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10-K
GTX INC /DE/ filed this Form 10-K on 03/08/2011
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Clinical Trials. In 2009, we evaluated CapesarisTM in healthy male volunteers in two Phase I clinical trials. In a single ascending dose study in 96 subjects, CapesarisTM was well tolerated and demonstrated a pharmacokinetic profile compatible with daily oral dosing. In a ten day multiple ascending dose study in 50 subjects, CapesarisTM was well tolerated and demonstrated the ability to increase serum SHBG and to reduce serum total and free testosterone. In September 2010, we announced that in a Phase II, open label, pharmacokinetic and pharmacodynamic clinical trial in young healthy male volunteers, CapesarisTM suppressed serum total testosterone to castrate levels, increased serum SHBG, and reduced serum free testosterone, the form of testosterone which is available to prostate cancer cells for growth. Medical castration (levels of serum total testosterone less than 50ng/dL) was achieved in the 1000 mg and 1500 mg treatment groups. The percentage of treatment compliant subjects receiving 1500 mg of CapesarisTM who achieved medical castration was comparable to rates of castration observed with LHRH agonists or antagonists therapies. CapesarisTM was well tolerated and no serious adverse events were reported in the study. We met with the FDA in February 2011 and confirmed that the primary endpoint acceptable for approval for this indication is total testosterone levels (achieve and maintain serum total testosterone levels less than 50ng/dL). In the second quarter of 2011, we plan to initiate a Phase IIb open label clinical trial evaluating CapesarisTM compared to Lupron® (leuprolide acetate), a LHRH agonist for first line treatment in men with advanced prostate cancer.
Toremifene
We have evaluated toremifene 80 mg, a SERM, as a once-a-day oral tablet to reduce fractures and treat other estrogen deficiency side effects of ADT in men with prostate cancer. In January 2005, we exclusively licensed toremifene from Orion for all indications in humans, except for breast cancer outside of the United States. We licensed rights to toremifene based on toremifene’s established record of safety in the treatment of postmenopausal women with metastatic breast cancer and our belief that SERMs can treat estrogen related complications resulting from ADT. Under a license and supply agreement with Orion, Orion manufactures and supplies us with FARESTON®, the 60 mg dose of toremifene citrate, for sale in the United States to treat advanced metastatic breast cancer in postmenopausal women. Additionally, Orion has agreed to manufacture our clinical supply and, if FDA approval of toremifene 80 mg is obtained, our commercial supply of toremifene 80 mg. In March 2011, we reacquired full rights to our toremifene program following the termination by us and Ipsen of our collaboration and license agreement, which was entered into in September 2006 and amended in March 2010. In exchange for reacquiring all of Ipsen’s rights under the collaboration agreement, we agreed to pay Ipsen a low single digit royalty on net sales of toremifene 80 mg in the United States if approved for commercial sale. Pending our ongoing discussions with the FDA regarding whether an additional single Phase III clinical trial of toremifene 80 mg to address the deficiencies identified in the Complete Response Letter can be conducted as a post-approval study, we do not plan to continue any further clinical development of toremifene 80 mg. In the event that the FDA allows this clinical trial to be conducted as a post-approval study and we are able to secure sufficient funding for the study through new partnerships or collaborations or through other financing, we will reevaluate whether to continue the development of toremifene 80 mg.
In May 2010, we announced that toremifene 20 mg failed to meet the primary efficacy endpoint in a completed Phase III clinical trial evaluating toremifene 20 mg for the prevention of prostate cancer in high risk men with high grade PIN. We do not expect to conduct additional clinical trials evaluating toremifene 20 mg for the prevention of prostate cancer in high risk men with high grade PIN or to submit a NDA to the FDA for this indication.
Toremifene 80 mg to Reduce Fractures and Treat Other Estrogen Deficiency
Side Effects of ADT in Men with Prostate Cancer
Scientific Overview. ADT is the most common treatment for patients who have advanced, recurrent or metastatic prostate cancer. ADT reduces testosterone, a primary growth factor for prostate cancer, to levels similar to that of castrated men. ADT is currently accomplished either surgically by removal of the testes, or chemically by treatment with LHRH agonists or antagonists. LHRH agonists and antagonists work by shutting off LH secretion by the pituitary gland, which stops testosterone production by the testes. Examples of commercially marketed LHRH agonists are Lupron® (leuprolide acetate), Zoladex® (goserelin acetate), Eligard® (leuprolide acetate), Trelstar® (triptorelin pamoate), and Vantas® (histrelin), as well as the LHRH antagonist Firmagon® (degarelix).
In men, aromatase converts testosterone to estrogen. By reducing testosterone to castrate levels, ADT depletes up to 80% of a man’s estrogen, resulting in multiple estrogen deficiency side effects. Estrogen deficiency side effects associated with ADT include accelerated and continuous bone loss, as well as high risk of fractures, adverse lipid changes which may lead to higher risk of cardiovascular diseases, hot flashes, gynecomastia, decreased libido, depression, and memory loss. Increased risk of skeletal fractures is a significant clinical problem because clinical studies have shown that prostate cancer patients who develop skeletal fractures have 39 month shorter survival rates. Hot flashes occur because of reduced estrogen levels in the brain. Hot flashes experienced by prostate cancer patients on ADT tend to be severe, frequent and protracted and are the side effect most frequently mentioned by prostate cancer patients on ADT.

 

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