Gene therapy’s 2017 scorecard – No alarms and no surprises (please)

Readers of this blog know I have high hopes for gene therapy, a field with a checkered history but disruptive potential that may finally be ready for primetime. After two years of dramatic progress 2017 is shaping up to be a year of incremental progress, focusing more on establishing and validating results seen to date.

Progress to date

To date, exciting data emerged from several gene therapy programs. These can be divided into four therapeutic areas: Liver (hemophilia), ophthalmology (RPE65- related retinal diseases), neurology (SMA, Sanfilippo A) and hematology (Beta thalassemia, ADA-SCID).

1) Liver Biomarin (BMRN) and Spark (ONCE) generated impressive proof of concept in Hemophilia A and B, respectively. Neither data set was flawless (immune reaction, excessive experssion of therapeutic protein etc.) but the two studies clearly demonstrate durable expression of a therapeutic protein in the liver, a dramatic clinical benefit (bleeding reduction) and no alarming safety issues.

2) Ophthalmology Spark is leading the way with what could become the first ever FDA-approved gene therapy. P3 data for Spark’s RPE65 program (Luxturna or voretigene neparvovec) were reported in 2015 and recently got published. They demonstrated a clear and dramatic improvement in night blindness and visual field. The company filed for approval in May and a decision is expected by January 2018. Beyond the therapeutic impact on patients, this trial proves that with local (subretinal) administration in the eye, gene therapy can deliver a meaningful and durable effect.

3) Neurology – Clinical validation is not as strong as in liver and ophthalmology but preliminary signs with programs from Avexis (AVXS) and Abeona (ABEO) are simply too good to dismiss. Avexis is developing AVXS-101 for SMA1 and Abeona is developing ABO-102 for Sanfilippo A, two genetic devastating disorders. Both companies give their respective AAV9-based products by intravenous injection based on the hope that AAV9’s can cross the blood-brain barrier and reach the CNS.

AVXS-101’s data (which I wrote about last year) are limited but very impressive from a clinical standpoint with an apparent dramatic effect on mortality and disability compared to historic controls. The primary weakness in Avexis’s data is the lack of a biomarker to prove the therapeutic protein is expressed in the target tissue. Abeona’s data (which I discussed here) is more preliminary but it demonstrated a clear reduction in disease biomarkers (Heparan sulfate, HS) in the CSF, which reflects exposure in the brain. Follow up is too limited to draw any conclusions about clinical benefit but there were some encouraging hints of efficacy in terms of cognition and behavior.

To me, the two data sets complement each other, suggesting that AAV9 can get into the brain and express meaningful amounts of therapeutic proteins.

4) Hematology – Bluebird Bio (BLUE) is a bit of an outsider because its technology involves a process more similar to stem-cell transplant (reprogramming cells ex vivo) using an integrating virus (lentivirus) whereas most other gene therapies are based on administering AAVs (adeno-associated viruses) locally or systemically. In that sense, CAR-T and TCRs can also be regarded as gene therapy products.

Bluebird’s platform proved very effective in beta thalassemia where its lead program, Lentiglobin, was able to generate significant levels of hemoglobin and decrease dependence on blood transfusions. Unfortunately, the company could not replicate these data in sickle-cell disease (SCD), a related blood disorder.

An investor perspective

Despite the tremendous progress the industry has made with gene therapy, it should still be regarded as a high risk field given its infancy. It is important to note that all these positive data sets include a small number of patients (tens at best) and limited follow up (in some cases less than a year) so a lot of things can still go wrong.

The primary challenges (and risks) are:

  • Demonstrating a favorable long term safety profile
  • Demonstrating the effect is long-lasting (at least several years)
  • Expanding to additional indications in the four tissue types (liver, eye, CNS, blood)
  • Expanding to new therapeutic areas (muscle, lungs, heart etc.)

This is why I prefer the “basket” approach of having a diversified portfolio of as many gene therapy stocks as possible. There are simply too many unknowns and too much complexity around key factors such as viral vectors, transgene design, indication and route of administration that make it very hard to identify the winners.

2H/2017 catalysts

For the remainder of 2017, investors shouldn’t expect major breakthroughs but hopefully gradual progress, one patient at a time, one month at a time.

Below is a partial list of catalysts for 2H/2017:

Spark Therapeutics is expected to present initial results for its hemophilia A program (wholly owned). Data will surely be compared with BMN-270’s data, especially FVIII expression and immune response. An update for the hemophilia B program will focus on durability and Pfizer’s registration plans. Toward the end of the year, the FDA may convene an advisory committee on Luxturna for RPE65-related retinal diseases. Approval is expected shortly after.

Biomarin is expected to present an update from BMN-270’s hemophilia A study. Investors will focus on durability but also on safety profile in patients who achieved higher than normal FVIII levels. The company expects to launch a multi-site P3 (current data are from a single site in the UK) that will enroll ~100 patients. Primary endpoint has not been disclosed but will probably include bleeding rates and safety measures.

Bluebird is expected to present initial data with an optimized protocol (“process 2”)  of Lentiglobin in SCD patients at ASH (December 2017).  Although investor attention shifted to the company’s multiple myeloma CAR program, there is still a lot of focus on the SCD study given the significant commercial opportunity.

Avexis is expected to provide an update from its P1, potentially on its next quarterly call this month. Focus will obviously be on durability of the clinical effect (motor and other developmental endpoints such a weight and feeding parameters). Later in the year, the company expects to get regulatory clarity from the FDA, which may allow filing based on P1 data.

The company also expects to enroll SMA2 patients (less severe form of the disease). Because SMA patients are older (most SMA1 patients die in infancy), AVXS-101 will be given intrathecally in this trial in order to minimize the required doses of drug. This illustrates the production challenges the industry is still facing.

Abeona will present updated results for ABO-102 in Sanfilippo A. Data are expected to include at least 6 patients (3 from the high and 3 from the low dose arms). It will be interesting to see the extent of HS reduction with the high dose at 6 months to understand whether the effect is real and whether there is a dose-dependent response. Cognitive and behavioral tests may also provide some efficacy signals. Importantly, the company is expanding the trial to an additional site which will make the P1 package more reliable (Avexis is getting a lot of criticism for having data from a single site).

If results with ABO-102 are compelling enough, Abeona should be in a position to start a pivotal trial in 2018. It also expects to put another gene therapy in the clinic, ABO-101, which targets Sanfilippo B.

REGENXBIO (RGNX) is expected to present preliminary data for its wet-AMD program, RGX-314 (AAV8), which started enrolling patients two months ago. By definition, the data set will be very preliminary and probably include a handful of patients with limited follow up. Avalanche, which merged with Adverum, tried a similar approach (subretinal injection, targeting VEGF) with a different vector (AAV2) but failed (despite some interesting signals in visual acuity and post-treatment Lucentis usage). Adverum is also developing a next-generation program that will be administered intra-vitreally, which is much simpler and less invasive than subretinal administration.

REGENXBIO is also expected to report initial results from its HoFH program, RGX-501 (AAV8). An efficacy signal in this indication should be apparent based on change in LDL-C levels.

Dimension Therapeutics (DMTX) – After axing its hemophilia B program, investors focus on the company’s OTC deficiency program. In contrast to the hemophilia B product that used AAVrh10, Dimension is using the more validated (for liver delivery) AAV8 capsid for the OTC program. The trial started in January 2017 so there should be enough follow up to see an efficacy signal. I like the program given the lack of competition and because it is targeting the liver. In addition, since the missing protein is an enzyme, even low quantities (AAV8 is considered less efficient than the new engineered vectors some are using) can have a meaningful clinical impact.

AGTC (AGTC) is expected to report clinical data for three ophthalmic programs for rare retinal diseases: XLRS (in collaboration with Biogen [BIIB]), CNGA3 achromatopsia and CNGB3 achromatopsia.

In the XLRS study, the drug is administered intravitreally   in contrast to other ophthalmic gene therapy programs where administration is subretinal. This adds another layer of risk although intravitreal administration is less invasive and safer. AGTC expects to present data for 12 patients. The achromatopsia programs are earlier in development and the company reported some issues with one of the trials following inter-patient variability which the company blames on differences in surgical techniques.

Adverum (ADVM) expects to start P1 for its A1AT program (ADVM-043) in Q4 2017. ADVM-043 is also based on the AAVrh10 but Adverum plans to inject it directly to the lungs. The company also has a preclinical program (ADVM-053) for the lucrative HAE market (Shire’s Cinryze, Firazyr, Kalbitor are expected to generate >$1.5B in 2017). ADVM-053 is expected to enter the clinic towards the end of 2018. Despite its immature pipeline, I plan to hold Adverum into 2018 given its differentiated pipeline, its solid cash position and negative enterprise value (expected to end 2017 with $165M, higher than current market cap of $110M). On the manufacturing front, Adverum has internal production capabilities using an insect based system (baculovirus/Sf9) which has the potential to generate large quantities of vectors compared to standard production systems (HEK293, adherent or in suspension).

Audentes (BOLD) has two programs that are expected to enter P1 this year: AT132 (AAV8) for XLMTM (a rare muscle disease) and AT342 (AAV8) for Crigler-Najjar Syndrome (a rare metabolic disease). Among the muscle wasting diseases XLMTM represents a smaller opportunity compared to DMD, but one potential advantage XLMTM has is the fact that the missing gene is an enzyme, so even marginal expression levels may be translated to a clinical benefit. Given its early stage, company’s valuation ($570M) is relatively high.

Voyager (VYGR) is expected to report data for its Parkinson’s Disease program, VY-AADC01. VY-AADC01 is injected directly to the brain, making administration more complicated. Voyager recently started P1 evaluating an optimized administration method to allow better exposure in the brain.

Portfolio updates

I am initiating a position in Sunesis (SNSS), which recently started a P1b for its next-generation Btk inhibitor (SNS-062). I wasn’t aware of the program and just recently learned about it from a colleague (thank you, M.). SNS-062 will have to compete with Imbruvica (a $4B+ franchise) and other late-stage Btk inhibitors from AstraZeneca (AZN), Gilead (GILD) and Beigene (BGNE), which are all covalent irreversible Btk inhibitors. SNS-062 has a different mode of inhibition that may render it more active against the C481S mutation, which is less sensitive to covalent Btk inhibitors. ArQule (ARQL) and Redx Pharma are two other small biotechs with reversible Btk inhibitors. SNS-062 is slightly more de-risked because it was already evaluated in healthy volunteers with favorable safety and exposure data.

Biotech portfolio – July 30th, 2017

biotech portfolio - July 30, 2017

biotech etfs - 30-7-2017

41 thoughts on “Gene therapy’s 2017 scorecard – No alarms and no surprises (please)

  1. Thank you Ohad for the updates. Really looking forward to DMTX updates later this year with OTCD. When do you see a capital raise? following 301 results assuming they are positive or later in 2018? . Cash runway appears to be the end of 2018 even with a possible Bayer milestone payment.


  2. Hello Ohad,

    thanks for the very informative new post.

    SNSS looks good. The only problem is that the current cash resources are only sufficient until the second quarter of 2018. But they have strong institutional holders.

    I just posted another question on the old theme, therefore I repeat it:

    Isn’t it now a good opportunity to buy BLCM? Especially when you compare the market capitalisation with other CAR-T companies. BLCM has some special features (e.g. safety switch technology). 501 far advanced. 601 interesting approach to kill solid tumors. 701 TCR.

    Thanks Toby

  3. Jaime Allen (DMTX) – Hard to say… If initial OTC data are good, I would definitely use that opportunity.

    Toby (SNSS) – Cash position certainly not idea but I assume this is already priced-in and explains the very low valuation. Hopefully, they’ll have some initial clinical data by then.

    Re BLCM – Prefer not to comment on CAR/TCR companies.


  4. Hi Ohad!

    Which market size do you assume for reversible BTK inhibitors?

    Isn’t it strange that none of the big players have one in development?


  5. REDX Pharma just sold its BTK-inh for 40 mio flat (no royalties or milestones) to LOXO

    hmmm, well it was preclinical

    wonder whether that is good or bad for Sunesis / ARQL

  6. Christian – Very hard me to speculate there… as you wrote the big players are going with improved covalent inhibitors with a focus on safety/tolerability. The reversible Btk hypothesis is still not validated in patients, especially those with the c481s mutation. In vitro data support this theory but activity in those tests is never all or nothing. Like always it will be a matter of risk/reward based on clinical data.

    LOXO – To me it’s positive despite the low numbers because it validates the approach (LOXO is a very smart company that knows a thing or two about kinase inhibitors).


  7. Hi Ohad,

    What’s the reason you can’t talk about LPTX? I know Pontifax is a shareholder, but without a board seat it would seem that Pontifax has the same amount of information as any other investor (e.g. not an insider). Just curious. Thanks.

  8. Hi Ohad
    Any comments on the E bullosa program at ABEO.
    Their PH 1/2 results seem good and looks like they are getting guidance from FDA to do a pivotal study in 2018.
    So possibly 2 pivotal studies in 2018 for ABEO?

  9. Ohad
    It looks that LOXO put a price tag on reversible BTK inhibitors – 40M.
    Isn’t it a concern the low anticipated value of the most promising SNSS program?

  10. Mrns

    For what reasons did you sell MRNS in the past? And why dont you reenter at current R/R ratio?

  11. Hi Ohad

    RGNX Do u think current valuation is attractive as an entry point?
    Great write up as always,


  12. Hi Ohad

    1. Couldn’t CRISPR make gene therapy obsolete in the future?

    2. Do you have a view on the Nanobody platform of Ablynx (ABLX.BR)?

    Many thanks

  13. Joel (LPTX) – I prefer to keep my real job seperated from this blog.

    roland (ABEO) – For the EB program is a free call, hard for me to assess the data they generated to date, feel much more comfortable with ABO102 and ABO101 despite the limited data.

    andre (SNSS) – Yep, it is a low price tag although the program is not inte clinic and SNSS have good safety and PK data in P1 in healthy volunteers. What is more a concern is the fact that LOXO decided to go with Redx Pharma’s program and not acquire SNSS (for a significantly higher price, of course).

    Magnifi (MRNS) – I decided to sell after the P3 failure in epilepsy, still haven’t made up my mind regarding getting back ahead of the SE data from SAGE and MRNS.

    Chris (RGNX) – Thanks. Yes, I plan on holding the stock given the broad exposure they have but also the internal programs. I am particularly excited about their earlier stage stuff (MPS 1 and 2) expected to get into the clinic soon.

    Prof. Dollar (QURE) – It’s the lack of near term clinical catalysts that keeps
    me on the sidelines.

    Kevin –

    1 – CRISPR – CRISPR will always have to be delivered using an AAV or something like it so I don’t see it necessarily as a threat. Inaddition, CRISPR/Cas9 is at its infancy and far less validated as an approach.

    2 – I think the platform is really cool scientifically but I am waiting for a differentiated value driver in their pipeline.


  14. Hi Ohad,

    First time posting here: How come no mention of CRSP, NTLA, EDIT? Their approaches are even more removed than the preclinical pipelines above, but isn’t the potential there humongous (from an investment perspective)?!?!

  15. $EXEL Are u still pessimistic about the HCC 2nd interim data readout ? What do you think of the current valuation visavis 1L RCC and possible or negative HCC positive readout.

  16. Luigi (SPHS) -From what I see they are doing local treatment for locally advanced prostate cancer. Not a big fan of the approach.

    Chaac (SGMO) – Sorry, don’t know them well.

    deSai (CRSP, NTLA, EDIT) – Welcome! Yes the potential humongous but some will claim that so are the barriers to human proof of concept. To date, all breakthrouhg technologies needed a maturation phase that took several years in order to be ready for primetime in humans. This is my working hypothesis is CRISPR/Cas9 too.

    curiousgeorge (EXEL) – Yes I am still pessimistic about the HCC study but will behappy to be proven wrong on this one. 1L broad use probably implies global sales of ~2B and most of this potential is already priced-in. HCC isn’t and a positive outcome should have a dramatic affect on the company’s valuation.


  17. Ohad
    AVEO has by far the best selectivity compared to other VEGF inhibitors. Should be helpful in PD1/ PDL1 combos, right? Any reason why they are running only one (w/ Opdivo), while Cabo (multi-target TKI) is running a few?

    BMS is paying 300M + 2B in milestones in a deal with IFM for … small molecule drug which probably has no value as a stand alone agent. If this is the new “retro” trend, do you know some other small companies with such “miracle” agonists. Any opinion about IDRA e.g. (not small molecule but TRL agonists which may work as good as IFM small molecule one).

  18. GEMP slumped because trial results were not as good as expected. Wiped out all gains :-(.
    Any thoughts?

  19. Hi Ohad,

    I really like AVXS, especially consider SPINRAZA pulled $203MM in Q2. The problem is the valuation, with phase 3 read out probably another year away and currently at $3B valuation for AVXS. Is now a good time to buy ?

    Thoughts? Thanks!

  20. andre (AVEO) – Agree that tivo has the cleanest safety profile of all VEGFR inhibitors.
    BMS’s deal with IFM demonstrates the hunger for new complementary targets and ther’s a lot f excitement about STING agonists (ADRO has a lucrative deal with NVS). Not sure about TLR agonists as they have been tested for years but so far with limited success.

    Ruhu (RGNX) – I plan to keep my position, trying to be as broad as possible.

    BIS – Yes I still think biotech valuations are too high and that the industry is going to face real challenges with their legacy products in terms of pricing power and biosimilar competition.

    Les (GEMP) – I am on ESPR’s camp…

    Justin (AVXS) – Agree it isn’t cheap but if the effect is real and durable, they have an amazing drug in a lucrative market (assuming they get approval for SMA2/3). As I said, I prefer to own many gene Tx stocks representing various investment profiles so I plan to keep AVXS despite the high valuation.


  21. ARQL – At June 30, 2017, the company had a total of approximately $31,007,000 in cash equivalents and marketable securities.
    not much.. what do you think?


  22. Ohad, I can’t stop buying shares of DMTX is there any help you can suggest for me?
    like a stock purchasing AA?

  23. Alex-

    EXEL – IMO the trial was big enough to generate a stat sig benefit already at the interim analysis. In addition, the indication is a very challenging one.
    ARQL – Agree, they are in a race against time to bring investors compelling data next year or they’ll have to raise money with unfavorable terms.

    robert goulet (DMTX) – Jokes aside, I don’t think a stock like DMTX should ever account for more than 5% of a portfolio. VERY high risk!


  24. Ohad
    About the 5% rule – is it for the initial or current investment is a single stock :)

    RGNX, Silverstein Foundation and OrbiMed launch Prevail Inc, for Parkinson’s Disease and other neurodegenerative diseases.
    RGNX starts to function as IONS – technology incubator.
    Let’s hope they get eventually the same market cap

    Any comment on the KURA data in SCCHN w/ HRAS mutant – another small molecule drug?

  25. andre (RGNX) – For me the 5% rule applies to the entire position. RGNX’s exposure to so many Gene Tx programs is a good thing but just like with IONS, share appreciation comes from specific products that are approaching or already commercialized.
    KURA – preliminary but encouraging results in HRAS+ SCCHN, not a huge indication but not aware of any direct competitors. They had to give a deep discount to get the secondary done.

    Barry Martin – Just like with gene therapy, I would own them all, very hard to predict who will become the dominant gene editing player. Personally, I prefer to wait until we see some data.


  26. Hi Ohad
    I’m a bit confused, EXEL to announce the interim analysis or the phase III results?


  27. Ohad, nice summary of the gene therapies in CNS by Bernstein:
    BOLD: Pompe (GAA gene)
    Prevail / RGNX: Parkinson
    VYGR: Parkinson, ALS, FXN gene, Huntington, Dementia / Alzheimer

    It looks VYGR has multiple targets and strong partner – SNY/Genzyme (most of them pre-clinical though)
    Is it a good fit to a gene therapy portfolio bringing additional diversification?

  28. Sorry :-)

    SNSS – Whats the size of milestones and royalty to Biogen Idec for SNS-062 ??


  29. Ohad,
    Trvn will file an NDA Sept./Oct timeframe. Along with that will be the FDA labeling. Looking at the available data, do you think trvn will be able to get a ‘comparative claim’ vs morphine at the .35 dose ? Thank you.

    respectfully, Conrad

  30. Hi Ohad,

    Would appreciate your opinion on IMDZ and SELB at current valuations.

    Many thanks, Cheris

  31. Hello Ohad,

    Regarding EXEL you say: “1L broad use probably implies global sales of ~2B and most of this potential is already priced-in.”
    Well, 2B$ in cabozantinib’s sales are certainly NOT priced in. In fact, such a biotech company would sell for at least 7x sales, up to 15x sales (depending on the rest of the pipeline, cash position, etc.) which would imply a much higher stock price even at 10x sales: EXEL is worth 8B$ today, whereas it’d have to be worth 20B$+ if cabo reached 2 B$ in sales. Even using a generous discount rate, the difference between the 2 numbers is too great.

    ARRY: why have you sold so early? On top of the obvious BRAF melanoma indication, have you considered the potential in colon cancer, and 797 before selling? Not to mention the rest of the pipeline…



  32. SGEN

    Hi ohad, the stock had a recent setback which created a buying opportunity.

    What do you think about current Valuation and next catalysts? ASH 2017?You said you like the bladder cancer Programs? What could be the upside from current Levels?

    Thanks for your thoughts!

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