Biotech portfolio updates – Esperion, Abeona , Sage and adding two more GTx names

It has been a hectic 5 months here at Pontifax (10 new investments, some yet to be announced) so unfortunately I didn’t have a lot of time to publish new posts. Going forward, I will try to make posts more concise so I’ll be able to publish stuff also during busy periods.Today, I will focus on what I consider to be the three winners in the portfolio in 2017 so far, not only from a stock performance but also from a strategic development perspective. All three will have important readouts in the coming 6 months.  

Esperion – Flawless execution, pivotal readouts in Q2/18

Despite its strong stock performance (+275% YTD), I still feel that Esperion (ESPR) and its management team don’t get the credit they deserve for their flawless execution in 2017. After starting 2017 with poor investor sentiment and great uncertainty about its clinical/regulatory strategy, Esperion is ideally positioned for pivotal readouts next year (Q2 2018). Although risk is still significant I am more excited than ever about Esperion for the following reasons:

Clinical profile continues to hold up– With a database of >700 patients, the effect of bempedoic acid (ETC-1002) on LDL and CRP is seen universally across patient populations (statin intolerant, diabetics, hypertension) and combinations (statins, ESPRezetimibe). Despite inhibiting the same pathway targeted by statins, the drug has a differentiated tolerability profile especially on muscle-related side effects. Long term safety is still a significant risk, as rare safety events require large studies and long follow up to emerge.

ESPR

Experience with PCSK9 drugs validates Esperion’s market assumptions – CV outcomes data with PCSK9 inhibitors earlier this year continued to validate the LDL hypothesis, and were probably an important part of FDA’s decision to keep LDL reduction as an approvable endpoint. The lower than expected effect size with PCSK9 may grow with more follow up but also suggests that CRP is also an important part of the equation (PCSK9 drugs do not reduce CRP). The lackluster commercial performance of Repatha and Praluent also support Esperion’s long thesis, showing that subQ administration and high pricing are barrierS for patients and payors, respectively. This makes bempedoic acid (especially in combination regimens) an attractive option: oral, well tolerated and relatively cheap.

CRP hypothesis supported by Novartis’ canakinumab – The recent data with canakinumab provided the first prospective proof that inflammation is an important driver of cardiovascular disease. Canakinumab inhibits IL-1 beta, a master inflammatory switch without any major direct metabolic functions. This supports Esperion’s claim about the importance of CRP reduction on top of LDL reduction. Canakinumab had a dose-dependent CRP-lowering effect (see figure below). Bempedoic acid appears to be the only drug in clinical development that inhibits both LDL and CRP (as statins do).

canakinumab - CRP

Source: Ridker PM. N Engl J Med. 2017 Sep 21;377(12):1119-1131.

Competitive threat from CETP inhibitors is gone – Merck’s decision not to file for approval for its CETP program (anacetrapib) followed by Amgen’s decision to terminate its CETP program it had acquired in 2015 leave the stage to Esperion’s bempedoic acid as the only late-stage oral lipid-lowering agent in development.

FDA acknowledges statin intolerant patients as a legitimate sub-population – One major achievement Esperion had is the agreement with the FDA on using the definition “statin intolerant” in order to identify patients who cannot or will not take even a low dose of statins. This group is still tricky to define but the acknowledgement of its existence and need of treatment alternatives is very encouraging. It is still unclear if and how statin intolerance will be reflected in bempedoic acid’s future label.

Esperion expects to have P3 data from four parallel P3 studies in Q2/Q3 2018, which will include LDL and CRP readouts. A CVOT (cardiovascular outcome trial) is expected to readout only in 2022.

Abeona – Three gene therapies now in the clinic

Abeona(ABEO) (+215% YTD) also had a strong year, moving from obscurity to a leading gene therapy company. Like Avexis (AVXS), Abeona’s programs utilize AAV9 to replace a missing protein in the CNS. Although Abeona cannot boast a spectacular clinical data set like that of Avexis (see recent NEJM publication), it has preliminary signs of biological activity in the CNS using biomarkers (which Avexis lacks). To me, from an investor perspective, the two data sets complement each other in validating AAV9’s ability to express clinically meaningful amounts of a therapeutic protein in the brain.

Abeona’s lead program (ABO-102) for MPS IIIA (Sanfilippo A) has generated a promising efficacy signal, making it one of the most promising gene therapy programs in development. The company recently started a clinical trial for a related condition (MPS IIIB, Sanfilippo B) for another gene therapy program (ABO-101). A third gene therapy program (EB-101) is expected to enter P3 for a rare dermatology indication (RDEB), unrelated to the company’s CNS pipeline.

During 2017, Abeona provided several updates from the ABO-102 trial (I discussed initial data a year ago here). Overall, updated results continue to look promising and indicate ABO-102 has the potential to alter the natural course of the disease. Findings include:

1) HS reductions in the CSF – Reductions in HS (a toxic metabolite that gets accumulated in MPS IIIA patients) in CSF were significant and dose-dependent. This is the most important biomarker readout as the CSF is thought to mirror metabolite content in the brain.

ABO-102 HS

2) Urine HS reduction – significant but with fluctuations, effect in the low dose group diminished at 180 and 360 days (despite the strong effect in the CSF). The medium dose had limited improvement but the single patient at the high dose had a remarkable 94% reduction.

ABO-102 - HS in urine

3) Liver volume reductions – At the low and medium doses, there were significant reductions after 360 and 180 days, respectively. The patient at the high dose cohort (who had the largest baseline liver volume in the trial so far) had a dramatic reduction already after 30 days.

AB0-102 - Liver

4) Clinical measures – Most importantly, there are hints of clinical stabilization based on the Vineland Adaptive Behavior Scale/test for the low dose cohort. A historical control cohort demonstrated a 14-point decline vs. a 2-point decline for the three treated patients. This observation is also aligned with other brain imaging endpoints that all point at the same direction.

ABO-102 - Vineland

In summary, data are preliminary and limited but all point to the right direction. During 2018, Abeona should have 1-year data for the medium dose cohort and initial biomarker data for the high dose cohort.

Regulatory strategy – Based on recent cases with rare pediatric CNS indications (Avexis’ SMA1 program, Biomarin’s CLN2 program), Abeona may be able to file for approval based on the ongoing study. It is still unclear how many patients and what follow up will be required by the FDA but if data from higher doses corroborate initial findings, the company may have a sufficient data package by Q1 2019 (1 year follow up for 12 patients across three doses). A BTD is likely to come by mid-2018.

Market opportunity and valuation – MPSIII A and B are ultra-rare indications and estimations regarding the relevant number of patients vary from 1500 to 4000, combined. Assuming a targetable population of 2000 and an average cost of $800k per patient, the cumulative commercial opportunity is $1.6B.  The RDEB opportunity is probably similar in size (Higher prevalence but lower cost per treatment). At a market cap of $700M, Abeona’s upside potential is still significant but not huge. Further upside could come from the two Batten diseases programs (CLN1 & CLN3), which are expected to enter the clinic by early 2019.

Lack of AAV9 license from Regenxbio (RGNX) is a risk going forward – Regenxbio holds IP around AAV9 and while Abeona indicated the two companies are in discussions, no agreement was announced to date. While this should not stall Abeona’s clinical development, it represents a commercial risk.

Sage – P3 POC achieved but real value lies in follow-on program

Sage Therapeutics (SAGE) reached an all-time high last week after announcing positive P3 data for its lead program brexanolone (SAGE-547) in PPD (post-partum depression). Brexanolone’s data set were from two P3 trials in severe and moderate PPD, respectively. Although benefit was not as dramatic as observed in P2 (placebo arm performed much better in the P3 studies, as usual…), brexanolone’s benefit in severe patients looks clinically meaningful (~ 5 points on the HAM-D scale) and should support approval in early 2019. Efficacy in the moderate PPD trial was not as robust (2.2 points) and did not reach statistical significance after 30 days.

While last week’s data may open up a $300M opportunity for brexanolone, they should be viewed more as a mechanistic validation for SAGE’s approach of using neuroactive steroids and as a positive read-through to SAGE’s oral derivative of brexanolone, SAGE-217. SAGE-217 is a novel oral drug with potentially superior properties over brexanolone, which is a formulation of a naturally occurring substance administered over a 60-hour IV infusion.

SAGE-217 is viewed by investors as Sage’s real value driver based on its improved properties, potentially superior efficacy (based on prolonged exposure with oral administration) and strong patent protection. It is currently in P2 trials in PPD and major depressive disorder (MDD), two indications that represent blockbuster potential for a novel oral agent.

SAGE

Sage is expected to report P2 data in MDD for SAGE-217 by year-end, which should have a significant impact on the stock. Positive data will open up a multi-billion opportunity in a market that has seen little innovation in decades. Negative data will probably push the stock towards the floor valuation provided by brexanolone in severe PPD (~$1.5B). A P2 study in PPD is also expected to read out shortly afterwards in Q1/18. This trial involves treatment for 14 days with SAGE-217 (in contrast to 2.5 days with brexanolone), which might lead to a more pronounced therapeutic effect.

Portfolio updates

Staying loyal to the gene therapy basket approach, I am adding Nightstar Therapeutics (NITE) and Krystal Biotech (KRYS). Nightstar is becoming a diversified gene therapy play in ophthalmology with a P3-ready program in choroideremia and a P1 program in XLRP (competes with AGTC/Biogen’s program).  Krystal has a preclinical program for DEB that in contrast to Abeona’s program, involves injecting a virus with the relevant gene (COL7A1) directly to the patients’ skin.

I am selling Trevena (TRVN) and ArQule (ARQL), which I won’t be able to discuss going forward.

Portfolio holdings – Nov 13, 2017

Biotech portfolio - 12-11-2017 - after changesbiotech etfs - 12-11-2017

117 thoughts on “Biotech portfolio updates – Esperion, Abeona , Sage and adding two more GTx names

  1. Hi Ohad

    glad to see a new post..
    why didn’t you add more XENE?
    and what about increasing ONCE?

    thanks

  2. Alex –
    XENE – I still plan on adding at these levels, the recent update from Genentech was quite disappointing.
    ONCE – Thinking about adding before ASH, waiting for approval decision first which might trigger a “sell on the news” trend.

    Mike (KRYS) – This is a high risk bet with low valuation (hence the low exposure). There is experience with HSVs but not for this setting as far as I know, their prospectus includes encouraging data in patient cells so tropism looks reasonable but hard to predict clinical effect and durability especially for a non-integrating virus

    Ohad

  3. Ohad–
    Thank you for your insights.
    I am trying to understand the market for Kura. At best, 5% of HNSCC with H-ras (if clinicians look for it). The preclinical data in AML looks exciting, but the AML-301 study in unselected pts showed only 8% CR, so hard to believe they are targeting NPM1/DNMT3A which are half of adult AML–at best, maybe the MLL-menin mutation. Do you see this differently and does 5% HNSCC and 10% adult AML justify continued investment at these levels? Thanks—Gary

  4. Gary (KURA) – HRAS+ H&N probably represents a ~3000 patient subset, which IMO justifies the current valuation and beyond.
    Agree that tipifarnib’s AML data are weak.In AML, I am optimistic about the Menin-MLL program for MLL-rearranged leukemias.

    Ohad

  5. I see you held onto AGTC despite its SP getting beaten up. Is there any short term data that can give the SP a lift out of the 3’s and into 4 -6 range? It’s book value alone is somewhere just above 6. Thanks Ohad

    Luigi

  6. Luigi (AGTC) – I don’t see any significant near-term catalysts as the XLRS program looks irrelevant and the ACHM and XLRP programs will take time to generate data. I still plan tohold the stock as part of the GTx basket.

    James (Denali) – Smart and very well funded. I am intrigued by the LRRK2 program and the decision to pursue it despite potential pulm toxicity. Based on the S1 they definitely did a lot of work to identify a Tx window and alleviate concerns. I am sure they have good explanations, Ryan Watts is last author on that paper: https://www.ncbi.nlm.nih.gov/pubmed/25653221

    Valuation will probably be too high anyway for a P1 company but good to see traction in CNS.

    Ohad

  7. Hi Ohad,

    Always look forward to your new columns especially when its a stock I own :-).

    The NY Times article and Nature articles on the boy with JEB was really amazing and quite actively mentioned on my twitter stream. Its a shame the treatment seems to have been first tried over a decade ago (I linked the original 2006 paper below). It sounds like a similar approach to EB-101 though they are treating a smaller area on the body and seem to have better durability (the child being active in soccer for example). At the R&D day the presenter said she believed the efficacy could be better in children than adults treated thus far. Is it fair to compare the results or are there scientific reasons why JEB and RDEB are very different? Is there a reason larger areas of the body couldn’t be treated with EB-101 as well?

    https://www.nytimes.com/2017/11/08/health/gene-therapy-skin-graft.html?smid=tw-share
    https://www.nature.com/articles/nature24487
    http://www.sciencemag.org/news/2017/11/boy-rare-disease-gets-new-skin-thanks-gene-corrected-stem-cells

    Older Paper:
    https://www.nature.com/articles/nm1504

    Thank you,
    Maurice

  8. Ohad–

    SNSS- do you think they will have some data at ASH this year?
    CALA- any thoughts on the CB-839 + Opdivo SITC data?

    Thanks,

    Chris

  9. Do you post entries anywhere? By the time I read some of your blog posts, you’re already up a significant amount and entry has been missed

  10. Ruhu (EXEL) – Yes I did (personally) but I’m down ~10%. Very limited excitement around CELESTIAL data, very surprising but perhaps people know something…

    Maurice (ABEO) – Unfortunately I don’t know the field well enough. Basically, it sounds like a group of similar disease with different etiology (mutated gene). Not sure what the limiting factor is for increasing treated surface area. Glad to see the field is taking off, see below another v interesting work on another gene (KRT14).

    http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(17)30377-5

    Chris

    SNSS – Don’t know. They started recruiting in July so it will be challenging to have something meaningful.
    CALA – As with all the other PD1 combos, hard to interpret given inherent patient variability.

    Kay Lee – If you refer to changes in the portfolio, I do them only as part of a new blog post. Don’t have any active notification services but I guess one can use RSS feeds.

    Ohad

  11. hi Ohad, CASC (ex ONTY) shows slight accumulation all over the year 2017, at stabilised price-range.

    what do you think of the main and the early programs?

    thanks!
    Christian

  12. any thoughts on imdz?….lots of heavy insider buys recently

    or an old bio looking to rise from the ashes Cycc?

  13. New here
    1. What are your typical hold lengths or plans? I see you’ve have some unrealized of over 100%+. You don’t get to that without having patience and holding for a looonnng time. When you enter a position, what are your typical hold lengths or plans? When/how do you decide to lock in gains?
    2. I noticed you’ve been buying lots of new IPO stocks in 2016/2017. Example – this blog post has 2 new positions and both are newly listed stocks. Does it concern you new biotech IPOs get listed at such high valuations? Back in the days, new biotechs get listed within valuations under 10mil. Nowdays, everything is already like ~500mil (if not more) valuation by the time it already goes public
    3. I noticed you work for Pontifax. Is this blog following you or Pontifax’s portfolio and thoughts?

    Thanks!!

  14. hi Ohad,

    XNCR has a lot going on and will have a busy year 2018, e.g.
    – start of own P3 next year for igG4-related disease, where they could be the first (5871)
    – readout SLE P2 (5871)
    – hopefully being able to partner 7195 (asthma), where the subq formulation seems to have less problems compared to the IV-formulation
    – multiple INDs and first readouts for several bispecs
    – Alexion program ALXN1210 (might be a nice follow-on to Soliris) and MorphoSys program (BTD, rather high milestone payments by MorphoSys in their contract despite it was partnered early)

    They are financed until 2020. market cap 1 billion USD, cash 373 mio USD end of September.

    what’s your take on them?

    As I understand you have a not so bright outlook on bispecifics in general?

    Thanks!
    Christian

  15. Kay Lee (EDIT/NTLA/CRSP) – Despite the huge potential and scientific excitement I can’t bring myself to owning any of them at the current valuations. Will try to get in during 2018 as programs make it to the clinic.

    Christian (CASC) – It’s been a while since I last looked at them (SABCS 2016). Hard to interpret their data from a 27-patient arm with capecitabine+Herceptin they used as a basis for a P3 trial.

    Robert goulet – Sorry, not following any of them…

    Steve –
    1 – Don’t have accurate statistics but I typically hold stocks for years, especially the successful ones. The question of locking in gains is a very tough one, wish I could say I have a working method there, missed a lot upside by selling too soon…
    2 – Yes, I am concerned about valuations that seem high (but perhaps not as high as 2 years ago). I added NITE and KRYS despite their high valuation because I want to maximize exposure to Gene therapy. Admittedly, I am less valuation-sensitive with GTx stocks given the disruptive potential and the need to diversify.
    3 – This blog represents my personal opinion only.

    Alex (EXEL) – Don’t think buyout is a likely option. Still considering whether to add it…

    Christian (XNCR) – Agree they have a lot of shots on goal but most are early and the advanced ones are not that exciting IMO. Hard to justify valuation…
    So far bispecifics are a major disappointment IMO, dual targeting of cancer targets isn’t that effective and CD3 engagers have serious safety issues. ZYME has an intriguing dataset though and I hope some of the new IO programs will pan out.

    rodolfo (ZIOP) – Survival data from small uncontrolled trials are very hard to interpret. We’ve all been there too many times (eg CLDX).

    Ohad

  16. Hi Ohad,
    Have been following up on ASMB for some time. Their novel approach to HBV “curing” seems promising although they are still in early stage. Do you follow them? have any opinion?

    Thanks,
    Laurence

  17. Laurence ORON (ASMB) – Agree, definitely worth following them. Still haven’t delved into the details but the Jefferies initiation report is on my “to do” list.

    Alex (INCY) – I guess people are getting cold feet on epacadostat’s melanoma study , hard to blame them with the high expectations priced in the stock right now.

    Ohad

  18. Any specific ASH17 readouts you are looking forward to?
    Any specific IPOs you are looking forward to?

  19. Hey Ohad

    Nice to read this update. I was not aware of KRYS. The market cap is low and they have many programs nearing the clinic.

    What about QURE now that they will use (same as ONCE) the Padua-variant (for H-B). Moreover AVV5 is less immunogenic than AVV8 and QURE has manufacturing sorted out. Do you still think ONCE will win this race?
    Also, I’m not clear what the patent situation is for ONCE relating to Padua-FIX, from QURE’s press release it seems they licensed Padua IP exclusively.
    Thanks!
    DAn

  20. Moreover, in previous post about ONCE you state that engineered vectors might be the solution or advantage to better GTx results. However, is this true? In comparing Biomarin vs ONCE maybe the bulk of the difference is a result of the Padua-FIX and not the engineered vector. To my knowledge Biomarin is using wild type.
    Thanks
    DAn

  21. Hello Ohad,
    I have noticed once in the past, and again now with KRYS- that these are companies with very few employees, ie in KRYS case, about 9 total (and that includes the founder and his wife). Is that “critical mass” sufficient for success, or perhaps really a long term view?
    Also, do you have any thoughts on OMER or AGEN?
    Thanks,
    Lawrence

  22. hello Ohad!

    there was some new TRIL data at recent conferences. did you have a chance to look at them?

    early but promising?

    thanks!
    Christian

  23. Steve –

    ASH17 – Anxious to see updated results for GSK’s BCMA ADC. I didn’t think originally they stand a chance vs. CARs but initial data are very compelling. Also looking forward to see ONCE’s HemA update.

    IPOs – Quite happy with some of the recent IPOs. ALNA in particular looks like a very nice story, oral ERT.

    DAn (QURE/ONCE) – QURE pulled off an amazing trick, of course we need to see whether they actually get the target FIX levels with their AAV5 capsid. Not clear about immunogenicity of AAV5 vs AAV8, in any case there will probably be a need for more than one product to cover the entire population due to neutralizing antibodies.
    I think investors are more interested in HemA, which represents a bigger market, where ONCE’S position looks solid so far.

    DAn (ONCE/BMRN) – BMRN’s product is HemA, irrelevant for Padua variant, which is for HemB. From what I recall both are using a similar transgene ( FVIII with B domain deletion).

    lawrence (KRYS) – That’s a valid point but don’t think it’s rare in early stage biotechs. Not very familiar with AGEN and OMER.

    Christian (TRIL) – Last update I saw was in the ASH abstracts. There’s definitely a signal there, need to track safety profile carefully.

    Ohad

  24. Hey Ohad!

    Thanks for the reply and analysis.
    Have you followed VKTX – they announced positive results this morning in hip fracture and the sp goes down (however, it ran up 100% in past two months). They have a diversified pipeline, NASH play, and market cam under $100M. Ph2 results in NASH months away, and their hip fracture candidate boosting lean body mass by 9% will enter ph3.

    Thanks!
    DAn

  25. If you think CRISPR stock’s valuation is bad, did you see what $DNLI is pricing at? ~$1.5bil valuation!!! Want to buy but omg! lol

    There’s another IPO coming too raising lots of money, Odonate Therapeutics $ODT, getting ready for phase3 – thoughts?

  26. Kay Lee (DNLI) – I’m not sure the 1.5B cap is correct.
    They are planning 8.3M shares at $17-19. According to the S1:
    “The number of shares of our common stock to be outstanding after this offering”: 24,718,512 + 806,000 + 443,800
    total: 25,968,312
    At $19 = market cap will be $493M
    at $23 (expected opening price) – market cap will be ~600M
    Not to bad considering that they are working on several pathway to cross the BBB. Just one of them to become successful would more than justify the IPO valuation.

  27. Ohad,

    Now FMI’s FoundationOne CDx received FDA’s approve and it finally got turned around. Do you have any plan to add more for the future potential? Thanks!

    Cloud

  28. DAn (VKTX) – Sorry, don’t know them well.

    Alex (FMI) – I think it could have a been a smart move (which I didn’t do) 😉

    DAn (ADVM) – Don’t think REGN’s failure changes anything, companies like ADVM and RGNX still need to show they can get durable expression in the eye.

    Kay Lee (DNLI) – Agree, hard to justify for their stage of development.
    Re ODT – don’t know them well but at first blush it’s hard to get excited about an oral taxane….

    Alex (ARRY) – Not high imo , their BRAF mel potential is priced and the CRC readout is too far.

    andre (DNLI) – From what I understand market cap will be 1.5B+

    Cloud (FMI) – Indeed an impressive turnaround! Not sure about adding more shares at these levels. An FDA approval might make them a more attractive target for Roche Dx.

    Ohad

  29. regarding ARRY
    “– Not high imo , their BRAF mel potential is priced and the CRC readout is too far.”

    doesn’t it fits Roche/Genetech as a long term investment?

  30. Alex (ARRY) – IMO no because Roche has its own BRAF+MEK combo and it has put a lot of dollars behind cobimetinib +atezo in KRAS+ CRC.

    Ohad

  31. Ohad
    DNLI – hopefully the revised S-1A will clarify the market cap.

    What do you think of ERYP technology?
    andre

  32. Hey Ohad
    What are implications of MDGL results for ESPR – seems that some investors believe today’s mini correction might be related, though the drugs are being studied in different indications. Market cap of MDGL now larger than Espr. Dr Phil, who led INCY to multi billion dollar cap is delivering again.
    DAn

  33. Ohad
    DNLI – you were right about the mcap. The published today S-1A bumps the “common stock to be outstanding after this offering” to 90M shares – 3.5 x more than the original S1 ?!?

    What do you think about the ZYME data.
    thanks
    andre

  34. Hey Ohad

    VKTX is surging, similar to MRNS, they are a fast follower… in their case to MDGL.

    Their NASH ph2 with a molecule with exact same MOA as MDGL’s will read out 1Q 18. Market cap is $120M compared to $1.6B for MDGL.
    I added to my position yesterday morning, right before the shares climbed up 25%.

    DAn

  35. Dan, what do you think of VK5211? not familiar in this field, but recent results looking good (clear dose response, highly statistically significant results, clean safety profile).

    looks like an interesting story. I bough some yesterday…..

  36. Hey Christian, yes, I think (and as the CEO and some investors have said) that the 5211 results were much better than expectations. There are no drugs on the market for that indication, so I think all this bodes well.
    It seems they’re looking for a partner to take it top3 and they should find one. The muted reaction of the market after the ph2 reveal was puzzling. Perhaps this is another reason (in addition to MDGL results) why the shares appreciated so much in the last two or three trading sessions.
    Definitely one of my top picks for 2018.

    DAn

  37. Dan, somebody posted this on VKTX re the NASH-drugs:

    “But there is difference $mdgl did not raise liver enzymes and actually decrease them at higher doses whereas $vktx raised them(moderately according to company) also $VKTX trial so far is only 14 days vs 12wks for $MDGL”

    any idea whether that is an issue with the VKTX-compound?

  38. Ohad
    in the previous blog you wrote that – engineered vectors (Spark 200) can be superior to naturally occurring vectors (BMN270 AAV5)
    In the new NEJM editorial (A Cure for Hemophilia within Reach – Dec. 9, 2017) they describe BMN270 as: “AAV5-hFVIII-SQ, an AAV serotype 5 containing a codon-optimized cassette for the SQ variant of B-domain–deleted human factor VIII”
    It imply that the MMN270 is also engineered, no?

  39. Christian
    VKTX’s compound is less selective than MDGL’s. From what I remember MDGL is X24 more affinity to B agonist, whereas VKTX x16 the affinity is important for side effects, however so far VKTX has had a clean profile.

    VKTX is taking 5 and 10 mg to ph2, which in their ph1 was comparable to $MDGL’s (80mgs I believe) in terms of results.
    VKTX is also testing 12 weeks for ph2.

    DAn

  40. The other difference between the two drugs is that VKTX2809 is a prodrug. I think it was tested at 5 to 40 mgs in the ph1B and “mild liver enzyme increases” were only seen at the “high doses.” The ph2 has 3 arms:
    5mg
    10mg
    10mg every other day

    so perhaps we they will show now liver enzyme increases, though duration goes from 14 days to 12 weeks.

  41. andre (ERYP) – Sorry, don’t know them well.

    DAn (MDGL/ESPR) – Not a NASH expert but the MDGL data look really nice imo, and they (as well as VKTX) clearly demosntrate an effect on LDL so potentially it’s a competing mechanism. Agree about Paul Friedman, some people simply know how to build companies…

    andre (DNLI) – Yep, one of these cases of great but too expensive company…
    ZYME – I think they continue to look good the response in gastric cancer was a nice surprise, can’t wait to see combination data given teh very good safety profile.

    DAn (VKTX) – Agree, I completely missed out on MRNS but VKTX could be an interesting bet. Their molecule is derisked (relatively speaking) based on their P1 data demonstrating lipid effect but safety is a long term risk we should be aware of.

    Christian (VKTX) – Agree about the favorable risk/reward profile although this is still a small cap biotech with very limited data. Safety bar is very high, especilly for liver tox, which may explain why investors are less excited about VK2809 based on the liver enzyme signal they saw (they might still have a viable dose going forward).

    Andre (BMRN) – No, from what I understand it’s a natural AAV5 capsid.

    Ohad

  42. Dan/Ohad – My point that Christian referenced is not so much whether or not VKTX will show a safety signal with their drug in future trials related to elevation of liver enzymes but the fact that the MDGL drug is going the other direction in showing a stat sig REDUCTION in liver enzymes. Seems like their drug is acting differently (perhaps due to being more selective as Dan referred to?).

  43. mcbio: I’m not clear as to what you are referring to by liver enzymes… it seems awkward that these would be tracked for statistical significance- we are talking about toxicities and SE? at least I was. I am confused.

  44. Dan: On MDGL, check their recent PR regarding P2 data in NASH. It notes: “Statistically significant improvements in liver enzymes in drug-treatment group.” And more specifically: “Statistically significant reductions in ALT and AST were observed in MGL-3196 treated patients; greater reductions in ALT and AST, statistically significant relative to placebo, were observed in the prespecified group of 44/78 patients with relatively higher MGL-3196 drug levels.”

  45. Ohad,

    seem Argenx (ARGX) has real drugs!

    see updates for AML (ARGX-110) and for Myasthenia Gravis (ARGX-113), both out today.

    Their IPO in US recently went very well… maybe for good reasons.

    What is your opinion on the (no longer very cheap) company?

    Thanks!
    Christian

  46. hi Ohad
    what is your reaction to spark’s new results and the sell off?
    thank you for this amazing blog
    Paul

  47. Hi Ohad,
    Any comments on ONCE? (How) Does the latest result change your view?

    Thanks, Martin

  48. mcbio316 (MDGL/VKTX) – With small molecules there is always a high degree of uncertainty about cilnical profile and the underlying cause for a clinical observation. The VKTX looks selective in the relevant assays (MDGL looks more selective but not dramatically…) . The LDL reduction implies it is working in the right direction,, to me, the liver enzyme signal is a safety issue, not a mechanistic one. Hard to interpret the subset analysis MDGL mentioned, the VKTX is not in NASH/NAFLD patients so these are apples and oranges imo.

    Georges Robitaille – They usually mean liver damage (if the effect is consistent and durable)

    Christian (ARGX) – Indeed , nice one! Didn’t know CD70 is relevant in AML and the MG data look promising, will look into the data.

    paul/Martin-2 (ONCE) – Clearly a disappointment, don’t think it’s the end for their HepA program but my early excitement was premature.

    Ohad

  49. Leerinks’ note on ONCE is pretty damning
    – behind QURE for HemA
    – Behind NITE (and with worse data) for CHM
    – Behind Biomarin (and no differentiation) for HemB
    Price target lowered to $49 (from $97.)
    Seems to be saying that NITE, QURE, and BMRN are better investments.

  50. Hello Ohad,
    in my opinion an overlooked IPO: Zealand Pharma from Denmark. The IPO price was $17.87, now around $13.25. They are focused on metabolic and gastrointestinal diseases. They have a collaboration with Boehringer Ingelheim. BVF Inc. bought a stake. Can you take a look? Thanks.

    Regards
    Toby

  51. Any thoughts on adding more ONCE and NITE at these current share price?

    Happy Hanukkah Everyone

  52. I am currently looking at NITE, I have also interests in GTs companies. Contrary to you, I am concerned and very sensitive about valuations that seem high also in GT companies, and waiting for the right price works for me. NITE did today a new 52wl. and traded at $12. How far is the company from next catalyst?

  53. Any thoughts on the ITEK/Rocket reverse merger? What do you think of Rocket’s gene portfolio?

  54. Hey Ohad
    have you had a chance to look at $GLMD, since we were talking about NASH cos.? They are from Israel. An interesting paper (pre-clinical studies NASH model) was released earlier this year, showing that their drug has a dual mechanism of action, decreasing fibrosis and inflammation of the liver by ~70% each. Their two ph2 studies read out in Q1 18. Former Tobira director, Carol Brosgart, joined the company earlier this year.
    DAn

  55. Hey mcbio316

    I just read the $MDGL press release, i think the reductions in liver enzymes they were referring to are ALT and AST, which VKTX also reduces (in ph1 comparisons, similar or slightly grater reduction for VKTX, compared to MDGL).

  56. Dan: What VKTX PR are you referring to? The one from 11/15/16 says: “Consistent with liver-targeted thyroid receptor activation, mild, asymptomatic elevations in liver enzymes and decreased thyroid hormone levels were observed at higher doses.” What other liver enzymes would they be referring to here beyond ALT/AST?

    I think it’s odd they call it a class-effect of raising liver enzymes at higher doses yet the MDGL drug at higher doses results in the stat sig decrease. On Ohad’s point, I don’t see it as apples-to-oranges comparison of MDGL vs. VKTX drug as different disease indication because VKTX makes that general comment that this class of drug results in raising liver enzymes at the higher dose (seems to imply not disease specific).

  57. Ohad
    do you follow AKTX?
    Soon (18Q1) they will have 1 Ph3 and 3 Ph2 programs – quite impresive for 60M company. The trails look derisked since they have the same MOA as Soliris.
    Thanks

  58. Ohad
    Any opinion on SPRO
    trading below its ipo price.
    I think you mentioned in past not much exciting novel antibiotic research going on in publicly traded companies.
    Their SPR741 IV abx potentiater program although early seems first in class. also oral carbapenem drug seems like a easy single as it is already approved in children in Japan.
    thanks

  59. avi (ONCE) – Clearly disappointing data, could still be saved with higher doses but then differentiation from BMRN is unclear.

    DAn (ONCE/QURE/NITE/BMRN) – Agree they are behind QURE in HemB but they actually have data with the padua variant as opposed to QURE. I don’t think CHM is a major driver for them, data is probably underwhelming, which is puzzling given NITE’s data. Despite this I still feel comfortable owning them as a core GTx play.

    druz (NITE) – Don’t think it’s related.

    Toby (ZELA) – Sorry don’t know teh field well. The only metabolic company on my watchlist is ZFGN.

    David (ONCE/NITE) – I don’t plan on adding at these levels. Would like to diversify the portfolio beyond GTx.

    Ruhu (IMUC) – Sorry, not following them. Not a big fan of vaccines …

    lgonber (NITE) – I guess that some of weakness can be attributed to the lack of major catalysts next year, they should have initial data in XLRP, where they have a lead.

    Richard Baker (ITEK/Rocket) – Definitely one to follow, curious to learn what their secret indication is with the AAV program.Their lenti pipeline is differentiated from BLUE which is a good thing.

    DAn (GLMD) – Sorry, not following them.

    Toby Spider (SNDX) – I think data at SITC were underwhelming, not a big fan of their target.

    andre (AKTX) – Still trying to understand whether their mechanistic differentiation is clinically meaningful as their drug has a short half life and ALXN is already working on a subQ version of their next-gen product. Agree that it’s very cheap and that regulatory route is clear.

    roland (SPRO) – Planning to learn more about them, personally I am more interested in more innovative approaches (new MOAs or drug types etc.)

    Alex (NVUS)- Sorry, I can’t comment.

    Ohad

  60. Ohad
    You wrote: “diversify the portfolio beyond GTx” – like in CRSP/EDIT/NTLA :):)

    AKTX – they will start Ph3 about 9 months earlier than subQ ALXN1210.
    Plus they are going after Soliris-resistant pts. Approvable drug in well defined market looks like a low risk investment at 65M cap, I guess / hope.
    Probably I am missing something since they have very low institutional investment.

  61. Voilà. Cabozantinib approved in first-line RCC. 2 months ahead of the deadline. Tell me EXEL is not a buy…

  62. Hey Ohad

    I am interested in seeing the cos (beyond GTx) that you will be adding!
    Are you considering VKTX, OVID or CFRX?

    DAn

  63. Ohad
    I would like to thank you for the valuable discussion on different technologies.
    Last spring you were talking about the value of the targeted therapies. After your positive comments about LOXO and RXDX (April 2016) I bought share in both companies. After the today acquisition of RXDX mine return is 350% (RXDX) and 250% (LOXO).
    I am investing in biotech since 10-12 years, but after following your blog in the last 2 yeas I became more focused and started to pay more attention to the underlining technology. Your blog is very valuable in that respect.
    Happy Holidays and New Year

    Any comment on the FATE programs? With Immuno-oncology/regulation they seem to be in the right trend.

  64. andre (CRSP/EDIT/NTLA) – Still not the time to jump into gene editing imo but these companies are making great progress. Fingers crossed!

    Lorenzo (EXEL) – Yes very good news that opens the door for 1B+ sales in RCC. HCC data will be a key readout, anything below HR = 0.75 is significant IMO.

    Alex (ARRY) – It wasn’t a licensing deal, just a clinical collaboration from what I understand.

    DAn – Will post something after the holidays.

    andre (RXDX/LOXO) – Thanks glad to hear and congrats on these gains, too bad I didn’t hold LOXO and RXDX …;)
    Happy New Year!

    FATE – I am more interested in their engineered products where they are trying to do off the shelf CARs but these programs are still early.

    Ohad

  65. Hey Ohad!

    Happy holiday and good wishes to you and everybody else on this board for ’18!

    I wonder if considering the recent RXDX acquisition there might be other targeted oncology companies that might warrant a closer look (besides our very own KURA)? Some investors have mentioned Mirati?

    I also wanted to ask you about valuation for ESPR, if everything goes well… Right now market cap is $1.6B. Do you see this climbing up to $120/share again? (Considering the dilution since two years ago).

    Have you still not looked at VTGN? I watched last year’s presentation by Carlos Zarate (NIMH), which is quite compelling (you can find it on youtube) and seems to point to effects of AV-101 on AMPA receptors, and seems to work through a pathway that does not produce the side effects (including addiction) of ketamine.
    Phase 2 for MDD should read out within 3-4 months.

    DAn

  66. Hi Ohad
    Did you look into SRRA? They claim much higher selectivity compared to other Chk1 inhibitors, especially no activity against Chk2, They say that the MOA is validated by Prexasertib but with superior efficacy and much better safety profile.
    Thanks

  67. Hey Alex

    Isn’t SRRA the old RNAI rebranded and with a new strategy? I think they are trying to replicate something similar to PARP (DNA damage). Maybe this time around they will be more successful. Seems better changes. Also well funded.
    DAn

  68. DAn
    I guess the old name was DNAI. Many companies have unpleasant past and failures (SNSS or ARQL come to mind as examples).
    If they prove that the new inhibitor works, the past will be forgotten. Data from two trails are coming in Feb 2018, so no need to wait too long for answers.
    What is very attractive (to me) was almost lack of any AEs – even no grade 2 in the dose escalation from 20 to 600 mg/day. Also the MOA is indirectly validated, so I am challenging my luck with a few 1000’s shares.
    Andre

  69. Andre
    Yes, you are right.
    I will keeping an eye on them. Seems they had a run already but they are well-funded.
    Results are due soon… what are the other companies with pursuing same target?
    Thanks

  70. DAn
    Ohad may know more. As far as I know:
    Genentech GDC-0575 is in Ph 1 for lymphoma or solid tumors. It was developed originally by ARRY..
    Eli Lilly: Prexasertib – Ph 2 in ovarian cancer and Ph1 in other cancers.
    They got some nice data – 75% DCR in small sell carcinoma, incl 1 CR

    SRRA claims 100 times higher selectivity (Chk1 / Chk2 ratio) which should improve the safety profile, or they can increase the dose and improve the response rate.
    There would be some ups and downs before the data in February, but I plan to hold through the data release
    –andre–

  71. Hi Ohad,

    In terms of Advaxis (ADXS), just to help, you may want to see these links:

    Phase I/II study:
    https://clinicaltrials.gov/show/NCT01671488

    And initial results in JCO:
    http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.e15072

    Very early to tell but the abstract confirms the safety side and so far the on the limited numbers PFS looks good. Two statements in the abstract seemed promising, “Eight of 9 patients (89%) are disease-free at a median follow-up of 34 months.”, and “Conclusions: ADXS11-001 can be safely administered with CRT for anal cancer. Promising PFS was observed in patients with locally advanced disease.”

    This data was published in the second half of 2017 with follow-ups to come.

    Best regards,

    Pete

  72. Hey Ohad

    APTO has interesting molecule about to enter clinic:

    pan-FLT3/pan-BTK inhibitor (non-covalent too, so will compete with ARQL and SNSS)
    in addition it is also pan-FLT3 which opens the molecule to larger markets. The CEO says because it is pan-FLT3 he expects it to had a broader market than most FLT3 inhibitors. Also claims that it is has thousand fold greater potency than ibrutinib

    Seems interesting, but still early.

    DAn

  73. BOLD released some data today.

    1. what are your general thoughts on it? how about regarding the safety concerns? the “elevated troponin levels” have me concerned…
    2. by now, you are up a lot, congrats! when do you plan to do some profit taking?

  74. Happy New Year Ohad ! What is your opinion of TOCAGEN {Toca] and their gene therapy platform ? Thanks in advance !!!

  75. Happy new year

    Thoughts on AGTC? Still holding in your portfolio ?
    ARQL??
    SPHS??

    Thanks

    Luigi

  76. Hi Ohad Happy New Year. Regarding $VKTX for VK 2809 primary endpoint percent change from baseline LDL-C at the end of the treatment period (Week 12) secondary endpoint liver fat content and other liver and lipid markers, as well as effects on safety and tolerability, and pharmacokinetic (PK) measurements. Without showing decrease in fibrosis with an MRI is this an fda approved endpoint for NASH?

  77. Richard Baker (ADXS) – No concrete opinion. They definitely have an interesting twist on cancer vaccines but I am still not optimistic about the approach in general.

    DAn (RXDX/MRTX) – Two names that obviously come to mind are LOXO and BPMC but valuation is too high IMO. There is also DCPH which is less advanced. MRTX is more similar to RXDX in the sense that its molecules are broad spectrum, looks like they are trying to find new niches in NSCLC, combo data with PD1 is limited.

    ESPR – If they get positive LDL/CRP data next Q, they can definitely go to $120 but safety profile will have to be very clean.

    Not very familiar with VTGN.

    andre (SRRA) – I am still not convinced that Chk1 is a viable target unless they come up with a biomarker for patient selection.

    Alex (TOCA) – Don’t know them well but I prefer to focus on other therapeutic approaches.

    thanks

    DAn on December 27, 2017 at 3:58 pm said: Edit
    Hey Alex

    Isn’t SRRA the old RNAI rebranded and with a new strategy? I think they are trying to replicate something similar to PARP (DNA damage). Maybe this time aroundthey will be more successful. Seems better changes. Also well funded.
    DAn

    creminofumagalli – Thanks, Happy New Year.

    Peter Lawson (ADXS) – Thanks, hard to interpret single arm combo data.

    DAn (APTO) – It’s been ages… will take a look.
    DAn

    druz (TRVN) – I am still not optimistic about their market position even if they get approval (which they should)

    Chris (ALNA) – I think they have a neat approach and valuation is not very high, definitely considering them.

    DAn (APTO) – Key issue here would be safety profile, we know both FLT3 and Btk inhibitors have safety issues. It may be challenging to establish a Tx window with such a broad spectrum agent imo.

    Kay Lee (BOLD) – I think data are exciting yet early (lesson from ONCE…). The fact they see such a clinical effect after a relatively short follow up implies the disease may be reversible. Agree about the troponin increase, need to see if it can be mitigated or whether or not it resolves. I plan to continue holding the stock.

    Bouschka (TOCA) – Not sure they qualify as gene therapy… Anyway, hard to get excited wit teh approach imo.

    Luigi –
    AGTC – Yes, still holding despite the setbacks. Cannot comment about ARQL.

    Bouschka (RGNX) – The AMD data was certainly not what people were expecting but the fact they see dose dependent increase in protein is encouraging. Not enough details, hope they communicate data differently next time.

    William Harrison (VKTX) – Not sure… I think that in order to get a NASH label they need to show reduction in fibrosis

    Dimitri (ATRA) – Sorry, no strong opinion there…

    Ohad

  78. Hey Ohad

    Re APTO, good point. But they seem to say (in vitro and in vivo mice studies so far) have not shown any toxicities a d that the molecule does not inhibit any of the kinases that generally cause toxs, and only inhibit FLT3/ CSF1R / BTK / AURK / ERK / AKT.

    DAn

  79. Ohad
    any comment on the DTX301 data?

    About DCPH – you wrote they are less advanced compared to BPMC.
    But they just started Phase III registration trail in 4-th line. In 1 year they will have data and can be on the market in early 2020.
    It’s difficult to say when BPMC will be on the market since they are still in Ph 1.
    Their data are indeed spectacular, but DCPH can beat them to the market by at least a year.

  80. Ohad, I believe you spoke positively about ADVM gene therapy drug for A1AT deficiency before. Aren’t you concerned that it and also the HAE drug are using the same vector (AAV10) that was used in DMTX hemophilia trial that had some safety issues?

  81. Ohad,
    You indicated a desire to expand your portfolio with new approaches. Are there any public companies that are focused on degrader molecules, protein knockout…… targeting E3 ubiquitin ligase or otherwise.
    If not current public companies, are there any IPO’s that are coming up in this arena?
    Thx
    Frank

  82. hey Ohad

    I just listened to the ESPR CEO chat with JpMorgan analyst.
    We are getting real close to results.
    He says that they’ve looked at blinded data, taken a conservative stance, and assigned all AE to BA cohort and still safety profile is in line with ph2 studies. This sound positive. However, there are many more weeks to go before the end of the studies and safety monitoring is only quarterly.
    Management seems very confident. Maybe even cocky…. not sure I like that. Until now they have been very humble and leveled. Maybe I’m reading this wrong… they also seem comfortable waiting for those readouts before finalizing a partnership or BO.

    What is your take / strategy for ESPR into the ph3 readings? Are you going to hold on to all your shares?

    Would appreciate you input.

    Thanks

    DAn

  83. Ohad, do you plan on adding more XENE soon? What is it exactly that you like about XENE?

  84. Hi Ohad,

    Do you think NKTR valuation is reasonable or you consider it as overpriced?

    Thx
    Chris

  85. Hey Ohad
    How much market share do you think $ESPR will get? we have zocor, lipitor, crestor, zetia, vytorin already in the generic market. Is it about LDL reduction, then existing agents are already there in the market. Any reason bempedoic acid will gain market share from the above agents?

  86. Hello Ohad ! Could you please comment on Norway Biotech BerGenBio ASA and its Axl Inhibitor? THANKS

  87. DAn (APTO) – The proof is in the pudding…

    ande (RARE) – I expected a better DTX301 data set, still can improve with higher doses.
    DCPH/BPMC – I was under the impression that BPMC could file earlier with single arm data. Ina ny case, they are more advanced in mastocytosis, which has become their most valuable program.

    mcbio316 (ADVM) – Their A1AT treatment is administered directly to the lung so we’re talking about a different route of admin and a different target tissue. Burden of proof is on them of course.

    Frank – Not aware of publicly traded companies with “degarders”. I won’t be surprising to see Arvinas going public this year although still not in the clinic yet but I don’t know of any specific plans there (or C4 or Kymera for that matter).

    DAn (ESPR) – Hard to speculate here, need to wait patiently for the data next Q… Yes, I am holding my shares.

    Richard Baker (XENE) – Yes, see yesterday’s post.

    Chris (NKTR) – Agree data are encouraging but too prelimary and hard to interpret without a control arm. Hard to justify valuation but hope the signal is real, we desperately need new IO drugs…

    Douglas williams (ESPR) – I don’t think anybody expect BA to compete with generic statins. It will be added to them in patients whose LDL levels are not adequately controlled or be used in combinatio nwith Zetia in intolreant patients.

    Bouschka (BerGenBio) – Intersting approach to tackle EGFR resistance not driven by T790M, Axl is a very intriguing target but still not validated. So far data are not very compelling, I would hope to see objective responses if Axl is truly a primary resistance switch. I like the trial design, though, wish more IO drugs (e.g. NKTR) would be evaluated that way…

    Ohad

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