GlaxoSmithKline has announced that it is halting all further development of its proprietary formulation of resveratrol known as SRT501.

A key factor in this decision, according to the company, was that it no longer feels the drug offers an adequate efficacy / safety trade-off as a potential treatment for multiple myeloma.

Earlier this year, Glaxo suspended its Phase 2 trial of SRT501 ^[1] in multiple myeloma because several patients in the trial developed kidney failure.

At the time, it was unclear if the kidney failure cases were due to SRT501, or if they were a natural consequence of the patients’ multiple myeloma. The form of kidney failure that was observed – cast nephropathy – is a common complication of multiple myeloma, so much so that it is often described as “myeloma kidney.”

According to a GlaxoSmithKline spokesperson, an internal analysis of the kidney failure cases has concluded that they “most likely were due to the underlying disease … However, the formulation of SRT501 was not well tolerated, and side effects of nausea / vomiting / diarrhea may have indirectly led to dehydration, which exacerbated the development of the acute [kidney] failure.”

For this reason, the company decided to terminate the Phase 2 trial of SRT501 in multiple myeloma and halt development of the drug as a potential myeloma treatment. The SRT501 formulation of resveratrol “may only offer minimal efficacy,” explained the Glaxo spokesperson, while increasing the chances of kidney failure.

It is currently uncertain why GlaxoSmithKline decided to terminate all further development of SRT501.  The company could have ended trials of the drug as a possible myeloma treatment, but continued to test the drug in trials for other diseases.  [See Update #2 below.]

The resveratrol in SRT501 is from a plant-based source. It is micronized, or milled into very small uniform particles, to maximize uptake into the body. Patients in the SRT501 multiple myeloma trial received a relatively high dose of resveratrol – 5 grams of SRT501 – once per day.

Resveratrol is a molecule found in small quantities in the skin of red grapes and in red wine. It is thought to be the source of red wine’s reported health benefits.

Previous studies have indicated that resveratrol may be effective at killing cancer cells, including multiple myeloma cells ^[2].

Scientific evidence for these claims has been controversial and confined mostly to the laboratory. The SRT501 trial was the first attempt to determine the effectiveness of resveratrol in treating multiple myeloma patients.

Update #1 (November 30, 2010; 4:10 pm) -  The full text of GlaxoSmithKline's statement to The Myeloma Beacon regarding its decision to halt further development of SRT501 is as follows:

GSK will terminate its phase IIa study of SRT501 in advanced multiple myeloma. We have taken this decision following a comprehensive analysis of the data which suggested this formulation of resveratrol may only offer minimal efficacy while having a potential to indirectly exacerbate a renal complication  common in this patient population.

This same analysis also reviewed the cases of acute renal failure in five study patients, which had triggered the suspension of new patient enrolment in April this year. This analysis concluded that these renal failure cases were most likely due to the underlying disease, as kidney complications related to myeloma occur in up to 50% of cases. However, the formulation of SRT501 was not well tolerated, and side effects of nausea / vomiting / diarrhea may have indirectly led to dehydration, which exacerbated the development of the acute renal failure.

Investigators and regulators in the UK and Denmark, where the study was being conducted, were consulted on the analysis of the data and unanimously supported the decision to terminate the trial at this time.  There are no further plans to develop SRT501.

Update #2 (November 30, 2010; 5:30 pm) - In a separate statement to The Myeloma Beacon, a Glaxo spokesperson explained the rationale for the company's decision to halt all development of SRT501.  Ending all work on SRT501, the spokesperson said, will allow Glaxo to focus its resources on the development of drugs that act similarly to SRT501, but have more favorable properties.  The spokesperson mentioned, in particular, SRT2104 and SRT2379 as drugs similar to SRT501 that the company is developing. Neither of these drugs, however, is currently being tested as a potential treatment for multiple myeloma.

The full Glaxo statement to the Beacon on this matter was as follows: "We are focusing our efforts now on more selective SIRT1 activator compounds that have no chemical relationship to SRT501 and more favorable drug-like properties.  Currently we have two of these latest generation compounds (SRT2104 and SRT2379) in several exploratory clinical trials."