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. 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.



  2. 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.


  3. 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.


  4. 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.



  5. 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


  6. 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 ?


  7. 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


  8. 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?


  9. 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.



  10. 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.


  11. 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?


  12. 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.



  13. 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?


  14. 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


  15. 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


  16. 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?




  17. 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.


  18. “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?



  19. 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.


  20. 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?


  21. 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!


  22. 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)


  23. 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


  24. 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?


  25. 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.


  26. 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.



  27. 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!


  28. 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



  29. 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…”! ;-))


  30. 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.



  31. 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.


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