Spark’s Hemophilia A data indicate best-in-class profile

Last month Spark Therapeutics (ONCE) reported initial results for SPK-8011, its hemophilia A gene therapy program. Despite their preliminary nature, the data are very positive and put Spark in a strong position vs. Biomarin (BMRN) and its Hemophilia A gene therapy, BMN270. Providing the signal is corroborated with additional patients, results may have broad implications on the liver-targeted gene therapy.

Spark disclosed data for only two patients who received a low dose (5×1011 vg/kg) of SPK-8011 and achieved 11% and 14% factor VIII (FVIII) activity after 23 weeks and 12 weeks, respectively. The company also disclosed that a third patient who received a higher dose (1×1012 vg/kg) had a higher FVIII expression but actual numbers were not given. Safety profile looks clean so far: No immune reactions, liver enzyme elevations or corticosteroid use were reported.

11%-14% FVIII activity is considered clinically meaningful (should obviate the need for chronic injection of hemophilia drugs), but the ultimate goal is getting patients to 40%-50% which is expected to allow patients to live almost normal lives without major bleeding events.

SPK-8011 has impressive potency

SPK-8011’s main competition is BMN270. BMN270 is expected to enter P3 in Q4/2017 based on a positive 15-patient P1 which demonstrated high (in some cases too high) FVIII activity levels. Although comparing SPK-8011’s activity with that of BMN270 is tricky (cross trial comparison, only two patients in Spark’s study etc.), SPK-8011 appears to be dramatically more potent based on the data for BMN270’s first two patients. BMN270 was given at doses that are 12-fold and 40-fold higher than SPK-8011’s initial dose of 5×1011 but FVIII activity was only 1-2% (see table below).

SPK8011 VS BMN270

Spark’s PR stated that the third patient who received 1×1012 vg/kg had FVIII activity that was “proportionally higher, consistent with the dose escalation”. This patient probably has limited follow up but it would be plausible to expect a stabilized ~25% FVIII activity at week 12, which means Spark is very close to reaching its P3 dose that will likely be an order of magnitude lower than BMN270’s P3 doses (Biomarin is testing two doses in its P3).

Dose level as an important differentiator

While the relationship between dose, safety and efficacy in gene therapy is an evolving area of research, there is a consensus around the need to use the lowest dose possible. This is true for all drugs but especially relevant for virus-based gene therapy, which involves flooding the body with huge amounts of virus particles the body views as foreign. To put things in perspective, the second dose in SPK-8011’s study involves injecting ~70 trillion viral particles, double the number of cells in the human body. Biomarin is using ~3500 trillion (3.5 quadrillion) viral particles in its BMN270 study.

There are two primary reasons for preferring lower doses: Safety and variability.

Safety – In gene therapy there is a clear correlation between dose and an immune reaction against the viral capsid. The higher the dose, the higher the risk is for an immune response. This may lead to side effects as well as destruction of the infected cells  that resultssin loss of protein expression. In BMN270’s study, most patients experienced some ALT elevation and some required steroid treatment. Spark also reported liver enzyme elevations in some patients in its hemophilia B program (SPK-9001). Although most of these elevations appear manageable with steroids, they require frequent monitoring.

On top of near term safety considerations, there is also the long term safety aspect. AAVs were chosen as gene therapy’s workhorse because they rarely integrate into the human genome, however, integration may still occur at a very low frequency. These integration events, no matter how rare, may carry the risk of carcinogenicity (there are other mechanisms in place to prevent that like tissue-specific promoters). Because integration events are dose-proportional (more viruses, more potential integration events), physicians are likely to prefer gene therapies that can be given at lower doses.

Variability –Although there is not enough data to enable us to draw firm conclusions, it appears that variability increases with dose, which may result in excessive protein production in some patients. In BMN270’s study, there was a wide range in FVIII activity in the seven patients who received the highest dose (20%-218%), including patients who had excessive levels that may increase long term risk of thrombosis. The range was much narrower in BMN270’s lower dose (24%-41%), which may explain Biomarin’s decision to test both doses in P3. The error bars in the figure below demonstrate the clear difference in variability between the doses.


As gene therapies are given once and from that point are impossible to control, there is a strong preference towards a predictable clinical profile (especially long term expression levels). In fact, some physicians may prefer a predictable profile over expression level assuming there is clinically meaningful protein expression.

Best-in-class vector may be relevant for other liver diseases

SPK-8011’s data are still very limited and require further corroboration but the emerging profile is of a best-in-class hemophilia A gene therapy that will be safer, more predictable, easier to produce and require less monitoring. This alleged superiority likely stems from Spark’s decision to use an engineered vector (Spark 200) that appears to be superior to that used by BMN270 (AAV5). This demonstrates the crucial importance of vector design and probably the first data which demonstrate that an engineered vector can lead to superior outcomes compared to naturally occurring vectors.

If the data hold up, Spark 200 may become the vector of choice in liver-targeting gene therapies, which cover a broad range of diseases. This is a clear threat to REGENXBIO (RGNX), which is the dominant liver gene therapy player following the acquisition of Dimension Therapeutics (DMTX). REGENXBIO also controls rights to AAV8, its flagship vector for liver diseases. It would be interesting to see data from Shire’s Hemophilia A program (SHP654/BAX888) which utilizes REGENXBIO’s AAV8 next year.

Portfolio updates

I am selling Dimension Therapeutics following the acquisition by REGENXBIO and buying more AGTC (AGTC). I am also adding a second position in Kura Oncology (KURA), which reported positive results for tipifarnib in HRAS-mutated head and neck cancer last week. More on Kura next time.


Biotech portfolio – September 10, 2017

Biotech portfolio - 10-9-2017 - after changesbiotech etfs - 10-9-2017

148 thoughts on “Spark’s Hemophilia A data indicate best-in-class profile

  1. Ohad, thank you for the blog.Want to have your opinion on Immunomedics ADC IMMU 132 in TNBC/UC. Duration of response, ORR, PFS, OS all seem promising.

  2. provocateur (IMUC) – Activity is definitely there and the approach of using less potent payloads seems to pay off given the limitations of new payloads (maytansinoids, auristatins etc.). Haven’t looked at them in a while, perhaps worth another look given challenges with new ADCs.


  3. Christian (ARRY) – Very nice! The BEACON run-in data look good, high ORR (41%) and durability looks good so far. For a triplet combination ,nice to see safety profile is reasonable.


  4. hi Ohad

    thanks for feedback on ARRY

    I guess you dont intend to add ARRY at current valuation (1,9 billion USD)


  5. Alex (SNSS) – Probably a glitch.

    Christian (ARRY) – Yes, valuation is quite high and data from BEACON is at least 2 years away (1ry endpoint is OS).


  6. Appreciate your thoughts as well especially GT!

    FWIW BRMN docs on calls seem to prefer normal range 50-150% then 10-40’s even with theoretical thrombotic risk. One doc mentioned hypothetically risk could be reduced in Hemophiliacs. Also concern with microbleeds when not in normal range causing problems (joints, cartridge etc.). Also the preexisting antibody issue would seem to favor BMRN in ability to address more patients.

    Nothing against ONCE as a company certainly one of the more successful GT companies and advancing multi programs well (as can’t be said for several others in the field)!

    With regards to AGTC are there any particular programs of interest/value or more a general GT bet/management bet?

  7. Should clarify that docs prefer the slight risk of being above the normal range then being below normal range.

  8. Hi Ohad,

    So far so good on FCSC!

    Another one i have is MRTX, Mirati therapeutics. Presenting next month on their drug Sitravatinib that is similar to LOXO/RXDX in precision oncology, however primary targets RET and others which is higher % of patients than TRK in NSCLC.

  9. Hi Ohad,

    Excellent article as always. Do you think now is a good time to buy ONCE? I think it’s fully valued at this moment but I really like their pipeline.



  10. Scott-

    NLNK – Data are surprisingly positive. Personally, they make me question my opinion on IDO (although I am still skeptic in the absence of randomized data). What is more impressive/suspicious (depends on your perspective) is the fact that indoximod is considered a rather weak, less selective IDO inhibitor.

    RXDX – Clear activity for both ROS1 and RET cohorts, still not sure the drugs are differentiated.

    jh (SAGE/MRNS) – I am sticking with SAGE to the end (hopefully not bitter). MRNS is definitely an option but their data is too preliminary.

    Maurice (BMRN) – Yeah, agree it’s debatable and nobody knows for sure what level is ideal. I think the fact even BMRN decided to take the 4×10^13 dose to P3 implies they are not sure either.

    AGTC – More of a general bet. They have several programs and plenty of cash.

    Rob (MRTX) – Their molecules have been in development for several years now and so far they couldn’t identify a path forward last time I checked. Their molecules are non-selective and inhibit VEGFR2. I prefer LOXO’s highly selective approach in biomarker defined tumors.

    Mike (SYBX) – Very innovative and cool approach. Still early and a lot of uncertainty as with all other microbiome companies but at least in their case the rationale is straightforward (in metabolic diseases like UCD and PKU).

    Chris (ONCE) – Thanks. I am considering adding more before ASH, prefer to wait until the Luxturna Adcom as expectations are very high.


  11. Andre (ITEK) – Yep. Let’s see how things look after the dust settles. Looks like they are going after the BLUE model – ex-vivo lentivirus-based treatments for hematology.

  12. Ohad I just listened to AGTC earnings. They stated they saw no biological evidence with their XLRS trial as of yet. Said they need a bigger pool of candidates as well as to evaluate the high dose group. Are u concerned? They seem to think its normal given small group dosed ??

  13. Ohad AGTC CEO stated it wasn’t unexpected that they wouldn’t see biological evidence in the dosed patients in the XLRS trial. I read the mice trial they conducted awhile ago and biological evidence was observed in a shorter period of time. Need your thoughts?? Thanks

  14. I am afraid XLRS is dead. After 15 pts they do not have any biological activity?!?
    And the argument for 6 additional pts is just silly:
    CEO: “So I think it’s the variability in the test combined with the variability from patient-to-patient that warrants us needing a higher number of patients before we can accurately analyze the data.”
    It does not make sense – variability should work in both directions. By now at least one should have been showing some biological activity, even by blind chance.

  15. I’m afraid also that AGTC XLRS is dead. The only chance is at high dose level we see biological activity. In their mice model they did observe activity and it didn’t take 6 months. Wanted to get Ohad’s view on this. AGTC share price was pummeled yesterday. If XLRS is dead where does this leave AGTC?

  16. Alex (DEPO) – Sorry, not following them.

    Luigi/andre (AGTC) – Yes I am concerned. Although it is hard to rule out an effect that will emerge later on, I have limited expectations for this program. Many of those rare diseases are uncharted waters in terms of clinical progress, it makes sense that in some indications more follow up is needed, I just don’t know if this the case in XLRS. The fact the drug is given intravitreally is another overhang as this mode of administration is yet to be validated for gene Tx in humans.


  17. hi Ohad

    I posted a link to critical SA-article on NLNK here the other day; could you look at it?

    Best regards

  18. Ohad Hammer on September 14, 2017 at 5:44 am said:
    Yep. Plenty of cash and multiple shots on goal.

    I think the recent CMO departure is related to the XLRS drug

  19. Mike I couldn’t agree more. Out of nowhere he abruptly quits to pursue other things. No mention of this by Sue Washer on call yesterday. Absolutely there is a link between CMO quitting and XLRS issue.

  20. CMO choosing not to inject subretinal cost him his job…I sold well over half just after the announcement…I saw the writing on the wall….still like them…could be a very nice buying opportunity like $dmtx was

  21. Any thoughts on reverse merger between ITEK and Rocket Pharma?
    Rocket Pharma seem to have some interesting GT vectors but seems preclinical, maybe about the same stage as ADVM or earlier. If ADVM has negative enterprise value, makes ADVM a better buy?
    Why not the IPO route given lofty biotech valuations?

  22. $ARQL Any thoughts on catalysts and the insider buying by the CEO, and financing models possible for ARQL at this point ? What is the likelihood of a buyout ? Seems to be that they have FGFR2 and a BTQ inhibitor which might be an attractive asset, what would make this a good buyout target ?

  23. Any observations on recent IPO of Clementia Pharmaceuticals (CMTA) and lead-asset palovarotene (in Phase 2 ) having first-to-market potential in fibrodysplasia ossificans progressive and multiple osteochondromas using retinoic acid receptor gamma agonists [RARs] that ‘are involved in the growth, shape and maintenance of tissues? They state they are also looking to begin Phase 1 ophthalmic formulation studies in early 2018 for the treatment of eye diseases.

  24. Ohad
    NITE prospectus is out:
    Choroideremia data look very strong – 94% keep or improve visual activity.
    Phase III to start in H1 2018.
    ONCE is quite a bit behind with Phase I/II dose escalation studies.
    Are you going to get some shares at IPO or wait the price to settle?

    Another interesting IPO – ZLAB, but probably you will not like it bc is not innovative, or I am wrong here…

  25. Ohad
    You may have soon to include SRPT into the gene therapy basket :):)
    They will start in Oct a Ph1/2 DMD trail with microdystrophin using AAVrh74 virus.Data at the end of February.
    In mice they had 100% skeletal muscle restoration. Hopefully they will reproduce that results in kids – two groups in the trail: one w/ 3 months to 3 years, and the other – 4 to 7 years kids. Hopefully it works well, bc the current exon skipping is a

    NITE published the prospectus. Their choroideremia data look very good and much advanced compared to ONCE. They are starting Ph 3 in H1 2018, while ONCE is still in p1/2 dose escalation studies.
    Any interest in their IPO?

  26. Ultragenyx Pharmaceutical Inc. (RARE) made a bid to buy Cambridge, Mass.-based Dimension for $5.50 per share or about $138 million.

    should have waited a little bit more.

  27. Christian (NLNK) – Didn’t see it.

    Mike (AGTC) – Don’t know for sure but definitely not good news…

    Jaime Allen (CFRX) – Haven’t looked at the for a while.

    Roland (ITEK) – ITEK needed a technology immediatelly and Rocket got a ticket to NASDAQ at a stage which is not IPO-relevant.

    curiousgeorge (ARQL) – Always good to see a CEO buying shares at the market price. Impossible to predict M&A.

    andre (NITE) – Agree although data set is limited. I plan to buy at the open market after the IPO.
    Will take a look at ZLAB.

    andre (SRPT) – Interesting idea but valuation is high based on the exon skipping data (which I believe is not meaningful).

    druz (DMTX) – Indeed ;(


  28. DMTX Scientific Advisory Board
    Emil D. Kakkis, MD, PhD; President and CEO, Ultragenyx Pharmaceutical
    It explains the higher RARE bid – he has first hand inside info about the OTC and G6P programs.

    BMRN is also a gene therapy company (AAV-VIII vector for Hemophilia A).
    But I guess is too big for your GT basket

  29. Ohad
    any comments / suggestions you can provide
    on VBLT / Vascular Biogenics.
    They had a nice run just recently.

  30. Hey Ohad
    Instead of SRTP , CAPR has had a low valuation (but had recent run 120% on DMD program expectations) and might be a better investment. They are in cell therapy business. Any thoughts about their program’s chances of approval?


  31. Hi ahsin Ohad

    Seems that all posts with link are deleted mow (I posted 2 times)

    Anyway the SA article I was referring to regarding NLNK is called “The curious case of the missing patients”. You can easily find it


  32. Ohad,

    I greatly appreciate your biotech acumen and cannot thank you enough for breaking down complex science for laypeople like myself. You are a true gentleman scholar.

  33. Hi Ohad,

    AKTX announced progress that doubled its valuation today. Any comments on the possibilities?

    Thanks for your insights as always!

  34. Ohad

    If I remember correctly, you had a position in Aurinia, but don’t currently see it in your portfolio. The company is enrolling patients in 75+ sites for there phase 111 in volcsporin a oral compound for lupus. What is your opinion regarding possible success for this drug. As I understand it, there are no approved drugs for this debilitating condition

  35. Hi Ohad, Any thoughts on Deciphera and Nucana IPO’ing next week? They both have good VC backing. Thank you.

  36. There is an interesting vaccine company in Austria: Valneva. Interesting because they have the only vaccine in clinic for Lyme disease + fast track designation. So your favorite words “differentiated” or “value driver” can be used :-) Maybe you can take a look?

  37. andre (DMTX) – Not sure what is disclosed to the SAB but he definitely knows the company well…
    BMRN – Following ONCE’s data I think it will be hard for them to compete, plus, as you mentioned, GTx contribution is limited.

    rodolfo (VBLT) – Sorry, haven’t been following them lately.

    Dan (CAPR) – Not a big fan of their approach. all those allogeneic treatments always work great in animals but not in humans…

    Christian (NLNK) – No conclusive opinion there. Limiting the sample size to previously reported patients is not common but I am not sure there is a conspiracy here.

    Coleman – Thanks!

    Les (AKTX) – Interesting story, need to delve deeper. The concept of treating Soliris failures is attractive, not sure what it is based on and how their approach fares vs. other C5 inhibitors.

    Dave (AUPH) – Lups nephritis represents a greeat unmet need but I am concerned about AUPH’s P2 data which were murky at best IMO (death imbalances, geographic subset analysis, dose response issues etc.)

    Deciphera – Their PDGFRb /KIT molecule looks similar to BPMC’s program, good activity in PDGFRb+ GIST but limited opportunity. KIT+ patients represents a large opportunity but efficacy isn’t stellar as monotherapy. The two other programs (TIE2 and CSF1R) have been pursued by other groups without great success.

    Nucana – A surprising IPO to me, next-gen chemotherapy isn’t very exciting imo.

    Mike (Cue Biopharma) – Looks like a neat version of vaccines with a focus on identifying strong epitopes and co-stim. signals, personally I am not a big believer in cancer vaccines. ..

    Toby (Valneva) – Will take a look, not a big vaccine expert…


  38. Are there any upcoming catalysts for TRVN? Price looks like it’s finally bottoming here. Why did you decide to hold after it’s “failure”? Thanks.

  39. Ohad

    RGNX science stems from Dr. James Wilson with DMTX as a sister company Dr. Wilson has ties to both companies. I would think there is a bias to merge under RGNX vs RARE if RGNX amended their bid and is competitive with RARE ?

    As always thanks for your reply.

  40. Hey Ohad

    I think CAPR has shown something in humans.

    Even the failed ph2 ALLSTAR in heart attack patients showed (not statistically signify ant) improvements, the scar size reduction of the control group performed extremely well (which is unlikely for the condition). The CEO noted that the treatment is so new that one of the issues might be that most centers were not trained in measuring scar tissue, here is a quote from CEO.

    “In order to actually measure scar, a dice called gadolinium is used and then the images are carefully reviewed to measure scar before and after treatment. In small numbers of patients done at very few top notch centers, these images were able to be read and analyzed with the high grade of accuracy. We think this carefully created assay of scar measurement by gadolinium enhanced MRI into many centers in larger clinical trials, the assay could not hold up and the noise exemplified that the reduced scar size in the control overcame the potential signal. We know that the use of gadolinium to measure scar by MRI is still an emerging technique.”

    Moreover they announce positive phase 1/2 HOPE DMD trial with statistically-significant improvements in measures of cardiac and upper limb function.
    They have clear regulatory path for DMD.

    it’s still a longshot, but I it has a low valuation and there the FDA has shown a willingness to approve DMD drugs, i.e. SRPT example,


  41. Ohad
    NITE and DCPH IPO prospectus are published by retailroadshow.
    NITE is impressive – solid lead in Choroideremia vs ONCE and in XLRP vs AGTC

    DCPH looks like BPMC in making. Moving into pivotal Ph3 in 4-th line GIST with no approved treatments. Looks a smart move to get to the market as fast as possible.
    BPMC is 2.5B company. Is 0.5-0.6M reasonable for DCPH?

  42. Further, regarding CAPR
    also optimistic about their chances of receiving Regenerative Medicine Advanced Therapy (RMAT) designation. The FDA approved ph3 endpoints for DMD are the same as their successful ph2.

  43. Thanks Ohad for your thoughts. MDGL Madrigal a liver-directed thyroid hormone receptor-ß (THR-ß) agonist used for the treatment of NASH is in P2 as well as VKTX Viking Therapeutics. Not sure of the quality of VKTX’s drugs. Appreciate any thoughts on the mechanism and pipeline.

  44. Ohad, I have missed your advm write up. Interested to know more about it. Can you point me to it? Thanks

  45. Hey Ohad
    GNCA terminated funding and activities for te heroes vaccine to focus on Neoantigens for i/o. What is odd is that they announce the restructuring before partnering or selling off their lead product. Will be harder to get a good deal now, I suppose. What do you think of the announcements and the May management handled this decision?

  46. Hi Ohad,
    Would u add more SNSS shares here? Has been down pretty much since you initiated a position.

    Thanks Chris

  47. Hi Ohad,

    How do you see FCSC’s recent p1/2 data in comparison to ABEO for RDEB? Any plan to add some FCSC?



  48. Shark (TRVN) – I guess next catalysts are filing for approval. Personally, I am leaning towards selling.

    Jaime Allen (RGNX/DMTX) – IMO it will come down to the highest offer, not sure RGNX will outbid RARE, which is more than double in valuation.

    Dan (CAPR) – Thanks, will take a look .

    andre –
    NITE – Agree, definitely a signal there, not sure why it appears superior to ONCE’s program (which doesn’t seem to be working)

    DCPH – Both drugs look active in KIT+ GIST but single agent efficacy isn’t spectacular (~15%). Had to justify BPMC’s current valuation IMO…

    Ruhu (EXEL) – I already made my choice as I feel current valuation fully prices in the RCC opportunity. HCC represents a significant upside but I am not optimistic there.

    Peanuts (MRNS) – I am also quite baffled by the recent move, especially following SAGE’s failure. Stock behavior is very impressive.

    Mike (MDGL) – Sorry not familiar with NASH programs.

    ADVM – Not sure I had a single dedicated write up. You can use the tag ADVM to find posts in which it is mentioned.

    Dan (GNCA) – They now have a more coherent story in a red hot field. Still early but I like the platform and think it has value for neoAg discovery.

    Chris (SNSS) – No plans to add more at the moment.

    jinyu (FCSC) – Very early and limited data set so hard to say. wound closure data did not improve with time and although they did see collagen VII expression they didn’t see anchoring fibrils. On the other hand, they used a low dose so higher doses may generate a clearer efficacy signal.


  49. Ohad

    Thanks for the response. Since this is an all stock transaction based upon the terms of agreement each share of DMTX leads to .1573 shares or RGNX. Therefore if RGNX share price gets to 37 dollars the two deals with be comparable?

    Based upon the share price increase I see this occurring very soon.

  50. Jon (SYRS) – They definitely have a unique angle on precision medicine in oncology based on novel targets and biomarkers. Personally, I prefer their CDK7 and CDK12 programs which are early in development. Not a big fan of the RARa program though. Bottom line for me : interesting but too expensive.

    Jaime Allen (DMTX/RGNX) – That’s an intersting dynamic… I am not familiar wit the details of RGNX’s offer (i.e is it capped at a certain price?) but in theory it could tilt the balance in favor of RGNX. Let’s see…


  51. Hello Ohad !!! Have you purchased Nightstar [NITE] for your portfolio ? If you have not ,when do you plan to add ? THANKS

  52. Hey Ohad,

    what are your thoughts about Five Prime Therapeutics (FPRX)?
    Thanks for your opinion.

    Kind regards

  53. Ohad
    I follow you since 2-3 years and do not remember you being interested in RNA companies. Any particular reason for that?
    I have a question about Arcrutus, still private but may become public via reverse merger with ADHD. Interesting platform (mRNA for rare disease) , interesting delivery, good partners for some of the programs (RARE, Takeda).
    Only 27M market cap with 40M cash, plus 1.5B potential milestone payments.

  54. Bouschka (NITE) – Not yet plan to add them on my next portfolio update.

    Martin (FPRX) – I a still on the sidelines as valuation is to high without a clear
    route to market for any of their programs. For cabira, data should start to emerge this year (later-breaker at SITC next month) and in 2018. The FGFR programs are not active enough as monotherapies so randomized trials are needed. Bottom line : a 1B+ valuation is not justified IMO.

    andre – I have been following the RNAi field but don’t consider myself an expert.Nice to see the good news recently with RNAi and oligos in general. Agree about Arcrutus being interesting, the major issue is development stage.

    If you’re interested in this area you should follow Dirk Haussecker on Twitter and his blog:


  55. Ohad
    Thanks for the RNAi link. The title of the blog is very intriguing, the content – not so much. Indeed some nice opportunities “beyond liver” but, as you use to say, “without a clear route to market”

    Using your “path to market” criteria, DCPH may look reasonably priced – 580M cap with clear path to 600M in 4-th line CIST with no approved treatment. They may start selling DCC2618 already in 2019 – about an year ahead of BPMC. Granted, BPMC is going after bigger fish (1.2-1.3B), but their path is more complicated.

    DCPH are also expanding GMB Ph1 trail to include more PDGFRα & KIT pts. They had one case with right kinase genes, which had 94% tumor reduction.
    If they get the same impressive responses in the Ph 1 expansion, they may look for a pivotal trail and be on the market by 2020-21.

  56. Hello Ohad

    after taking a look at Neon and Gritstone Oncology and the huge amount of financing they raised, I decided to open a GNCA position. The market cap is $40M. I know there are chances of dilution, but right now the market values the company 0$. Moreover their first oncology candidate will be in p1 early next year, and their platform could open the doors to collaborations/partnership money.
    What do you think?

    Regarding XENE – they have been awfully quiet.

  57. Ohad,
    On the 22nd of August you told me (regarding Array): “CRC data are too limited imo.”
    In light of the data just presented, have you changed your opinion?

  58. Hi Ohad, what is your take on LIFE (atyr)? It seems to be on fire since the private placement about a month ago…with very favorable conditions.

  59. andre (DCPH) – Agree that doing a placebo controlled trial using PFS as an endpoint could give them a broad label (without the need for a confirmatory trial). Based on their data they seem to reach a PFS of ~6 months in a heterogeneous population that includes both KIT and PDGFRa mutated GIST so that should beat placebo. I am more concerned about competition from BPMC’s agent which looks terrific in PDGFRa+ but in KIT+ patients efficacy wasn’t that great but it is still a viable 3rd/4th line candidate.

    Agree about GBM representing important upside. I guess I would choose DCPH over BPMC given valuation.

    Dan (GNCA) – Agree with your rationale. Their platform could be valuable for a neoAg player especially with this valuation.

    XENE – Agree, they are looking at a significant period of new news (except for Genentech’s P2 plan with the Nav1.7 program). I like their epilepsy programs though.

    Luigi – Busy times, will try to post something this month. No current plans to add AGTC.

    Lorenzo (ARRY) – At least to some degree yes, there is an efficacy signal there, results compare favorably vs. other EGFR+MEK or MEK+BRAF inihibtors in BRAF+ CRC.

    Dan (LIFE) – Haven’t been following them lately. Same phenomenon with MRNS, ECYT. Guess they were oversold tarded around 0 EV…


  60. VYGR presentations at ESGCT Oct 17-20 Berlin:
    “Translation of Intravenous Delivery of AAV Gene Therapy for the Treatment of CNS Diseases.”
    “Translation of Intrathecal Delivery of an AAV Gene Therapy Targeting SOD1 for the Treatment of ALS.”
    “AAV Gene Delivery of an Anti-Tau Antibody using a Novel Blood Brain Barrier Penetrant Capsid
    “Selection of an AAV Gene Therapy Targeting Huntingtin for the Treatment of Huntington’s Disease.”
    “Intraputaminal AADC gene therapy for advanced Parkinson’s disease

    In my opinion VYGR is the most diversified CNS-focused gene company. It looks quite logical to have it in a GT basket, right?

  61. Dan (xene/trvn) – Yes and yes.

    andre (VYGR) – It was definitely a mistake to exclude it from the basket given the ~250% climb… Agree about the diversification in its CNS-related pipeline (and their sf9 baculovirus production system), the problem is that all these programs are preclinical.


  62. Hi Ohad what do you think of $RYTM? MC =2.5+ bill. Obesity market, 100K population? Valuation too high?

  63. Hello Ohad,
    These companies are high risk and should own a basket to spread risk but how many should be in such a basket? Will this basket be “too diversified” that might prevent future positive returns?

  64. Thank you for your rec on AGTC
    very interesting company with solid science to back it up.
    My concern is that the 2 diseases (XLRS and achormatopsia) they are treating have very variable and slowly progressive natural courses as noted in their PR on natural course study on achromatopsia today. Assuming efficacy, it may take them years of follow-up to show it. Even with NITE, they only showed visual acuity improvement in 2 of 6 pts, although there are clear signs of effficacy in 3 of the other 4.
    How do you see AGTCs path to commercialization?

  65. $RYTM MC=49.7Mill * 25 = 1.25 B. With 2 phase 3 assets: POMC Deficiency, Leptin Receptor Deficiency; 4 Phase 2 assets for obesity. Severely undervalued. Ohad what is your opinion?

  66. Sumit (RYTM) – I really like their approach around MC4R- driven obesity focusing on “clean” genetically defined population where biology risk is low. I don’t know if their MC4R agonist is relevant for broad obese population and the current indications are ultra rare (several thousands per indication in developed countries). Valuation could be justified if you assume a 10k prevalence and a rare disease pricing strategy but personally I don’t feel comfortable with the valuation for this stage (plenty of risk and uncertainty ahead).

    Sam – Intuitively I would say up to 10 stocks but if GTx is a winner, there will be many winners given the different approaches.

    roland (AGTC) – Agree, these are not RPE65 IRDs, getting a asignal may be tricky and in general many of these indications are uncharted waters.

    Dean (RYTM) – See my response to Sumit. Great company, a long road ahead and valuation is very generous.


  67. hello again Ohad,

    regarding PIRS: if the claimed advantages of anticalins work out (much smaller than antibodies etc. -> better penetration, potentially administration by inhalation (!) etc.), this would be quite exciting for them given their IP-position.

    partners seem to like their tech, although everything is a bit early.

    their current market cap is about 276 mio. USD after nice run-up due to 2 big collaborations.

    anyway, if they really “own” this class of drugs, this seems low.

    Any opinion on this?


  68. Just to clarify about RYTM MC. There are different numbers from Sumit and Dean, but according to the prospectus:
    Common stock to be outstanding after this offering: 26,073,984 shares
    Option to purchase additional common stock: 1,057,500 shares
    Total 27.13M shares or $680M at $25/ share.

    If I am not misreading something, the 680M does not look overstretched considering 2 Phase III and 4 Phase II (granted, only 3 with prove of concept – so far). They can be on the market in 2020 for POMC, in 2021 for LepR and in 2022 for Bardet-Biedl.

  69. What do you think of MEIP? Solid management with Robert Maas from Genentech as CMO. Good partner in Helsinn. No debt. Cash not a problem. Market cap is under $100 million. Helsinn is funding the Phase III of Pracinostat in AML. Phase II showed outstanding results. Helsinn is also funding the trials in MDS. Decent pipeline with a better version of Zydelig in Phase II. BreakthroughTherapy Designation for Pracinostat.

  70. $AGTC …i like them but their two lead programs have a lot of issues…
    I believe neither will be successful…
    too many issues with enrollment, target strategy and variability with techniques and results…I think eventually some of their programs will experience success but no time soon…jmho

  71. Ohad. ADVM as a GT company seems to be flying under the radar with bullish comments within the sector and significant increases in MC in other GT companies. They will be behind RGNX in Wet AMD however which indication do you think will be their greatest value driver for the company going forward. I like their manufacturing capabilities. what are your thoughts on intravitreal vs subretinal vector administration in Wet AMD indication?

  72. Hey Ohad

    I was curious about your opinion on MBVX. The company is the doldrums, valuation very low, they have short-term cash an liquidity issues and have hired an investment baker to explore options (partnerships, selling product candidate or company outright.)

    They have an interesting technology having developed antibody candidates form immunological responses to antigen specific vaccines. they have shown very high affinity (validated by the uptake of their complementary pet imagining agent.)

    I have read an old seeking alpha article speculating that this kind of technology would be ideal for a CAR-T player, providing new targeting mechanisms (unique new target) and CAR-T modification options.

    What do you think?


  73. hello again Ohad,

    VSTM – duvelisib results DUO and DYNAMO. I don’t know the competitive landscape well. are those results meaningful; will there be a market for the drug? market cap quite low….


  74. Ohad
    what is your take on SRRA (Sierra Oncology, former ProNAi Therap., DNAI)
    and its approach to cancer with DNA Damage Response DDR ?

  75. Christian (HALO) – Sorry, not following them closely.

    Christian (PIRS) – The proof is in the pudding… There are a lot of elegant platforms but to date I haven’t seen anything that panned out in humans.

    andre (RYTM) – Thanks, that makes much more sense. I would still feel more comfortable with a lower market cap given the early stage of their data package and the rarity of POMC deficiency.

    Richard Baker (MEIP) – I don’t think the drug is attractive, hard to understand FDA’s decision re: BTD.

    Robert goulet (AGTC) – Agree about the issues they are facing but they need a single program in order to ignite the story.

    BP (GLYC) – Don’t know them well….

    Jaime Allen (ADVM) – Agree and think they have a compelling risk/rward at the current valuation. I personally like the A1AT program, not sure about te AMD program, needs to be something really unique to justify intravitreal administration.

    Dan (MBVX) – Sorry, don’t know them.

    on October 10, 2017 at 2:30 pm said: Edit

    Jonathh (Bold / Advm) – BOLD is in the clinic with two programs and is supported by a lot of big names. I own both.

    Ken (ONCE) – I am thinking about adding more before ASH, hope the HemA data hold up.

    Christian (VSTM) – That’s a good question, not sure about the answer. The drug is clearly active but in CLL the market is going with Btk inhibitors, B cell lymphomas could be a different story in combination with CD20. Need to look into this.

    rodolfo (SRRA) – Sorry, Don’t know them well.

    STEVE (PTCT) – IMO no but after the SRPT circus anything can happen…

    Shark (EXEL) – Wow, good for them, glad to be wrong on this one….
    I bought some shares pre-market, if the OS benefit is meaningful (we don’t know) this has huge implications. Potentially additional 1B in sales globally.


  76. Ohad
    FPRX is moving up in an anticipation of Ph 1b data on SITC (late brake presentation). It is CSF1R antibody combo w/ PD-1. The thesis is that CSF1R can open the door into solid tumors. Many analysts are busy rising the PT of FPRX to $100-110, obviously expecting stellar data. You have been skeptical in the past about CSF1R, but if the data are good, could it be the next big story in IO.

  77. Ohad,

    Cotezo in 3rd line crc will probably read out in first quarter 2018. Roche has been pretty busy about the trial. What odds of success do you give that trial and market opportunity?

    I think that one is running under the radar.

  78. Hi,

    Tocagen, TOCA, has a data update on the 27th for their BTD brain cancer therapy using RRV. Trading at IPO levels this one looks like it will rise.


  79. Hi Ohad. Thoughts on the AGTC partnership with Bionic Sight? Sounds interesting. Will these prove to be fruitful in your opinion? It sure sounds promising after reading about it at length. Thanks. Luigi

  80. Ohad
    QURE nice progress – pivotal trail with BTD.
    They were talking today about something interesting – no immune suppression even in pts with preexisting neutralizing antibodies. It looks they can cure anybody, even re-apply the treatment – if needed. Sounds like they managed to crack down one of the weakest point in gene therapy – immune response. It’s probably due to the mutant of the AAV5 vector (Padua mutant) they are using.
    Could this lead to a breakthrough in gene therapy in general or it is only applicable to Hemophilia A/B ?

  81. ONCS had recent interesting data with their drug using a non traditional approach. The drug appeared to convert cold tumors into a “hot” tumors where Merk’s PD1 inhibitor was able to engage. Any thoughts on its potential to extend potency of PD1 inhibitors

  82. Hello Ohah,

    in January 2015 you wrote: “MOR208 (Anti-CD19), licensed from Xencor (XNCR) is in phase II for CD19+ blood cancers. Despite clear efficacy, I view this product is undifferentiated and in many cases inferior to other CD19-targeting therapies (including bispecific antibodies and CARs). In addition, the competitive landscape in most of the pursued indication has become very challenging.”

    Is this still actual respectively your opinion?

  83. Ohad

    Are you selling $TRVN before the approval or after? It seems like it may have a good shot at approval, do you not think so?

  84. andre (FPRX) – The industry has been throwing every possible IO agent into combination trials with PD1 antibodies but so far very few agents demonstrated a signal and those signals were in single arm studies in PD-1 naive patients (e.g. IDO). I hope FPRX will have good data at SITC but it will still be hard to interpret without a control arm (unless something really dramatic happens).

    Chris – Market opportunity is obviously significant (KRAS+ is 20-30% of the market), I assume a 30% likelihood of success (a meaningful not just stat sig benefit). Agree that it’s flying under theradar, haven’t heard anybody speaking about it.

    John (TOCA) – Not optimistic about their approach. GBM and gliomas need new therapeutic approaches, not increased chemo exposure imo.

    Luigi (AGTC) – Fascinating area but I don’t think it will generate value inthe near future.

    Alex – Interesting target.

    andre (QURE) – Very nice trick indeed! Good for them. It definitely keeps them in the race given their strong manufacturing capabilities and AAV5 may be relevant in patients with high AAV8 titers (assuming their FIX activity is comparable). The padua variant refers to the transgene, not the vector. I don’t think they bring anything new in terms of immune responses against viral vectors.

    Don Barton (ONCS) – Sorry don’t know them well.

    Toby (XNCR/MOR) – Yes I still think the bar for CD19 products is high but believe there is room for highly efficacious treatments. To date the only exception has been ADC Therapeutics’ CD19 program with pretty good efficacy but data set is early.

    Chris (XENE) – I personally bought more because I like their epilepsy and NaV1.7 programs but this is a very high risk bet and exposire should be limited.

    Jinyu (EXEL) – That’s a tough question. I am puzzled by market reaction and until we see data it will be hard to answer that question.

    Chubi (TRVN) – I plan on selling it on the next portfolio update.


  85. re: MEIP You wrote: “I don’t think the drug is attractive, hard to understand FDA’s decision re: BTD.” What don’t you find attractive about the drug? It was generally agreed that if MEIP could show an OS of 12 months vs. 10.2 months for Vidaza alone, the drug could be approved. Pracinostat + Vidaza showed a 19.2 month OS in a Phase II. MEIP has a nice partnership with Helsinn, which is funding both the AML trial as well as the MDS trials. The company also has a P13K Delta inhibitor in the clinic. Dr. Robert Maas is the CMO and came over after a 12-year stint at Genentech. For a company with an almost zero EV, there seems a lot to like here.

  86. Is it not a little late to sell TRVN now? Their product is worth “something”, right? Anything new in TRVN’s presentation today, or just the same info?

  87. Hey Ohad

    have you had a chance to listen to the latest investor’s conference by ESPR?
    pretty enlightening concerning LDL-c theory… they have put together a great team of PIs. seems that both inflammation and LDL lowering are key to reducing cardiovascular risks. Fourier results not has stellar because trial only 2 years long. Explanation was also provided by experts as to why CETP inhibitors trials failed.
    This gives me confidence in ESPR chances of success, considering CVOT trial is 5 years long and for patients with no background of statins (statin intolerant).
    Also, it seems that the combination pill will be their go-to drug. Pricing will be in the range of Crestor Lipitor before parents expires. ESPR thinks target population is 12M in US and an additional 12M in Europe.
    What do you think they will do now? Partner for Europe and Japan? Remain independent, or sell the company? and when do you think these choices will mature?

    Thanks for your perspective

    I was going to sell some of TRVN but share price went even lower

    any opinions on OVID similar play as SAGE MRNS – baker brothers are investors.


  88. by the way… AMGN just shelved their CETP inhibitor which they acquired two years ago for $1.55B! Valuation of ESPR at $1B at the moment… where do you see, if everything goes well, BO valuation for ESPR?

  89. Richard Baker (MEIP) – I get those reasons, I just don’t find their single arm data credible enough.

    VSTM – Sorry, still haven’t looked at VSTM, too much work…

    Shark (TRVN) – I just don’t feel they have a compelling story to convince te relevant stakeholders.

    Rob (IMGN/IMMU) – I am tracking both companies. Have been burned so many times there but still I hope that ADCs will find their way to the mainstream. IMGN has a novel payload which ay be better tolerated than SGEN’s PDB so perhaps we’ll havea positive surprise in AML.

    Dan (ESPR) – I am listening to it today (in fragments). Great event, personally increased my confidence in them, they’re doing a terrific job. I don’t think they will partner before topline data next year, especially in statin intolerant patients which is an emerging indication (regulation-wise).

    OVID – I like the story, not a big CNS expert though… they’re on my watchlist

    ESPR – Yes I remember how the Dezima deal raised a lot of questions around ESPR. This leaves ETC-1002 as the only oral drug in town, now they need to prove it works in P3…


    any opinions on OVID similar play as SAGE MRNS – baker brothers are investors.


    Dan on October 26, 2017 at 6:46 am said: Edit
    by the way… AMGN just shelved their CETP inhibitor which they acquired two years ago for $1.55B! Valuation of ESPR at $1B at the moment… where do you see, if everything goes well, BO valuation for ESPR?

    Dan on October 26, 2017 at 6:46 am said: Edit
    sorry… total deal was $1.55B not upfront payment

  90. Ohad
    do you have an opinion about small size antibodies (Simple antibodies – ARGX; or Nano-antibodies – ABLX).

    ARGX is focused on rare auto-immune disorders. They had indirect MOA confirmation – lowering of IgG which are correlated to a number of auto-immune diseases. Cap 630M is quite high but a lot of programs and partners

    ABLX – can be first on the market in EU (H2 2018) and US (beginning of 2019) for aTTP. P-value in Ph3 was impressive (<0.001) and AEs were comparable to placebo. Expected 1B peak revenue. Currently no approved treatment. Cap 1.4B does not look expensive considering high probability for approval and many additional programs and solid partners

  91. Hey Ohad

    thanks for the reply.

    Any more comments on EXEL? where de you see the valuation going if the results HCC are solid? They have executed very well this year, commercially and in terms of development. They are also talking about relaunching their discovery efforts (focus on validated targets).

    Any opinion of the recent news for KURA (also the preclinical news)
    And what about this morning’s STML press release?



  92. Hi Ohad,
    AZN Acalabrutinib BTK inhibitor just got FDA approved for patients with mantle cell lymphoma. Any thoughts about the BTK inhibitor space with regard to your positions ARQL SNSS.? do u regard it as positive? ARQL is down 8% today.

  93. “FDA Grants Rare Pediatric Disease Designation to ArQules Miransertib (ARQ 092) for the Treatment of Proteus Syndrome.”

    Is this new info, i.e. a positive catalyst for the company’s value?


  94. If they get a pediatric disease voucher, it will be rather huge news for them – but that is not yet clear as I understand

  95. rChristian and Shark, Re: ARQL – voucher will be released to company if the drug for the indication (Proteus Syndrome) is approved.

  96. Hi Ohad. AGTC. Have u heard any news that their XLRS collab with Biogen was terminated? AGTC stock price is getting crushed. I can’t find anything.

  97. HI Ohad
    What do you think of XNCR and their just published Ph2 data in IG4-RD.
    They have also Ph 3, one undisclosed. Why keep undisclosed late stage trail?

  98. I think with undisclosed you are refeerring to the Alexion mab – follow-on to Soliris? If so, it is certainly because of their contract w Alexion, ie not allowed to talk about.

    Also interested in Ohad’s take on study results p2, thanks!

  99. Christian, agree, XNCR is under embargo from ALXN. But I was curious – why keep undisclosed Ph 3 trail. That’s quite rare

  100. Andre, actually lists 2 P3 studies with ALXN1210, so drug seems only undisclosed by Xencor, but not by Alexion.

    In any case should be quite a big deal for XNCR if it comes through, although royalty rate is low (mid-single digit if I recall correctly)

  101. Hi Ohad,

    FPRX – Are you still on the sidelines? After validation came down is it the right time to step in or to cancel from the watchlist?

    Thanks, Martin-2

  102. Congrats and great to see Pontifax on Arqule’s board. This should (hopefully) end up being a really good investment! Does this mean you won’t be able to comment on ARQL anymore on this board?

  103. Wow $ONCS

    I know small n, but it looks huge given their micro cap??

    Bought some premarket just for the fun :-)

  104. Interesting article in NYT: “Gene Therapy Creates Replacement Skin to Save a Dying Boy”. Very impressive
    They are using Retrovirus, apart from that it looks similar to ABEO. Even the pictures of the gene-corrected skin in both presentations look identical.
    If EB101 works well why they develop EB201 (AAV vector)?
    Sometimes backup solution indicate problems with the lead drug and it’s typically a red flag.

  105. andre (ARGX/ABLX) – Still haven’t seen real proof that fragments do a better job than full IgGs despite their perceived advantages (primarily tissue penetration).

    ARGX – I like their science but still haven’t seen any groundbreaking application so market cap isn’t justified IMO.
    ABLX – Don’t know the indication well but the graphs didn’t look too impressive …

    EXEL – Still puzzled by market reaction, I guess people think it will be just another anti-VEGF with limited uptake. Sounds like people expect a HR of 0.75 vs. placebo, which is still pretty impressive, safety is a key concern in these patients as well.
    KURA – Overall looks good despite the small numbers, I really like the menin/MLL program. I understand the scaffolds they got are challenging hope they were able to work around issues because the biology is great and markets well defined.

    STML – Looks approvable on the face of it, didn’t have time to delve deeper.

    Chris/Shark/Christina et al (ARQL/SNSS) – Cannot comment about ARQL anymore, sorry.

    Luigi (AGTC) – Didn’t hear anything on that although the program doesn’t look good. Their XLRP collaboration with Biogen should become the next primary focus for the collaboration.

    Declan (TRIL) – Their title is a little misleading but even a single CR as monotherapy is good news.Safety issues still linger but perhaps they are manageable, probably keeping them from exploring higher doses than the very low dose they are using (0.2 mg/kg qw).

    andre/Chroistian (XNCR) – Having been following them , will take a look. Agree it’s unusual to withhold information about P3 program. In any case, not sure ALXN will be able to charge Soliris prices for ALXN1210 in an environment of Soliris biosimilars.

    Chris/Christian (ONCS) – Not very familiar with the data.

    Martin-2 (FPRX) – Yes, especially following the recent data which I don’t find that compelling, definitely doesn’t justify valuation imo.

    Manish (ARQL) – Thanks. That’s correct, I won’t discuss ARQL anymore and plan on removing it from the virtual portfolio on my next update (hopefully on Sunday)

    Dan (SNSS) – Everything depends on the data next year.


  106. Hey Ohad
    Just listened to the ARQL CC – they are executing very well.
    Added some shares today with the breakout.
    What is your take on the SAGE data. Market reacted well, but there is also some disappointment compared to ph2 results.
    Looking forward to your new post!

  107. Hi Ohad

    Please tell Pontifax that I want dividend for my ARQL shares as well 😉

    It is a pity that you cannot comment on it anymore, in any case good luck to all of us


  108. I think if you were able to comment on ARQL in the future, it would be something like -“I like the prospects, they just need the right guiding hand…”! ;-))

  109. Alex (ONCE) – Prefer to wait despite the near-ceratin approval.

    Dan (SAGE) – I think results in severe PPD were good (although placebo-adjusted effect was lower). This is a good mechanistic POC but the real value driver is SAGE-217.


  110. Ohad, What do you think about $ONCE sell off today after #ASH17. Your thoughts are appreciated. Seems like it was just a lower dose but due to $BMRN data this was trashed.

Leave a Reply

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