Last month, I attended two days of hearings at the FDA campus in White Oak, MD. The first day concerned two neuroscience molecules, gabapentin and paroxetine, both being evaluated for the treatment of menopausal vasomotor symptoms.
Gabapentin was originally developed as an anti-seizure medication, and is also approved to treat post herpetic neuralgia, a profound distressing complication of shingles herpes zoster infection. A company here in the Bay Area has formulated gabapentin in a unique slow release delivery system, and has been seeking to expand the indications for this formulation to include the treatment of menopause related vasomotor symptoms.
The back story on gabapentin and vasomotor symptoms is interesting. Since the publication of the Women’s Health Initiative (WHI), which demonstrated that menopausal estrogen/progestin use may increase the risk of breast cancer, and does not, counter to a developing zeitgeist at the time, provide cardio-protective benefits. Between 2002 and 2012, menopausal hormone use in the USA dropped almost 80%. Women have been desperate for alternatives.
Various OTC products glittered and shined, only to lose their sheen when they failed to provide any significant measure of relief. Soy and black cohosh were very popular, each enjoying a figurative “15 minutes” of fame.
During this same period, menopause experts prescribed a number of neuroscience drugs off label, including venlafaxine, paroxetine, and gabapentin. The effect of gabapentin on hot flashes popped up rather serendipitously. Gabapentin was prescribed to a women with headaches, and while it had a limited effect on her migraines, coincidentally she reported a marked reduction in her hot flashes. Small randomized trials confirmed that gabapentin effected a 40-60% reduction in vasomotor symptoms.
Putting gabapentin into a time release delivery system, it was postulated, might provide sustained symptomatic relief, while minimizing the sedation and somnolence commonly seen with the drug. And while gabapentin is now off patent, in this unique delivery system, it would be a patented protected product. If approved for this indication, it would be the only approved non-hormonal option. The FDA imprimatur would confer exclusivity and special insurance status as the only non-steroidal treatment for symptoms. This special status would help to insure a good return on developing the drug.
But this is not really a new drug. It is an old drug in a new dress, and thus is compelled by FDA to carry the same black box warnings that all other brands and formulations of gabapentin carry…a warning about a potential risk of suicidal behavior and ideation. Ultimately, “suicidality” killed this drug, and the other drug, paroxetine, reviewed that same day for the same indication.
Let’s face it, no one ever died of a hot flash. I don’t mean to be flip. I don’t mean to make light of the problem. Menopausal women and cancer patients treated with anti-estrogens and anti-androgens suffer mightily from hot flashes and night sweats, but perspiration does not cause expiration. The approval of a drug for a non lethal indication allows very little tolerance for a potential lethal side effect.
Suicidality as an identified risk came to light in depression trials and post market surveillance of antidepressant drugs, and the risk may be emergent even when these drugs are used for other indications. In addition, almost 20% of adult women suffer from chronic depression, and 40% of women will suffer a depressive episode some time during their
lives. Any drug that might induce suicidal ideation or action must be prescribed with considerable
Restraint and gabapentin cannot be used in the same sentence. Use of gabapentin has been extravagant. It has been prescribed off label for a stunning array of disorders including bipolar disorder, peripheral neuropathy,
diabetic neuropathy, complex regional pain syndrome, attention deficit disorder, restless legs syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep, migraine headaches, and alcohol withdrawal syndrome. Off label use was so lucrative, so widespread, so abusive, that ultimately Warner Lambert, “a division of Pfizer Inc…. agreed to plead guilty to two felonies and pay $430 million in penalties to settle charges
that it fraudulently promoted the drug Neurontin [brand name for their version of gabapentin] for a string of unapproved uses.”
All of this may seem like much ado about nothing. But there is a larger overarching story here that relates to the turn and direction drug development has taken in recent years…a direction that has resulted cut backs in R&D, fewer research jobs, and a lack of initiative and innovation. In-house R&D at many pharmas has been cut by as much as 50%. Research efforts, energies and resources, according to Audrey Erbes, have been directed to “incremental”
rather than revolutionary projects. Companies don’t explode new targets. They aim at soft targets like the
- line extensions with new dosages
- new delivery systems for older drugs
- combinations of old drugs taken together
- new indications for old drugs
- if the current “model” is a pro-drug, develop the active molecule
- If the current drug is active, find a reason to deliver the “pro-drug” or a develop a different salt or isomer
And so it goes, lesser ambitions require lesser minds and fewer of them.
After the FDA hearings, I felt badly for friends and colleagues who worked so hard on their drug development projects. But I was not entirely disappointed that these two “antiques,” gabapentin and paroxetine, were not given new lives. Why?
Beyond the suicide concern, neither one of these two drugs was very effective, compared to hormone therapy. But more importantly, investing attention and focus on these older compounds has been a distraction, a diversion from any efforts to develop a truly novel, effective, non-hormonal approach to treatment. If you asked me which would I rather take — estrogen or a psych drug for hot flashes — my answer would be “Is there a door #3?”
Don’t get me wrong. There have been some stunning reanimations of moribund old drugs. Note the impressive resurrection is thalidomide. Originally developed as a sleep aid in the 1950s, it was also effective in treating the morning sickness of pregnancy. The drug proved to be highly teratogenic, causing several defects, most notably phocomelia, a foreshortening of the limbs. Yet it has been relaunched in recent years under strict regulations to guard against use during pregnancy, and plays an important role now in the treatment of multiple myeloma, erythema
nodosumleprosum, and HIV.
Pharma is coming around to the realization that R&D is the essence, the core of their business. And as pharma returns its focus to research, perhaps venture capital will return as well, and jobs will rebound for the life science grads, particularly in the area of personalized medicine, where diagnostics, genomics and treatments are highly tailored and targeted. More about that next time…