Replies to post #71963 on Biotech Values

[jbog]

GXTI Notes:


London, 22 January 2009
Doc. Ref. EMEA/23282/2009

Questions and answers on the addition of contraindications for Fareston (toremifene)

As part of its continuous monitoring of medicines, the European Medicines Agency (EMEA) has reviewed the available information on the safety of Fareston (toremifene), in particular the medicine’s effects on the heart. The EMEA’s Committee for Medicinal Products for Human Use (CHMP) has concluded that Fareston’s benefits continue to outweigh its risks. However, it recommended that patients at risk of disruptions to the electrical activity of the heart should not be prescribed Fareston.

What is Fareston?

Fareston is a medicine that is used to treat hormone-dependent metastatic breast cancer in women who have been through the menopause. ‘Metastatic’ means that the cancer has spread to other parts of the body, and ‘hormone dependent’ means that it grows in response to the hormone oestrogen. The active substance in Fareston, toremifene, works by blocking the effects of oestrogen, reducing the growth of the cancer.

Fareston has been authorised in the European Union since February 1996, and is marketed in 18 Member States.

What is the issue with the safety of Fareston?

The CHMP reviewed the safety information for Fareston because of concerns over its effects on the heart. In particular, the Committee was concerned that Fareston could cause the ‘QT interval’ (part of the heartbeat) to last for longer than normal. This side effect, called ‘QT prolongation’, is known to be linked to fainting and disruption of the heart rhythm.

The Committee reviewed a study of 250 men who were given Fareston at one of three doses, moxifloxacin (a medicine that is known to cause QT prolongation) or placebo (a dummy treatment).

The patients who took Fareston were shown to have prolongations in the QT interval, which were similar to those in patients taking moxifloxacin. The effect of Fareston on the heart was greater with higher doses of Fareston.

Although the study was carried out in men, the results were also considered to be important for women, particularly because women tend to have longer QT intervals than men and may be more susceptible to this side effect when they take Fareston.

The Committee completed its review at its meeting of 19-22 January 2009.

What are the conclusions of the CHMP?

The CHMP concluded that Fareston’s benefits continue to outweigh its risks for the treatment of hormone-dependent metastatic breast cancer in postmenopausal women. However, it recommended a change to the Product Information to include a contraindication to the use of Fareston in patients at risk of having prolonged QT intervals.

The Committee recommended that Fareston must not be used in patients who already have prolonged QT intervals or in combination with other medicines that can cause QT prolongation. It also recommended that it must not be used in patients who are at risk of disruptions of the heart rhythm, including patients with the following conditions:

•altered levels of salts in the blood, especially low potassium levels;

•a very slow heart rate;

*an inability of the heart to pump enough blood to the rest of the body;

•a history of abnormal heart rhythm.


What is the advice to patients and prescribers?

•Doctors should prescribe Fareston according to the updated Product Information.

•Patients who are taking Fareston and have any questions or concerns should talk to their doctor or pharmacist.

The CHMP opinion will now be sent to the European Commission for the adoption of a formal decision, applicable in all EU countries.

For further information, see the updated Product Information adopted by the CHMP on 22 January 2009.

[poorgradstudent]

GTXI:

Doesn't look good, and I don't really have a decent explanation.

I'm unsure what to do with GTXI right now. What I had was profits left in the stock, so I may take the money and run. I had doubts as to how well they could sell toremifene even with an expanded label, so this definitely compounds those doubts and reduces the incentive to see how the PIN results come up.

[Biowatch]

GTXI PhIII bone fracture; toremifene for ADT prostate cancer

This PR seems to emphasize that placebo patients can get bone fractures, rather than toremifene "demonstrated statistically significant reductions compared to placebo in new morphometric vertebral fractures (the primary endpoint)..."
Were the results not as good as they wanted, or is the placebo data the most important result?


>>First Ever Prospective Fracture Study in Prostate Cancer Patients on ADT Reveals These Men Are at High Risk for Skeletal Fractures

Data from GTx’s Phase III clinical trial evaluating toremifene 80 mg for the prevention of fractures in men with prostate cancer on androgen deprivation therapy presented at 2009 Annual Meeting of the American Urological Association

* On Monday April 27, 2009, 7:00 am EDT

CHICAGO--(BUSINESS WIRE)--GTx, Inc. (Nasdaq: GTXI - News) announced today that in a recent Phase III clinical trial of advanced prostate cancer patients being treated with androgen deprivation therapy (ADT), nearly one in four placebo group subjects developed bone fractures or critical bone loss (>7% loss) within two years. This analysis of placebo group data from the Phase III clinical trial evaluating toremifene 80 mg for the prevention of bone fractures in men with prostate cancer on ADT was presented yesterday in an oral presentation at the 2009 Annual Meeting of the American Urological Association in Chicago.

An analysis of placebo group subjects from the clinical trial demonstrates the risk of fracture for men with prostate cancer on ADT. During the two year trial, 9.9% of these men had a nontraumatic fracture (morphometric vertebral fracture or clinical fragility fracture), and nearly one in four, 23.9%, experienced either a nontraumatic fracture or greater than 7% bone loss, a predetermined level of bone loss at which men were considered to be at high risk for fracture and were removed from the study for safety reasons. These data are from the modified intent to treat population: subjects who had a minimum of one dose of study drug or placebo and at least one on study radiograph, n=970.

“The toremifene 80 mg Phase III clinical trial is the first large prospective study evaluating fractures in men with prostate cancer on ADT. The data from this clinical trial underscore that men on ADT are indeed at high risk for skeletal fractures,” said Daniel Lin, MD, Associate Professor and Chief of Urologic Oncology, Department of Urology, University of Washington School of Medicine, and a Principal Investigator in the study. “ADT is an important treatment for men with prostate cancer. However, ADT itself over time can cause serious, life threatening side effects, such as fractures. As urologists who use ADT, it is our responsibility to monitor and to treat bone loss in our patients to reduce this high risk of fracture.”

About the Study

The two year, double-blind, placebo-controlled, randomized study of 1,389 ADT patients, was conducted at approximately 150 clinical sites in the United States and Mexico. The primary endpoint was new morphometric vertebral fractures measured by dual X-ray absorptiometry (DEXA). Key secondary endpoints included bone mineral density, lipid changes, hot flashes, and gynecomastia.

In the study, toremifene 80 mg treatment demonstrated statistically significant reductions compared to placebo in new morphometric vertebral fractures (the primary endpoint), in all nontraumatic fractures, and in first of either a nontraumatic fracture or greater than 7% bone loss. Toremifene 80 mg treatment compared to placebo also resulted in statistically significant increases in bone mineral density at the lumbar spine, hip, and femur; improvements in lipid profiles including a reduction in LDL, triglycerides and total cholesterol and an increase in HDL; and improvements in breast pain and tenderness.

Toremifene 80 mg was well tolerated. Among the most common adverse events that occurred in over 2 percent of study subjects were joint pain (treated 7.3 percent, placebo 11.8 percent), dizziness (treated 6.3 percent, placebo 5.0 percent), back pain (treated 5.9 percent, placebo 5.2 percent), and extremity pain (treated 5.0 percent, placebo 4.4 percent).

About ADT for Prostate Cancer

ADT, primary treatment for advanced prostate cancer, has improved survival in men with prostate cancer. Approximately 700,000 men with prostate cancer are being treated with ADT and an estimated 100,000 initiate ADT each year.

ADT is accomplished either surgically by removal of the testes, or more commonly by injection with LH releasing hormone (LHRH) agents. ADT works by reducing testosterone to castrate levels. The reduction in testosterone from ADT also results in very low estrogen levels, because estrogen is derived from testosterone in men. Estrogen deficiency side effects associated with ADT include high risk of skeletal fractures, adverse lipid changes, hot flashes, gynecomastia, depression, and memory loss.

Of patients on ADT, up to 77 percent develop significant bone loss, making them susceptible to fracture. Recent studies indicate that the annual risk of fracture in men on ADT is 5% to 8%. Fractures are serious and can reduce survival in men on ADT by more than three years.

About GTx

GTx, Inc., headquartered in Memphis, Tenn., is a biopharmaceutical company dedicated to the discovery, development, and commercialization of small molecules that selectively target hormone pathways to treat cancer, osteoporosis and bone loss, muscle wasting and other serious medical conditions. GTx is developing toremifene citrate, a selective estrogen receptor modulator, or SERM, in two separate clinical programs in men: first, a completed pivotal Phase III clinical trial evaluating toremifene 80 mg for the treatment of serious side effects of androgen deprivation therapy for advanced prostate cancer, and second, an ongoing pivotal Phase III clinical trial evaluating toremifene 20 mg for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. In 2006, GTx and Ipsen Group entered into a development and collaboration agreement for toremifene in all indications except breast cancer for Europe and the Commonwealth of Independent States (CIS). GTx has made application for marketing approval and, if approved, plans to commercialize toremifene 80 mg in the United States. In December 2007, GTx and Merck & Co., Inc. formed a collaboration to discover and develop selective androgen receptor modulators, or SARMs, a new class of drugs with the potential to treat sarcopenia, which is the loss of skeletal muscle mass resulting in reduced physical strength and ability to perform activities of daily living, as well as cancer cachexia (cancer induced muscle loss) and other musculoskeletal wasting conditions. Merck and GTx are evaluating multiple SARM product candidates, including Ostarine™ (designated by Merck as MK-2866) and MK-0773 for sarcopenia in several Phase I and II clinical trials. Merck and GTx are planning additional clinical trials for Ostarine™ for the treatment of cancer cachexia and are evaluating additional muscle wasting indications for SARMs development. GTx also is conducting a Phase I clinical trial evaluating GTx-758, an oral luteinizing hormone inhibitor, for advanced prostate cancer.
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