MODE OF ACTION

Teverelix trifluoroacetate (Teverelix TFA) is a gonadotrophin-releasing hormone (GnRH) antagonist with a novel formulation. GnRH antagonists rapidly suppress the effects of sex hormones by limiting their production.1 This is therapeutically valuable for conditions that are controlled by sex hormone secretion, including prostate cancer, benign prostatic hyperplasia, and endometriosis. Recent data suggest that GnRH antagonists may have multiple therapeutic advantages over the traditionally used GnRH agonists, and therefore have the potential to supersede GnRH agonists as the gold-standard treatment.

GnRH agonists and antagonists are similar in that they both bind to the same therapeutic target, the GnRH receptor in the pituitary gland. However, they have distinct mechanisms of action.

Mode of action

Gonadotrophin-releasing hormone (GnRH) regulates the production of sex hormones. It is released from the hypothalamus in the brain, and activates GnRH receptors at the pituitary gland to stimulate release of the gonadotrophins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones stimulate the production of sex hormones (testosterone and oestrogen) in the testes or ovaries.

GnRH agonists mimic the actions of GnRH by binding to the receptor and eliciting the same response. When applied therapeutically, GnRH agonists are given at high doses which flood the system by overstimulating the GnRH receptor. This increases FSH and LH release which ultimately up-scales sex hormone production. Therefore, this leads to an initial spike of sex hormones which may exacerbate symptoms, cause unpleasant side-effects, and raise the risk of developing complications.1,2 For this reason, additional therapy may be required to control the spike of sex hormones. The GnRH receptor is slowly downregulated (desensitized) by negative feedback loops which alert the brain to the excess of sex hormones. This then reduces GnRH secretion and gradually suppresses sex hormone production.

The process can take several weeks to produce a meaningful effect. Additionally, it reduces sex hormones to a negligible level, which may not be best suited to benign indications. It is also well established that GnRH agonists increase the risk of developing diabetes and cardiovascular complications,3 although the way in which this happens is unclear.

In contrast, GnRH antagonists act by competitively blocking the GnRH receptors at the pituitary gland. This inhibits release of FSH and LH which rapidly reduces the production of sex hormones.

Gonadotrophin-releasing hormone antagonists substantially reduce sex hormone levels without first overstimulating the GnRH receptor. This means that there is no initial flare of sex hormones which reduces the risk of exacerbating symptoms and of flare-related complications,1 and does not require additional therapies.

Emerging evidence has suggested that GnRH antagonists are less likely to cause cardiovascular adverse events in patients with pre-existing cardiovascular disease compared with GnRH agonist treatment.4

Treating prostate cancer

Prostate cancer growth is dependent on testosterone, which is why treatment focuses on reducing testosterone levels. GnRH antagonists may offer an advantageous therapeutic option for prostate cancer compared with GnRH agonists for several reasons:

  • Unlike GnRH agonists, GnRH antagonists do not cause an initial spike of testosterone, which promotes tumour growth and exacerbates symptoms.1,2 GnRH antagonists eliminates the need for additional androgen deprivation therapy (ADT) and reduces the risk of complications

  • Studies have demonstrated that GnRH antagonists delay disease progression for longer than GnRH agonists. GnRH antagonists extend the time before prostate cancer progresses in the absence of testosterone and are effective even when patients switch from a GnRH agonist to an antagonist5

  • The rapid onset of GnRH antagonists is of particular benefit to men whose cancer is advanced or who experience bothersome symptoms.1

Treating benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is the non-cancerous enlargement of the prostate. It is a common disorder which causes urinary symptoms and reduces quality of life. Enlargement of the prostate is primarily caused by testosterone and therefore GnRH antagonists may be a beneficial treatment option for BPH.

Current treatment options are limited. Some may take several months to have a meaningful effect,6 or only treat the symptoms not the underlying cause. Additionally, 5-alpha reductase inhibitors, which are commonly used to treat BPH, can increase the risk of developing high-grade prostate cancer.7 Potential side-effects can impair sexual functioning, which reduces quality of life.8 Unsurprisingly, adherence to medications is low.9 The advantages and disadvantages of various therapies for BPH are highlighted below.

Class (drug) Onset of action Addresses underlying problem Common side-effects Increase risk of hihg-grade prostate cancer
5-alpha reductase inhibitors (5-ARIs)* Slow6 (months)  
  • Sexual dysfunction9,10
Yes7
Alpha-receptor blockers* Rapid11,12 (days)  
  • Dizziness13-15
  • Low blood pressure13,15
  • Headache13,14
  • Sexual dysfunction13,14
No established link
Phosphodiestera se inhibitors Moderate16 (weeks)  
  • Headache17
  • Indigestion17
  • Muscle pain17
  • Nasal congestion17
  • Flushing17
No established link

*Medications may be taken in combination.

Gonadotrophin-releasing hormone antagonists offer a much-needed alternative that has the potential to target both the cause and symptoms of the condition. They have faster onset of action and may increase quality of life.

References

  1. Shore ND. Ther Adv Urol 2013; 5: 11-24

  2. Thompson IM. Rev Urol 2001; 3(Suppl.): S10-4.

  3. FDA drug safety communication: update to ongoing safety review of GNRH agonists and notification to manufacturers of GNRH agonists to add new safety information to labelling regarding increased risk of diabetes and certain cardiovascular diseases. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-update-ongoing-safety-review-gnrh-agonists-and-notification (accessed July 2019).

  4. Albertsen PC, et al. Eur Urol 2014; 65: 565-73.

  5. Crawford ED, et al. J Urol 2011; 186: 889-97.

  6. Elterman DS, et al. Ther Adv Urol 2012; 4: 77 –83.

  7. FDA Drug Safety Communication: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-5-alpha-reductase-inhibitors-5-aris-may-increase-risk-more-serious (accessed August 2019).

  8. Alcaraz A, et al. Int Urol Nephrol 2016; 48: 645-56.

  9. Cindolo L, et al. BMC Urol 2015; 15: 96.

  10. Proscar® summary of product characteristics.

  11. Narayan P, et al. J Urol 2003; 170: 498–502.

  12. Marks LS, et al. J Urol 2009; 181: 2634–40.

  13. Avodart® Summary of Product Characteristics.

  14. Rapaflo® Summary of Product Characteristics.

  15. Flomax® Summary of Product Characteristics.

  16. Roehrborn C, et al. J Urol 2008; 180: 1228-34.

  17. Cardura® summary of product characteristics

  18. Cialis® summary of product characteristics