RAD 140, 17 of the 22 participants (77.3%) encountered undesirable effects (TEAEs) believed to be associated with the administration of RAD 140. Of these individuals, 7 (31.8%) faced significant (Grade 3) negative consequences.

It is hard to compare the two in terms of a profile in risk/reward ratios considering the difference in the reasoning behind the administration and the difference between the diseases. However, data suggests that Ostarine was more effective in promoting lean body mass and overall, the primary outcome designed for its study. 

Even though RAD 140 only went through a phase l study, each study and its investigators concluded that both of these compounds showed what was to be considered a convincing profile of safety compared to the standardized protocols of these subjects.