Sage and Marinus – Not the typical CNS story

CNS is probably the toughest segment in the drug industry with a frustratingly low success rate and a diminishing pipeline. This is best exemplified by the disproportionally low number of CNS programs that received Breakthrough Therapy Designation (BTD). Of almost 70 designations, only three (J&J’s esketamine, Neurocrine’s NBI-98854 and Acadia’s pimavanserin) were for CNS indications and all three are hardly as exciting as other BTD drugs (anti-PD-1, CARs, Harvoni etc.). Not surprisingly, there are very few “hot” CNS-related stocks.

Sage (SAGE) and Marinus (MRNS) are two exceptions, with two of the few exciting CNS projects out there. Sage’s SAGE-547 and Marinus’ ganaxolone, which have the same mode of action (MOA), are developed for the treatment of epileptic seizures. Unlike other CNS projects in late-stage development, SAGE-547 and ganaxolone are significantly de-risked based on a clear clinical proof of concept and understanding of MOA.

Both drugs activate GABA-A receptors, a family of receptors in the brain that reduce neuronal activity. GABA-A activation is a well validated mechanism used by many tranquilizers and anti-anxiety drugs such as Ambien and Valium. SAGE-547 and ganaxolone are distinguished from available GABA-A drugs based on to their ability to activate a wide spectrum of GABA receptors, including those found outside of the synapse (extra-synaptic). This may allow the two agents to overcome resistance to existing drugs and maintain a durable anti-seizure effect.

Despite the similarity between SAGE-547 and ganaxolone, each company is pursuing a different development path. SAGE-547 is an injectable formulation of a naturally occurring substance (allopregnanolone) for the treatment of super-refractory status epilepticus (SRSE), a severe form of uncontrolled seizures. Ganaxolone is an orally bioavailable derivative of allopregnanolone for the treatment of epilepsy.

The most notable difference between Sage and Marinus is valuation. Sage’s $1.33B market cap is 10-fold higher than that of Marinus ($129M). This gap can be ascribed to the different data packages for each drug, as SAGE-547 has a clear advantage in terms of unequivocal efficacy and time to market. Marinus, on the other hand, has positive (albeit not spectacular) results from a randomized phase II in epilepsy and an established safety profile.

Sage – impressive activity in SRSE

SAGE-547’s activity in SRSE is nothing short of remarkable. To date, the company reported clinical experience in 30 patients whose seizures could not be managed with available treatments. These patients are typically put into a medically induced coma with general anesthesia followed by weaning off anesthesia in an attempt to stop seizures.

Of 26 evaluable patients who received SAGE-547 on top of standard of care, 19 (73%) were successfully weaned off their anesthetic agents with successful resolution of seizures. Although the trial had no control arm, this figure compares favorably to historic success rates of 25-30%. Importantly, the effect persisted after discontinuation of SAGE-547. Based on these results, Sage expects to initiate a randomized phase III trial evaluating SAGE-547 as adjunctive therapy to standard of care in the coming months.

Marinus – Awaiting P3 validation in epilepsy  

Marinus’ ganaxolone was originally designed as a chronic anti-seizure treatment. The drug was created as a close derivative of allopregnanolone using a minor chemical modification (see figure below). This modification was introduced in order to solve two issues that prevent allopregnanolone from becoming a chronic drug: It is not orally bioavailable and it can be converted to a steroid in the body. Importantly, the minimal modification enabled ganaxolone to retain significant GABA-A activity.

chemistry

 Source : Marinus Pharmaceuticals

 P2 data in epilepsy point to a differentiated profile – Ganaxolone’s phase II was conducted in epilepsy patients whose disease was not adequately controlled with standard of care. The drug led to a statistically significant mean reduction in seizure frequency of 19.6%. The difference in median percent reduction in seizure frequency was 15.7%, which did not reach statistical significance. A responder analysis (proportion of patients with 50% decrease in seizures) also demonstrated numerical differences that did not reach statistical significance.

Ganaxolone - P2

 Source : Marinus Pharmaceuticals

So far, safety profile appears favorable with a clear differentiation over most approved agents (most common side effects were fatigue and sleepiness). A benign safety profile is crucial in epilepsy as patients take multiple drugs with complementary MOAs. The lack of any signs of reproductive toxicity (predominantly from animal experiments) is particularly relevant for women in childbearing ages.

Effect size appears clinically meaningful – Ganaxolone’s effect size across the different endpoints is at the low range of what has been seen historically with anti-epileptic drugs. Still, a median 15.7% reduction in seizure frequency (if corroborated in phase III) is clinically meaningful and should allow ganaxolone to capture some market share given its favorable safety profile. Vimpat (lacosamide), one of the recently approved anti-epilepsy drugs with annual sales of $500M, demonstrated a similar effect (15-17%) in its two pivotal trials. (see figure below).

Vimpat - P3

Sources: Halász, Epilepsia 2009 and Chung, Epilepsia 2010

Data from ongoing P3 expected in Q1 2016 – Marinus is enrolling a phase III trial with a similar trial design with the goal of replicating the P2 data (Results expected in Q1 2016). If results are positive, Marinus plans to conduct another phase III (Regulators require 2 trials for approval) which is expected to read out in 2018.

Exploring additional indications with ganaxolone – P3 readout next year is by far the most important event for Marinus, but ganaxolone may have value in additional indications, including those pursued by Sage. Marinus is evaluating ganaxolone in two genetic orphan indications characterized by dysregulation of GABA-A signaling.

Fragile X Syndrome is the leading genetic cause of autism and intellectual disability. Decreased GABA-A signaling has been observed in mouse models of the disease and a recently published paper reported a treatment effect with ganaxolone in animal models. Data from a randomized double- blind phase II are expected to be released in the coming months.

PCDH19 female pediatric epilepsy is a recently identified subset of pediatric epilepsy characterized by cluster seizures. The disease, caused by a mutation in the PCDH19 gene, is characterized by low levels of allopregnanolone forming the rationale for evaluating ganaxolone. A 10-patient study was initiated last month with potential preliminary data in Q4 2015. As a single-arm study, the trial will evaluate changes in seizure frequency on ganaxolone vs. baseline seizure frequency.

IV ganaxolone is Marinus’ wild card

Marinus is working on an injectable (IV) formulation of ganaxolone, which is expected to enter the clinic in 2015. Although no concrete plans were disclosed, it is natural to expect Marinus to pursue SRSE or similar conditions characterized by severe uncontrolled seizures in hospitalized patients.

Based on the striking resemblance between ganaxolone and SAGE-547, and the latter’s strong proof of concept, likelihood of success is relatively high, assuming ganaxolone and SAGE-547 are truly interchangeable in their GABA-A modulation. Ganaxolone clearly has significant GABA-A activity but there is always the risk for a slight chemical modification to alter a drug’s biological activity.

Recent comparison data from Sage should be noted but are not a show stopper – Sage is understandably trying to differentiate between SAGE-547 and ganaxolone. Last year, the company presented a poster comparing the two drugs as well as a next-generation drug (SAGE-217). In some models, ganaxolone had comparable (in some cases even superior activity) to that of SAGE-547, but in some settings ganaxolone appeared inferior to SAGE-547 (and both drugs were inferior to SAGE-217). The primary concern stemming for this poster is that ganaxolone has a lower effect on extra-synaptic GABA-A, which is believed to be a crucial property for activity in SRSE. (see figure below)

SAGE vs. ganaxolone

 Source : Robichaud, EILAT XII 2014

On the other hand, some of the differences may be technical artifacts (due to formulation, protocol etc.) and variability, which is always an issue in preclinical experiments, let alone in neurology. Therefore, Sage’s poster creates some uncertainty but given the striking similarity and the large body of scientific evidence for ganaxolone, the drug still has significant potential in SRSE.

IV ganaxolone could narrow the SAGE/MRNS valuation gap SRSE alone represents a $~2B global opportunity (assuming 70,000 cases per year and a $30,000 treatment cost), so even a 15-20% market share represents a significant commercial opportunity. Using a 50% likelihood of technical success (i.e. that ganaxolone and SAGE-547 are equally effective) can support a $170 valuation excluding all other chronic (epilepsy, fragile X, PCDH19) and acute care settings for ganaxolone. Therefore, SRSE and similar indications could become meaningful value drivers for Marinus even before actual clinical results (H2 2016).

Summary

I intend to hold both Sage and Marinus. Sage is significantly de-risked based on its early clinical data in SRSE and a high likelihood of success but this is already priced in. Potential upside may come from expansion to other indications as well as next-generation GABA-A modulators that are expected to start entering the clinic in Q4 2015 (targeting earlier stage status epilepticus). Marinus, on the other hand, is a high risk bet with a lower likelihood of success but the company has a lot of catalysts in the coming year, starting from early data in orphan indications by year-end 2015 followed by epilepsy P3 readout in Q1 2016. IV ganaxolone could add significant optionality value when clinical testing begins and concrete development plans are disclosed.

Portfolio holdings – April 12, 2015

portfolio - 12-4-2015

biotech etfs - 12-4-2015

88 thoughts on “Sage and Marinus – Not the typical CNS story

  1. Ohad
    Thanks for the comprehensive overview of these 2 stocks
    DO you have an opinion about GWPH and CORT – both are also involved in the CNS field.
    thanks

  2. Ohad, I think MRNS is testing a bit higher dose in the ongoing P3 for ganaxolone aren’t they? If so, hopefully that provides further comfort they will be able to reach stat sig despite not doing so in P2 (on top of being a larger trial of course).

  3. mcbio, I understand it is 2 different formulations, which shoul yield same exposure.

    Ohad, thanks for the article, very well done as always!

    What level must they reach in the pending P3 to make it a success?

    Also I learnt that the fragile-X study was pretty lame with recruitment (IST sponsored). do you know whether that is on track now?

  4. andre – Sorry, don’t know them well.

    mcbio (MRNS) – Right. They are using a different dosing regimen (BID) based on a different formulation (capsule vs.oral suspension ) and reach a total dose of 1800mg per day. The dose is higher but the PK profile is probably altered to some extent as well.

    Christian (MRNS) – Thanks. P3 will be successful if they can replicate the reduction in seizure frequency they observed in P2. They might get approval with a smaller difference but I am not sure how market acceptance will look like then. In the EU, the need to use responder analysis as the 1ry endpoint.

    Ohad

  5. Hello Ohad
    “Regulators require 2 trials for approval” – so sage have to do another III trail?

    do you follow ACAD?
    They have management problems and entering the market delayed
    But pimavanserin have a huge potential

    Thanks

  6. Hey Ohad
    Any opinions on CLDN? The P2 are expected this month. The stock has been highly volatile and lost most of its gains in the past week or ten days. BMS And QURE Seem to be going after similar target for congestivenheart failure.
    Finally, any thoughts on VCEL, it is in similar cardio field, with low valuation
    Thanks
    Dan

  7. Ohad,

    Thanks again for you effort. Your track record speaks for itself. As you know ADXS is working on a cancer vaccine using a the listeria bacteria and in a resent webcast listed below on slide 46 Dr. Samir Khleif states this Hypothesis “Combination of Listeria-based vaccine with PD-1/PD-L interaction blocking antibody will improve the overall anti-tumor efficacy of immunotherapy”

    It appears the Merck is interested as the currently requiting KEYNOTE-046 study would attest.

    I know you seldom comment on companies or techniques outside of your focus and attention, but PD1 was prominent in your 2014 ASCO article. I am wondering you have any comment on Dr. Khleif’s hypothesis?

    Here is the webcast if you are interested.

    http://edge.media-server.com/m/p/kbdinfjq

    Best regards,

    Pete

  8. Alex (SAGE) – SAGE is pursuing a rare and severe subset of epilepsy so the FDA requires only 1 study. Sorry, not following ACAD.

    Dan (CLDN) – Don’t know the field well but if I had to bet I would go for a negative outcome as teh data set they have has been generated from subset analyses and a small number of patients, looks too good to be true imo. Don’t kow VCEL.

    Pete (ADXS )- Thanks. I remain quite cautious reagrding cancer vaccines as a whole but the industry sentiment is dramatically better these days (but as you wrote, I am no expert on vaccines). I prefer to stay focused on treatment modalities with proven success such as immune checkpoints and adoptive cell transfer.

    Ohad

  9. Ohad,

    Thanks for the reply. Perhaps vaccine is the wrong word, but I think we get the idea. One more combo upcoming is with MedImmune’s MEDI4736. It would appear that the proof of concept of ADXS’s approach at least in combo will be forth coming. You have to admit it is an intriguing story.

    Best regards,

    Pete

  10. Ohad, just wanted to thank you again for sharing your knowledge with everyone in the blog! It is much appreciated!

  11. Ohad

    With the first release of phase 111 data for Aeri for their drug Rhopressa,can you shed some light on the superiority they saw versus TImolol regarding efficacy. Also,was there any indication regarding durability of response in their phase 11 trial or is this something we will hear for the 1st time.From a stock trading perspective seems like stock has absorbed a lot of the early investor selling that has taken place.

  12. Ohad
    Nice jump in SAGE today. A bit unexpected after the secondary though.

    MRTX will report data in mid 15 for NSCLC (targets MET and Axl).
    What you expect to be the outcome? They have companion diagnostics which might help to increase the efficiency.

  13. Pete – Agree it’s an intriguing story, there’sstill a long way to shoeing it actually helps patients.

    Dan S. – Thanks, glad you find it useful.

    Dave (AERI) – From what I recall, the P2 results did not have a Timolol arm, which is considered inferior to latanaprost. If Rhopressa performs similarly in P3, it should easily beat Timolol. Agree about durability as an open question as this will be the first time we see 3-month data.

    andre – Agree regarding SAGE’s move today, I didn’t expect it to jump given the price at the secondary.
    Re: MRTX – they said they reach sufficient exposure but I am concerned about their selectivity profile (VEGFR2 activity, in particular). In MET, there will probably have some activity but there are better selective MET inhibitors in development. Axl is the real wild card as it is still unclear whether Axl fusions exist in NSCLC and whether they are sensitive to Axl inhibitors.

    Christian (AERI) – Yes I do.

    Ohad

  14. Hey Ohad
    Thanks for your reply.
    BIOD had a seconday announced yesterday and the stock rebounded to its alltime lows. Market cap is $27M but with the new shares it might double.

    I think the opportunity for BIOD is the guacagon rescue kit. Market data points out that there are no satisfactory products on the market. Please take a look at the press relase two weeks ago, showing the superiority and ease of use of the biodel kit to current marketet products. NDA expected early 2016

  15. Hi Ohad,

    I was wondering if you are interested in taking a look at ARWR. Its ARC-520 has the similiar indication for HBV infection as CNAT but using RNAi approach. They are currently conducting phase 2B trial for ARC-520 using multiple 1mg/kg doses (up to 4) doses. If successful. the potential will be huge. A recent article on this stock from seekingalpha is in here: http://seekingalpha.com/article/3071536-buy-arrowhead-research-corporation-on-the-dip

    Your opinion is much appreciated.

    Jinyu

  16. Dan (BIOD) – I used to follow them in the past but am not familiar with recent developments. On paper, both ultra-fast insulin and the glucagon program make sense on paper but just looking at the continued disappointing stock performance, I would be very careful based on the assumption that there are a lot of issues wit these programs.

    JINYU (ARWR) – I am following ARWR as part of the HepB segment. Note that CNAT is addressing liver damage in patients who are cured of hepatitis (predominantly HepC) whereas ARWR is going after the virus itself in patients with active disease. To me, ARWR has been punished by investors for poor expectation management, as they clearly had an efficacy signal. The main concerns are whether the reduction in viral load is sufficient and whether the surrogate endpoint they used will be translated to higher cure rates. There is also competition from TKMR, which now has the broadest HepB pipeline and ALNY, both of which may have superior delivery solutions.
    Bottom line – ARWR is still too expensive, I would go with TKMR if I had to choose.

    Ohad

  17. Hi Ohad,

    AZD9291 data was presented in Geneva earlier this morning; did you have the chance to check the results? Could be interesting reg. CLVS….

  18. Christian (AZN/CLVS) – AZD9291’s PFS of 13.5 months in centrally confirmed T790M+ patients was really impressive, better than ~10 months reported at the last update. This raises the bar for CLVS although I still believe the two drugs are comparable in terms of efficacy. It is also hard to compare data from the 2 studies which evaluated several doses, have both investigator and independent assessment of progression and include patients who are both T790M+ and negative. This may create variability between the different subsets.

    Alex – Don’t know them well. From what I recall, their ability to identify adenomas is not that high. Sensitivity for tumors is better, though. Don’t know if having a blood test will be attractive enough vs. stool-based tests.

    Ohad

  19. they about to get an aprovel in the us
    the blood test can be added to a regular check up after 50 ..

  20. Ohad,
    do you have an opinion about ATRA?
    They have 3 interesting technology: CMV-CTLs and EBV-CTLs; both are currently in Phase 2 and WT1-CTLs in Phase 1
    They had a huge run since February, but still “only” 1.3B capitalization.
    thanks

  21. Hey Ohad
    have you looked at the TROV?
    It seems they might render biopsys obsolete, which would be great since they are invasive.

    What do you think of the latest release (today) regarding precisely the FMI and CLVS partnership– TROV can detect the T790 mutations in urine more accurately than with a biopsy/array.

    Dan

  22. Richard, on LOXO, their entire pipeline was in-licensed from ARRY. Given that ARRY itself is still an unestablished small-cap biotech, why would they give up the bulk of rights to these drugs if so promising? Also, beyond the Trk inhibitor, what is so special about the rest of LOXO’s pipeline? How are they differentiated from the myriad of other RET, FGFR, and FLT3 inhibitors out there? Not knocking, but just honestly curious (have no position either way). I would assume the Trk inhibitor is their most interesting asset but it’s also early days on proving Trk inhibition in the clinic and the merit of that.

  23. ohad

    do you follow Xenon Pharm?Seems like a very low EV with a market cap of 200m and approx. 65 million in cash. and surprisingly looks like Wilbur Ross holds a nice size stake in company.Wouldnt expect that type of investor in a bio stock.Stock has sold off from 18 to 14 over last month as lockup period expires next week.

  24. McBio, you may well be right about LOXO. But with less than 3 million shares in the float and over $100 million in cash, the valuation makes this a decent risk/reward gamble. As you would say, for better or for worse.

  25. Did you get a chance to list to Aeri CC after trial results? Should this be considered a big disappointment? Thanks as always.

  26. hi Ohad

    IMGN289 back to research/preclinic – I think you liked the target?
    any other negatives or positives from ImGN?

    brgds
    Christian

  27. andre (ATRA) – I am tracking them but don’t know them well enough for a concrete opinion. Both parts of their pipeline are innovative, I wonder how much of the value is ascribed to the EBV/CMV programs. For the TGFb superfamily programs, they are competing with XLRN and others (NVS with its ActRIIb antibody), don’t know how differentiated they are.

    Dan (TROV) – Don’t know them well but there is a strong push towards “liquid” biopsies in the industry. I even think AZN have such test in their European label. Will take a look.

    Richard (LOXO) – I think they have a high likelihood of success and have the best Trk inhibitors (more selective than RXDX). The main issues here are timelines (just started enrolling Trk mutated patients) and the unknown prevalence of Trk+ tumors. I personally plan to add some during the year, long term they have a good strategy and excellent discovery partner (ARRY). Owning ARRY is another way to get exposure to the story, of course.

    mcbio (LOXO) – These are valid points but even if they end up with 1 or 2 best in class molecules the company is attractive. For Trk, I expect them to lead and in the other targets you mentioned they’ll have to differentiate themselves from competition.

    ruhulla (MRNS) – Nothing that I am aware of but this type of volatility is typical of small cap biotechs.

    dave (XENE) – I have been following them for the last couple of months and like the story very much, especially the NaV1.7 program with Genentech. They have a diversified pipeline beyond that. Plan to add in 2015.

    Dan S. / Christian (AERI) – In one word : OUCHHH!!!
    Still didn’t have time to hear the CC but this is a huge disappointment even if you believe the 24 vs. >26 mmHg analysis. Another lesson in humility from biology…

    Christian (IMGN) – Yep, I really liked IMGN289 but apparently the biology doesn’t work. SNY gave back the CD19 program but I don’t think it was that interesting to begin with. 2 primary catalysts remain GATSBY and IMGN853 in ovarian cancer at ASCO.

    Ohad

  28. hi Ohad

    do you plan to bail out of AERI? why/why not? would be nice to hear your thoughts

    thanks
    Christian

  29. regarding MRNS:

    I did not understand it correctly last time, but it seems the majority of patients in the P3 is now treated with a HIGHER doses as in the phase 2. Phase 2 was with 1500mg oral suspension (3 x 500), phase 3 started with 2 x 600 = 1200mg capsule, which is supposed to have approx. the same bioavailability as the 1500mg oral suspension. About 50 patients were treated with 1200mg; the remaining approx. 250 patients will receive up to 1800mg daily capsules formulation totally. In my opinion, this should increase the likelihood that the P2 results with approx. 20% can really be replicated. Would you agree here?

    Regarding countries for the P3, in fact they have also active study centers in Russia, Buglaria, and a few other countries, but only the US sites are listed on clnicaltrials.gov.

    Concerning this video about the girl with PCDH19 epilepsy, she was not yet treated with ganaxolone, but is one of the participants of the PCDH19 study.
    I think the PCDH19 study (ininital results late 2015) is interesting. I am not sure about the other trial in fragile-x and would think it has a rather low chance of success.

    I don’t see how this can be a 130million dollar company if they achieve the 20% in the epilepsy P3, and given the huge safety database (partly also long-term, also in kids etc.), new safety issues aside from the known ones are very unlikely I assume.
    Would you guys agree?

    brgds
    Christian

  30. Hi Ohad,

    Any speculation on what IMGN will use their >$300mm in cash (after the $200mm advance on TDM1 revs) after that cc?

    They now have 4 wholly owned compounds they could advance after demoting one and getting one back but 2 (IMGN529, and IMGN779) are very early stage and IMGN853 is only advancing into Phase 2. I recall you said that you weren’t impressed by SAR3419, any specific reason? It seems like going it alone in a P3 w/ this one is the only reason to have that much cash now, otherwise they could probably wait for royalties and partnership milestones to run late stage trials when their other candidates are ready, any thoughts?

    Regards,
    Bif

  31. Ohad
    Did you discuss in the past CYTR? They have Ph 3 w/ drug conjugates (albumin-bound aldoxorubicin) which has a good chance of approval for Soft Tissue Sarcomas.
    It is not very exiting as the new technologies, but it seems it works
    It does not look expensive for a Ph 3 company (<$300M) with NDA filing in 2H 2016 and potential approval in 2017.

  32. Hi Ohad,

    Any thoughts on CLDN failure and how it might affect AAVL? Binary events are worrying!
    Thanks as always
    Chris

  33. Hey Ohad
    I did my due diligence regarding CLDN and sold my position a few days ago ($16-17). As you mentioned in your last replay to me and I verified though other articles, there simply were too many shady areas and things that looked worrisome regarding the trial and the results. I wanted to thank you for sort of encouraging me to take a more skeptical view.

    regarding AERI – what do you think we should do, wait for the next P3 results, later this year? How do we explain the discrepancy? also, as you had warned (potential risk), the positive/therapeutic effect decreases over time. I would very much appreciate you thinking/strategy about what to do next, also considering that ITEK is now going to be closer and they have a different MOA, which means it might work better (or worse).

    Thanks
    Dan

  34. Dan/ Christian (AERI) – My initial preference is selling the stock. Looking at the data they might have an efficacy signal in a subset of patients but Rhopressa doesn’t look better than Timolol, which is very disappointing and indicates the drug is not as active as I hoped.

    Christian (MRNS) – Agree about higher dose that may lead to a better clinical outcome but it also adds another layer of uncertainty (especially in CNS drugs where dose and effect are not always correlated).
    I am also more optimistic about the PCDH19 study vs. FXS because the endpoint is seizure reduction and the story makes more sense biology-wise.

    Wildbiftek (IMGN) – If IMGN853 has solid efficacy at ASCO IMGN will probably pursue this agent very aggressively starting from a single arm P2 through randomized P3 trials, combination studies and expansion to additional indications (lung, endometrial). This is easily a $100M effort over 2-3 years not including establishing a US sales force. Assuming a burn rate of $80M for other programs and G&A, $300M doesn’t look that high.
    SAR3419 is competing with a lot of programs (targeting CD19 as well as other targets such as CD79b and PD-1). I don’t think its profile makes it differentiated from all the rest of the programs.

    andre (CYTR) – Don’t know them well but from what I recall their data was not that exciting and the indication is very tough due to patient heterogeneity (e.g. ZIOP)

    Chris (CLDN/AAVL) – While I don’t think CLDN’s failure is relevant to other gene therapy projects (let alone ophthalmology projects), this is an important reminder on the binary nature of the industry. There is a decent likelihood for AAVL to fail its p2b as well but risk reward is favorable with the current valuation imo.

    Dan (CLDN) – Glad to hear you bailed on time. CLDN’s data set was much weaker compared to other gene therapy projects. Re: AERI, my current thinking is getting out of the stock in the near future, will decide by the next portfolio update.

    Ohad

  35. Hi Ohad

    What do you think of HALO right now? any chance to buyout for big boy?

    Thank you
    steve

  36. RE: IMGN
    Hi Ohad,
    With Sanofi ending the partnership on SAR3419, and also with the company stopping the early human testing of IMGN289……and with the over 20% drop in the last few days…is this changing your opinion about the stock? Is this still a buy in your opinion? Or wait for better entry point?
    best,
    dan

  37. dan (IMGN) – No, these events don’t change my opinion about IMGN (although I really liked the story behind IMGN289…). Key value driver is now IMGN853 so it all depends on data at ASCO. If they don’t show 30% response rate in FRa+ ovarian cancer, that will make me reconsider the investment hypothesis.

    Ohad

  38. Hey Ohad
    any chance to look at TROV yet, the shares got slapped today
    They claim to be the only company doing blood and urine based liquid biopsies– and that there are advantages to the latter
    also, one of the managers just joined from Illumina.
    Thanks for you perspective
    Dan

  39. hi Ohad

    Innate Pharma entered an impressive agrrement with AZ last week (250 EUR upfront etc.)

    you are still on the skeptical side I assume, what are actually your concerns?

    thanks!

  40. Dan (TROV) – Haven’t had a chance to take a look. This is not an area I am familiar with at all.

    steve (ADRO) – They are way overvalued imo as I don’t think their vaccines have a high likelihood of success. Data is from a small underpowered study in an indication nothing truly works. Same goes for HALO.

    Christian (IPH) – Impressive deal, good for them! Yes I am still skeptic about their NK targeting antibodies which have not generated any signal of efficacy to date. The NKG2A has data only in healthy volunteers.

    Ohad

  41. Hi Ohad,

    any thoughts on AQXP? Phase II data for AQX-1125 (COPD, “SHIP-trials”) is expected this summer. Pfizer and J&J are major shareholders. AQXP says to have PoC already. Market cap $80M.

    You make an outstanding work!! Thanks a lot!

    Marc

  42. Hi Ohad,

    Do you think IMDZ has any chances to shine in the IO space? They seem to offer an off the shelf approach that may be more attractive and they appear to have a pretty diverse pipeline.

    The lead drug targets ny-eso similar to ADAP.

    Thanks.

    Richard

  43. Hi, Ohad

    Halo’s PEGPH20 could be a blockbuster or not? people worry about the data can be mainipulated, if patients can not test HA level before the treatment. here is the link http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3682&sKey=25eaa706-c1aa-4401-b55b-62662c0c22f3&cKey=dabd8afe-1e3c-414a-a56b-ed3b2ab2fc12&mKey=19573a54-ae8f-4e00-9c23-bd6d62268424 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712709/

    what you think Ohad?

    Thank you
    Steve

  44. Marc (AQXP) – I am not too familiar with the story so my input should be taken with a grain of salt. I think the company should be commended for the indications they pursue and the robustness of the studies in COPD and IC. I am struggling with their proposed MOA both in terms of relevance to these diseases and differentiation from PI3K inhibitors. Bottom line, I am not optimistic.

    richard (IMDZ) – NY-ESO is a validated target but I have doubts about IMDZ’s approach and its ability to generate a clinically meaningful immune response. So far, cancer vaccines failed to generate benefit even in targets that today we know are good targets (NY-ESO, gp100 ETC.).

    steve (HALO) – I would like to see a more substantiated data set, what they have is simply not robus enough imo.

    Ohad

  45. Any feeling about MGNX at these levels. Wonder when the biotech sell-off will finally end

  46. test123 on April 30, 2015 at 2:16 pm said:

    Any feeling about MGNX at these levels. Wonder when the biotech sell-off will finally end

    =================

    well one can wonder when it will finally start 😉

    my guess is same correction as end of Feb to middle April last year, but who knows….

  47. hey Ohad
    Are you thinking of adding some AAVL? Given the correction (down 25%) from last month.
    Thanks

  48. Hi Ohad,

    Any thoughts on CLDX – your previously owned company? THey seem to have some near term catalysts. Cash balance of 350 million enough into 2017.
    ReACT study of Rintega will be presented along with data from the METRIC study of glemba at the ASCO in late May. Alos, a possible meeting with FDA on early rindo filing.
    ofcourse, one has to get behind the science though? I appreciate your comments especially after the recent pullback.
    Peter

  49. hello Ohad!

    have you looked at AUPH?

    Somehow, there are some similarities with MRNS (be it positive or negative):

    – small company (11 FTEs end 2014, lot of experience with the compound and with the disease Lupus Nephritis)
    – one-drug company (Voclosporin)
    – large safety database (about 2000 patients tread in other indications)
    – some proof of concept that calcineurin inhibitors when added to SoC in LN (i.e. Cellcept, with only 9% complete remission) improve outcomes considerably
    – rather low valuation (approx. USD 120 mio)
    – considerable unmet medical need (LN)
    – important read-out of P2b towards end of the year

    would be nice to hear your opinion!

    questions to me are e.g. whether the other 2 calcineurin inhibitors (which are generic) can be a threat or not; company claims they are not suitable for LN in combination with Cellcept due to adverse event profile respectively interaction with Cellcept.

    PS: this link on their homepages gives a good overview: http://www.auriniapharma.com/dnn/AboutAurinia.aspx

  50. Christian,
    Ohad Hammer wrote on March 26, 2015 at 7:47 am said:
    JB (AUPH) – Actually I started tracking them closely a couple of months ago and think it’s a compelling opportunity based on reasonable likelihood of success in a decently powered study, potentially differentiated profile vs. cyclospronie and high unmet need (lupus nephritis).

    Ohad

  51. Christian,

    I think generics risk is non-existent. If voclosporin + MMF is superior to MMF alone, then it is the logical choice for FDA approval which will then become new SOC.

  52. Hi Ohad, thanks for your very informative blog. I was wondering if you followed CALA and wanted your thoughts on their arginase inhibitor program. They seem to be one of very few researching this area and with the recent Duke news on Alzheimer’s, CALA may be immensely undervalued at these prices?
    https://today.duke.edu/2015/04/arginine

  53. test123 (MGNX) – I still prefer to wait until I see data for their CD123 program in AML.

    Mike (STML) – No changes I am aware of. BPDCN is still the primary driver with data potentially at ASH this year. The XPO1 program is also very interesting imo given KPTI’s data but that’s a late- 2016 story. MGNX’s CD123 is the biggest threat.

    Dan (AAVL) – Yes I do and it will be the topic of my next write-up. Good risk/reward ratio given the relatively derisked P2.

    Peter (CLDX) – Don’t have a concrete opinion as I like Rintega (the only cancer vaccine I really like) but stakes are already high. The biggest question is whether OS data at ASCO will corroborate the trend in 2nd line GBM.

    steve (HALO) – Reaching understandings with the FDA is a positive but I still think results to date should be interpreted with caution.

    Christian (AUPH) – I like AUPH , as conveyed by what Chris posted (thanks). I tend to accept AUPH’s arguments regarding a differentiated profile that should allow them to capture a meaningful market share.

    Chrsitian (ESPR) – After AERI, I take nothing for granted but I expect the hypertension study to be positive and a positive feedback from the FDA later inthe year. Hard to interpret insider selling…

    Dan (CALA) – I am tracking them closely and am very interested in cancer metabolism (personally involved in a cancer metabolism company here at the fund). I like their approach which is distinct and riskier compared to AGIO, who are targeting mutated enzymes directly. For the glutaminase program, they have target engagement in humans, which is important but does not justify the current valuation (even after the sharp drop this week). Re: arginase as a target, imo the jury is still out re: direct evidence implicating it as an important player in cancer metabolism. Don’t know if the target is truly relevant in Alzheimer’s (models are questionable) and whether CALA’s inhibitors are suitable for this indication (safety, brain penetration etc.).

    Ohad

  54. Hello Ohad
    insider selling appers in many shares in April, espr mrns aavl stml and more
    just a coincidence?

    Thanks
    Alex

  55. Alex – It’s no secret that valuations are quite rich.

    Mike – Thanks, very interesting. It clearly raises issues about the long term effect of RPE65 gene therapy. Not sure how relevant this is to AAVL, which relies on gene therapy as a way to replace chronic administration of VEGF mAbs and re-treatment every several years is still way better than 6 shots a year.

    Ohad

  56. AERI: haven’t seeing or heard any news…..any idea why the jump? Short covering ?

    dan

  57. hi Dan,

    it is perfectly normal to have a counter-move of the share price after the severe drop of the last few days in my opinion. I do doubt it has anything to do with news.

  58. Ohad,

    Seems after the deal settled with Roch, FMI is going down every single day. Are you worried by it’s movement?

  59. Chris Trau (MRNS) – I am always worried when a stock goes down but I amnot aware of any major developments. I plan to hold the stock going into Q1:16 P3 data given the low valuation.

    Cloud (FMI) – Yes, very surprising given the fact that more than 50% of shares are held by Roche. Still early to tell whether this has to do with something fundamental or just sympathy with the biotech sector.

    Ohad

  60. re FMI: I think that one of the reasons behind the current fall could also be yesterday’s announcement of IBM entering the market of cancer genetic analysis. I am long FMI too, but in the future I see Watson can have potential as a SaaS for commoditized NGS market. Of course things are far more complicated (liquid biopsy, companion diagnostics, etc.) but would be nice to know your opinion.

    As far as I understand, it’s to a large extent in direct competition with current FMI offering. At least on the patient’s side.

    http://www.reuters.com/article/2015/05/06/us-ibm-cancer-idUSKBN0NQ1YQ20150506

  61. Hey Ohad
    Have you ever looked at VNDA? They have a non 24 drug, a condition blind people have that relates to internal clock and sleep. They just released results for quarter andit seems sales are picking up. They are also awaiting EU decision, which will expand their market potential. I find the company as one of the few low cap biotechs with approved products that investorw will judge on market execution. If you are able to take a look, let me know your opinion. Market cap is 400M.
    Thanks
    Dan

  62. Ohad,

    Could you please elaborate a bit more about $170 valuation calculation for MRNS? Given this number, the market cap is much higher than SAGE. Does this make sense?

    Thanks!
    Cloud

  63. Cloud,

    MRNS market cap is $105M, Sage Market cap is 1.5B. Given these numbers how could MRNS market cap be higher than SAGE?

    Chris

  64. Chris, $105M is for price $7.9 per share. As Ohad mentioned, $170 value will give market cap $2.26B, which is even higher than SAGE.

  65. Cloud,

    I understand that 15-20% market share out of $2B gives ~ $340M market cap,
    Using a 50% likelihood of technical success i.e. that ganaxolone and SAGE-547 are equally effective as Ohad mentioned = $170M valuation. 62% more than current valuation.
    Please correct me if I’m wrong.
    Chris

  66. That is excluding all other chronic (epilepsy, fragile X, PCDH19) and acute care settings for ganaxolone as Ohad mentioned.
    Chris

  67. Milos (FMI) – Competition is constantly growing, which is expected. The big question would be whether FMI’s experience, software tools and user interface can enable it to stay the leader (now with the help of Roche). I believe so but it’s impossible to predict.

    Luis (ARQL) – There wasn’t a lot of new stuff, next catalyst is ASCO for the FGFR program but I am not sure they’ll have another FGFR+ cholangiocarcinoma patient by then (so far one of the FGFR+ patients progressed based on the AACR poster). The Proteus study is moving forward which is also positive but data will take time to emerge.

    Dan (VNDA) – Sorry don’t know them well.

    Cloud (MRNS) – I was referring to market cap, not share price. (thanks, Chris)

    Ohad

  68. Hi Ohad,

    Thanks, very good article.
    IN CNS field, I think the best risk/opportunity is on Zogenix with a very interesting pipeline focused on epilespsy (Relday) and Dravet Syndrome (ZX008) : Milestones/royalties of Zohydro will give enough cash to conduct this two products enough to end phase 3.

  69. Hello,I read your blogs named “Sage and Marinus – Not the typical CNS story | Open Reading Frame” like every week.Your story-telling style is awesome, keep doing what you’re doing! And you can look our website about تحميل افلام.

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