Viking Therapeutics Inc (VKTX)

[hptaxis]

VK-5211 Lean Body Mass [LBM]

LGD-4033 [VK-5211] has been shown previously to significantly increase LBM at the 1.0 mg dose, although by a whisper [0.047 Figure 3; Basari et al.]. This would seem to bode well for VK-5211, particularly since they included a higher 2.0 mg dose. However, the study was done in “Healthy Young Men” who likely had a good diet with adequate protein. This might throw a curve for the VK-5211 trial in elderly patients. Maybe, that is why they added the 2.0 mg dosing.

Also, will they include other testing. More specifically, T, E2, & HDL. I am highly doubtful, but willing to be surprised. The reason being the LBM is a way to pump the share price. The HDL effects are dose dependent and will by themselves be consequential for any approval [that will not occur]. And, E2 effects will surely show a significant decrease in levels. This would throw a huge red flag wrt BMD.

One more consideration is there is no breakdown of the hip fracture cause. I fail to see a MOA in eugonadal patients. The E2 effects might even be harmful. Expect to see some subgroup analysis for continuation at some point.

Those Hungary, Romania, & Serbia sites are a real plus!!! It would be cool if they provided individual site data.


Basaria S, Collins L, Dillon EL, et al. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men. The Journals of Gerontology: Series A. 201068(1):87-95. https://academic.oup.com/biomedgerontology/article/68/1/87/548321

Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity.

Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.

Methods. In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.

Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing.

LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only.

Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation.

Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations.


Finkelstein JS, Lee H, Leder BZ, et al. Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J Clin Invest 2016;126(3):1114-25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767351/

BACKGROUND: Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain.

METHODS: One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone.

Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men.

RESULTS: As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites.

Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men.

CONCLUSIONS: Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton.