Endocyte – And now for something completely different

Last week’s approval of Alnylam’s (ALNY) Onpattro, the first FDA-approved siRNA drug, serves as a reminder for the bumpy road new technologies go through on their way to the market. From an investor perspective, siRNA has gone in and out of fashion over the years with dramatic shifts in market sentiment. It started with unrealistically high expectations, deteriorated to deep pessimism due to clinical setbacks, followed by gradual sentiment improvement in recent years (with some hiccups along the way).

This pattern is typical for many fields in biotech (recent examples are gene therapy, immuno-oncology, genomics), which sometimes took decades to realize their potential. The good news is that once a depressed field “rises from the ashes” it is usually for a good reason, i.e. it is backed by real progress. This appears to be the case in targeted radiotherapy (TRT), a neglected field until recently that may become the next big thing in oncology.

Targeted radiotherapy’s checkered past…  

In contrast to siRNA, targeted radiotherapy (TRT) has never been very popular with investors. It had a brief wave of activity in the early 2000’s, culminating in the approval of Bexxar and Zevalin in lymphoma. Despite good clinical efficacy, the two agents (both targeting CD20) were commercial failures because they couldn’t compete with Rituxan-based regimens that were more straightforward to use. TRT agents come with a host of logistic issues: They have a short shelf-life, require special shipping and handling, necessitate special training and carry radiation exposure risks. It isn’t surprising physicians preferred the simpler alternative…

More importantly, antibody-based TRT (also called radio-immunoconjugates) like Bexxar and Zevalin have a long circulation time in the body, leading to significant bone-marrow toxicity as well as damage to highly perfused organs (liver, lungs). This profile may be sufficient for efficacy in lymphomas (cancer of the bone marrow) but not in solid tumors where higher exposure is required.

…but recent data point to a revival

Data from three different TRT programs are behind resurgence in investor interest: Bayer’s Xofigo for prostate cancer with bone mets, Novartis’ (NVS) Lutathera for neuroendocrine tumors (NET) and Endocyte’s (ECYT) Lu-PSMA-617 for prostate cancer.

A key feature of all three is the use of small targeting moieties (In Xofigo the radioisotope is also the targeting moiety), which leads to a short exposure and quick clearance via the kidneys. This exposure profile enables the administration of higher radiation doses, leading to better tumor accumulation with limited toxicity (kidneys are relatively radio-resistant and can be further protected pharmacologically).

First demonstration of efficacy was with Bayer’s Xofigo, approved for prostate cancer based on a modest survival benefit. Xofigo does not have a targeting moiety and it accumulates in bones based on a structural similarity of Radium-223 to calcium. In 2014, Bayer bought Algeta, Xofigo’s original developer, for $2.9B. Xofigo is considered a disappointment with $400M in annual sales (partly attributed to its narrow label) but it still serves as a proof of concept for a radiopharmaceutical. It also clinically validates alpha emitters as a therapeutic class.

The next validation came from Novartis’  Lutathera(via the $3.9B acquisition of Advanced Accelerator Applications), approved for NET. Lutathera is comprised of a peptide targeting somatostatin receptors linked to Lutetium-177. In a P3 study vs. an active control, Lutathera led to an impressive PFS benefit (HR = 0.21) and a strong OS trend.

Lutathera P3

Source: Strosberg J. N Engl J Med. 2017 Jan 12;376(2):125-135.

It is still early to assess Lutathera’s commercial performance (approved by the FDA in Jan 2018) but launch trajectory looks good with sales of $24M in Q2/2018.


Endocyte – Transformational deal, strong P2 data

Endocyte is a newcomer to the TRT field following the in-licensing of Lu-PSMA-617 from ABX. This small transaction transformed Endocyte (and its market cap), which now has the most prominent TRT program in development. Lu-PSMA-617 consists of a small molecule targeting PSMA linked to Lutetium-177. The company recently started P3 based on strong P2 data that were published earlier this year. Lu-PSMA-617 led to a PSA response in ~60% of patients, and more importantly generated an objective response in 82% in 17 response-evaluable patients with soft tissue lesions.


These results compare favorably to other approved agents and may under-represent Lu-PSMA-617’s effect as the ongoing P3 is evaluating a longer treatment regimen. Importantly, the drug was active in patients who failed Zytiga or Xtandi, the leading prostate cancer drugs and the effect was consistent irrespective of prior treatments. Lu-PSMA-617 is being evaluated as monoterapy but it can potentially be combined with other agents in the future given the different MOA and relatively mild safety profile.

Significant commercial opportunity

There are four prostate cancer drugs on the market that can be used to gage Lu-PSMA-617’s commercial opportunity: Zytiga, Xtandi, Xofigo, and Jevtana. Their respective commercial performance varies widely, as Zytiga and Xtandi generate $3.5B and $2.5B, respectively, whereas Jevtana and Xofigo are niche products with ~$400M in global annual sales. Lu-PSMA-617 should be somewhere in the middle as it appears more efficacious and better tolerated than Xofigo/Jevtana. Despite its potential broad applicability (85% of prostate cancer patients should be treatment-eligible based on PSMA expression), logistics issues may prevent it from becoming a multi-billion franchise like Zytiga and Xtandi, but peak sales of ~$1.5B appear achievable.

Endocyte just strated a P3 study which will take 12-18 months to readout (interim analysis, depending on regulatory feedback expected this year regarding approvable endpoints). The only important near-term catalyst could be data from an investigator sponsored study comparing Lu-PSMA-617 to Jevtana that started in January.

Despite the lack of catalysts and potential for negative ones (technical , safety issues), Endocyte may become an attractive acquisition target given the strong efficacy, favorable safety profile, novel MOA in a highly competitive and lucrative market (Zytiga will become generic soon). Many companies are not (yet?) interested in radiopharmaceuticals but an obvious acquirer is J&J given on their franchise in prostate cancer and involvement in another TRT company (Fusion Pharmaceuticals).

Portfolio updates

I am selling Foundation Medicine (FMI) at a 510% profit following acquisition by Roche, announced in June.

biotech portfolio - 13-8-2018 after changes biotech etfs - 13-8-2018

80 thoughts on “Endocyte – And now for something completely different

  1. Have you ever looked at ATNM? Also using radiatherapy… corporate history does not bode much confidence, but I remember seeing that their safety profile is very good compared to the SGEN program that was terminated due to toxicities.

  2. MBIO just bought a GTx program form St Jude’s hospital. It is already in ph1. Wonder if you have any opinions about it? MBIO has low valuation. I suppose they’re diversifying their pipeline because of how competitive the CAR-T is becoming.

  3. Dan (ATNM) – Thanks. I don’t think whole IgG is the way forward with targeted radiotherapy. From what I recall, their AML data was somewhatnoisy and hard to interpret.

    MBIO – Not familiar with the program, need to understand the differentiation from other SCID programs.


  4. Ohad
    Thanks for the interesting write up on TRT. I remember 4-5 years ago it was considered a loosing concept – logistics, special treatment centers, and such… Nice to see a revival of this fairly straightforward ADC type of concept.

    Any opinion on CKPT – they have a late breaker oral presentation on WCLC, Sep 24 – targeted therapy for NSCLC with EGFR mutation
    They claim 3-d generation EGFR TKI, activity against T790M with no activity against wild (normal) EGFR.
    Late breaking oral could mean that they have some positive data for efficacy and safety form their Ph1/2 trail.

  5. Hello Ohad,
    Thank you for this forum- it has really been helpful in more ways than financial gain.
    I had posted a question at the end of the previous segment- if you are aware of the work being done by private biotech company Bexion? (The reason that I ask is that they do allow placement of private funds, albeit at higher levels)
    Their “star” patient with glioblastoma m seems to be approaching the 5 year mark (although only the most recent 20 months seems to be with their drug). And now John McCain also seems to be under treatment. Hmmm,

  6. Hey Ohad,
    have you had a chance to look at RLMD – they are running a phase 2 study in MDD. The PI is Maurizio Fava, the inventor of the sequential parallel comparison design. Study is recruiting only 60 patients so could read out quickly.

  7. sector sentiment

    Are you Holding the companies in your Portfolio During the Next quarters? Do you Plan to increase your BIS Position?

  8. Hey Ohad,
    CGEN is about to initiate two ph1 programs (one partnered with BAY). Some people have lofty expectation for their lead program, or hopes it may be as effective as checkpoint inhibitors. Any views? I started a position yesterday.

  9. Ohad

    XENE is expecting to present data from its XEN1101 Phase 1b TMS pharmacodynamic study at the end of the month. Is this a final readout from there interim results they announced in May and is there anything you will be most focused on with the upcoming data. Also does the XEN1101 or XENE901 program have greater value enhancing possibilities for the company.

  10. Hi Ohad,

    My question was posted on your last article, but was wondering if you have any opinion on Adruo $ADRO STING upcoming data? Pre-clinical looks like they are on to something big. Large milestone payments upcoming with Novartis and EV of only $155M as of now with $300M cash.

  11. Hello Ohad,

    do you know Arix Bioscience plc (LSE:ARIX) ? They do similar things like Pontifax Ltd :-) For example they have a big stake in $AUTL. Actual the share price is very low. Do you have an opinion?

    Today Ladenburg gave $ACHV a PT of $12. Actual the pps is only around $3. Laden lead the last offering, the price was $4 in May. They are developing a drug for smoking cessation. The potential looks enormous. They use Cytisine for the drug, this is a plant-based alkaloid. The company is off the radar. Do you think this a good gamble?

    Thanks Toby

  12. …$ACHV
    There already exists drugs with Cytisine especially from Bulgaria. The question is will Achieve Life Sciences be able to protect their new drug with a patent? It’s a natural substance. I couldn’t find a statement on their website.

    It’s a very little company. If you have no time or interest I can accept and understand!

    But I think ARIX.L is interesting for you.

  13. Hi Ohad
    I recall you invested in EXEL privately ,still holding? What is the reason for the weakness in the share?
    Do you think now its a good price to enter?

  14. Hi Ohad!,

    what are your thought about the future catalyst that will move the needle in SNSS?. Do you expect them before the next CC.?

    Are you invested in SNSS because the valuation gap with ARQL or because you think is better science?

    Thank you!

  15. Ohad
    Do you follow ATRA? They expect approval next year and to be on the market in 2020. Nice pipeline but not a single partnership?!
    Is it a red flag or they just don’t need that. Cash is ~450M – enough until approval

  16. Nice development at BOLD – RMAT granted for XLMTM. They might expand the current P1/2 into pivotal and shorten the path to market by 1 year (from 2021 to 2020).
    By that they are “promoted” my 2020-graduation-club (ABEO, BLUE, NITE, VYGR, QURE, ATRA, ECYT ONCE ALNY)

  17. Ohad–Thanks again for an insightful report. Lutathera may overestimate physician adoption of PSMA-617 since there are so few systemic options in carcinoid tumor, unlike prostate cancer. As you correctly state, the logistics also include oncologists “referring away” to hospital-based nuclear medicine or whatever mechanism has been set up to deliver the radioisotope. There always seem to be some resistance there as well. That being said, I agree with you that the data from Lancet Oncology are promising and the drug will likely get approved barring an unforeseen safety issue. Hopefully, drugs like Lutathera will help improve treatment pathways for oncology/nuclear medicine interaction.

  18. Hi Ohad,
    1. Endocyte paid $12 million plus some stock to acquire PSMA-617, while Bayer bought Algeta, Xofigo’s original developer, for $2.9B and Novartis for $3.9B. I am wondering why would ECYT get PSMA (potential cancer blockbuster) so cheap?

    2. Do you think PSMA be way more expensive than Xofigo due to the need to pre-screen with dual PETs? where do you think it cost compare to Xofigo.


  19. News yesterday out of U of Penn regarding GTx for retinitis pigmentosa.
    I think U of Penn is licensing the GTx from OPTH.
    OPTH collapsed tears ago after it’s failed drug to compete with Eylea (REGN).
    Do you see any potential for OPTH given its current low valuation and this news from UPenn in R.P.?

  20. Hey Ohad,

    What do you think of CFRX and the release just out now indicating their drug drug can resensitize bugs (such as Staph Aureus) to penicillin and other antibiotics. This may make their drug a combo therapy used with any antibiotic course? If this is the case this could be huge.

  21. Hi Ohad, Epizyme (epzn) showed some weakness in recent months due to the partial clinical hold. Do you think it’s a good time to get in right now? Thanks!


  22. Hello Ohad ….. Would you please comment on the late breaking oral presentation by ESPR at the European Society of Cardiology Congress that is in the news today.Thanks in advance!

  23. andre – Yes, I don’t know what is more mind boggling: the amount of time much time it takes some technologies to mature or the fact they eventually do.
    CKPT – Don’t know their EGFR program well but it is going ot be an uphill battle vs. Tagrisso unless they have a clear differentiation, which will be hard to demonstrate in P1 imo. They could eventually take market share as Tagrisso is the only approved 3rd gen EGFR inhibitor but I prefer to wait for the data.

    lawrence sheff (Bexion)- Thanks. Not familiar wit the company but after a quick look at their corporate deck I feel data are quite limited and the story is not robust enough imo (mechanism/exposure in humans/ efficacy). There have been a lot of programs with such index patients, especially in GBM and unfortunately usually they don’t pan out.

    Dan (RLMD) – Wasn’t aware of them, looks like they have an oral NMDA antagonist, an interesting proposition, IP is probably weak (methadone derivative), not sure how strong their biology is. In these type of projects I prefer to wait for the data.

    Anger (BIS) – It’s definitely something I am considering as we are in one of the longest bull run in history in general and in biotech as well. I do intend to keep the stocks I own long term because it’s impossible to predict near term stock movements but overall I still think correction is due and valuations are fairly high.

    Dan (CGEN) – I prefer not to discuss Israeli companies.

    Dave (XENE) – Beyond the TMS signal, the most important readout is the safety profile in te MAD portion. Even a rare safety event could kill these programs.

    John (ADRO) – Agree preclinical data for STING agonists (as well as similar targets like RIG1) is very inteersting, the problem is that so far the translatability to humans with IO agents has been very weak. Prefer to wait for the data, which will probably be inconclusive to some extent given the trial design.

    Toby (ARIX) – Prefer not to comment on the stock as we are collaborating with them, good guys. I do like AUTL, though. Early data but rationale is very strong imo.
    Don’t know ACHV, sorry.

    Alex (EXEL) – Yes, still holding a small portion. Not sure what is the cause of te current weakness, but this isn’t unusual for companies 2-3 years post launch when the dream factor is gone and there are hard numbers. Their current run rate is ~$600M so if it continues to drop could be an interesting opportunity.

    James (SNSS) – Prefer not to comment. Pontifax is an investor in ArQule.

    andre (ATRA) – Sorry, don’t have a concrete opinion there.

    andre (BOLD) – Yes but not overly surprising given te indication and data. Perhaps not a home run like the initial AVXS but definitely a signal.

    Gary (ECYT) – ECYT is targeting last line patients without a lot of treatment options so if they generate good P3 data I think ‘617 will be well received.

    AJ (ECYT) – That’s a very good question, one of the best BD deals ever in biotech, no doubt. I think the NVS/AAA deal contributed a lot to 617’s visibility. At the moment I am not concerned about costs, pricing will be driven by clinical benefit at the end of the day imo.

    Frank (OPTH) – Didn’t think it was related as they were using gene editing.

    Dan (CFRX) – Sorry, don’t know the story well.

    Jinyu (EPZM) – Stock is still at 800M so not that cheap imo given the recent safety overhang.

    bouschka (ESPR) – Not a lot of new information, next P3 readout will be much more important.

    Surab (ESPR) – Hard to speculate but given the 1-2B sales potential I think a 4B
    buyout is realistic.


  24. Ohad, you mentioned that biosimilars will have a significant market Share in the (Near) Future but you dont hold any stocks.

    Whats the reason for this ? Too expensive? Do you like Momenta i.e.?

  25. Ohad

    Regarding ESPR data readout. In reviewing there data just released it appears that BA + Zetia combination resulted in 3x the rate of developing a urinary tract infection than either BA or Zetia alone in a 12 week study. Is that a concern?

    Regarding AUTL doesn’t the valuation appear rich at 1b?Would you wait for the price to come in before starting a position

  26. ESPR

    Are you more Optimistic about BA Approval After the recent Data release?

    What do you think about the Cvot requirement?

    Btw uric acid level was Noted before. Not a big Issue imo.

  27. Hey Ohad,
    Would love to hear your view on ESPR and XENE results.
    For XENE seems like they will be able to enroll a ph2 and generate results rather quickly.
    Also, what do you make of the AFMD deal and NK / cell therapy cos. How do you rate FATE, especially since you say you like AUTL.

  28. Karlos (ESPR) – Not very concerned there, key safety finding will be Study 2 next month. Efficacy on top of Zetia was somewhat disappointing.

    Carlos – I focus on innovative products and not very familiar with the biosimilar field. Nevertheless, most biosimilars are being developed by large biopharmas (Amggen, PFE, BI, Biogen) so not a lot of pure plays.

    Dave (ESPR) – Not overly concerned.

    AUTL – Ideally yes but I don’t expect price to come down significantly unless a major market correction occurs (or negative data, of course).

    Labut (ESPR) – I am slightly more optimistic on the safety front but the Zetia combo data was a little disappointing. I still think there are enoughpatients who could benefit this drug (interesting subset analysis in statin resistant pts that needs to be corroborated prospectively).
    I think it will get approved without CVOT, but they will have to show some benefit in order to become a dominant product.

    Habulm (XENE) – Data are positive, largely expected, always nice to see a relatively clean safety profile and TMS signal looks good.

    Dan – Re ESPR and XENE , see above. I would characterize both is positive but nothing overwhelming.

    AFMD – Good for them! I was never a big believer in their approach but apparently Roche are.
    FATE and AUTL are very different IMO, prefer AUTL even with the valuation gap.


  29. ADVM: what is your take on the long-term NHP efficacy data? It shows prevention of Grade IV CNV in the animal model and exhibits 3 ug/mL of aflibercept (not sure the level in vitreal and retina). Is anti-VEGF activity Cmax driven or steady state driven? Is 3 ug/mL clinical meaningful? In the aflibercept trial, the vitreal Cmax is 900 ug/mL.

    For the A1AT program, AGTC tried and failed with a different vector and route of administration. Does ADVM have a shot with AAVrh10 and IV/IP administration?

    How does the HAE program look like?

  30. Ohad

    for KURA, J&J recently gave up on the right to be first to (re)negtiate for an exclusive license for tipi. do you read anything into it?

    the drug is rather old, so patent life is short… is that considered in your calculation?



    Are you still positive at current valuations?r/r? What key catalysts are you waitiing for in 2018?

    Thanks to you Ohad, very nice work!!

  32. Hey Ohad,

    What’s your take on the Stanford study on Ketamine and use of opioid receptor blocker? They are suggesting Ketamine works in different phases – first activating the opioid receptor, then the glutamate. Although researchers say Ketamine does not have high affinity to opioid receptor, this study raises questions about addiction, etc.

    What do you think are the implications for the 5-6 companies involved in the field?


  33. Ohad
    What do you think about AXON Parkinson Lentiviral vector program.
    The capsid contains three genes required for dopamine synthesis ?!?
    The primate data look really solid – dopamine level and symptoms improvement – both stat significant..
    They had a checkered history, failed in the 2 x past badly.
    But it looks they refocused into gene therapy, got some good new hires – CTO from ONCE, VP R&D from AGN, VP clinical dev from PFE

    Their story starts to look like ECYT – a lot of failures, until they licenced something valuable, less than a year ago. They were trading 1.40, today 19.70.
    And the stock price of AXON looks similar to the onset of ECYT after Oct 2, 2017 ECYT – up from 1.40 to 6.50 on the news, retreat to 3, and from 3 to 20 in a remarkably steady increase
    AXON – up from 1.50 to 6.60 on the news, retreat to 2.10, today at 2.50, I guess on the way to 20 in 1-2 year :):)

    What about adding them to the GT basket – strong science (from Oxford Bio) strong team, 100M cash, low valuation (300M), non-human primate proof of concept, no induced dyskinesia compared to levodopa…..
    Plus a second program in Oculopharyngeal Muscular Dystrophy, Ph 1 to start early 2019. And pre-clinical programs in ALS and FTemp Dementia.
    Looks a perfect fit to your GT-CNS basket

  34. Ohad,
    Last May, Sesen bio. (formerly Eleven biotherapeutics) published 3 month data from their ongoing Ph III Vista trial. The are using a next-generation ADC. 13-F filings for the second Q were impressive. Would you look at the science please and let me know if there are any obvious red flags ?

    Thanks, cb

  35. Liang (ADVM) – From what I understand you need long term expression, once you saturate the target (VEGF), more protein likely won’t change anything. Not sure how much expression is optimal, 3 ug/ml sounds meaningful as VEGF levels are typically in the ng/ml range and in some cases hundreds of pg/ml (but VEGF is a smaller protein so you need 4x more Eylea to reach the same molar level). Be that as it may, expression levels cannot be extrapolated directly from animals to humans with AAVs.
    The A1AT program is indeed a long shot but I like it because it’s unique.
    HAE program is less interesting IMO, there are good alternatives and delivery/exposure requirement are unclear to me.

    Christian (KURA) – Hard to say, definitely not a positive but we’ll see updated data soon. Agree about IP, it will be protected only by 7-10 years of market exclusivity which puts a cap on upside.

    Sppi (ONCE,ABEO, RGNX) – Yes I am still positive on all three as all will have clinical readouts in the coming 12 months. For ONCE, it’s HemA, of course and people are starting to look at Pompe. For ABEO, focus is on San Filippo programs and for RGNX it will be on AMD and MPS1/2.

    Dan – Honestly don’t know how to factor that in, very hard to translate scientific data for CNS indications, clinical data trumps everything and very unpredictable in depression.

    andre (AXON) – Ilike their new direction, not familiar with the PD program. The main difference from ECYT is that ECYT knew the drug works in humans. Agree they fit into the GTx basket, need to learn more about their programs.

    conrad barker (Sesen) – From what I see they are doing immunotoxins, hard to give them systemically to get efficacy in solid tumors due to toxicity and immunogenicity. This is why their lead program is for topical bladder cancer


  36. Hi Ohad, would like to know your thoughts on SYBX (especially in light of the recent positive ph1/2a data) and ALRN (given the increased scientific recognition of ALRN-6924 and stapled peptides). Thanks as always.

  37. Ohad –

    What did you think of the SGMO data? It’s exciting we are at this stage of gene editing, but investors seem to have doubts that the approach is working due to lack of IDS enzyme in blood. However, how can you see a decrease in GAGs, dermaten sulfate, heparan sulfate without some therapeutic benefit ascribed to gene editing? Those numbers won’t drop by chance.. Seems like a good buying opportunity to me, but curious to get your thoughts.


  38. Voyager (VYGR) and Uniqure (QURE) both have a gene therapy program AAV-miHTT, but with different AAV type and different design of vector. Based on the pre-clinical data, is there differentiation between them?
    For CNS indications, Voyager licensed a new vector from CalTech. With this new type of vector, what is the likelyhood of success to target CNS with IV administration?

  39. MEIP received FDA’s feedback on their PI3K-delta inhibitor for follicular lymphoma. In the feedback, FDA requested a randomized phase 2 trial to compare the compound with the standard of care for R/R FL. Both daily and intermittent dose regimens will be included. Apparently, MEIP can use a single-arm study. What is your take on this feedback on the registrational trial design? Do you think if their PI3K-delta inhibitor could be a best-in-class molecule as some of the analysts claim, in term of its efficacy and tolerability? The response rate in the phase 1 study of CLL/SLL and FL seem to be high.

    Any other merits in MEIP’s other pipeline programs (HDAC for AML and MCL inhibitor for AML)?

  40. MEIP received FDA’s feedback on their PI3K-delta inhibitor for follicular lymphoma. In the feedback, FDA requested a randomized phase 2 trial to compare the compound with the standard of care for R/R FL. Both daily and intermittent dose regimens will be included. Apparently, MEIP will not be able to use a single-arm study and most likely cannot use ORR as the primary endpoint. What is your take on this feedback on the registrational trial design? Do you think if their PI3K-delta inhibitor could be a best-in-class molecule as some of the analysts claim, in term of its efficacy and tolerability? The response rate in the phase 1 study of CLL/SLL and FL seem to be high.

    Any merits in MEIP’s other pipeline programs (HDAC for AML and MCL inhibitor for AML)?

  41. Richard Baker (ALRN) – Their platform looked really promising initially but it doesn’t look like they have good translation in humans.

    MGTA – I like the approach but clinical data are too sparse IMO. Prefer to wait on the sidelines for now.

    Xavi –
    SYBX – I really like the approach, perfect sense for some metabolic disease like PKU. Not sure what they have qualifies as clinical poc but moving in the right direction.
    ALRN – See above, so far data are weak imo.

    Nick (SGMO) – I think data are inconclusive and I am still skeptical about ZFN as a tool for gene editing. Agree the GAG drop in the higher dose cohort is inthe right direction but patients were getting ERT which probably had a confounding effect. Hope they see IDS in the next cohort….

    Liang (VYGR/QURE) – Too early to tell but Huntington is definitel a promising indication following Roche/IONS data.

    Liang (MEIP) – I don’t have high hopes for this class in general, crowded market. Same applies to their HDAC program.


  42. Hi Ohad,

    Thanks for all the great informative that you share.

    Does the recent announcement by XENE Change your valuation? “Xenon Expands Ion Channel Neurology Pipeline with Addition of XEN496, a “Phase 3 Ready” Potassium Channel Modulator for the Treatment of Epilepsy”

    Not sure what the market is for the drug considering it was pulled previously but GSK is allowing the FDA to leverage their filings to support XENE.

    Any input would be much appreciated!

  43. Hi Ohad,

    How do you see ARWR’s ARO-HBV data? Some say they might be the next GILD. 1.7B cap already, is it too expensive to get in? Thanks a lot!


  44. Hello Ohad. Very much intrigued with FIXX and their Gene therapy/editing approach. Stem cell derived AAV and homologous recombination. No cutting of the genome that remains a concern with crispr and potential off target effects. HR is the body’s own mechanism of repairing faulty code. Partnership with Novartis. Preclinically they are seeing excellent precise gene sequencing minimizing side effects. Still early but could be a game changer

  45. What upside do you expect for $nite? For a p1/2 Company the stock is quite expensive (700 mil MC). You claimed before that you dont add such stocks to your basket so why is nite an exception? Thank you!

  46. What is your take on ARWR new HBV data? Is HBsAg reduction an acceptable clinical endpoint?

    How do you like their targeted RNAi technology?

  47. Hi Ohad do you Plan to expandiert your GT basket? If yes do you like These companies: VYGR / MGTX? What about their Programs and Price?

  48. Ohad
    You probably missed the last posts from the previous article. Here is part of it:

    FCSC: I was reading the transcript of the concall. You were right – the recent financing is concerning- warrants, etc. However there were some interesting info in it:
    – they started Ph2 and already enrolled 4 pts. Goal is 6-8 pts,
    – expected enrollment completion Q3, data in early 2019
    – it looks they already applied for BTD and RMA, at least did not deny it
    – if they get RMAT, they will expand the trail to pivotal, potential approval 2020.
    Cash until Q4 2019, enough to complete the pivotal trail and announce the data.
    How about FCSC as a hedge to ABEO and KRYS? Three different approaches (injections, patch, gel), hopefully at least one may work.

  49. Hi Ohad,

    Are you still positive about BOLD?

    There has been some insider selling from May to July of this year by CEO and SVP Chief Med. Officer in the range of $38-45.


  50. Hello Ohad,

    It seems that resolving the c486 mutation for non-covalent BTK inhibitors may not work. The PLC gamma mutation is another problem that develops downstream. So there will likely be a need for a third generation BTK inhibitor. Moreover, this may also point to one of the potential flaws of targeted drugs: while they work in the short/medium-term (Ibrutinib is a good example), they can lead to resistance and mutations, and become ineffective.
    Any thoughts on this–I know you are quite big on targeted therapeutics?

  51. Adam |(XENE) – Honestly I don’t understand this move… don’t see a lot value there given Potiga’s issues, pricing challenges.

    Jinyu (ARWR) – That’s an impressive recovery! Not an expert on HepB so hard to say…

    Jaime Allen (FIXX) – Agree, very intriguing approach, applicable for multiple pediatric indications, I wish they would have published more because up until now I haven’t seen a lot of supportive experimental data showing they can edit liver cells in animals (note their 1st program is standard AAV gene therapy). Their vector looks super efficient based on what they published. Agree such a technology could avoid issues associated with nucleases and strong promoters. Key question is efficiency as HR is a rare event.

    Josefb (NITE) – Agree NITE isn’t cheap but it is a P3 company (choroideremia) and has several other programs so I thought they should be part of the GTx basket.

    Liang (ARWR) – sorry not very familiar with HBV.

    Kekse – Yes I am looking to add more shares. Currently the one on top of my list is AVRO. With VYGR and NITE I m still on the sidelines.

    Roy – Thanks!

    andre (FCSC) – I think I am scheduled to meet them next month, need to understand their data better.

    Anna (BOLD) – Yes, still positive on their XLMTM data whoch aren’t perfect but still encouraging. They also have a nice emerging pipeline.

    Dan – Yes resistance a primary issue with targeted therapies which means we should try to be one step ahead in this arms race, similarly to the dynamics with antibiotics.


  52. Ohad

    ECYT. News from the FDA that rPFS is a alternative endpoint and can possibly push up the approval timeline almost a year as well as a 175m secondary announced after the close.How do you view the regulatory update and does this news from the FDA increase the likelihood of approval and in turn make them a more attractive candidate for a possible BO?

  53. Agtc

    Why does the market hate Agtc so much? Still Trading under Cash value although they have multiple GT programs. When Could the sentiment change ?

  54. Hi Ohad,

    Interesting transaction announced for XENE to buyout 39.6 million of milestone payments and all royalties owed on future sales of XEN1101 for 6 million up front. Any thoughts about why they would do this now? Possibly stronger position for future partnership negotiations? Thanks!

  55. Ohad

    You had mentioned a couple weeks ago that additional weakness in EXEL may present a buying opportunity. The stock is down close to 8% today, due to PFE/MERCK-KGaA drug shows better PFS than Sutent monotherapy in 1st line RCC. Is the selloff warranted?

  56. Ohad,

    Happy healthy New Year! Quick question on ECYT. I noticed in the recent prospectus the have to pay royalties starting at mid teens not to exceed mid twenties. This might suggest they in reality own only half of this asset. Based on this, does that suggest the upside might not be very attractive from the price of the secondary offering 18.50. Thank you!!!

  57. Hi Ohad,

    Will appreciate your thoughts on PGNX following its recent failure and announcement of acceptance of AZEDRA for radiotherapy. Also on the continued decline of EXEL. Thanks for all your guidance.

  58. Ohad,

    What are your thoughts in general on high dose gene therapies? I’m seeing quite a few new therapies that are as high as 10^15 in certain heavier patients where the therapy is weight based (vg/kg) delivered locally either IT or through other targeted delivery. Where do you stand on this and do we have enough data to date to suggest 10^15 is safe enough?

  59. Hello Again Ohad……. I would be VERY interested in your take on the RADICAL price fluctuations in RGNX !??

  60. VKTX – nice data, especially safety
    Actually Nash was not its main focus; the primary endpoint was change in LDL-C, and with only 20% reduction they failed in that. The Nash-relevant endpoint was exploratory, and they hit the jackpot in that indication.

  61. Hi Ohad,
    Congrats on VKTX
    What do you think about MDGL falling following this news? Is this justified?

  62. Hi Ohad,

    What is your take on OMER? The drug 721 bagged two BTD in the last year also. What is the potential market size for the 721?

    What are the potentials for their other pipeline assets such as PDE7, PDE10, and GPCR platform? They claim that they strong IPs on GPCR and potential applications in CNS.

  63. VKTX: once again, congratulations on a good nose. At first glance, the VK2809 data is even better than the MGL-3196 data. Does VKTX still have catch-up potential? VKTX (1.2b$) vs. MDGL (3.2b$)
    In addition, what are your prospects for the NASH ph3 candidates Eflafibranor/Genfit (ph3 interim: 2H19) and Ocaliva/ICPT (ph3 interim:1H2019)?
    ICPT (3.6b$) vs. Genfit (0.74b€) –> Genfit appears cheap.

  64. Hi Ohad,
    Do you think if the TSRO’s lung caner development plan (PD1+Parp or PD1+TIM3) has a good chance to succeed?

    TSRO presented the combination data for Niraparib and Pembro. In the 1st NSCLC (PD1 naive), 9/14 showed response (both confirmed and unconfirmed) and all exhibited tumor shrinkage. Do you think if the signal real or just another IDO story?


  65. Hey Ohad,
    Nice early surprise with VKTX results! Been an investor since the $2s. What now? Do you think they are likely to get bought ahead of MDGL – similar to what happened with Ignyta (which was bought before Loxo because it was cheaper?).
    CEO clearly stated they are open to what’s best for shareholders. Gap with MDGL is $1.4-1.5 billion? (MDGL has 500M cash) could that be the floor to a BO target price? About $3B?

  66. Hi Ohad,

    I wonder whether you have an opinion on TOCA, 230M Capital, phase 3 on brain cancer, breakthrough therapy awarded. Bought some, will add more with your endorsement.

    Thanks a lot!


  67. Ohad

    It’s been awhile since you spoke about SAGE. The stock has been meandering the last 9 months since its explosive move at the end of 2017.If I remember, you were most excited about the prospects for SAGE-217 and it’s many potential indications. Anything you can add at this time as they have moved this compound into Phase 111 for postpartum depression. Are you at all impressed with Brexanolone for the same indication or do you think SAGE-217 offers better potential for women who suffer from this disorder. Would you add to your position or take a wait and see at this point

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