Ligand Pharmaceuticals Inc. (Public, NASDAQ:LGND)

[Michael Scally MD]

Ligand Pharmaceuticals Inc. (Public, NASDAQ:LGND) http://www.ligand.com/home
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Ligand is a BioPharma company with a business model that is based upon the concept of developing or acquiring royalty revenue generating assets and coupling them to an efficiently lean corporate cost structure. Ligand's goal is to produce a bottom line that supports a sustainably profitable business. By diversifying the portfolio of assets across numerous technology types, therapeutic areas, drug targets, and industry partners, we offer investors a de-risked opportunity to invest in the increasingly complicated and unpredictable pharmaceutical industry. We believe Ligand has assembled one of the largest and most diversified portfolio of current assets in the industry for a company of its size, currently exceeding 60 programs, with the potential to generate revenue in the future. These therapies address the unmet medical needs of patients for a broad spectrum of diseases including hepatitis, muscle wasting, Alzheimer's disease, dyslipidemia, diabetes, anemia, COPD, asthma, rheumatoid arthritis, osteoporosis and cancer. Ligand has established multiple alliances with the world's leading pharmaceutical companies including GlaxoSmithKline, Merck, Pfizer, Bristol-Myers Squibb and AstraZeneca.


SARM
http://www.ligand.com/research#SARM

Medical Need: To produce the therapeutic benefits of testosterone on muscle and bone with improved safety, tolerability and patient acceptance.

Primary Medical Targets: The clinical applications for SARMs include the treatment of aging-associated sarcopenia, cancer cachexia, osteoporosis, and male hypogonadism.

Description - Selective androgen receptor modulators (SARMs) are novel drugs that selectively modulate the activity of the androgen receptor in different tissues. Ligand is developing LGD-4033, a non-steroidal, orally active SARM currently in a Phase I multiple ascending dose study.

 

[Michael Scally MD]

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: Biological Sciences and Medical Sciences. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men

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.

 

[Michael Scally MD]

Gain 1.5 kg lean body mass with three-week course of LGD-4033
Gain 1.5 kg lean body mass with three-week course of LGD-4033

Significantly, this graph shows it took ~35 days for testosterone to return to normal after a 21 day SARM administration. I am unable to tell from the abstract or ergo-log about the LBM change in this time, but, IMO, more than likley ALL of the LBM gain was LOST. [If anyone has access to the full-text (pdf), please let me know.]

 

[Michael Scally MD]

(A) The effects of LGD-4033 selective androgen receptor modulator on serum total testosterone levels. Change from baseline in serum total testosterone levels are shown. The data are mean ± standard error of the mean (SEM), n = 33 in the placebo group, 18 in the 0.1-mg dose, 11 in the 0.3-mg group, and 14 in the 1.0-mg group. BL = baseline. The shaded area highlights the 21-day treatment period.

(B) Change in the free testosterone levels from baseline. Change from baseline in serum free testosterone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1-mg dose, 11 in the 0.3-mg group, and 14 in the 1.0-mg group. BL = baseline. The shaded area highlights the 21-day treatment period.

(C) Change in sex hormone–binding globulin levels from baseline. Change from baseline in serum sex hormone–binding globulin levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1-mg dose, 11 in the 0.3-mg group, and 14 in the 1.0-mg group. BL = baseline. The shaded area highlights the 21-day treatment period.

(D) Change in luteinizing hormone (U/L) levels from baseline. Change from baseline in serum luteinizing hormone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1-mg dose, 11 in the 0.3-mg group, and 14 in the 1.0-mg group. BL = baseline. The shaded area highlights the 21-day treatment period.

(E) Change in follicle-stimulating hormone (U/L) levels from baseline. Change from baseline in serum follicle-stimulating hormone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1-mg dose, 11 in the 0.3-mg group, and 14 in the 1.0-mg group. BL = baseline. The shaded area highlights the 21-day treatment period.

(F) Change in prostate-specific antigen (ng/mL) levels from baseline. Change from baseline in prostate-specific antigen levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1-mg dose, 11 in the 0.3-mg group, and 14 in the 1.0-mg group. BL = baseline. The shaded area highlights the 21-day treatment period.


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: Biological Sciences and Medical Sciences. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men