Novel drug development for endometriosis: GnRH antagonist competition and nonhormonal target exploration

By April Chen

At present, the main development direction of new EMs drugs is focused on GnRH antagonists that inhibit estrogen levels, such as AbbVie Elagolix, Pfizer Relugolix,

Women's health has received far less attention and investment in R&D than other disease areas, and is often an area of ​​divestment by pharmaceutical companies

Endometriosis (EMs) refers to the endometrial cells that should grow in the uterine cavity.

Clinically, the goal of treatment is better pain control to reduce the number of surgical interventions (eg, laparotomy or laparoscopy), primarily through oral contraceptives, NSAIDs, opioids, gonadotropins Pain control with GnRH antagonists

01 GnRH antagonist competition

At present, the main development direction of new drugs for EMs is still focused on GnRH antagonists that inhibit estrogen levels.

Elagolix is ​​one of AbbVie's current mainstays in women's health, and another product, Oriahnn capsules (consisting of Elagolix, estradiol, and norethisterone acetate), was approved by the FDA in May 2020

The biggest competition in the GnRH antagonist space comes from two other GnRH antagonists, Pfizer's Relugolix and ObsEva's linzagolix

At present, relugolix 40mg combined with estradiol 1.

ObsEva's linzagolix has recently attracted attention.

Three GnRH antagonists used in EMs test results

There are no head-to-head trials of the three GnRH antagonists, and in a cross-sectional comparison, the three drugs were equally effective in the high-dose group, but because both Relugolix and Linzagolix were combined with hormones, the risk of bone mineral density loss was relatively reduced

02 Bayer explores non-hormone-related targets

In addition to AbbVie and Pfizer entering the field of women's health treatment with GnRH inhibitors, Bayer is undoubtedly the current leader in the field of women's health.

At present, the fastest progress is the P2X3 receptor antagonist, Eliapixant

In addition, the P2X3 receptor is also specifically expressed on primary sensory neurons, and its high expression and activation can lead to pain sensitization in chronic pain model animals, resulting in changes in physiological and pathological pain regulation

The role of P2X3 receptors in sensory organs

P2X3 receptor antagonists are getting more and more attention.

Judging from the published announcements, it may still be related to safety.

In addition, Bayer has three other products targeting EMs that are in Phase I, and from the targets announced so far, they are all exploring non-hormone-related targets

Bayer develops clinical-stage drugs for EMs

03 The Ogallon expansion pipeline after the spin-off

Women's health drugs have often become an area of ​​divestment by pharmaceutical companies.
Most of the companies that did not involve women's health pipelines before are deployed through acquisitions or cooperation, including the previous AbbVie and Bayer
.
Although there have been many small biopharmaceutical companies focusing on women's health listed in the past few years, Ogaron's re-split operation and listing from Merck has attracted much attention.
Its post-split business mainly involves women's health, classic Branded hospitals and retail businesses,
etc.

In November 2021, Ogallon announced the acquisition of Forendo Pharma for up to approximately $954 million, the third women's health deal since the spinoff
.
Mainly to obtain the compound FOR-6219, which is in clinical phase II development for EMs, is a 17β-hydroxysteroid dehydrogenase type 1 (HSD17β1) inhibitor, designed to inhibit low-efficiency estrogen in isolated endometriosis lesions.
The conversion of ketones to highly potent estradiol, known as the endocrine mechanism, is what causes endometriotic lesions to spread and cause pain
.
Unlike current drug therapy that systematically lowers estrogen, it has the potential to act locally in target tissues without affecting systemic hormone levels and may serve as a long-term treatment option for endometriosis
.

Phase I trial results showed that FOR-6219 was well-tolerated and safe in postmenopausal women in Phase Ia with single doses ranging from 2 mg to 75 mg and multiple doses up to 150 mg twice daily
.
Pharmacokinetic results are proportional to dose and reach steady state within 3 days, with a half-life of 16-18 hours allowing once-daily dosing
.
In 36 healthy premenopausal women in stage Ib administered FOR-6219 for 14 days during the menstrual proliferative phase, it was observed that these premenopausal women experienced persistently normal ovulatory menstrual cycles - showing that systemic estrogen was not affected
.