This is my first article in Seeking Alpha. I’ve loved following a number of the top quality articles by biotech specialists Jonathan Faison, Bhavneesh Sharma, Bret Jensen, Jerome Verony, Altum Research and others. SA is a superb platform from which I’ve already discovered quite a bit and feels that there’s a very robust biotech-targeted funding group within the making. I need to continue learning, be challenged by readers and colleagues and have enjoyable by giving my perspective on corporations, as time permits.
In the next article I add my perspective on ObsEva (OBSV), an fascinating European firm which focuses on women’s health.
Company and administration
Founded in 2012 and based mostly in Geneva, ObsEva focuses “on providing therapeutic solutions for women between the ages of 15 and 49 who suffer from reproductive health conditions that affect their quality of life, ability to conceive or that complicate pregnancy and the health of newborns.”
ObsEva’s portfolio at present consists of three in-licensed merchandise (OBE2109, nolasiban and OBE022) in medical improvement in 4 indications: ache related to endometriosis (OBE2109), heavy menstrual bleeding related to uterine fibroids (OBE2109), enchancment of reproductive outcomes in women present process synthetic reproductive methods (ART) (nolasiban) and preterm labor (OBE022).
ObsEva launched within the Nasdaq market at 15 USD/share and presently trades at round 10-11 USD, with a market cap at round 400 M USD. Institutional buyers maintain 35% of shares, together with properly-revered SOFINNOVA, NEA and ORBIMED, which personal a few third of the corporate.
ObsEva has a robust administration group with vital expertise within the subject of women’s health. Ernest Loumaye, MD, PhD, board licensed OB/GYN and CEO was head of medical improvement for reproductive health in Serono, the place he led the medical improvement of Gonal-F, Luveris and Ovidrel, three essential merchandise within the core therapeutic space of ObsEva. In 2006, he co-based PregLem. He led the corporate to the profitable European registration of Esmya for uterine fibroids. PregLem was later acquired by Richter group.
Overview of merchandise in improvement
OBE2109 is a GnRH receptor antagonist that was in-licensed by ObsEva from Kissei in 2015. Nolasiban (oxytocin receptor antagonist) and OBE022 (selective inhibitor of PGF2a) have been found and initially developed by Merck Serono and have been in-licensed by ObsEva in 2013 and 2015, respectively.
OBE2109 is being developed for the remedy of ache related to endometriosis and heavy menstrual bleeding related to uterine fibroids. OBE2109 is at present in part 2b (EDELWEISS trial) in endometriosis and in part III in uterine fibroids (PRIMROSE program). The EDELWEISS trial reads out within the first half of 2018 and the part III PRIMROSE program is predicted to learn out within the first half of 2020.
Both indications serve giant populations of sufferers for which present remedy choices usually are not optimum.
Endometriosis is a painful dysfunction through which the endometrium grows outdoors of the uterus. Endometriosis causes month-to-month bleeding and persistent inflammatory reactions and could be a reason for feminine infertility. According to the company there are 2.5 million women within the US recognized and handled for endometriosis yearly, citing aprox 200,000 surgical procedures yearly. Uterine fibroids are widespread non-cancerous tumors that develop within the muscular wall of the uterus. The foremost signs of uterine fibroids are heavy menstrual bleeding, anemia, stomach ache, and reproductive dysfunction. The firm estimates that there are four million women recognized and handled for uterine fibroids yearly within the US, citing 200,000 hysterectomies and 30,000 myomectomies per yr.
There are a number of remedy choices for each circumstances, by which one of many confirmed therapeutic approaches is to regulate ranges of estradiol ((E2)) with a purpose to handle the signs of illness. Over-suppression of E2 ranges, nevertheless, causes antagonistic occasions. This stability is vital, and right here is the place GnRH antagonists come into play.
Currently, first line brokers for the remedy of endometriosis are oral contraceptives and NSAIDs. Following the failure of first-line therapies, choices embrace GnRH agonist injections and surgical procedure.
First line merchandise present symptom aid and are efficacious in delicate sufferers, however efficacy in average/extreme sufferers is, nevertheless, restricted. On the opposite aspect of the spectrum injectable GnRH agonists (eg. Lupron) are efficacious, however have essential limitations associated to the predictability of E2 suppression (onset of motion is delayed and results are lengthy-lasting after the remedy ends) and related negative effects (discount of bone mineral density) on account of intense suppression of E2 ranges. So referred to as “add-back” remedy is advisable past three-6 months of remedy with GnRH agonists. Add-back remedy, because it identify implies, goals to revive the degrees of E2. Add-back remedy isn’t perfect as a result of 1) it interferes with efficacy (restores E2 ranges), 2) cardiovascular danger evaluation is beneficial previous to initiation of remedy (Lupron label) and three) it might produce some unwanted effects, like breast ache or water retention.
Uterine leiomyomas, additionally referred to as fibroids, are the most typical type of benign gynecological tumors. These are hormone delicate tumors and the position of estrogens and progestogens within the pathogenesis of the illness has been described. The remedy paradigm, broadly talking, consists of (once more) oral contraceptives, GnRH agonists and selective progesterone receptor modulators, like Esmya.
Similar to endometriosis, the danger-reward is pushed by the stability between symptomatic management and opposed occasions, which is the results of hormonal management. Oral GnRH antagonists are an excellent match for average to extreme instances of each circumstances, by which first-line brokers are usually not working correctly, the place GnRH agonists have essential limitations and, in fact, previous to surgical procedure.
OBE2109 was in-licensed from Kissei. Kissei accomplished a Phase 1 medical trial in wholesome feminine volunteers and three Phase 2a medical trials in Japan in sufferers with endometriosis, together with one double blind placebo-managed trial in a subgroup of sufferers recognized with each endometriosis and uterine fibroids.
OBE2109 was noticed to have a linear PK profile, low quantity of distribution, a half-lifetime of aprox 15h, and to induce a predictable dose-dependent suppression of estradiol in a dose vary that was properly-tolerated and offered symptom aid. A second phase I study carried out by ObsEva has confirmed the PK/PD profile.
The particulars of the molecule’s PK are essential, not only for its relevance on the pharmadynamics and efficacy, however as a result of they’re an necessary level of differentiation from different GnRH antagonists, which we’ll remark afterward.
(Source: company presentation)In the part II trial (KLH1202), which was placebo managed, OBE2109 achieved statistically vital reductions in ache, analgesic use and bleeding in sufferers with endometriosis. E2 ranges have been lowered in a dose-dependent method.
OBE2109, subsequently, has been studied in 2 part I packages and three part II research, considered one of which is placebo managed (107 sufferers). With all of the caveats from an early improvement program, this can be a comparatively compelling early dataset that factors in the appropriate path because it pertains to the result of the part IIb and part III packages in endometriosis.
In the EDELWEISS medical trial, 330 sufferers with endometriosis throughout websites within the United States and Europe are anticipated to enroll. The similar four doses (50 mg, 75 mg, 100 mg and 200 mg), every with no add-again remedy, are being studied, together with one arm that permits for dose titration relying on E2 ranges. The main endpoint is the discount from baseline at week 12 within the imply general pelvic ache rating. The key secondary endpoint is bone mineral density after 24 weeks of remedy. This design bodes nicely for a aggressive benefit if ObsEva manages to convey to market quite a lot of doses that produce symptom management with out want for add-again remedy and a positive antagonistic impact profile associated to bone mineral density preservation.
One of the three Phase 2a medical trials in sufferers with endometriosis that Kissei carried out (KLH1202) included a subgroup of 57 sufferers with each endometriosis and uterine fibroids. In this research, a dose-dependent discount within the proportion of days with bleeding and discount in uterine quantity through the 12-week remedy interval was noticed.
(Source: Company presentation)
In the PRIMROSE program the first endpoint would be the discount from baseline at week 24 of menstrual blood loss. Two doses (100mg and 200mg), every with and with out add-again remedy, are being evaluated. ObsEva believes that the 100 mg dose of OBE2109 might management signs in a big proportion of sufferers with out requiring add-again remedy.
OBE2109 is just not the one GnRH antagonist in improvement. Elagolix and Relugolix are additionally being developed in endometriosis and uterine fibroids.
Elagolix is first within the race. AbbVie (ABBV) and Neurocrine Biosciences (NBIX) had phase III results on endometriosis revealed in NEJM in 2017, with an accompanying editorial, which highlights that no new drug courses have been authorised for endometriosis because the FDA accredited the GnRH agonists greater than 25 years in the past.
Elagolix was studied with out add-again remedy in two doses, 150 mg/day and 200 mg BID. Although each doses had efficacy vs placebo, the upper dose stood out when it comes to medical efficacy on ache. Rates of response have been 75.eight% (greater dose), 46.four% (decrease dose) and 19.6% in placebo. However, the fascinating efficacy of the upper dose comes with a big discount in bone mineral density that might warrant add-again remedy. The significance of attaining the correct degree of E2 suppression involves the fore on this trial.
As for Relugolix, Myovant Sciences (MYOV) is conducting the SPIRIT 1 and SPIRIT 2 trials, with add-again remedy.
To summarize, OBE2109 might obtain vital ranges of E2 suppression with out want for add-again remedy in a big proportion of women. On prime of this, versatile dosing, PK properties that permit for as soon as-day by day dosing, low quantity of distribution, administration with out regards to meals and lack of interplay with CYP3A4 make OBE2019, for my part, a possible greatest-in-class GnRH antagonist.
(Source: firm presentation)
AbbVie submitted an NDA for elagolix to FDA in September 2017 for endometriosis and uterine fibroids trials are ongoing. Myovant Sciences initiated a Phase three program in endometriosis-related ache in June 2017 (estimated completion in December 2019) and a Phase three program for uterine fibroids in January 2017 (estimated completion in December 2018).
OBE2109 comes after elagolix (first entrant) and near relugolix, particularly in uterine fibroids. There are a number of evaluations on the subject, however the affect of the so important time to market will depend on quite a few elements: size of delay, variety of merchandise in market, diploma of differentiation between merchandise, prescriber setting, measurement of the indication, and so on. Despite OBE2109 being the third entrant, I consider that that the dimensions of the market, the market dynamics, and the differentiated profile will permit OBE2109 to realize a big proportion of market share.
Nolasiban to enhance IVF outcomes
I additionally need to touch upon nolasiban, within the intriguing indication of enhancing being pregnant outcomes in infertile couples present process synthetic reproductive methods (ART).
ObsEva administration cites the European Society of Human Reproduction and Embryology, which estimates that about 1.6 million ART remedies are carried out worldwide. In Europe, ART remedies doubled from 2000 to 2010, and roughly 620,000 IVF remedies have been carried out in 2012. In the United States, IVF remedies elevated by 41.7% from 2010 to 2014, with roughly 210,000 remedies carried out in 2014. In Japan, roughly 325,000 IVF remedies have been carried out in 2012. ARTs are pricey ($eight,000 to $15,000 within the United States), medicine accounting for a big proportion of that value and couples typically require a number of remedies.
The speculation is that nolasiban would enhance medical being pregnant outcomes by enhancing the uterine receptivity for the embryo, by decreasing uterine contractions and enhancing uterine blood move.
There are a number of critiques on the subject of discount of uterine contractions and outcomes of ART, and, though there isn’t any clear consensus (most likely as a result of lack of excellent trials), there’s a comparatively robust organic rationale for this strategy. If nolasiban can enhance the charges of success of an ART cycle, this may be a big achievement when it comes to discount of prices, psychological misery for couples and alternative prices of a failed ART try.
Nolasiban was in-licensed from Merck Serono, with beforehand accomplished preclinical research and Phase 1 medical trials in 103 wholesome feminine volunteers. ObsEva accomplished a Phase 2 medical trial of nolasiban in women present process IVF (IMPLANT trial). In the IMPLANT trial, nolasiban did not attain the first endpoint. However, administration believes that the shortage of statistically vital profit was resulting from an imbalance in sufferers with excessive progesterone ranges in one of many dosing teams (300 mg), arguing that prime progesterone ranges can shut the embryo implantation window. The correction of this imbalance offers a statistical vital end result and a clinically related one.
While we’ve got to stay cautious about publish-hoc analyses, the literature (article here) appears to help the notion that elevated ranges of progesterone end in lowered implantation charges. Moreover, a systematic review of atosiban (associated to nolasiban) used off-label on this setting appears to help the position of oxytocin receptor antagonists in enhancing ART outcomes.
A second research (IMPLANT2), that controls for ranges of progesterone, is being carried out in Europe and its learn-out is predicted in Q12018.
I feel this indication has a comparatively low chance of success, however I feel it’s intriguing. It matches a transparent unmet want and, if the result is constructive, it might add a whole lot of credibility to administration when it comes to experience, confidence and execution, and naturally would add to the corporate’s valuation. A really good upside.
OBE022 in preterm labor
Lastly, OBE022 is a PGF2α receptor antagonist for preterm labor (PTL). This is one other vital indication with an important unmet want (morbidity and mortality for the pre-time period child) and financial burden. According to the National Center for Health Statistics that ObsEva administration cites, the United States’ preterm delivery fee was 9.6% in 2014.
There are merchandise used off label within the context of pre-time period labor, however efficacy is restricted they usually include unwanted side effects for the mom and the child. NSAIDs, which additionally scale back the manufacturing of prostaglandins have vital uncomfortable side effects for infants, because of non-selective impact in PGE2, which produces vasoconstriction (lowered blood movement to the fetus).
In pharmacology, PK and toxicology research carried out by Merck Serono, OBE022 was noticed to be a extremely selective, aggressive and reversible PGF2a antagonist. OBE022 has proven to scale back spontaneous uterine contractions in a preterm labor animal mannequin. ObsEva has carried out a Phase 1 medical trial assessing the security, tolerability and PK profile of OBE022 and a phase II trial is ongoing (PROLONG Trial) whose learn-out is predicted within the second half of 2018.
Summary of financials and milestones
According to Q3 quarterly report, analysis and improvement bills have been $13.9 million and common and administrative bills have been $three.zero million for the quarter ended September 30, 2017. As of September 30, 2017, ObsEva had money and money equivalents of $68.four million, which doesn’t embrace internet proceeds of roughly $56 million raised in a personal fairness financing of October 2017.
The following milestones lie forward:
- Announcement of main endpoint outcomes for the Phase three IMPLANT2 medical trial within the first quarter of 2018.
- Announcement of main endpoint outcomes for the Phase 2b EDELWEISS trial of OBE2109 in endometriosis in mid-2018.
- Announcement of preliminary outcomes of PROLONG trial for OBE022 in pre-time period labor in late 2018.
I can’t try and construct a valuation mannequin for the corporate, as that is clearly pushed by chance of success of the totally different packages. But if we focus solely on endometriosis and uterine fibroids, we’re speaking, roughly, about 10 million women recognized and handled in US and Europe. Take any conservative assumption on market share, uptake, pricing and the gross sales potential is considerably above present market cap. The different indications, though early, are to not be uncared for by any means, and will probably add vital upside for my part.
Risks embrace, amongst others, the likelihood that merchandise do not ship as anticipated, the emergence of hostile occasions, competitors, and danger of dilution. Although the corporate is properly resourced for the brief time period, the corporate will increase capital as progress in the direction of milestones will increase investor curiosity and the wants for later stage improvement and commercialization additionally improve. I might not be stunned to see this occurring maybe in the direction of the second half of 2018.
Disclosure: I’m/we’re lengthy OBSV.
I wrote this text myself, and it expresses my very own opinions. I’m not receiving compensation for it (aside from from Seeking Alpha). I’ve no enterprise relationship with any firm whose inventory is talked about on this article.