Pfizer agrees to produce drug alternative to HRT

Pfizer​ is developing the drug that relieves hot flushes by targeting the mechanism covered by a patent issued to the University of Rochester in 2001. Under the terms of the nonexclusive license, Pfizer's investment includes paying the University an initial fee. In addition, two clinical milestone payments are to be made if the drug clears the development process.

The development of a non-hormonal drug to treat the symptoms of menopause received little attention until widely publicized studies appeared to alter the HRT risk benefit ratio. One of those hardest hit was US pharmaceutical company Wyeth and its combination hormone replacement therapy, Prempro (oestrogen/progestin), was linked to breast cancer and cardiovascular disease with the product.

Following reports of this study along with others, doctors shortened the length of time patients where treated with HRT. Millions of women also stopped taking the drug completely.

There are currently about 42 million women in the US who are over 50, the average age at which menopause begins. About three-quarters of menopausal women experience hot flashes. In 2002, before data from the new study were reported, sales of hormone replacement drugs topped $3 billion (€2.36 billion) and Wyeth's hormone replacement drug Premarin was the third-highest selling drug in the U.S.

The patent claims that treatment of hot flushes using a non-hormonal approach may be equally effective, citing a specific mode of pharmacological action to treat hot flashes.

Claudia Stewart, senior manager of Biomedical Licensing at University of Rochester told DrugResearcher.com​: "Pfizer intends to develop an analog of gabapentin for hot flashes. It will be a drug that binds specifically to the alpha-2-delta subunit of voltage gated calcium channels."​

"Gabapentin itself is an amino-acid type compound, as are its analogs, which is related to GABA, gamma-amino butyric acid, but functions differently."​

The compound binds to the subunit of a voltage-gated calcium channel in the hypothalamus, the region of the brain that regulates body temperature. Hypothalamic calcium channel activity has been implicated as a mediator of temperature regulation.

The research, which was lead by Dr.Thomas Guttuso at the University of Rochester's School of Medicine and Dentistry, also confirmed the compound's viability as an anti-pyretic agent (for treating fever) or as an anti-emetic agent (for treating nausea and emesis).

Stewart said that the University had already completed a separate license with another company for a method of use of gabapentin for the treatment of hot flashes.

The fallout from the controversy surrounding Wyeth's HRT drug threatened to place the entire class of drug as a health hazard. Numerous studies that continue to cite HRT as a potential cause of cancer and heart disease do nothing to calm the debate.

The 2002 study, by the Women's Health Initiative found that combination HRT with Prempro increased the risk of cardiovascular disease and also the risk of breast cancer by 26 per cent in comparison to a placebo.

The results indicated stroke incidences increased by 41 per cent in the Prempro group. Myocardial infarctions increased by twenty nine per cent. Although the therapy appeared to reduce hip and other fractures and lowered the chances of developing colon cancer, the risks far outweighed the benefits.

The results of this pivotal study threatened to derail Wyeth's $1 billion-plus sister drug Premarin. However, there has never been conclusive evidence that Premarin increased the risk of breast cancer in women following this course of therapy.

The prospect of non-hormonal drugs that effectively treat the symptoms of menopause has increased considerably ever since the claim was made that HRT could be hazardous to your health.

Currently, two known compounds, gabapentin and pregabalin, can be effectively administered as a treatment for hot flushes. These compound's pharmaceutical mode of action are similar acting on the specific subunit of the voltage gated calcium channel (VGCC). Moreover, because gabapentin is well tolerated, its use according is not believed to raise any new health concerns.

Gabapentin is a gamma.-aminobutyric acid (GABA) analog which has also been used previously in the treatment of epilepsy, neurogenic pain, restless legs syndrome, essential tremor, bipolar disorder, and migraine.

Pregabalin, another GABA analog, which is normally used as an anticonvulsant, has been explored on the specific subunit of the calcium channel. Pregabalin has been shown to possess even higher binding affinity for the subunit of VGCC than gabapentin.

Pfizer's pregabalin, its follow up to its anticonvulsant drug Neurontin, which patent is due for expiration. It is a 3-substituted analog of gamma-amino butyric acid (GABA). Its mechanisms of action, binding to the calcium channels, modulating calcium influx has resulted in analgesic, anxiolytic, and anticonvulsant activity.

Studies have shown two key differences between the drugs. Pregabalin provides equivalent efficacy at lower doses, and because of this, pregabalin is unlikely to be associated with dose-related adverse events, such as fatigue.

While not specifically designed to treat menopausal symptoms, market researchers, Datamonitor, expects off-label prescriptions of pregabalin to be a profitable source of sales, as has been the case with Neurontin. However, this is a risky strategy and Pfizer must consider several key issues surrounding off-label usage to avoid negative publicity.

Stewart commented: "With regard to market penetration, we think that a nonhormonal drug for hot flashes will be very successful. We estimate that within 5 years, $1 billion of the retail market could be captured by a drug with existing approvals for other indications."​