Immuno-oncology – Key themes for 2014

A lot has been written about the immuno-oncology (cancer immunotherapy) field and how it is expected to revolutionize cancer treatment. In 2013, excitement around immuno-oncology and PD-1 antibodies in particular reached record high levels. In 2014, the trend is expected to continue on several fronts. These include potential approvals, new combination regimens, new indications and new targets.

Below is a review of key catalysts and drivers for immuno- oncology in 2014.

key points

Accelerated approvals for Merck’s and BMS’ PD-1 – potentially in 2014

The most important data readout will be for BMS’ (BMY) nivolumab in squamous non-small cell lung cancer (NSCLC). Results are expected in Q2 2014 and may serve the basis for accelerated approval already in 2014 (assuming BMS submits its BLA in Q2). A response rate of >20% is considered sufficient for approval due to limited options for these patients (few known driver mutations, ineligible for Avastin and Alimta). Good response durability will further increase likelihood of approval.

This is BMS’ most imminent chance to get nivolumab approved. Other pivotal trials will read out only in H2 2014/H1 2015.

Merck (MRK) is pursuing melanoma as a bridgehead to market based on phase I data in Yervoy failures (Response rate >40%). Earlier this year the company surprised the market by announcing a rolling submission in Yervoy failures. The rolling submission mechanism implies Merck plans to submit additional data beyond the phase I results but no specifics were given. These additional data will likely come from a large melanoma phase II comparing MK-3475 to chemotherapy in Yervoy-failures. The trial, which completed enrollment in October 2013, is an open label trial that allows cross over, so Merck is already aware of the data and believes the response and PFS results are sufficient for approval.

PD-1 combination regimens – Yervoy and Avastin

On the heels of stellar activity as monotherapy, companies are trying to differentiate their PD-1 programs by combining them with other drugs. In 2014, companies will present multiple combinations with PD-1 antibodies that may clarify their strategic positioning.  The most straightforward combination is with CTLA-4 antibodies like Yervoy, as they employ a similar mode of action.

BMS leads the pack with nivolumab +Yervoy combo – The combination is being pursued  in an aggressive development program across many tumor types. Last year, the company presented impressive preliminary results in melanoma demonstrating a high response rate and more importantly very deep responses as most patients experienced near complete eradication of tumors (see figure below). The combination is being evaluated in melanoma, lung, renal, colon and brain cancer.

Wolchok 2013

Still no decision on lung P3 for nivo+Yervoy – At ASCO 2014, all eyes will be on nivo+Yervoy combination data in lung cancer. BMS’ recent earnings call curbed expectations to some extent, as the company did not announce a decision to advance the combination to phase III as some had hoped. In addition, management’s tone during the call was perceived as cautious, implying that so far lung data are not phenomenal. On a positive note, the company announced its decision to start a phase III for nivo+Yervoy in renal cancer.

PD-1 +Avastin as another high priority – Combining PD-1 antibodies with Avastin is practically straightforward as the latter is approved in 2 of PD-1’s imminent indication (NSCLC, renal cancer). In recent years, VEGF has been characterized as an immune suppression factor on top of its role in angiogenesis, making the combination even more logical. Animal models presented by Roche demonstrate synergistic activity for the combination.

PD-L1+VEGF

PD-L1+Avastin combinations are important for Roche – Roche is evaluating its PD-L1 antibody (MPDL3280A) in combination with its VEGF antibody, Avastin, across several tumor types with an emphasis on NSCLC and renal cancer. Although BMS was the first to pursue Avastin in combination, Roche has a broader program for MPDL3280A+ Avastin and is expected to present top line results at ASCO 2014. As Roche markets Avastin, any Avastin combination regimens may give it an edge over competing PD-1 programs, especially if nivo+Yervoy disappoints. Good combination data may also offset concerns about MPDL3280A’s lower efficacy as monotherapy.

Roche recently started a randomized phase II of MPDL3280A+Avastin vs. Sutent in renal cancer.

New indications for PD-1 – Lymphoma, bladder and breast cancer

PD-1’s core indications are lung, melanoma and renal cancer, where the three leaders (BMS, Merck, Roche) are running neck and neck. Understandably, companies are trying to expand beyond those indications and try to differentiate their programs via new indications.

In lymphoma, 1st mover is BMS – BMS has an ongoing phase I in blood cancers for nivolumab, which may have first results in 2014. The company recently posted 2 phase II trials in DLBCL and follicular lymphoma, respectively, which indicates the phase I demonstrated a sufficient level of efficacy as single agent. Interestingly, it looks like BMS views the DLBCL study as a potential pivotal trial as responses will be assessed by an “Independent radiologic review committee” (IRRC).

Bladder cancer pursued by Roche – Rumors about strong activity in bladder cancer surfaced in the past months. Earlier this month Citi’s analyst, Andrew Baum, issued a report titled “Immunotherapy: Bigger, Broader, Bladder”, in which he predicts compelling data for Roche’s MPDL3280A in bladder cancer at ASCO 2014. According to the report, there may be over 50,000 eligible patients for PD-1 therapy, which translates to a $4B opportunity.

Initial signs in breast cancer – The biggest surprise in 2014 may come from breast cancer, with an emphasis on triple-negative breast cancer (~20% of cases). TNBC is associated with a poor prognosis due to tumor aggressiveness and lack of effective treatments .  BMS and Merck both have follow on trials that list TNBC as 1 of 4 relevant tumor types. Both trials started in the middle of 2013 but there are already clear signals of efficacy. After decades of stagnation, there are finally 2 promising classes of drugs for this indication: PARP inhibitors and PD-1 antibodies.

New targets beyond PD-1

So far, PD-1 is the only target with clear efficacy in humans. There are many programs that explore new immunotherapy targets employing various different approaches. To date none have demonstrated anything similar to PD-1 as monotherapy. These programs are being evaluated as monotherapy or as add-on to a PD-1 backbone.

The hottest targets can be divided to co-inhibitory checkpoints like PD-1 (where the goal is to inhibit their function) or immune activators (where the goal is to enhance their function). The first group includes LAG3, IDO, TIM3, KIR and BTLA. The second group includes CD137 (41-BB), OX40 and CD27.

Programs expected to generate data in 2014

Incyte’s IDO inhibitor – There is a huge buzz around Incyte’s (INCY) IDO inhibitor (INCB024360), which in contrast to most programs is a small molecule inhibitor. Monotherapy data for INCB024360 did not demonstrate meaningful activity in patients but Incyte’s management indicated that an ongoing combination trial in melanoma is demonstrating encouraging signs of efficacy. The trial evaluates the drug with Yervoy in melanoma patients and per management’s comments, activity seen with this combination exceeds historic response rate with Yervoy alone (~10%). This was enough to spark investors’ and analysts’ imagination with expectations for a 30-40% response rate. As a result, analysts have plugged in $2-3B of INCB024360 revenues in their models without even seeing data from a single arm 20-patient data set (Expected at ASCO 2014). Incyte and Merck recently announced a combination trial for INCB024360 and MK-3475. The drug is also in phase II for ovarian cancer. 

Newlink (NLNK) has 2 IDO inhibitors in development. Results from the 1st generation compound (indoximod) are expected at ASCO 2014. A 2nd generation compound (NLG919) is expected to start Phase I imminently. The interest spurred by Incyte led to a significant step up in the company’s stock price.

Targeting macrophages via CSF-1R – Roche is expected to present a large data set for its CSF-1R antibody alone and in combination with chemotherapy. This antibody is designed to inhibit tumor promoting macrophages that are found in many solid tumors. Conceptually, it is complimentary to T cell activating drugs like PD-1 as it removes an important immune-suppressive component from the tumor microenvironment. Early biomarker data were encouraging but it is still unclear whether this will translate to clinical efficacy. 

CD27 as a novel co-stimulatory target – Celldex (CLDX) is expected to present updated results for CDX-1127, an agonist antibody for CD27. The company is enrolling patients with melanoma and renal cancer and should have ~15 patients per tumor type. Phase I results presented last year showed preliminary signs of efficacy in the form of 1 durable complete response (Hodgkin lymphoma) and 2 cases of tumor shrinkage that did not qualify as objective responses (colon cancer and NHL). There were also intriguing immunologic effects such as reduction in regulatory T cells and enhanced T cell activation. Initial results from the melanoma expansion cohort has so far been disappointing.

Preclinically, Celldex presented an additive effect when CDX-1127 was combined with anti-PD-L1 (see figure below).

cdx1127

Anti-KIR combination data from BMS – BMS is running 2 combination trials for lirilumab (Anti-KIR, licensed from Innate Pharma) with Yervoy (CTLA-4) and Nivolumab (PD-1), respectively. As KIR is a family of co-inhibitory checkpoints on NK cells, lirilumab has the potential to complement T cell activation by PD-1/CTLA-4 with NK activation. Lirilumab is the only KIR antibody in clinical development for oncology and these combinations could create an important differentiating factor for its PD-1 franchise.

Awaiting more data for B7-H3 – Macrogenics (MGNX) is expected to report clinical results for MGA271, an anti-B7-H3 antibody in phase I. Although B7-H3’s biology is poorly characterized and the antibody employs additional modes of action, the fact B7-H3 belongs to the same family of PD-L1 results in high expectations for this program. Phase I results reported in 2013 did not include meaningful efficacy but updated results in B7-H3 positive tumors are expected in 2H14.

LAG-3 as a widely pursued target– LAG-3 is one of the better characterized immune checkpoints and is pursued by multiple companies. LAG-3 has been shown to be an important immune checkpoint with resemblance, co-localization and potential cross talk with PD-1. Similarly to PD-1, LAG-3 was initially identified as a general immune suppressor receptor on T cells. Only recently researchers started publishing its role in the context of tumor immunity. In animals, combining PD-1 and LAG-3 antibodies proved synergistic (see figure below).

PD-1+ LAG-3

BMS has the most advanced anti-LAG-3 antibody (BMS-986016), which is currently in phase I. The trial started in October 2013, so it might have preliminary results during 2014. Last week, Novartis (NVS), who until recently did not have a strong presence in the immune checkpoint arena, acquired CoStim which has a preclinical LAG-3 program.

New targets on the horizon

2014 will see a record number of new immunotherapy programs. Several programs are expected to start phase I or to be officially disclosed as late stage preclinical programs.

AstraZeneca leads pursuit of OX40 agonists – OX40 is a co-stimulatory protein which is pursued by at least 3 companies: AstraZeneca (AZN) (licensed a from Agonox), GSK (GSK) (licensed from MD Anderson) and Pfizer (PFE) (internally developed). All programs may enter the clinic during 2014. OX40 is an intriguing target given clinical experience with an old murine antibody developed by Agonox’s founders. Although the antibody was administered only 3 times over a week, anti-tumor activity was observed in 12 of 30 patients. The waterfall chart from the trial clearly shows that some patients had a 20%+ reduction.

OX40

There are multiple programs that are either early stage or whose targets are undisclosed.

J&J (JNJ) has a VISTA antibody, which was licensed from Immunext in 2012.

Roche has several preclinical antibodies in development to undisclosed targets. Preclinical results with 2 of those programs demonstrate striking activity alone or with an anti-PD-L1. 

Roche - NMEs

New immune checkpoints discovered by Compugen – Through its computational discovery engine, Compugen (CGEN) discovered 9 potential members of the B7 family (of which PD-1 and CTLA-4 are members). For some of the new targets, the company presented mechanistic and animal data which validate their immunologic role in cancer and autoimmune diseases.  In contrast to the situation with other targets, Compugen may be the only one with real “proprietary” immune checkpoints.  Last year, Bayer and Compugen announced a $540M licensing deal ($10M upfront) for 2 of the novel immune-checkpoints.

Portfolio holdings – March 2nd, 2014

biotech portfolio - Mar 2nd 2014biotech etfs - March 2nd 2014

 

73 thoughts on “Immuno-oncology – Key themes for 2014

  1. Ohad
    Very informative summary of the immuno-oncology.
    Unfortunately these area is dominated by big pharma like BMY, MRK and Roche.

    Do you follow AGEN? They recently acquired 4-Antibody AG, a Swiss company, and with that 6 targets – GITR, OX40, CTLA-4, PD-1, TIM-3 and LAG-3. In addition they have now a program for rapid discovery and optimization of fully-human antibodies, which is similar to CGEN.
    AGEN had demonstrated activity with Prophage – OS of 23.3 months. They expect to improve the outcome combining it with several checkpoint inhibitors, mainly with CTLA-4 and PD1.
    The already started Prophage + CTLA4, and will initiate soon another one with PD1.
    Any opinion about their program? Are they going to play any role in the checkpoint field? They have modest valuation – $170M with $70M cash with low burn rate.
    thanks –andre–

  2. Andre – Agree, not a lot of pure play biotechs in the field. There are a couple of private companies but they are snatched fairly quickly (e.g. CoStim).
    Re AGEN, teh pipeline they got from 4-Antibody certainly checks all the boxes in terms of hot targets. What is unclear to me is how advanced these programs are because several companies are pursuing each of these targets. In other words, if AGEN reaches 5th to market I am not there will be much left.
    Agree about valuation but I don’t like their cancer vaccine and the rest of the pipeline is very early.

    Ohad

    Ohad

  3. Ohad
    I share your skepticism about cancer vaccines. However a combo with CTLA-4 and latter with PD-1 may increase significantly the chases for success.
    The situation look similar to IDO which was not impressive as monotherapy but a combo with CTLA-4 is considered a hot subject and that added couple of Billions to the INCY cap.
    AGEN already started Phase II with Prophage +CTLA-4 combo. In that sense they are a step ahead compared to INCY’s IDO+CTLA-4 combo trail.
    If the excitement about combos with checkpoints can add several billion to large companies, than adding even one billion to the cap of AGEN would mean 10 x return. I took my chance, knowing the negative sentiment about cancer vaccines, and started a position in AGEN on Feb 13, after the 4-Antibody announcement.
    thanks–andre–

  4. I am very impressed with the BOD of ESPR. The physicians are luminaries in the lipid field and the businessman have deep experience in the lipid commercialization field.

    I am pretty optimistic about ARRY- 507 for relapses/refractory myeloma. Even though it is fighting for a position in a fairly crowded field, there is still room for an agent that works via a new pathway and can help patients with advanced disease. Myeloma physicians and the Myeloma Society are quite positive about the drug.

  5. Andre – AGEN has about 70M fully-diluted shares for about a $350M fully-diluted market cap. So, adding $1B in market cap would really only be about 4x return from here, not 10x.

  6. Andre – Good combination data with Yervoy may be an important catalyst. In INCY’s case, the underlying appreciation for management is playing an important role as well imo.

    Leonard – Agree, if anybody knows how to develop LDL lowering drugs it’s ESPR. Re ARRY-520, it’s definitely active but there are other more efficacious investigational agents (CD38 abs). Eventually the drug can find its place as a part of combination regimen, which implies longer and riskier development.

    mcbio – Thanks for the info.

    Ohad

  7. Nice piece.

    Amazing that MRK likely beats BMY to market, shows you who has a good regulatory team.

    The expectations for the INCY IDO data are too high in my opinion. Not much buzz in the patient community boards and that’s where this stuff has turned up first. Second, combo of Yervoy + IDO needs to be better than PD1 alone, if not, don’t think anyone should care much. Once PD1 approved, Yervoy is toast.

    NLNK lead program isn’t even a real IDO inhibitor and has crappy IP.

    CLDX single agent data were meh to me, the one CR was in a patient who had recently(less than 4 weeks) received Adcetris. KOLs less excited about gas pedal checkpoint inhibitors.

    Agree on AGEN, there is a limit to how many preclinical checkpoint inhibitors will be of value. 5th to market might as well be tenth. Also, how’d they get it for so cheap? Color me skeptical of these guys. Management is grade A sleeze. I remember them trying to convince me of the vaccine bologna. Peptide vaccines are mostly junk.

  8. Thanks James.

    Agree that MRK’s move was brilliant, even though the race is still on and nothing is decided. Paradoxically, they had the luxury of treating Yervoy failures because they were a couple of years behind BMS.

    Re: INCY’s IDO, I don’t people view Yervoy+IDO as the ultimate goal but just as a proof of concept with an immune checkpoint inhibitor. Anything that is achieved with Yervoy will have read across to the MK-3475 combo study.

    CLDX – Agree, activity as monotherapy is modest but perhaps combination regimens are the way forward. In general, co-stimulatory targets are less validated but I have high hope for OX40 based on preliminary data from Agonox.

    Ohad

  9. Is this all personal opinion based on secondary data? Any interviews with physicians, industry people? Just curious.

  10. Looks pretty good! The Th2 subset analysis fits the proposed MOA and the safety profile looks clean. The lower incidence of asthma exacerbations is also a good indication. This should be enough for a deal imo.

    Ohad

  11. Chris – I assume Metmab’s failure casts a shadow on the entire MET field. With respect to your question, I am still struggling to find an answer…
    On the one hand ARQL can now pursue MET+ NSCLC and be first to market but on the other Metmab’s failure increases the risk. We need to wait for the ATTENTION data in MET+ patients. If it is similar to what ARQL saw with MARQUEE, than the NSCLC should be back on the table imo.

    Ohad

  12. Hi Ohad. What do you think of Tivozanib’s future? Is the drug dead or do you think there will be some interest now that AVEO has regained the rights? AVEO is still trading below cash. Thanks.

  13. The only place tivozanib might have value is in a setting where a selective VEGFR inhibitor is needed. The only opportunity I can think of is with a selective FGFR inhibitors in order to replicate results of CLVS’ lucitanib. If I were AZN or NVS I would buy AVEO practically for free and pursue co-formulation of tivo+ their respective FGFR inhibitor in order to compete with dual VEGFR/FGFR inhibitors.

    Ohad

  14. Dear Ohad,
    Wedbush initiated coverage today on Foundation One(FHI) with an outperform rating and PT of 50. I would appreciate your thoughts.
    thank you
    Leonard

  15. Hi Ohad,
    do you have an opinion on medigene after their last aquisition of trianta?
    Still very early, but they aquired 3 different plattforms in io. Alltogether with their stake in immunocore and the rest of their pipeline (endotag moving to PIII, rhudex) still seems undervalued to me. Thanks.
    Ike

  16. jh – I don’t think they’ll scrap ganetespib, that’s their primary asset. I also don’t expect strategic changes until a new CEO is appointed.

    Leonard – FMI is one of my current favorites, waiting for a good entry point. Basically, it’s one of the best ways to capitalize on personalized medicine. 5-10 years from FMI’s tests (or one of its competitors) will become a standard in diagnosing cancer and treatment decision.

    ike – Sorry don’t know them very well from what I recall I wasn’t impressed.

    Ohad

  17. Snta CEO resigns. Dr. Freidman from Incyte joins board. Snta scientist report
    P13k/mTOR inhibitor inhibits HSP70 and enhances ganetespib. Incyte has
    research ongoing with P13k. Your thoughts?

  18. Ohad
    You are positive about BLUE technology. What is your opinion about another gen therapy stock – uniQure (QURE). They have already drug on the market (only in EU though) plus 4 Ph 1 trails.
    thanks –andre–

  19. Duane – Having Friedman on board is excellent news for SNTA given hos track record and drug development expertise. I wouldn’t conclude anything beyond that.

    Andre – I am still learning the field but at first glance I prefer BLUE’s approach and programs that ficus on diseases that can be treated with bone marrow transplant. Commercial potential is also much greater for beta-thal.

    Ohad

  20. Ohad
    The FDA concerns about PCSK9 due to neurocognitive adverse effects may profit ESPR. I guess ESPR will get a lot of attention after negative article about statin associated with memory loss and now FDA warning to REGN, AMGN, SNY
    Do you see the news as a game change for ESPR or just a good news.
    thanks –andre–

  21. Hey Ohad
    thanks for your nice overview of immuno-oncology. Very informative.
    I have a question. It seems that everybody including you is very hot on PD-1 etc, and less so on other immuno-oncology targets. Most of the players in pursuit of this target are big-pharma. So I wonder, of the small and medium size caps (Besides INCY), which are the companies worth paying close attention to. And what in your view is the most promising target after PD-1? I mean, if does not seem like you have issued a buying recommendation from your analysis, so I wonder about that. Thanks a bunch
    Dan

  22. Regarding CGEN
    what impressed me is that the majority of executives are women! Nice one.

  23. Andre – Yes, ESPR could improve its positioning as a result of those potential safety issues but only if ETC-1002’s safety profile continues to be favorable. I wouldn’t call it a game changer.

    Dan – You are right, the leaders in PD-1 are all major pharma and I can’t think of a lot of small companies who have pure-play immuno-oncology assets. (Perhaps CGEN, CLDX, NLNK). My favorite target after PD-1 is OX40 given the preliminary signs of clinical activity with the murine antibody. Yes, a lot of smart women at CGEN, and they’re nice too :)

    Ohad

  24. Hey Ohad
    one more question. Or for anybody on the board. Any opinions on XOMA?
    Seems the recent drop in price may represent a buying opportunity. They have 2 phase 3 and various indications in phase 2, for their IL-1 drug. I listened to recent CC. It seemed very positive to me, they are doing as INFI or INCY, trying to expand the number of indications for their drug.

    Thanks
    Dan

  25. Ohad,

    SNTA is downgraded by BMO with a price target of $1. what do you think?
    Thanks as always,
    Chris

  26. Dan – CD47 is a very interesting program, especially in light of recent findings about better selectivity to tumors with soluble SIRP proteins.
    Re XOMA, I still think they are too expensive. All they have is good preliminary data in behcet and non-infective uveitis, which is nice but early and valuation is an issue imo.

    Chris – $1 is a little harsh… yesterday’s conference call was pretty good imo, although I am still not optimistic about GALAXY2. Looking on the bright side, they do have several randomized trials ongoing so I am hopeful ganetespib will have utility in other indications.

    Ohad

  27. Hello Ohad
    what was Jefferies note on exel? do you think the recent decline is a good entry point?
    what your opinion on Onconova?

    Thanks
    Alex

  28. You mentioned in an earlier post you really liked FMI but were looking for a good entry point. Do they have something unique or were they just one of the first with what they do? After reading their 4th quarter and year end results announced recently it seems as though their business is exploding. Thanks as always.

  29. Alex – I haven’t seen that note on EXEL. I continue to hold EXEL into P3 data this year. EXEL will be a classic binary stock wit hall the associated risk/reward. Re ONTX, until they show a robust randomized data set with clear endpoints I wouldn’t be excited with their drug (especially given the failure in high risk patients).

    Bridgette – I am somewhat skeptic about OXGN’s data, reminds me of KERX’s perifosine data in CRC: Relatively small trial among several studies, endpoint is PFS and mode of action is not compelling. Re: EXEL, I am long but acknowledge that P3 success is anything but guaranteed.

    Dan – FMI is one of those companies that I can’t imgaine the future without. Their technology is at the sweet spot of the oncology field and will become a crucial piece of cancer diagnosis and treatment within several years imo. I am sure there will be others but the market is huge (several $billions in the US alone) and they have a significant headstart.

    Ohad

    Ohad

  30. Richard – My concern is not related to any intentional data falsification or fabrication but simply to that fact that small studies can often generate false positive signals.

    Richard Baker – This is an Israeli company so I can’t comment.

    Ohad

  31. Ohad
    anything interesting from the AACR abstracts? It looks that Targeted Immunotherapy will be in focus.
    –andre–

  32. Hey Ohad
    have you looked at KBIO, a recent IPO. The valuation is at $100M. What do you think of their antibody technology? They call it Humaneered. I struggle to understand if it really offers additional benefits. Also, they have a couple of drugs in phase 2, and the one targeting anti-EphA3 seems interesting.
    Dan

  33. Hello Ohad,

    is the target Cbl-b also interesting? I found that Aperion biologics and Evotec are working with this target. Do you have an opinion?

    Toby

  34. Andre – I already went over the AACR abstracts and indeed there is a lot of interesting stuff. Typically though, rseults are preclinical so not a lot of impact on publicly traded stocks. AACR is a very good place to identify industry trends and identify new programs (for example, SGEN’s partners unveiled several new programs making their way to the clinic).

    Dan – I looked at them in the past. I like the anti-infective program but it will take time to generate data there and the risk is high.

    Toby – Thanks for sharing I wasn’t aware of that one, interesting approach. Nice to see an E3 ligase inhibitor in the clinic! Will try to learn more.

    Ohad

  35. Hey Ohad
    I was reading about exomers as a new way to diagnose many diseases. Hvae you looked at this? there is a company in this area of science that seems interesting. AEMD
    Let me know what you think, and if this area may grow in importance.
    AEMD signed an agreement with DaVita, the dialysis center company to test their filter technology on patients. I think they are moving forward with a phase 2 soon.
    Thanks
    Dan

  36. Dan – Exosomes are very interesting as a phenomenon. Utilizing them for diagnostic purposes is still very early.

    Robert and Alex – The drop in EXEL is puzzling imo. I guess people expected a positive outcome already at the interim. The good news- there was a risk of early stop due to futility which didn’t materialize.

    Ohad

  37. Patrick Sikorski ‏ on twiter
    @adamfeuerstein $Exel

    given the size of the study, if the drug was working you would have expected it to end early

    that’s the reason?

  38. Additionally on twitter –
    Credit Suisse says : “Overall Survival Not Met in COMET-1 Prostate Cancer
    Interim Analysis; New TP of $5 “

  39. People are always hopping, the question are EXEL and CLDX still a buy? Giving the circumstances will you accumulate?
    Thoughts?
    Dan

  40. Ohad, regarding Clovis: is this good enough?

    “In the 22 evaluable T790M positive patients across efficacious dose levels, 14 RECIST partial responses (PRs) have been observed to date, for a 64 percent objective response rate (ORR). The median duration of response cannot yet be estimated in the T790M positive patients. However, PFS greater than six months has been observed in evaluable T790M positive heavily-pretreated patients and the median has not yet been reached.”

    Thanks
    Hubert

  41. Ohad:

    “The good news- there was a risk of early stop due to futility which didn’t materialize.”

    I dont think there was a futility analysis.

    “The current interim analysis after 387 events was also planned to assess if the trial achieved its primary endpoint; it did not include a futility analysis. ”

    http://www.exelixis.com/investors-media/press-releases?cpurl=http%3A%2F%2Fir.exelixis.com/phoenix.zhtml?c=120923%26p=irol-newsArticle%26ID=1912367%26highlight=

  42. Hi Ohad,

    So here is my buy list based on the recent sell off. Any NOs in your opinion?
    ARRY – $4.50s
    AMBI – market value
    EXEL – market value
    ICPT – $300-$325
    BLUE – $20-$22
    And finally – INCY & ALKS both at $40.
    What do you think? Any opinions from others on the board?

  43. Dan – For EXEL I think the answer is yes (will try to publish something soon)

    Hubert – I thought the data were awesome but the market is not impressed.

    Summer – You are right. What I meant is that although the interim analysis didn’t include a futility analysis, I think the IDMC looks at death rates in both arms from a safety perspective. So if, for example, there are more deaths in the cabo arm they should stop the study as well. I fon’t know this for a fact but that’s my understanding.

    Manish – Agree to all except ICPT and ALKS where I don’t have a concrete opinion. I also like FMI very much.

    Ohad

  44. Hey Ohad
    the market is a little scared… I think it shows in the weir reaction to the CLVS results on 1686. There was a spike at $87 and then the stock collapsed.
    I have a question… what do you think of the AstraZeneca in the race with 1686? How important is it to get to market first and what will the FDA do about Breakthrough status, is it conceivable to give it to one drug and not the other? seems like a thorny issue here?
    Thanks
    Dan

  45. Hi Ohad, thank you for this blog, I always look forward to reading your comments.
    Regarding Clovis, I think mostly everyone acknowledged that the data is good.
    And actually, the first market reaction was to push the stock price up. The concern might be more the valuation of the company itself, in these times of market “bio defiance”. Their most advanced compound is the PARP which is not their most exciting, you have to wonder if Clovis is worth more than 2 bn at this point of time…..
    In this market a lot of companies have become too expensive, I wish we will revert to more realistic valuations similar to AMBI for instance.
    What do you think? Thank you again!

  46. Ohad
    I was looking into FMI and their web page is not very informative. I could not find for example their collaborations. I know from CLVS web page that they are developing
    companion diagnostic to identify biomarkers for rucaparib. Reading through the old press releases I found collaborations with ARIA, AGIO and AZN. Do you have a list of all of their collaborations?
    thanks — andre–

  47. Dan – I am sure the negative sentiment around smid biotechs didn’t help but it appears people were worried about CO-1686’s QTc signal. Getting to market first is clearly important, as you can see from the PD-1 scene. It becomes less important if one of the companies manages to differentiate its drug. I don’t think there is anything that prevents both drugs to receive BTD.

    Kimi – Thanks. I acrually don’t think CLVS’ valuation is inflated if you take lucitinib’s huge potential into account. I know most people aren’t, but hopefully it will change when more data is presented.

    Andre – Sorry, I don’t have such a list.

    Ohad

  48. Candidate drugs of curiswhic use differentiating approach are very much undervalued. The market is focused on the immuno without looking at what can be done well. The results presented recently for CUDC-427-907 and CUDC debio0932 are very exciting and Erivedge which has already a record could be use in other cancers.
    Curis is an exciting challenger.

  49. for me, the current valuation of curis is incredibly low and does not reflect the absolute value of its drug candidates.
    What is your opinion?

  50. The problem with CRIS is negative sentiment towards Erivedge in oprable BCC. Their other programs a restill early but could generate meaningful data next year.

    Ohad

  51. Ohad, we will hopefully get meaningful data on at least 907 later this year. I’m going to continue to hold CRIS here.

  52. Thanks. Of the 3, 907 is the one I least excited about. 427 has the biggest potential assuming the liver tox issue can be managed.

    Ohad

  53. I gotta respectfully disagree as I find 907 with most promise. We should have a sense of whether the new dosing schedule alleviates the prior safety issues and allows them to ramp dose for better efficacy sometime later this year. I think there may be rationale for dual PI3K/HDAC inhibitor. One highly refractory patient at lowest dose in prior dosing regimen had SD well past a year at last update. Will be interesting to see data for the higher doses on new schedule later this year.

  54. Debio 0932 is very promising and also Debiopharm is a Swiss company that has a very strong clinical expertise.
    About Erivedge the potential of royalties is strong (look at the Q4) and Roche initiated a phase 1b/2 in Relapsed/Refractory AML and High Risk MDS…

  55. mcbio – Even if 907 demonstrates some efficacy, the field is packed with novel rteatments with good efficacy/safety profile. I doubt that something so broad will be able to compete with that.

    caesar – I agree that Debio0932 has a lot of potential as an oral Hsp90 inhibitor. I just don’t think the ongoing combination trial in lung cancer can generate anything meaningful.

    Ohad

  56. Fair comments Ohad and you may well be right. I’m just willing to gamble at this valuation that any future positive data alone for 907 (if it occurs) will be enough to move the dial on CRIS shares here.

  57. What about Cancer Vaccine?
    I think it will be the next step for immuno-onco : combination cancer vaccine with immune chekpoint like anti-PD1/PDL1, specially for advanced stages of cancer where anti-PD1 has limitations.

  58. Hi,

    What do you think of the first disappointing results around nivo/yervo combo in NSLC?
    Combination of immune checkpoinit inhibitor unadapted for NSLC?

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