Minerva: Get Ahead Of The Rush?

As part of my ongoing series on companies that are marketing and/or researching antidepressant medications, I will now cover Minerva Neurosciences (NERV). Minerva is a developmental biotech with four compounds currently listed in their pipeline. Two of these four have current potential antidepressant indications. For those wanting to read my previous articles about antidepressant companies, they are listed at the end of this article.

Minerva's Pipeline:

Source: Minerva Slide Presentation


MIN-101 is Minerva's lead compound and is in Phase 3 study for the treatment of the negative symptoms of schizophrenia. Negative symptoms of schizophrenia include flat mood, withdrawal from social interaction, lack of pleasure, and limited speech. Negative symptoms are often present even in patients with schizophrenia that are currently thought to be "well treated" due to their relative absence of positive symptoms. However, negative symptoms create a significant strain on social functioning. They limit the individual's ability to seek and maintain employment (and are thus a major reason why patients with schizophrenia are often on government disability programs). Negative symptoms of schizophrenia also tend to be more chronic - whereas positive symptoms are generally more episodic. Positive symptoms of schizophrenia include hallucinations, paranoia, delusions, agitation, and other problems with thought processes. None of the antipsychotics currently used to treat schizophrenia have indications for negative symptoms. Antipsychotics generally are very good at treating positive symptoms, but sometimes seem to worsen negative symptoms. Cognitive impairment often accompanies negative symptoms and antipsychotics can worsen cognitive impairment as well.

MIN-101 works by blocking two receptors. The first of these is the 5-HT2A receptor. The 5-HT2A receptor is a serotonin receptor that is generally thought of in terms of its blockade for antidepressant purposes. Drugs that block this receptor include mirtazapine (Remeron), trazodone, and most atypical antipsychotics. However, MIN-101 is differentiated from all of the above in terms of its other receptor action. While mirtazapine and trazodone impact other serotonin receptors, MIN-101 is more selective. Mirtazapine also has an impact at histamine receptors that MIN-101 does not have. Perhaps more importantly, atypical antipsychotics also impact many other receptors most notably including dopamine receptors. An excellent table showing these receptors can be found here. Rather than direct action at dopamine receptors, MIN-101 impacts sigma-2 receptors. Sigma-2 receptors impact other systems within the brain including the dopamine system. However, acting through the sigma-2 system seems to generate a more targeted impact on negative symptoms rather than positive symptoms. In fact, sigma-2 receptor activation has been considered as a possible mechanism for treating positive symptoms. Sigma-2 receptors have been found to be decreased in patients with positive symptoms of schizophrenia. This further illustrates the fact that the treatment of positive vs. negative symptoms is often diametrically opposite and the treatment of one can worsen the other. That is where one of the major risks for MIN-101 comes in - particularly with a monotherapy study. Blockade of sigma-2 receptors could theoretically worsen positive symptoms of schizophrenia while improving negative ones. However, Minerva's Phase 2b results for MIN-101 were notable for a lack of increase in positive symptoms. This was an excellent finding that supported the potential for monotherapy in maintenance once positive symptoms are cleared (the Phase 3 study setup).

Not only do antipsychotics lack an indication for negative symptoms in schizophrenia, but there are not any other currently marketed drugs for this indication either. There is one currently marketed drug that is testing for this indication. That drug is Nuplazid (pimavanserin) by Acadia (ACAD) - which is being tested as add-on therapy (versus monotherapy for MIN-101). The negative symptom study for Acadia is only in Phase 2 and thus is behind MIN-101's Phase 3 study, but the fact that Nuplazid already has initial approval (for Parkinson's psychosis) will give it an advantage. Even if MIN-101 were to get approval for the indication first, it would need to be marketed prior to Nuplazid Phase 3 results to gain a significant advantage. The other potential advantage for MIN-101 over Nuplazid is that MIN-101 has been formulated to reduce QT prolongation. If this is successful in Phase 3 studies, then it should offer a fairly significant safety advantage in head to head comparison.

Seltorexant (MIN-202)

Seltorexant is a selective antagonist of the orexin-2 receptor. Seltorexant has a quick onset (30 minutes) and a short half-life (2 hours). Minerva has partnered with Janssen/J&J (JNJ) to investigate this compound in both treatment resistant depression as well as insomnia. Together, they have started three Phase 2b studies of seltorexant in the last 6 months.

The first of these trials was started in September 2017 and focuses on adjunct therapy of seltorexant vs. placebo in treatment resistant depression. It is currently estimated to complete in December 2018 and Minerva has indicated that results would be available in early 2019. This is the only one of Minerva's current studies where I believe it is possible to have early results in 2018. Enrollment progress will be the key here and enrollment that is announced as ahead of schedule could indicate the potential for early results. However, I would suspect that many patients are being given the option of the second trial as well and some may prefer it due to the lack of a placebo.

Seltorexant's second Phase 2b trial in depression is very similar, but has a longer duration and tests seltorexant vs. quetiapine XR (Seroquel XR) as adjunct therapy. Positive results in this study (or even non-inferior results with an improved safety profile) would bode very well for approval. Physicians and patients alike are seeking better adjunct therapy options than atypical antipsychotics like quetiapine and aripiprazole (Abilify). While these show some positive effect, their side effect profiles are concerning for this indication in particular and a drug with similar efficacy and an improved side effect profile would be well received.

With regards to depression, results for seltorexant should be informative about the role of sleep in treatment resistant depression. The drug does not have a sufficient half-life to suggest that it will help throughout the day with once daily dosing. However, insomnia is frequently associated with depression and some other sedative antidepressants (like trazodone) have short half-lives as well. For this reason, I believe that success as adjunct therapy is very possible. I do not see seltorexant ever being a possibility for depression monotherapy unless they develop a longer acting form (ideally with the same onset time).

Seltorexant also has a Phase 2b trial for insomnia. This trial evaluates seltorexant vs. placebo vs. Zolpidem. Investors will also likely want to compare these results to historical results for suvorexant (Belsomra). Suvorexant is also an orexin receptor antagonist (both orexin-1 and orexin-2 receptors) and Belsomra is a Merck (MRK) product approved for insomnia. I would suspect that there is a fairly high likelihood that this study will be positive for efficacy. Tolerability including daytime fatigue will be the major concern to follow. This study does not take a long time (2 weeks) once a patient is enrolled. The study is currently projected to complete in April 2019 per clinicaltrials.gov. While I suspect it could complete earlier if enrollment progresses well, it is unlikely to finish early enough for results to be this year.


MIN-117 is the other antidepressant in Minerva's portfolio. It is an unpartnered drug that has action at several receptors including 5-HT1A, 5-HT2A, Alpha-1 adrenergic, and Alpha-2 adrenergic. It also targets serotonin and dopamine transporters. Often medications that have this many targets have significant side effect issues. In Minerva's Phase 2a study of MIN-117, there were no significant side effects observed compared to placebo. This was a favorable comparison to paroxetine (Paxil), which is often considered the worst SSRI with regards to side effects. Modest depression and anxiety benefits were seen with MIN-117. Minerva believes that this is worth pursuing as a depression treatment option for patients with comorbid anxiety. They plan to initiate a Phase 2b study for this soon.

After reviewing the Phase 2a data, I am not sure that I'd encourage Minerva to pursue this. The results were barely significant and not consistently significant. There was no significant difference between the 0.5mg dose and the 2.5mg dose. While Minerva comments on the Paroxetine arm in their most recent slide presentation, they have never shown Paroxetine vs MIN-117 in the same graph. Biotech Beast included the following graphic in a May 2017 article about Minerva - the graphic originally came from a MIN-117 poster presentation at the American College of Neuropsychopharmacology conference in December 2016.

Biotech Beast commented that MIN-117 "did not appear to be more effective than paroxetine" despite Minerva reporting that "the drug was superior to paroxetine in terms of the number of patients achieving a 50 percent reduction in MADRS score." I'll be a little more pessimistic than Biotech Beast was - my first impression (even before I saw the graphic above) was that the data did not appear to be as good as typical SSRI/antidepressant data. This is even given the fact that SSRI/antidepressant data is typically less impressive than the data for compounds for other indications. The side effect profile compared to paroxetine is good - but that's not really saying much considering they chose the antidepressant with one of the worst side effect profiles for comparison. This may be a harsh assessment for a Phase 2a study that did show some significant results with regards to efficacy. However, I believe that Minerva can afford to be selective in which drugs/indications that they pursue and therefore I would have a higher bar for advancement here.

At best MIN-117 can be another antidepressant alternative with similar efficacy to current antidepressants and a better side effect profile. It would likely be 4th or 5th line therapy behind several generics. I think there is an equal or better chance that it also could be inferior to current therapies with regards to efficacy. There's also the likelihood that a large study will uncover more side effect issues given the number of receptor/transporter targets that the drug has. Ultimately - I do not like the risk/reward profile here and I would prefer that they shelf the compound and put resources to the other compounds in their portfolio. However, Minerva has indicated that they intend to pursue this which may be the largest negative that I see with regards to investing in the company.


The final compound in Minerva's current portfolio is a recombinant neuregulin-1β1 peptide that is designated MIN-301. It is a preclinical product which Minerva intends to advance to Phase 1 studies in the near future. The company believes that the compound has the potential to repair brain tissue damage in patients with Parkinson's Disease. This is a lofty goal but comes in an area where new ideas are very welcomed.

Thoughts on Other Potential Studies

After review of the pipeline, I find their two lead drugs (MIN-101 and seltorexant) very encouraging and MIN-117 not as encouraging. Rather than spending additional money on a Phase 2b study of MIN-117, there are several other avenues I'd rather see Minerva pursue. Most of these other possibilities Minerva has indicated that they are considering.

Advancing MIN-301 to Phase 1 Sooner - This is likely going to happen anyway, but if cost is an issue then I would rather see money put towards the Phase 1 Study of MIN-301 than the Phase 2b Study of MIN-117 Early Stage Study of MIN-101 in Autism Spectrum Disorder - I will note that this disease is my personal passion/bias (and is present in about 50% of my patients), but I see significant potential for MIN-101 in teens with ASD and flat affect. I realize that this is historically a difficult diagnosis for biotech to address, but I like the mechanism here as a fit for some teens with ASD. I'll also note that any teen indication for MIN-101 would likely extend the market exclusivity of the drug. Early Stage Study of MIN-101 in Anergic (Low Energy, Flat Affect) Depression - I believe this has more market potential in depression than MIN-117 does Early Stage Study of MIN-101 in Alzheimer's Disease - Like ASD, this would likely have some increased side effect risk. I like the general concept here for Alzheimer's, but I don't see it as quite as good of a fit as ASD. Formulation and Early Testing of Seltorexant XR - Ideally this could be an IR-XR "gobstopper" formulation with quick onset (from IR) and longer duration (for XR) - I would like this even better than the current form for the depression studies (although daytime sedation could be a significant risk) Likely a Buy, but When?

Ultimately, I believe that the positives outweigh the potential negatives and believe that Minerva is a good long-term investment for those seeking speculative mid-to-late stage biotech stocks. However, most if not all of the studies will complete and report results in 2019. Therefore 2018 could be a relatively silent year with regards to significant catalysts. There is always the potential of partnership or buyout, but I don't see these as likely enough to consider buying for that reason. Therefore, I believe that some patience before investing could pay off. I would expect buying to pick up in late Q4 2018 in anticipation of results. There are several things I would watch between now and then before initiating a position:

Does cash burn pick up significantly with the initiation of studies? - A significant portion of the studies are financed by J&J, but Minerva has significant expenses with MIN-101 and potentially MIN-117. If cash burn accelerates, then a secondary offering could come before 2019. The company currently has sufficient cash to make it until 2019, but given the time until results I believe one could watch cash burn for another quarter or two to be assured of this. Is there a drift/pullback due to lack of activity? - Should the stock price make it back to 4.95-5.20 and show support there, then this may represent a good entry point Is there a secondary offering? - This relates to #1, but if a secondary offering was made in the next year it would erase any questions of available cash. I would consider buying the offering unless it came at the very end of the year right before results are released in 1Q 2019. Offerings just before results are not often a positive indicator for the results. What is the health of the market and biotech sector in particular? - If there is a general market or sector pullback then waiting for signs of a bottom may be a good time to buy Minerva. Does Minerva go a different direction than MIN-117? - As I said above, Minerva currently indicates that they are committed to moving MIN-117 forward. However, they originally said Late 2017 for the start of the Phase 2b study and it is February 2018 now and the study has not yet started. A decision to abandon MIN-117 may produce a negative market reaction, but I would actually see it as a positive for the stock and would strongly consider buying any negative reaction.

Author's note: Thank you for reading my article. Please follow me for additional articles covering the biotech space with an emphasis on neuroscience. As always, I will disclose below which drug companies I have mentioned in the article for which I am the recipient of direct marketing. My articles include my personal opinions and are neither financial nor medical advice. They are solely intended to show my perspective and due diligence on a given subject. Please consult with the proper professional if you are looking for specific advice for your situation. If you would like to read my other articles about companies featuring antidepressant compounds, they are listed below for convenience:

Does Sage's Antidepressant Franchise Make It An Acquisition Target? Is Allergan The Best Buy If You (Or Your Portfolio) Are Depressed? Esketamine Could Give Johnson & Johnson The Next Major Psych Blockbuster VistaGen: Risky Anti-Depression Play Marinus Pharma's Ganaxolone: If At First You Don't Succeed... Alkermes: A Solid CNS Portfolio With An Option For Depression Axsome: Potentially More Pain Than Gain

Disclosure: I am/we are long JNJ.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: As a physician, I receive direct marketing from many companies which generally consists of marketing lunches provided to myself and my staff. I have not received these from the mentioned companies in the past year. Prior to the past year, I have received lunches and/or samples for patients from J&J and Merck. I anticipate that the majority of them will market to me in the future if/when they have psychiatric medications to market. I have never been paid by a pharmaceutical company for speaking, writing, or any other similar action.

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