Recently Approved and Future Testosterone Related Products

Nelson Vergel, author of “Testosterone: A Man’s Guide” discusses several recently approved and future testosterone-related products:

Underarm Spray:

In an attempt to reduce the risk of transference of testosterone to others, a company called Acrux  developed Axiron, a testosterone underarm product.  Axiron has been studied in 155 men in six countries and 26 sites. The product got approved last November (https://investor.lilly.com/releasedetail2.cfm?ReleaseID=532924 )

With this product men were permitted to use an underarm deodorant or antiperspirant during the trial. More than half of the men continued to apply an underarm deodorant or antiperspirant as part of their daily routine.  An analysis of these subgroups showed that this had no impact on the efficacy of Axiron treatment.

Two percent gel:

The same company that is hoping to launch Aveed (Nebido) in the United States, Endo Pharmaceuticals, recently got FDA approval for Fortesta (TM) (testosterone) 2% Gel for men diagnosed with low testosterone.  (http://www.fortestagel.com/ )

Aveed (Nebido outside the United States)

There is a new long-acting product being reviewed by the FDA in the United States called Aveed (Nebido is the brand name worldwide) that contains testosterone undecanoate, which is injected at a dose of 1,000 mg in Europe (the FDA may not allow that large of a dose in one injection, though) and which produces sustained total testosterone levels above 400 nanograms/dl in four to five months.

This testosterone ester may stay longer in your system so that less frequent injections may be needed. The injection is usually given once every 10 to 14 weeks, though the frequency will depend on your individual testosterone levels. After your first injection you may be asked to come back for another injection at week six. The company claims that only five injections a year are needed.

In an open-label study which enrolled 130 hypogonadal men with blood total testosterone levels below 300 ng/dL at study entry, Aveed was dosed as an intramuscular injection (750 mg) at baseline, at week four, and then every 10 weeks throughout the remainder of the 21-month study. Approximately 70 percent of patients completed all injections and 94 percent of them had total testosterone from 300 to 1,000 nanograms/ml through the entire study.

After  Nebido was approved in Europe a small number of European patients experienced respiratory symptoms immediately following an intramuscular injection of 1000 mg in a  4 cc injection volume, (versus the 750 mg, 3 cc injection volume used in the United States). The makers of Nebido believe, and the FDA concurs, that the reaction is likely the result of a small amount of the oily solution immediately entering the vascular system from the injection site.  This known yet uncommon complication of oil-based depot injections may be related to inappropriate injection technique or site.

The problem is characterized by short-term reactions involving an urge to cough or a shortness of breath. In some rare cases the reaction had been classified as serious or the patient had experienced other symptoms such as dizziness, flushing or fainting. In U.S. clinical trials of Nebido 750 mg (3 cc injection volume), the proposed dose in the U.S., there was a single, mild, non-serious case of oil-based coughing.

The U.S. manufacturer, Endo Pharmaceuticals, is gathering data to address concerns about the respiratory symptoms. It is not known how much longer it will take the get this product approved in the United States as of June 2010. And even if it gets approved, it may not be widely available for people to buy through private health insurance if the company decides to price it as high as gels.

Libigel (testosterone gel for women)

Results of Phase II

Treatment with LibiGel in BioSante’s Phase II clinical trial significantly increased satisfying sexual events in surgically menopausal women suffering from female sexual dysfunction (FSD). The Phase II trial results showed LibiGel significantly increased the number of satisfying sexual events by 238% versus baseline (p<0.0001); this increase also was significant versus placebo (p<0.05). In this study the effective dose of LibiGel produced testosterone blood levels within the normal range for pre-menopausal women and had a safety profile similar to that observed in the placebo group. In addition, no serious adverse events and no discontinuations due to adverse events occurred in any subject receiving LibiGel. The Phase II clinical trial was a double-blind, placebo-controlled trial, conducted in the United States.

Progress and Plans in Phase III

On January 24, 2008, the US FDA notified BioSante that it had completed and reached agreement with BioSante on a Special Protocol Assessment (SPA) for BioSante’s Phase III safety and efficacy clinical trials of LibiGel in the treatment of hypoactive sexual desire syndrome (HSDD).

Both Phase III safety and efficacy trials are underway and are double-blind, placebo-controlled trials that will enroll approximately 500 surgically menopausal women each for six-months of treatment.

The last issue beyond efficacy has been the question of safety of testosterone therapy in women, even though there are no data to indicate that low dose testosterone causes any serious adverse events in women. Therefore, in addition to the two Phase III safety and efficacy trials described above, BioSante is conducting one Phase III cardiovascular safety study of LibiGel. The safety study is a randomized, double-blind, placebo-controlled, multi-center, cardiovascular events driven study of between 2,400 and 3,100 women exposed to LibiGel or placebo for 12 months. At the end of 12 months BioSante intends to submit a LibiGel new drug application (NDA) for review and possible approval by FDA. BioSante will continue to follow the women enrolled in the safety study for an additional four years after the NDA submission and possible approval of LibiGel.

BioSante already fully enrolled the women in this multi-national cardiovascular-events-driven safety trial. Therefore, BioSante expects to be able to submit the LibiGel NDA for a potential approval and launch in 2011.( http://www.biosantepharma.com/LibiGel.php )

Androxal® (isomer of clomiphene or Clomid) for men
A company called Repros in Houston is attempting to get eventual approval of their clomiphene isomer Androxal . They completed a small Phase 2b proof-of-concept trial in men being treated for low testosterone levels who want to improve or maintain their fertility and/or sperm number and function.

While it remains to be seen if this clomiphene isomer has any effect on sexual function as a sole therapy without testosterone replacement remains to be seen.  I personally have my reservations about this claim.

Selective Androgen Receptor Modulators

Oral selective androgen receptor modulators (SARMs) are investigational agents.  Studied since 1998, they are still very much in the infancy of their development and marketing. SARMs may be able to provide the benefits of increased muscle mass and bone density, and fat loss that testosterone and other traditional anabolic/androgenic steroids provide but without the unwanted side effects (liver dysfunction or prostatic enlargement). SARMs are not intended to be a form of testosterone replacement therapy. I know, I know – so why am I talking about them? Besides replacement therapy, testosterone and other anabolics can be useful in the treatment of certain aspects of disease.  This is a topic close to my heart since this kind of medical use saved my life and that of many others.  Excuse me while I digress from the current topic.

Weight loss is common in a number of medical conditions (e.g., HIV/AIDS, burns, trauma, cancer, chronic obstructive pulmonary disease).   The loss of too much weight, especially muscle mass, increases the risk of complications, including death.

Cancer cachexia, or the unintentional loss of muscle mass and body weight, may lead to a loss of protein stores, severe weakness and fatigue, immobility and a loss of independence.  It can impair the ability to tolerate and to respond to cancer treatments. An estimated 1.3 million cancer patients in the United States have cancer cachexia. Cancer-induced muscle wasting is thought to be responsible for greater than 20 percent of cancer deaths.

There are no drugs currently approved for the treatment of cancer cachexia.. Physicians often prescribe different medications that have the side of effect of increased appetite in an attempt to fight weight loss. Megace, a progesterone-based appetite stimulant, is commonly used to increase weight. Unfortunately most of this weight consists of fat (lean body mass, not fat gain, has been correlated to increased survival.) Megace also increases the chances for blood clots and bone death.

Anabolics like nandrolone undecanoate and oxandrolone have been prescribed by progressive physicians to treat wasting in patients with non-androgen dependent cancers (colon, throat, lung, stomach, etc.). Androgens are contraindicated for people with prostate and breast can­cer, as they can worsen these types of cancers. Anabolics are usually prescribed along with testosterone replacement even if the patient starting them for wasting syndrome has normal testosterone levels. Anabolics have the same inhibiting effect as testosterone on the HPGA and they decrease testosterone blood levels if no testosterone is used in combination with them. Many doctors fail to remember this and treat wasting patients with anabolics alone, which results in loss of sexual function in patients using them for a few weeks. So, testosterone replacement therapy is essential when prescribing oxandrolone or nandrolone to patients with HIV, cancer, or other debilitating wasting conditions.

Oxandrolone (brand name: Oxandrin), an oral anabolic agent, is FDA approved as “adjunctive therapy to promote weight gain after weight loss following extensive surgery, chronic infections, or severe trauma, and in some patients who without definite pathophysiologic reasons fail to gain or to maintain normal weight, to offset the protein catabolism associated with prolonged administration of corticosteroids, and for the relief of bone pain frequently accompanying osteoporosis.” (From the product’s package insert). Adjunctive means it is an additive or supportive therapy but it does not treat the underlying condition directly. In some patients and depending on the dose and duration, oxandrolone can increase liver enzymes and/or decrease high density cholesterol (HDL), the good cholesterol. Both side effects reverse when the drug is stopped. The usual dose for men is 20 mg/day (it can be used in women with wasting at 5-10 mg/day). As previously mentioned, testosterone is needed with it since it reduces testosterone and potentially sexual function after a few weeks in some patients. It is expensive at $1200 per month for 20 mg/day but insurance companies pay for it with some restrictions.

Nandrolone decanoate (brand name: Deca Durabolin), an injectable anabolic steroid, is the most studied anabolic agent for wasting syndrome. It requires a weekly injection of 200-400 mg plus testosterone replacement (100-200 mg testosterone cypionate a week or 5-10 grams of testosterone gel per day). Nandrolone is legally prescribed in an off-label manner to treat wasting syndrome since it is indicated for the management of the anemia of renal insufficiency and has been shown to increase hemoglobin and red cell mass. No liver toxicity has been observed, but decreases in HDL and other side effects typical of testosterone have been observed in those using higher doses.   Nandrolone is no longer available in regular pharmacies but it is available cheaply in compounding pharmacies by prescription (there is a list in the Appendix section). The average cost for 200 mg/week is $40 per month and it may produce the same effects on lean body mass than oxandrolone at 20/day.

The only drug that is actually approved in the United States for HIV wasting syndrome that does not require an off label prescription is Serostim (human growth hormone made by Serono), although doctors prescribe oxandrolone and nandrolone a lot more  due to cost and lower side effects. Depending on the dose used, Serostim can cost $3000 to $6000 per month.  This product can cause joint aches, water retention, and diabetes.  More details on treatment of wasting syndrome can be found in “Built to Survive” which I co-authored with Michael Mooney (the book is available on Amazon.com in a print or electronic version and has been translated into Spanish).

So back to the SARMs:

Ostarine is an oral agent that has demonstrated the ability to increase lean body mass and improve muscle strength and performance in postmenopausal women, elderly men, and men and women with cancer cachexia. Ostarine is made by the company GTx’s and has been studied in seven Phase I, Phase II, and Phase IIb clinical trials in 582 subjects.

It had no serious adverse events reported. Ostarine also exhibited no apparent change in measurements of serum prostatic specific antigen (PSA), sebum production (which causes acne), or decreases in blood levels of LH (which hints that it may not affect the HPGA at the doses tested).

SARMs have anecdotally not helped increase sexual function, so they probably will not replace testosterone for treatment of hypogonadism. They also decrease the body’s production of testosterone, just like anabolic steroids do.  So, testosterone replacement will most probably be still required with their use for illness or aging associated loss of lean body mass.  We await more data on these interesting compounds as they may have the same clinical benefits as anabolic steroids without the stigma and possibly without their side effects.