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A Potential New Therapy for Cancer-Related Weight Loss

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A Potential New Therapy for Cancer-Related Weight Loss

March 24th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/03/24/a- ... ight-loss/

There is a common problem in cancer patients, particularly in those with lung cancer, of anorexia-cachexia syndrome (ACS), which is a spiral of poor appetite and loss lean body mass. This is associated with weakness and worse quality of life in patients, as well as shortened survival. It’s not clear, however, how much it is a cause of worsening outcome or whether it is more of a symptom of generalized decline in patients who are doing worse because of progression of their underlying cancer.

A new agent known as GTx-024 (or variably Ostarine™ or enobosarm) works as a selective androgen receptor modulator (SARM). As the name suggests, this class of agents activates the androgen receptor, which then causes the initiation of transcription of a wide range of genes in the cell. The activation of these genes ultimately leads to increased muscle mass, increased bone mass, and often an increase in mood, energy level, sense of well being, and libido. The potential negative effects of this class include primarily increased hair growth/virilization in women, prostate stimulation in men, elevated red blood cell counts (potentially to levels above normal), a drop in HDL cholesterol (the “good cholesterol” associated with exercise and decreased risk of cardiac events), and possibly abnormalities in liver function tests.

Early research with GTx-024 enrolled patients with cancer-associated weight loss, and these phase I and II trials have rather consistently shown that after 16 weeks, recipients of daily oral GTx-024 is associated with a modest (about 1-2 kg) increase in lean body mass, while recipients of placebo had no change or a trend toward slight further weight loss. Studies with GTx-)24 have also evaluated physical function using a stair climb test, measuring the time a patient needs to climb stairs, as well as “power”. These tests follow a similar pattern as the findings with body mass; specifically, you see a modest but statistically significant improvement in stair climb function for those patients who take GTx-024, while those who receive placebo show no change or a mild worsening over time. The investigators enrolled patients with many types of cancer but concentrated in particular on a subset with NSCLC. You can see results from the NSCLC subset of the largest trial here:

(Click link above to view image)

Additional work also shows that patients who did better functionally, as defined by the stair climb test, also tended to show the best results in terms of quality of life (QoL) using an “anorexia-cachexia scale” (this QoL scale used questions were specifically related to eating and weight issues, not more global QoL). But more importantly, a subset analysis also suggests that while placebo recipients had a worse survival associated with weight loss, this wasn’t the case for the recipients of GTx-024. However, this very preliminary work certainly needs to be validated in larger studies.

At this point, the company developing GTx-024 (GTx) is running two global clinical studies for patients with NSCLC, who will be randomly assign to receive GTx-024 or placebo, as they concurrently receive standard chemotherapy with either a combination of a platinum with a taxane chemotherapy, such as Taxol (paclitaxel) or Taxotere (docetaxel) in the “POWER-1” trial, or a platinum with a non-taxane chemo in the “POWER-2” trial:

(Click link above to view image)

These trials are designed to assess the primary endpoints of lean body mass and physical function, comparing results at the time of study entry with the findings after 84 days (approximately 3 months).

My own personal perspective is that I have been somewhat wary about a new, potentially (probably) expensive supportive care medication that may or may not actually demonstrate“clinically significant” improvements for patients, which isn’t the same as demonstrating statistically significant improvements on a test custom-selected to make a novel therapy look favorable. If it ends up costing patients a few hundred dollars per month in a co-payment, I’m not sure it’s meaningfully valuable for a less than 5 pound (2 kg) weight gain and ability to go up a flight of stairs 10-20% faster after 3 months. That is a very individual judgement. However, it’s possible that these studies and growing clinical experience with GTx-024, and potentially other SARMS over time, will lead to a very real, clinically important benefit in weight gain, patient quality of life, and daily function. In the best of all worlds, a drug like GTx-024 might even be able to improve a patient’s status enough that it enables them to better tolerate anti-cancer therapy and, ideally, even live longer after starting it. If that’s the case, d I’ll definitely be convinced of the value.

The early work offers hope that it may be a valuable supportive medication for lung cancer patients and likely also others with advanced cancers, so I’ll be eagerly following the development of GTx-024 and potentially other similar supportive care agents that might improve patient QoL, function, and perhaps even survival with other anti-cancer treatments.

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