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

58 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.

Leave a Reply

Your email address will not be published.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