Nuggets on Neurocrine (NBIX) part 1: focus on Elagolix in uterine fibroids *** UPDATE 8/27/15 at the end of page ***

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

Some quick thoughts on BioDelivery Sciences International (BDSI) imminent P3 readout

This weekend I did a mini dive into BDSI topical clonidine program. This is not going to be an extensive post (I still have some questions in mind), but since results of a Phase 3 trial are supposed to be announced any time soon, I figured it would be nice to share some thoughts.

BDSI is testing the analgesic effects of a topical clonidine gel in patients affected by painful diabetic neuropathy. Clonidine is an alpha2-adrenergic receptor agonist known for its analgesic effects when administered systemically. Alpha2 receptors are present also on peripheral nociceptive fibers. Activation of these receptors is known to induce analgesia in rodent models (Dogrul 2004). BDSI licensed from Arcion Therapeutics a gel formulation of clonidine for topical use.

What do we know about clonidine topical use in patients? There are a couple of older trials in which clonidine was administered as a transdermal patch (Zeigler 1992; Byas-Smith 1995). These trials did not show consistently significant effects of the drug in reducing pain. However, this is actually positive for BDSI. In fact, transdermal application was not used to affect pain locally but as a way to systemically administer the drug. In other words, the patch was not positioned on the region affected by pain but away from it. The only possible effect for this patch might have been via an increase in the blood concentration of clonidine, and likely the concentration was too low to be too effective centrally.

There are only a handful of papers (a not too quick search turned two papers plus an abstract) on topical application of clonidine in patients and they seem encouraging. Mind you, they are all from the Hopkins group that performed the studies that lead to the clonidine gel. One paper (Davis 1991) is a small proof of concept (few patients) and shows the potential efficacy of topical clonidine in sympathetically maintained pain (a form of chronic pain).

The second paper presents the Phase 2 trial results for the drug currently in Phase 3 (Campbell 2012). The trial featured 179 patients suffering from painful diabetic neuropathy, 89 in the treatment group and 90 placebo (placebo gel). The treatment was a gel of clonidine 0.1%. Notably, the authors explain in the methods the rationale for the dose; previous unpublished data showed that 0.05% was not effective, and 0.2% was not more effective than 0.1%. As a matter of fact, in an abstract presented few years earlier (Campbell 2009) 0.2% appeared less effective than 0.1%. While it is always unpleasant not to see dose-response, the weaker effect of 0.2% might be due to the lower volume of gel, or, in my opinion, to a stronger tolerance for clonidine. Indeed, tolerance development (i.e. progressive loss of effectiveness) is a well-known issue with clonidine, and occurs also with topical administration (Dogrul 2004). After a baseline period, patients entered 12 weeks of treatment. Each day they had to self-administer the gel (three times/day morning, afternoon and evening) and self-report the subjective perception of pain using the numerical pain rating scale (NPRS) once a day. The treatment lasted 12 weeks, and each week patients were assessed at the clinic and rated on a Brief Pain Inventory (BPI) scale. A subset of patients underwent a biopsy in the affected region to quantify nerve fiber density. In addition, all the patients underwent a capsaicin test. 0.1% capsaicin was applied over a 1 cm diameter area on the affected zone. Patients were asked to rate the pain evoked by capsaicin. Biopsy and capsaicin test were used to assess the presence and the function (or hypersensitization) of nociceptive fibers. I am still trying to figure out the consensus on the interpretation of this test, but it seems rational to me.

When the entire population was analyzed, no significant difference (p = 0.07) was seen between clonidine gel and placebo gel. However, a subgroup analysis based on the capsaicin test revealed a more positive picture. Indeed, when only patients with a response to capsaicin were analyzed (i.e., supposedly those with less nerve damage), the treatment appeared significant. For the group showing capsaicin pain equal or greater than 2, the significance reached p < 0.01.  In other words, the idea is that only patients with a less extensive damage to nociceptive fibers are likely to benefit from the topical treatment. In fact, no capsaicin-induced pain might mean excessive damage to nociceptive fibers (or in alternative less sensitive fibers).

The latest result lead to the inclusion of the capsaicin-induced pain test as one of the selection criteria for the ongoing Phase 3 trial. Only patients with at least a pain rating of 2 in response to capsaicin were admitted to the Phase 3.

Top line results for the trial were initially guided for EOY2014, however in the Summer 2014, upon interim analysis, BDSI decided to add 80 patients to the trial. The company stated that they were “encouraged by the outcome of the interim analysis”, but given  double blinding no data, nor statistics were presented .  

In summary, what are the encouraging aspects suggesting a positive readout of P3?

- the rationale for the MOA of topical clonidine is sound and convincing;

- the results from clonidine trials (particularly the subgroup analysis) are overall positive;

- the rationale for the subgroup analysis makes sense (but I need to look more into this);

- the target population can easily be identified using a simple test (capsaicin reactivity);

How about the caveats and the points of concern? Well, here they are:

- 0.1 mg clonidine works best than 0.2 mg clonidine, and I personally never like too much the lack of dose- response data. 

- the trial primary endpoint is change in pain as measured using the NPRS. NPRS records come from daily self-assessment by patients and this can introduce variability.

- similarly, self-administration of the gel can introduce more variability;

- while I have no problem with increasing the n after interim analysis (higher n is a good thing), and while I am not a fan of reading tea leaves in PR, still interim analysis with no mention of stats might raise some concern; [PS: Thanks to @BiotechSage and @Biowreck for pointing out that data were not unblinded to management and so company could not unveil any stat - on the basis of this information, this concern carries much less weight now].

To conclude, I lean toward thinking that BDSI has a good shot at goal with this Phase 3. Definitely, not a slam dunk! Indeed, one needs to clearly consider the risk of a trial whose primary endpoint measure might be rather noisy and affected by placebo, and whose previous interim analysis was defined encouraging, but not disclosed.

If science were simple we all would be millionaires (a fuzzy attempt at guessing Pimavanserin P2 in ADP)

 

Acadia (ACAD) is expected to submit the NDA for Pimavanserin in Parkinson’s Disease Psychosis (PDP) soon. Hopefully! (I know the slow NDA submission is raising some questions). Obviously, the regulatory path for Pimavanserin will make 2015 a rather eventful year for Acadia. But there’s another catalyst that will keep  all the eyes pointed to ACAD in the mid term … the much anticipated Pima Phase 2 (P2) trial readout in Alzheimer’s Disease Psychosis (ADP). This is the subject of this post.

  

Is Pimavanserin going to work in ADP? The first instinct might be to think that psychosis is psychosis and whether it is observed in PD or AD shouldn’t matter much. So if Pima works for PDP, why shouldn’t it also work for ADP (or for any other case of psychosis from schizophrenia to Loewy body dementia)? Well, it is not known whether PDP and ADP share similar pathophysiological mechanisms and hence offer similar therapeutic targets.

  

The successful P3 Pimavanserin trial in PDP, demonstrated that selectively (and almost exclusively) targeting the Serotonin 5HT2a receptor is a valid therapeutic approach. Could the same apply to ADP?

  

What do we know about the relationship between ADP and 5HT2a? Here’s a list of links involving 5HT2a in ADP, (some of them featured in papers on Pimavanserin):

  

- EVIDENCE: visual hallucinations, a hallmark of in ADP (and PDP), can also be induced by some 5HT2a agonist [1-2]. CAVEAT: Of course, the fact that some 5HT2a agonists can induce visual hallucination does not imply that there is only a single mechanism for inducing them [2]. In other words, the presence of ADP visual hallucination does not necessarily imply a 5HT2a dysregulation.

  

- EVIDENCE: there is a positive association between polymorphisms for the 5HT2a gene and psychotic symptoms in AD [3]. CAVEAT: This results has been confirmed by a meta-analysis of literature, but some studies failed to find a significant association, suggesting that even if it exists it might not be super strong. In addition, the functional significance of this association is not entirely clear.

  

- EVIDENCE: preclinical work shows that Pimavanserin can be effective in reducing psychotic-like symptoms in a rat model of AD [4]. As a matter of fact, the effects in the AD model are equal or better than those in the rat model of PD [5].  CAVEAT: the predictive value of this rat model of ADP is not entirely clear at the moment (obviously the PDP model did point to a solid effect in PDP).

- atypical antipsychotics have a high affinity not only for dopamine receptors but also 5HT2 receptors [6]. Risperidone, olanzapine and clozapine share this feature. Risperidone, and olanzapine can show some efficacy in reducing psychotic symptoms in AD, however their adverse effects (AEs) offset the potential efficacy and reduces their clinical relevance [7-8]. Some of the AEs of risperidone, and olanzapine in ADP result from D2 antagonism, suggesting that the doses clinically used target both 5HT2a and D2. Hence, it is difficult to attribute the possible efficacy of risperidone, and olanzapine in ADP to 5HT2a antagonism. Clozapine, an antipsychotic widely used for PDP for his lack of motor AEs [9], has not been used much for ADP due to its AEs. Interestingly, risperidone has showed some efficacy also in PDP [9], suggesting that some drugs can work in both conditions.

  

In summary, at this stage it is difficult to determine if selective targeting of 5HT2a receptors could be beneficial in ADP. I do not see any strong evidence either in favor, or against this hypothesis. 

  

So how to behave in the face of this uncertainty? Given the uncertainty, I assume speculations will keep fueling the stock price in anticipation of P2 ADP results, particularly if the regulatory course of Pimavanserin will be smooth. As a matter of fact, approval of Pimavanserin for PDP could be an extremely important step for further understanding its prospects in ADP. Indeed, AEs and safety issues of current antipsychotic therapies will open the door to potential off-label use of Pimavanserin in ADP. If that will happen, the chatter around Pimavanserin will increase, further fueling interest in the results and providing hints (albeit anecdotal) to Pima’s prospects for ADP.

  

Until then, yours truly will continue to look into this issue and try to find a way to guess the outcome of P2.

REFS

[1] Sinforiani E et al - Neurol Sci. 2007 Apr;28(2):96-9.

[2] Rolland B et al - Biomed Res Int. 2014;2014:307106

[3] Ramanathan S, Glatt SJ. - Am J Geriatr Psychiatry. 2009 Oct;17(10):839-46

[4] Price DL et al - Behav Pharmacol. 2012 Aug;23(4):426-33

[5] Price DL et al - Behav Pharmacol. 2011 Oct;22(7):681-92

[6] Meltzer HY et al - J Pharmacol Exp Ther. 1989 Oct;251(1):238-46

[7] Schneider LS et al - N Engl J Med. 2006 Oct 12;355(15):1525-38

[8] Sultzer DL et al - Am J Psychiatry. 2008 Jul;165(7):844-54

[8] Eng ML, Welty TE. - Am J Geriatr Pharmacother. 2010 Aug;8(4):316-30

[9] Ellis T et al - J Neuropsychiatry Clin Neurosci. 2000 Summer;12(3):364-9