After a long stagnation, is CNS starting to crack?

After being the industry’s graveyard for over 20 years, there is finally room for optimism in CNS (central nervous system) disorders. The void created in the field is now being filled by small companies which are using novel therapeutic (gene therapy, antisense, antibodies) and development (genetic validation in humans, biomarkers for patient selection) approaches. While clinical results are early and sparse they may represent the beginning of a new innovation cycle in CNS.

Tackling old problems with new tools

A lot of the progress stems from using new treatment modalities in order to modulate targets previously regarded as underuggable.

Gene therapy is making headways in rare genetic diseases led by Avexis’ (AVXS) SMA program and Abeona’s (ABEO) Sanfilippo programs. For these programs, as biology is already sorted out (driver of the disease is known) the challenge lies in delivery to the brain and duration. So far results with AAV9-based programs look promising but sample sizes are small and follow up is limited. If the data hold up, and AAV9 vectors can lead to meaningful protein production in the brain/CNS, the implications cannot be overstated. CNS is a particularly attractive domain for AAV-based gene therapy because neurons don’t replicate so the transduced cells should not be diluted with time.

Antisense drugs are proving to be a useful tool to modulate targets in the CNS (via repeated intrathecal administration). Biogen/Ionis’s (IONS) Spinraza, the first FDA approved treatment for SMA1, works by enhancing production of an alternative protein to SMN1 which is mutated in the disease. Last month, Ionis and its partner Roche reported that another antisense drug (IONIS-HTTRx) demonstrated target engagement, this time in Huntington disease. Although it is too early to conclude anything about efficacy, the dose-dependent reductions of mutant Huntingtin in the CNS are a remarkable achievement.

Antibodies are a successful class of drugs but their use has been predominantly limited to oncology and inflammation. After years of setbacks that included the never-ending beta amyloid farce and safety concerns with anti-NGF antibodies for pain, looks like anti-CGRP antibodies will become the first approved class of antibodies for a CNS indication (migraine). Multiple data readouts from Alder (ALDR) Amgen (AMGN), Lilly (LLY) and Teva (TEVA) validate this class and are likely to result in FDA approvals in 2018.

Promising small molecule CNS programs

The lion share of CNS drug development is still based on small molecule drugs. This segment has benefited from genetic research in humans that can validate targets more reliably (preclinical CNS models are notoriously hard to translate to humans) and more efficient drug discovery tools. Nav1.7 is the poster child for CNS target validation based on humans genetics (lack of pain sensation in people with Nav1.7 mutations) although the target has proven challenging to date.

My top three CNS picks in this group are:  Sage (SAGE) in depression, Xenon (XENE) in epilepsy and Minerva (NERV) in Schizophrenia and insomnia.

Sage – Potential breakthrough in depression

Despite a complete failure in preventing epileptic seizures, Sage’s GABA agonists are emerging as a novel class of antidepressants, potentially the biggest advancement in depression in decades.

In October, the company announced positive P3 data for SAGE-547 in PPD (post-partum depression), which will probably lead to the first FDA approval in this indication (especially in severe PPD where the effect was more pronounced). It is hard to estimate the commercial opportunity in severe PPD as there is no benchmark to rely on, but epidemiological studies and literature suggest an annual incidence of 40k in the US (1% of ~4M births) which translates to a global market opportunity of ~$500M.

In November the company announced positive P2 results for its proprietary next-gen oral drug (SAGE-217) in MDD (Major Depressive Disorder), a huge indication that has been in stagnation since the 1990’s. Results were highly positive with a 6.9-point placebo-adjusted decrease in HAM-D (a commonly used depression scale), the primary endpoint, with only two weeks of treatment. At day 15, the drug led to a remission (no signs of depression) rate of 64% vs. 23% in the placebo arm. The most striking pieces of information were the very fast onset (statistically significant benefit already after 1 day) and the long lasting effect (separation from placebo at 4 weeks, two weeks after the last dose).

These data are from a relatively small study (89 patients) and need to be corroborated by larger trials, but the emerging profile of SAGE-217 is very compelling. Efficacy is at the (very) high end of the spectrum of what is commonly seen in MDD and most depression drugs take several weeks to reach this effect. Safety profile continues to look benign and highly differentiated from approved antidepressants. Such a profile will likely make SAGE-217 an overnight blockbuster, if approved.

The primary risk for SAGE-217 is its long term safety profile, which is still an open question given the limited treatment period in the P2. The company claims it already has animal tox data covering chronic use but in CNS indications, even a low rate of severe adverse events can lead to termination.

SAGE-217 may compete with J&J’s esketamine (P2 data recently published) and Allergan’s (AGN) rapastinel. It is hard to compare across small studies that used different endpoints and design, but sage’s molecules appear to have a clear advantage on safety and route of administration ( Esketamine is given intranasally whereas  rapastinel is given IV).

Xenon – Genetically validated targets for epilepsy

Sentiment around Xenon is understandably poor following the setbacks in its pain programs with Genentech (on hold following preclinical tox findings) and Teva (failed multiple P2s). In 2018, investor focus will shift to the company’s epilepsy programs (XEN1101 and XEN901), which I view as attractive and de-risked based on genetic validation in humans. Xenon intends to pursue XEN1101 and XEN901 in rare genetic pediatric epilepsies in parallel to the general adult population, a strategy that has never been tried and will require the FDA’s blessing early on.  Long-term safety is another major overhang, as is the case with most CNS programs.


XEN1101 was in-licensed from 1st order Pharmaceuticals in 2017. The drug works by opening Kv7 ion channels, an approach validated by human genetics (inactivating mutations in Kv7 are seen in a severe form of childhood epilepsy) and clinical data (ezogabine, a predecessor of XEN1101 had been approved for epilepsy in 2011 but was later withdrawn due to safety issues). Ezogabine was a highly efficacious antiepileptic but prolonged use led to pigmentation in the eye and skin that at the time raised concerns about vision loss and skin toxicity, which in turn triggered a black box warning. Although later the FDA softened its language and stated that pigmentation had no adverse effect on vision or other tissues, sales of the drug plummeted until it was withdrawn from the market in 2017.

XEN1101 was developed by Valeant (who co-developed ezogabine with GSK) and was designed to avoid pigmentation, which is believed to stem from dimerization of the drug and binding to melanin. In contrast to ezogabine, XEN1101 does not dimerize or bind melanin so it should not lead to pigmentation (needs to be validated in the clinic). XEN1101 is also more potent and selective and appears to be superior to ezogabine in animal models.

Xenon recently initiated P1 in healthy volunteers with XEN1101 and incorporated an imaging endpoint that could demonstrate biological activity already in P1. A P2 in adult patients is slated to begin in H2/2018 with the potential to reach clinical proof of concept in 2019. The company plans to pursue a subset of pediatric patients with Kv7.2 mutations in parallel to the adult development program. This is a novel approach that has never been tested (typically, drugs are first approved in adults before moving to pediatric indications) so it remains to be seen if and how the FDA will address this. From a clinical perspective, treating these patients early could be critical for preventing long term cognitive damage. The company estimates there are ~1500 patients with Kv7.2 mutations in the US.


XEN901 is Xenon’s internally developed Nav1.6 inhibitor. Similarly to the case with XEN1101, the target is validated by activating mutations in Nav1.6 observed in a rare form of childhood epilepsy, making it a “driver” mutation. The drug is expected to enter P1 in Q1/2018 and its development plan is similar to that of XEN1101 (start with P2 in adults and in parallel pursue the rare pediatric indication).

Minerva – Traditional CNS pipeline with convincing P2 data

Although Minerva’s lead programs look “old-fashioned”, reminiscent of the traditional Pharma CNS pipeline, its lead programs, MIN-101 for schizophrenia and MIN-202 for insomnia and depression, have encouraging data sets that point to clinical differentiation.

In its P2, MIN-101 demonstrated a significant effect on negative symptoms (apathy, poor social functioning) as well as cognitive symptoms with a mild safety profile. While the effect was not dramatic, it appears clinically meaningful (no other drugs have a proven effect on negative symptoms, some drugs are used off label) and dose dependent. A P3 for MIN-101 started last month with data expected in 2019.


MIN-202 is Minerva’s orexin-2 inhibitor, originally in-licensed from Janssen in 2014. The drug recently started two P2 studies in MDD and insomnia patients based on preliminary positive efficacy in a small P1b study in MDD patients who also suffer from insomnia. Orexin 2 antagonist could be a safer alternative to traditional sleep medicines as well as Merck’s recently approved dual orexin 1/2 inhibitor, Belsomra.

Limited composition of matter patent protection is a significant issue since Minerva is not going after orphan diseases. The company hopes its formulation patents to prevent (or at least delay) generic competition. The primary issue with owning the stock in 2018 is the lack of catalysts but valuation is attractive ($242M with $130M in cash expected at year end).

Two additional CNS stocks to watch: Denali and Ovid

Two other CNS stocks on my watchlist are Denali Therapeutics (DNLI) and Ovid Therapeutics (OVID). Both employ a more “precision medicine” like approach by pursuing genetically validated targets and or biomarker-defined patient populations.

Denali’s lead program is DNL201, a LRRK2 inhibitor for Parkinson’s disease that just completed P1. While there is a strong rationale for targeting LRRK2 in Parkinson (activating mutations are linked to Parkinson), DNL201 (while at Genentech) generated a safety signal in monkeys that prompted the FDA to issue a partial clinical hold. Last month, the FDA lifted the hold, which will allow Denali to test the therapeutically optimal doses of the drug in patients. P1 data demonstrate very good target engagement, which further de-risk the program. The company is expected to start P2 with DNL201 or a backup compound later in 2018 so efficacy data is still 18-24 months away. The company has a broad preclinical pipeline for other diseases including Alzheimer’s and ALS, all programs will utilize a biomarker for patient selection.

Ovid’s lead program is OV101, an isoform-selective GABA agonist that was originally developed by Merck and Lundbeck for insomnia (generated P3 data). Similarly to Sage’s molecules, OV101 can activate a discrete subset of GABA receptors (extrasynaptic, delta subtype) but according to Ovid, OV101’s unique feature is its ability to activate the receptor even in the absence of the natural ligand, GABA. The company is pursuing 2 genetic disorders (Angelman and Fragile-X syndrome) where GABA levels are decreases, but the drug does not directly target the underlying genetic defect in these syndromes. Another factor to bear in mind is the short patent protection which means the company will have to rely on market exclusivity for orphan diseases. Ovid’s second drug is a CH24H inhibitor for rare genetic types of epilepsy, currently in a small P2.

In both cases, I amwaiting for a cheaper entry point given valuations. ($1.54B for Denali, $234M for Ovid).

Portfolio updates

I am buying more Xenon and initiating a new position in Minerva. While neither company is expected to generate clinical proof of concept data in 2018, I still think valuations are compelling. I am also initiating new positions in Zymeworks (ZYME), Madrigal (MDGL) and Viking (VKTX).


Portfolio holdings – January 14, 2018

portfolio - 14-1-2018 - after changes

biotech etfs - 14-1-2018

70 thoughts on “After a long stagnation, is CNS starting to crack?

  1. Thanks Ohad for this very interesting update (as usual!).
    I wanted to comment on SAGE-547 in PPD. The most severe PPD
    being often bipolar depression (diagnosed or not yet diagnosed)
    SAGE-547 could be quickly “discovered” by psychiatry (i am myself)
    as bipolar depression is an area of treatment resistance. Could then
    have a wider reach clinically…

  2. Thanks Ohad
    Very informative review of the CNS field.
    You left aside VYGR – a company entirely focused on CNS. As focused as DNLI but less expensive. A lot of data in 2018 from their Parkinson program plus IND in ALS, Huntington and Friedreich’s ataxia.

  3. Just to add a little bit of information about the incidence of PPD in the general population the rate is more between 5-15% of post-partum episodes. The higher bracket (10-15%+) seems more clinically sound. With bipolar it is more like 30-50% risk of PPD and hypomanic/manic psychotic episode. Also the impact on the child attachment is very detrimental and lifelong. I am an adult (25% clinical time) and child psychiatrist (75%). For a recent article see Rasmussen (2017) on PubMed.
    A fast acting molecule that works and is well tolerated and doesn`t induce manic episodes could be a real game changer!

  4. Ohad…..Thanks for the update ! Will you be responding to the questions you had on the last update from Jan. 9th – Jan. 13th ? I would be VERY interested in your comments on ZYME ! I had the impression that you were not a big fan of Bi-Specific Antibodies.

  5. thanks a lot for the update!

    XENE current cash lasts about 1 year acc. to them – not sure how they will finance. any concern for you?

    Would be nice to hear your brief rationale for both ZYME and VKTK (owning both myself). I like the P2 results of SARM program (VKTK) although most seem to be in it for the NASH opportunity (due to MDGL results)


  6. Thx, Ohad, for your expertise and generosity. You’ve held BIS in your online portfolio since June 2015. I’ve read that leveraged ETFs aren’t recommended as long-term holds because of daily rebalancing. I’m curious — do you actually own BIS, and do your updated gain/loss statements accurately reflect your account? Or are you just checking share price periodically and calculating valuation from that? Also, do you plan to hold BIS?

  7. Georges18 (SAGE) – Thanks for this info, very interesting. From the get go, SAGE characterized its molecules as agents that “cool down” the brain so given the fluidity within different psychiatric conditions it could be, as you say, discovered by psychiatry although they haven’t announced any plans to go there. The next expansion is actually essential tremor.
    I realize my PPD numbers are low, I just try to be super conservative there as I am still unclear how a PPD drug will be viewed by physicians and regulators.

    andre (VYGR) – You are right, they are definitely on my watchlist, I am especially interested in their earlier stage programs (HD, ALS, FA…)

    Bouschka (ZYME) – Yes I will. In general I am disappointed with bispecifics to date. T cell engagers (xCD3) have a narrow therapeutic window and the other ones are simply not efficacious. ZYME’s ZW25 is the first time I see decent single agent activity (preliminary and not very durable, but still).

    Christian (XENE) – Yes, their financial situation is definitely a concern but I feel the current valuation already factors that in. I think their epilepsy molecules have a high likelihood to become drugs and the market will hopefully start to realize it.

    ZYME – See my response above.
    VKTX – I view them as a fast follower to MDGL. Safety profile is a concern.

    cg (BIS) – Yes I actually hold BIS in my personal portfolio too. I view it as a hedge and a way to go short on large biotechs which I am not optimistic about (biosimilars, pricing pressure, patent expirations etc.) while still investing in smal/mid caps which will have to be acquired by large companies in order to provide topline growth. I plan on holding BIS.


  8. Thanks for the write up Ohad. Good to see you like NERV. FWIW NERV claims in its latest 10Q that MIN101 already has a granted patent upto 2035 and they have filed for an additional patent to give them protection beyond that.

  9. Hi Ohad,

    Thanks for sharing this interesting post.
    How do you view MRNS vs. SAGE?
    On the Ketamine front – you mentioned Eskatemine and Rapastinel. Do you follow also VTGN?


  10. Hi Ohad
    what are the 2018 catalysts for ABEO and BOLD?
    does SAGE at those levels is still a buy?

  11. paul – Thanks! I

    on January 15, 2018 at 4:19 am said: Edit
    hi Ohad
    once again a fantastic new blog entry… best biotech blog
    do you have a opinion on any of these: GERN, GTHX, ARMO (,,
    best regards, Paul

    richard trent on January 15, 2018 at 5:53 am said: Edit
    Thanks for the write up Ohad. Good to see you like NERV. FWIW NERV claims in its latest 10Q that MIN101 already has a granted patent upto 2035 and they have filed for an additional patent to give them protection beyond that.

    Amit on January 15, 2018 at 6:45 am said: Edit
    Hi Ohad,

    Thanks for sharing this interesting post.
    How do you view MRNS vs. SAGE?
    On the Ketamine front – you mentioned Eskatemine and Rapastinel. Do you follow also VTGN?


    Alex on January 15, 2018 at 6:47 am said: Edit
    Hi Ohad
    what are the 2018 catalysts for ABEO and BOLD?
    does SAGE at those levels is still a buy?

  12. paul – Thanks! I know GERN and ARMO to some extent but don’t have a concrete opinion there. ARMO’s concept is certainly unique and provocative, not sure how string the clinical signal is.

    richard (NERV) – Right but that’s not a composition of matter patent.

    Amit (MRNS/SAGE) – Not sure I am the right person to answer that after selling MRNS at its 52 week low… SAGE-217’s poc represents a major threat to MRNS as it is oral, highly potent and selective. Don’t know VTGN well.

    Alex (ABEO/BOLD) – For both stocks the main catalysts are clinical updates. For ABEO, updated data on ABO102’s high dose and preliminary data for the MPSIIIB program. For BOLD, updated XLMTM data and A first look at the CN program.

    Yes, I am still holding SAGE at these levels. The potential in depression is too big to ignore.


  13. i have found this blog looking for biotech investments which i hardly know anything about except for a few trading success way back. i’m mostly into high tech for much of my investments.
    in comparison to other biotech infos online, i like this the best and have bought a basket of stocks since last december, perhaps 2 days after reading the latest 3 blogs.
    i certainly don’t want to miss what you guys are having.

  14. It’s seems like there were no surprises judging by the muted price action in $exel shares when their abstracts were released earlier today. What is the next catalyst that can move shares in the near term besides earnings?

  15. hi Ohad

    have you ever looked at ADVM Adverum?

    seems go be trading close to cash – rather well financed for a small company. first IND last year, now two more INDs planned for second half of this year.

    maybe you have looked at them?

  16. *lol*

    I searched for ADVM in this thread, but of course it doesn’t search graphics. so thanks a lot.

    chart looks really good for this one…. bottom fishing

  17. Ohad
    Solid Bio started P1 in DMD using AAV9 to deliver microdystrophin.
    Is there concerns w/ high systemic doses? And what is considered high dose?

    SLDB didn’t talk in the S-1 about the doses but in animal tests used 2 and 4xE14 vg/kg. Last week Wilson resigned from the SAB due to “emerging concerns about the possible risks of high systemic dosing of AAV”
    Should we get concerned about other GT with systemic delivery.

  18. hey Ohad,
    Nice to read this new update about CNS area. Yes, seems it’s come a long way, also thanks to companies like SAGE. You were an early investor in SAGE when the company was just testing its hypothesis. One of my top picks in the CNS is VTGN– hopefully with some positive ph2 in the next 6 months. The company is in exactly the same market as SAGE (depression, which as you state is huge). VTGN market cap is $30M. The positive readout for Esketamine seems to point at the potential of VTGN.

    I wonder if you have looked at Mustang Bio – they just hired Car-T veteran Leitchman as CEO and seem to be making some good progress.

    Thanks for you insight!

  19. RAM – Thanks and welcome.

    Larry (ATRA) – Haven’t looked at them for a while

    Sam (EXEL) – Yep, that’s what the market expected. Enough for approval but commercial prospects are unclear. The next big event is atezo+cobi P3 data, it’s a high risk event especially based on the underwhelming data from ASCO GI this week.

    Christian (ADVM) – I also like their low EV. Still no clinical data but their indications and strategy are unique.

    andre (SLDB) – That’s a good question. We know from AVXS that 10^14 AAV9 is safe in babies but in order to reach the muscles efficiently they may have to go higher. Same applies to SRPT’s GTx.

    DAn (VTGN/Mustang) – Sorry don’t know them well, will take a look.


  20. Hi Ohad,

    Happy new year!

    What’s your detailed take on the ASCO GI results for Atezo+Cobi’s PIb in mostly MSS CRC? The A+C median OS figures of 10 months for mostly MSS patients seem better than what you might see w/ Regorafenib with a median of 6.4 months and this is the control. There will be fewer KRAS mutant patients in the PIII and it’s also unclear if the MSI status in PIb will be comparable.

  21. Ohad
    ABEO expects to have 3 products on the market in the next 12-24 months, plus 2 trails in late stage Phase 3.
    That’s remarkable but it looks that the market cap does not reflect that – only 700M. Why such scepticism ?
    Using a simple metric- cap per drug on the market in 2021/22 – it is by far the least expencive stock in your portfolio.

  22. hi Ohad

    what do you think of the updated Enco + Bini + Cetuximab data in BRAF-mutant metastatic colorectal cancer ?

    — Median PFS of 8.0 months at time of analysis —
    — 48% confirmed ORR, including 3 complete responses —

  23. “The next big event is atezo+cobi P3 data, it’s a high risk event especially based on the underwhelming data from ASCO GI this week.”

    What!! Underwhelming?

    Your kidding right?

    42 MSS patients with median OS of 13 months. Total 84 patients around 10 months median OS. Only 18 patients out of 84 didn’t receive 5 or more lines of prior therapy. Regorafenib arm is only expected to perform at 6 months median OS. This phase 3 is about as close to a slam dunk as you can get.

  24. Ohad
    SNY is in talk to buy BIVV for 11.5B, mainly for the Hemophilia A and B drugs.
    Hem A – 7B and Hem B – 1.8B plus about 3B for the rest of the pipeline and cash.
    It would be interesting to see how ONCE and QURE trade tomorrow.
    QURE will be on the market in 2020 with Hem B (if trails go well), so quite a bit of room to grow in the next 2 years.
    Any interest to add them to the GT portfolio?

  25. isn’t ARRY a good takeout-candidate for 2018…?

    hardly anbody mentions this name on their potential M&A-lists, but ARRY could be interesting for a bigger player imo.

  26. Wildbiftek (EXEL) – I actually thought the data were disappointing. ORR shrank to 8% and the OS assumptions are not reliable in my opinion. Not optimistic about P3 data, not to mention the fact that we are talking about two targeted expensive drugs.

    Andre (ABEO) – Both Sanfilippo programs are exciting but their market potential is limited (~2000 patients), which may explain the discrepancy. The DEB market is larger but there I am not sure the market ascribes high likelihood of approval.

    Christian (ARRY) – With the caveat of a single arm 3-drug combination study, I think results look very strong. Much better than atezo+cobi (for a different CRC subset).

    Chris (EXEL) – It’s hard to rely on OS in this trial setting without a control arm imo. Hope I am wrong…

    andre (BIVV) – Can’t understand that deal in light of emerging programs (GTx +
    emicizumab). Still on the fence regarding QURE, interested in additional programs they advance.


  27. “Chris (EXEL) – It’s hard to rely on OS in this trial setting without a control arm imo. Hope I am wrong…”

    I hear you, but we’re you expecting a higher response rate in 5th line plus setting? Trying to get a grasp of what you expected in the salvage setting disease population?

    The phase 3 study has 3 arms total patient population of 360. Only 120 patients in each arm demonstrates the confidence Roche has in this phase 1 signal.

  28. Hey Ohad

    is it time to take a look at IMGN again, with pivotal results due in next 6 months?

  29. Ohad- You had previously stated you weren’t too familiar with VTGN. Have you had a chance to do any due diligence?Very small market cap that is involved in depressive disorder and will be giving a update on their phase 2 study of major depressive disorder at Noble Con on Monday after the close. This small name may start to get a lot of attention.Also just raised money at 1.50 a couple months ago, so dilution isn’t something that is needed at this time.

  30. Chris (EXEL) – Hope I am wrong but a 8% response rate with two novel agents doesn’t get me excited, hope I m wrong…

    bouschka (CLDX) – Hrad to say…. need to revisit their pipeline

    DAn (IMGN) – IMGN will always have a warm place in my heart. I was glad to learn they also have a BCMA ADC program with amgen. It’s in the clinic for more than a year, i think so don’t know when to expect data and whether it’s good. I really liked the GSK data. I have mixed feelings on the FRa program, definitely active but not sure efficacy is sufficient as monotherapy.

    David (VTGN) – Sorry, still didn’t have a chance to dig in deeper.


  31. Hey Ohad,
    Thanks for sharing your perspective on IMGN! I was intrigued by mitochondrial peptides company CWBR they are going after metabolism diseases such as NASH an diabetes. Still preIND company but with several molecules about to enter clinic. I like the concept and wonder if you have any opinions? Market cap is quite high given stage of development but seems that investors are quite high on expectations for meaningful results

  32. Hi Ohad,

    Thanks for all your insights and so good to see so many if your expectations come to fruition!

    In the wake of Juno, Kite and Blue’s progress can you comment on BLCM, CLLS? Also Citi’s views on ESPR v/s MDCO?


  33. hardly a month as a newcomer to biotech, my basket of 15 of the cheap stocks from this portfolio has gained 16.48%.
    i thinks many of them will continue with gene therapy’s progress.

    january of 2016 was the turning point in cloud computing and networking after a brief correction when we scooped up the best of them. i wish i knew in 2017 about biotech events and opportunities as briefly and clearly explained here. i’m glad to be catching up. thanks a lot Ohad.

  34. HI Ohard,

    AGTC currently under net-cash if I saw it correctly. do you see any really interesting programs in their pipeline?


  35. Ohad
    important day for ABEO is approaching – WORLDSymposium 2018 On Lysosomal Diseases; Thu, Feb 8, 11:00am; Kevin M. Flanigan
    “A phase 1/2 clinical trial of systemic gene transfer of scAAV9.U1a.HSGSH for MPS IIIA: safety, tolerability, and preliminary evidence of biopotency”

    They may present data everybody is waiting for – neurocognitive results.
    Any concerns about the data since they were delayed from Q4-2017

  36. Hello Ohad

    have you heard about the paper from Jim Wilson, who is reporting on severe side-effects with high doses AAV9 in NHPs?

    could be something not to ignore. several GT companies punished today.

  37. Christian
    my first impression is that Wilson was using engineered AAV9 (AAVhu68) vector, while AVXS – native AAV9. This might explain the higher toxicity in his experiments.

  38. SGEN acquiring CASC, another ARRY-work

    price is anyway somewhat disappointing after the long way southwards of the stock. I think that even with this takeover price my position is a little under water… but anyway small position

  39. DAn (CWBR) – Never heard of them, will take a look.

    Les –
    BLCM – need to re-visit following the recent clinical hold. I still like their technology for CAR applications because it’s clinically validated.
    CLLS – Waiting to see more data following the AML story.

    ESPR/MDCO – To me they don’t compete for the same segment. For most patients, an oral alternative will be the preferred way to reach target LDL levels.

    RAM – Thanks and good luck.

    tom (RGLS) – I like the re-orientation towards renal indications, preclinical data look quite good , still a lot of risk related to the delivery of antagomirs to the kidney and target selection.

    Christian (AGTC) – I like the XLRP program with Biogen (compete with NITE), still no clinical data though.

    andre (ABEO) – Indeed, I am anxiously waiting to see neurocognitive data from cohort 2 although I am not sure they will have sufficient follow up (1 year). I don’t think the delay has any implications, good or bad.

    Cloud (ALDR) – No strong opinion there. There is going to be stiff competition…

    Christian/andre (AVXS) – Although the Wilson paper used a variant of AAV9
    and material wasn’t GMP-grade, it is hard to ignore and clearly disconcerting. Demonstrates the need to find vectors with good CNS tropism and all of the sudden AVXS’s decision to use intra-thecal admin for SMA2 looks pretty smart…

    Christian (SGEN/CASC) – Strange deal, I think CASC got an attractive deal.


  40. Hi,

    Any opinion on Arcturus, $ARCT? Moderna is similar in RNAi and now being valued at $7.5B while ARCT is at $75M, with over $5B in potential milestones down the line with big name partnerships.


  41. hi Ohad

    there were some inital data on AFMD, see release 1. Feb. What do you think of them?

  42. Ohad
    I am also interested in your take on the AFMD data.
    Especially as a single agent in relapsed/refractory CD30 lymphoma data
    N is very small (3) but they had 100% DCR (1 CR, 1 PR and 1 SD). And this with the lower dose in the dose escalation study. Probably the opportunity is small (2-d line) but their valuation is also small (ev ~30M)

  43. Ohad,

    Why ALNA looks attractive? Did they fail the P2 study by missing primary endpoint?


  44. Hey Ohad,

    Another CNS play for which this might be good timing, considering it went down 30-40% on news or resignation of CMO combined with Kerrisdale short attack, is PRTA– they are partnered with Roche for a program targeting PD and other orphan CNS diseases, it targets the synuclein pathway.
    Have you ever looked at them?
    High risk but strong science.
    Read out coming for their amiloydosis program in Q2.

  45. Hello Ohad, What is your take on the secondary offering announced by ADVM? They don’t seem to desperately need the money and they are having some clinical data after first patient dosages in less than a month…Why they didn’t wait to release that data (assume they will have to release as is material info) and raise cash after that data, if data is good the PPS would appreciate and they could rise at higher price, are they not expecting perhaps that good data? thank you for your take.

  46. Ohad
    ABEO trail – some positive neurocognitive data in the presentation by Kevin M. Flanigan.
    – 2 of 3 in Cohort 1 improved neurocognitive score at 1 year vs NHS
    – 2 of 3 in Cohort 2 improved neurocognitive score at 6 mo vs NHS
    – time and dose dependent effect
    Not a home-run (improvement in the absolute score) but at least stabilization. Hopefully higher doses in Cohort 3 would do better
    What is your take on these data

  47. Hi Ohad, Biotech’s are taking a beating today. Are you treating all of the market action as transient/correction and do nothing? an opportunity to buy? (Little late to sell?). Any action on BIS? Would love to get your thoughts/approach.

  48. Ohad curious your thoughts on any of these

    Cdtx – has early stage ADC
    Kalv – kallikrein inhibitors
    Selb – Anti-Drug Antibody (ADA) Mitigation Programs
    SYBX – Microbiome

    Still can’t comment $lptx? Just blink twice if you like it 😂

  49. AVEO/EUSA just reported preliminary Phase 2 Tivozanib/Nivolumab combination results for RCC. About 2/3 partial response with typical 40% tumor shrinkage, and 1/3 stable disease, e.g. 100 percent control rate over first 4-8 months of treatment.
    Combination was well tolerated. Basic question is, how do these results compare
    with present treatments (measured over the same time span)? If they were to hold up in a larger sample (presently about 20 patients, 1/2 treatment-naive), are they good enough to justify any accelerated consideration by FDA? An exploration of the triple combo with ipilimumab appears to be in order.

  50. Biosimilar

    Ohad do you invest in Biosimilar companies? How do you like the prospects of Biosimilars?

  51. John (ARCT) – Indeed a much cheaper play on mRNA compared to Moderna. Have to admit I am still skeptical especially on the enzyme replacement approach for liver diseases, need to see data in humans with an emphasis on durability and ability to dose multiple times.

    Alex (SNSS) – No idea.

    ALEX/andre (AFMD) – Hard to interpret the data another PD1 add-on…

    Cloud (ALNA) – Approach is interesting and novel, not sure about failing P2 but agree data were somewhat underwhelming.

    DAn (PRTA) – I am starting to look at them given the recent pullback. The synuclein program is a high-risk one, similar to the Abeta hypothesis. AL amyloidosis P2b data is imminent but from what I recall the biomarker they are looking at did not generate a clear clean signal in a previous study. Still a good capable team.

    lgonber (ADVM) – Very surprising given their strong cash balance. Not sure what type of data they should have by now.

    andre (ABEO) – Agree not a home run but I tend to go with the biomarker data and believe neurocognitive improvement will emerge with time especially in younger patients.

    Les (BIS) – Hard to say, I have been waiting for a correction for a long time but it still hasn’t happened. I plan to keep my BIS position as a a hedge vs long position in smid caps, large biotech stocks are starting the feel the heat from biosimilars and pricing pressure.

    Alex (OVID) – Still waiting…

    Robert Goulet – Of the two I am following SELB and SYBX. The SELB program could become very important for gene therapies but they need to show clinical validation. SYBX – I like the approach of engineering bacteria to secrete proteins in the gut, but also need to wait for clinical validation.

    Chris (AVEO) – Looks too little too late for an accelerated path but perhaps the benign safety profile will help in the future.

    Hoalo – No exposure to biosimilar stocks but I am a strong believer in the field and it will have a significant impact on US pricing imo given what we see in Europe.


  52. Hey Ohad. APTO has a pan-FLT3 / BTK program. They will start testing this year in AMD and CLL. You like the approach or any concerns regarding safety?

  53. Ohad
    There are new FDA guidelines on some CNS diseases:
    DMD, ALS, Alzheimer/Parkinson, Migrane, Epilepcy.
    They somehow supports what you said about the importance of the bio-marker data (ABEO case). They are now considering accelerated approval based on bio-markers, not clinical data?!?

    Your portfolio covers well ALS and Epilepsy. I am wondering I you would consider expanding it with stocks in the field of DMD (SRPT, SLDB, WVE…) and Alzheimer/Parkinson (VYGR, SGMO PRTA…).

  54. Hey Chad,
    I have been following SELB since the deal with ONCE. cash position is $100M, market cap $190M. Would this be a good entry point, also considering pending gout results?

  55. Hello Ohad ! I see where OVID has dropped substantially. Will you be adding it to your portfolio ?

Leave a Reply

Your email address will not be published. Required fields are marked *