During the weekend I tweeted some
thoughts about Neurocrine’s (NBIX) and Abbvie’s (ABBV) imminent (2H15) read out
of a Phase 2b trial testing Elagolix on uterine fibroids.
I do not have a time for a full post, but I decided to copy (and elaborate a bit) these ideas on the blog. As always, this is not a recommendation to buy or sell; it’s mostly me thinking out loud a possible investment thesis.
1) There are three catalysts for NBIX which will read out relatively soon: a) Elagolix uterine fibroids; b) valbenazine TD; c) valbenazine Tourette.
2) All three trials seem to have a good rationale; all three have lots of background literature or results that allows for good DD. So lots of readings ahead for those interested.
3) This series of quick thoughts focuses on Elagolix/fibroids, I’ll tweet/post about valbenazine later (doing DD on this one too, I am familiar with it since I read a lot about it during ASPX DD).
4) Elagolix is a small molecule oral GnRH antagonist (first that I know making it so far in the clinic); it could replace GnRH agonists [GnRH agonists are actually inhibitory, replacing pulsatile natural GnRH stimulation with constant stimulation leads to downregulation of the system].
5) GnRH agonists (Lupron, Goserlin) are used for endometriosis, uterine fibroids and other indications. GnRH agonists are effective for several indications but have significant AEs.
6) Elagolix had +ve res on endometriosis. Question is can Elagolix work on fibroids too? Here's the link to the trial: https://clinicaltrials.gov/ct2/show/NCT01817530
7) Fibroids are heterogeneous in position, size and symptoms - this adds noise to trials results, ie not all pts respond the same way. This variability needs to be accounted in trying to assess the likelihood of success of the trial.
8) Variability can be seen in the
literature and even in companies report. For instance this link http://www.fibroidfacts.com/treatment-with-lupron-depot.cfm
shows that Lupron can be successful in reducing bleeding (one of the main
symptoms of fibroids), but not in all patients (80%).
9) Endpoints typically used are
reduction of excessive menstrual bleeding, reduction in size of fibroid and of uterus
10) Primary endpoint for Elagolix
Phase 2b trial is reduction of bleeding. If Elagolix has reduction comparable
to Lupron that would be a very pos IMO
11) It's important to note that
Lupron (and possibly Elagolix if it works) might face competition from progesterone-rec
modulators: http://newsatjama.jama.com/2012/02/02/studies-show-drug-treats-uterine-fibroids-without-adverse-effects-that-mimic-menopause/
12) Worth mentioning that the
indication of all these drugs (as far as I understand) is pre-surgical volume
reduction.
13) So can Elagolix work in
fibroids? There is basis to think it could. 1) GnRH agonists work, see page
6-7: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019943s034,020011s041,020708s034,203696s001lbl.pdf
14) Second reason for elagolix
potentially working: other GnRH antag (NON-oral tho) have shown clinical
responses: http://www.ncbi.nlm.nih.gov/m/pubmed/16930803/
and http://www.ncbi.nlm.nih.gov/m/pubmed/15842290/
15) Of course all this needs to
be weigh in with the following considerations: 1) Elagolix is oral, 2) Elagolix
uses different primary endpoint than previous 2 links, 3) I don't see criteria
for patients inclusion (which would take into acct variability) in the trial
design.
16) All in all I don't see
anything that scares me away from NBIX in the Elagolix fibroids trial. Actually
I tend to be moderately optimistic.
I hope these flashes help a bit.
I am long NBIX but I strongly discourage anyone from buying a stock without
having done their own DD. Hopefully this page will help with links and thoughts.
*** ADDITION 8/27/2015 ***
Yesterday night I read some transcripts from NBIX earnings calls and I found this interesting answer to a question asked by Robyn Karnauskas (DB) on the uterine fibroids program. The answer is from Chris O'Brien (CMO):
"That’s a very good question because this is an interesting situation with Elagolix because we know Elagolix reduces menstrual bleeding and uterine bleeding. We know that’s true in endometriosis. As we have seen with our data that we did in our trial developed in our trials. But we have also seen that AbbVie ran a Phase 2a study in which they saw proof of concept which allowed them to start the Phase 2b study. Now although they didn’t release data, they said we found proof of concept and we moved into Phase 2b. So the end point and the only end point for uterine fibroids for the FDA is uterine bleeding and menstrual bleeding. And a reduction in uterine bleeding was the basis from them moving from Phase 2a to Phase 2b. The people at AbbVie formerly Abbott and TAP were the ones that helped work with the FDA over a period of many years to design and reach consensus with the FDA on what that primary end point is. In this case there is an objective and there is also a subjective way of measuring uterine bleeding and AbbVie has did it for both of those things.
So I don’t think there is an efficacy risk here and particularly you can get a sense of that if you look at clinicaltrials.gov and you see what the Phase 2b study looks like. And you will see that they are studying doses in the cohorts of Elagolix that are – they are looking at a dose that they haven’t specified but one can assume that it’s higher than what we have studied in endometriosis because they are using a low dose oral contraceptive as so-called add-back. And the only reason you do that is if you suppress estrogen or estradiol so much that you begin to have impact on bone mineral density. So, if you use a low-dose of an oral contraceptive and approved add-back, you can mitigate that risk of impact on BMD. So, what you see when you look at clinicaltrials.gov is they are not really looking at Elagolix, they know Elagolix works. They are looking at which does of add-back is the best to take forward into Phase 3. And so, I think we don’t have a major efficacy risk here on uterine bleeding and the issue is do they have a dose they are comfortable with in conjunction with a dose of add-back that gives them the kind of safety profile they need going forward and the literature is replete with examples of low-dose add-back taking care of BMD risk even with profound suppression drugs like Lupron."
The conference call transcript comes from:
http://seekingalpha.com/article/2900766-neurocrine-biosciences-nbix-ceo-kevin-gorman-on-q4-2014-results-earnings-call-transcript?part=single
*** ADDITION 8/27/2015 ***
Yesterday night I read some transcripts from NBIX earnings calls and I found this interesting answer to a question asked by Robyn Karnauskas (DB) on the uterine fibroids program. The answer is from Chris O'Brien (CMO):
"That’s a very good question because this is an interesting situation with Elagolix because we know Elagolix reduces menstrual bleeding and uterine bleeding. We know that’s true in endometriosis. As we have seen with our data that we did in our trial developed in our trials. But we have also seen that AbbVie ran a Phase 2a study in which they saw proof of concept which allowed them to start the Phase 2b study. Now although they didn’t release data, they said we found proof of concept and we moved into Phase 2b. So the end point and the only end point for uterine fibroids for the FDA is uterine bleeding and menstrual bleeding. And a reduction in uterine bleeding was the basis from them moving from Phase 2a to Phase 2b. The people at AbbVie formerly Abbott and TAP were the ones that helped work with the FDA over a period of many years to design and reach consensus with the FDA on what that primary end point is. In this case there is an objective and there is also a subjective way of measuring uterine bleeding and AbbVie has did it for both of those things.
So I don’t think there is an efficacy risk here and particularly you can get a sense of that if you look at clinicaltrials.gov and you see what the Phase 2b study looks like. And you will see that they are studying doses in the cohorts of Elagolix that are – they are looking at a dose that they haven’t specified but one can assume that it’s higher than what we have studied in endometriosis because they are using a low dose oral contraceptive as so-called add-back. And the only reason you do that is if you suppress estrogen or estradiol so much that you begin to have impact on bone mineral density. So, if you use a low-dose of an oral contraceptive and approved add-back, you can mitigate that risk of impact on BMD. So, what you see when you look at clinicaltrials.gov is they are not really looking at Elagolix, they know Elagolix works. They are looking at which does of add-back is the best to take forward into Phase 3. And so, I think we don’t have a major efficacy risk here on uterine bleeding and the issue is do they have a dose they are comfortable with in conjunction with a dose of add-back that gives them the kind of safety profile they need going forward and the literature is replete with examples of low-dose add-back taking care of BMD risk even with profound suppression drugs like Lupron."
The conference call transcript comes from:
http://seekingalpha.com/article/2900766-neurocrine-biosciences-nbix-ceo-kevin-gorman-on-q4-2014-results-earnings-call-transcript?part=single
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