Synta – Implications from Infinity’s Hsp90 failure

Last month’s failure of Infinity’s (INFI) Hsp90 inhibitor (retaspimycin) has mixed implications for Synta (SNTA), whose Hsp90 inhibitor (ganetespib) is in phase III for lung cancer. On the one hand, ganetespib’s most advanced competitor is now eliminated but on the other, the failure raises doubt about targeting Hsp90 in lung cancer. In that sense, Infinity’s failure gives another reason to question the validity of Synta’s phase II results (that are already quite controversial). As background, I discussed Synta’s results here

Are all Hsp90 inhibitors interchangeable?

It is still unclear whether retaspimycin failed because Hsp90 inhibition is ineffective in lung cancer or because the drug itself is not a good Hsp90 inhibitor. Infinity’s drug belongs to the first generation of Hsp90 inhibitors that are considered less potent and more toxic than second generation drugs such as Synta’s ganetespib and Novartis’ (NVS) AUY922. Therefore, any failure for retaspimycin could be explained by the fact that it does not lead to the deep and broad Hsp90 inhibition required for clinical benefit. For example, one can claim retaspimycin-associated toxicities and poor PK profile prevented Infinity from reaching effective exposure.

Retaspimycin is probably an inferior drug but it is clearly active to some extent, at least in ALK-mutated lung cancer where the drug demonstrated activity in 3 patients. This appears to be an Hsp90 class effect, validated by responses with ganetespib and AUY922.

Infinity’s phase II trial evaluated retaspimycin in a similar (but not identical) setting to Synta’s phase II trial: 2nd/3rd line NSCLC in combination with Taxotere with overall survival as the primary endpoint. One major difference is Synta’s focus on adenocarcinoma vs. Infinity’s focus on smokers and squamous carcinoma. Both trials were large enough to be able to generate a survival signal.

Infinity published only top line results, which makes it challenging to draw a final conclusion, but the press release gives the impression there were no signals across the different subgroups (including adeno tumors).

Same target, different outcome

Are drugs that employ the same mechanism interchangeable? Not always.

In oncology, there are many examples of 2 drugs that looked similar “on paper” but greatly differed in terms of clinical activity. This discrepancy cannot always be explained, although in some cases there are hypothetical reasons ranging from biochemical features to dosing and clinical design. Below are 2 historical and 2 recent examples.

Example #1 – Tarceva and Iressa – Both drugs are EGFR inhibitors with a similar activity spectrum in cells and animals. While Tarceva led to a survival difference in its phase III, Iressa failed to do so and was consequently withdrawn from the market. Interestingly, both drugs have strong activity in EGFR-mutated lung cancer but only Tarceva had activity in the entire patient population. The underlying cause for the difference is unclear. Some suggested that Tarceva led to better target inhibition as it was dosed at its maximum tolerated dose in contrast to Iressa, which was dosed at a third of its MTD.

Example #2 – Yervoy and tremelimumab – The 2 anti-CTLA-4 antibodies were developed in parallel for melanoma. While both agents demonstrated activity in the form of exceptionally durable responses in <10% of patients, only Yervoy led to a survival difference in the entire patient population in phase III. It is unclear whether tremelimumab is truly an inferior agent, with some blaming dosing regimen and inclusion criteria as potential reasons for failure.

Example #3 – Ibrutinib and CC-292 – Both drugs are covalent Btk inhibitors with activity in CLL, among other blood cancers. Ibrutinib is much more advanced and follow up for CC-292 is limited, but based on available data ibrutinib looks significantly more efficacious in CLL. The reason for this difference is still unclear given CC-292’s potency and selectivity profile.

Example #4 – CO-1686 and AP26113 – Although the two drugs have a different profile (CO-1686 is a covalent inhibitor selective for mutated forms of EGFR, AP26113 is a dual ALK/EGFR inhibitor), both were shown to inhibit cancer cells with a “Tarceva- resistant” mutation (T790M). Despite strong preclinical results in EGFR mutated cancer, AP26113 failed to generate activity in patients with T790M lung cancer. In contrast, CO-1686 had clear activity in T790M patients with responses in 3 out of 4 patients treated at the highest dose tested.

Exelixis’ MEK inhibitor as a fresh example

Genentech recently published a research paper which demonstrates how 2 different inhibitors of the same target (MEK) can have different activity profiles, even at the molecular level.

Researchers compared 2 MEK inhibitors: GDC-0973 which was licensed from Exelixis (EXEL) and GDC-0623 which was developed internally. Exelixis’  MEK inhibitor appeared more effective in tumors with BRAF mutations whereas the internally-developed MEK inhibitor was more effective in KRAS-mutated tumors. This difference was explained by the distinct MEK activation states each mutation confers (MEK is downstream of BRAF and KRAS).

The implications for Exelixis are mixed, as results bode well for success in BRAF-mutated melanoma but also imply the drug is not suitable for KRAS mutated tumors (especially lung cancer), which represent a larger commercial opportunity.

Summary   

It is important to note that Synta still has a large data set with a real signal that can justify the ongoing phase III trial and the inclusion criteria. In addition, as Hsp90 is involved in the function of so many client proteins, it is plausible that ganetespib has a different spectrum of activity resulting in a better inhibition profile. Lastly, Hsp90 inhibition has great potential in molecularly defined subsets of lung cancer (ALK, ROS1 and RET rearrangements), not to mention additional indications.

While I have strong conviction in ganetespib’s superiority over other Hsp90 inhibitors, the approach of Hsp90 inhibition in unselected lung cancer patients is still unvalidated. For now, Infinity’s failure slightly decreases the attractiveness of Synta’s approach.

As a result, we are decreasing exposure to Synta by selling one of our 3 positions. We plan to hold the current position going into data readouts next year.

Portfolio holdings – October 6th, 2013

Biotech portfolio - 6-10-2013 - after changes

Biotech etfs - Oct 6th 2013

111 thoughts on “Synta – Implications from Infinity’s Hsp90 failure

  1. Ohad
    SNTA: where did you find HR 0.9 for the ITT population? In the press release they only talk about the chemosensitive population. The OS for the G+D arm is the same – 10.7 months, however the OS of D arm increased to 7.4 from 6.4 months. Why do you think it is a concern for the success of Galaxy-2?
    thanks –andre–

    Like

  2. Ohad
    the market reaction confirmed your assessment of the SNTA data!
    However I am still puzzled how the HR 0.9 in ITT affects the Galaxy-2, since it is based on a better responding subset of pts. Also they identified the source of the problem (two East EU countries) and this is rectified in Galaxy-2. In that sense the results are positive – identified the demographic and patient issues. It looks to me that that increases the odds of success of Galaxy-2.

    Like

  3. I intend to keep a position in SNTA as I am a strong believer in Hsp90 as a class of drugs and SNTA’s drug appears to have an optimal clinical profile (potent with no ocular toxicities).

    Going forward, I am assuming GALAXY2 low likelihood of success (10-15%). More value can be found in other settings.

    Ohad

    Ohad

    Like

  4. Christian – Absolutely! These newly discovered fusion proteins are very attractive although the commercial opportunity is modest (1% of pts).

    Duane – Only if they reproduce these HR in p3 🙂 The problem with those retrospective analyses is that they are rarely corroborated in larger prospective trials.

    Ohad

    Like

  5. Neo – I believe the drug will eventually be back on the market at least for last line patients or T315I patients. A lot depends on the safety profile seen with 30mg.
    Valuation is becoming attractive imo (as I previously wrote, I would consider buying under a market cap of $400M)

    Ohad

    Like

  6. Ohad
    CYTR: Do you have an opinion about their technology (Aldoxorubicin – doxorubicin conjugate). They just publish the preliminary Ph 2 results for sarcoma (STS). Response rate is 22% compared to D arm – 0%). Top line data with PFS in Dec.
    thanks–andre–

    Like

  7. mcbio, PR says following: The second study will evaluate ARRY-520 as a single agent in a robust global Phase 2 trial in patients with RRMM including both low- and high-AAG patients. It also says: This trial is also designed to support future regulatory submissions. But what does that mean? Its quite vague and not one analyst in the CC asked if single agent P2 showed good ORR in low AAG, does it mean its good enough for approval? Is this based on FDA recommendation? Right now the estimated completion for the P3 with Kyprolis is 2-3 years (based on CC). Not sure if single agent P2 will complete before then or before interim results from P3 are available. I do like how their overall strategy has been designed for faster enrollment and greater revenue (Kyprolis combo). I hope it doesnt back fire with dosage adjustments for Kyprolis based on their P3. Regardless, I plan on adding more if it hits $4.50 where there appears to be good support.

    Like

  8. Hello Ohad,
    what is your opinion about OncoMed. The IPO price was $17, now they are at $13, the high was $31. They have partnerships with Bayer and Glaxo and targeting cancer stem Cells with their monoclonal antibody therapeutics. Thanks.

    Like

  9. hi ohad
    any thought on imgn announcement today, the price drop, AF blog about the tec at-large. you were waiting for a price drop to poss take a position…thanks

    Like

  10. Boston Investor – I like the technology and find it compelling but it’s way too early for ascribing meaningful value to this platform.

    Andre — Haven’t looked at them for a while, don’t recall they had impressive data, will check.

    mcbio – Right so there is still room for a positive surprise, I still view their decision to start with a combination trial as somewhat disappointing.

    Toby – Still too expensive imo in light of the limited efficacy data and safety issues with both of the main pathways they target (Wnt, Notch).

    Roy – I was never a big fan of the program. Of course, every failure has an impact but with Kadcyla as a proof of concept, validation for IMGN’s technology is robust. The only issue is linker and payload selection for a given target and turns out that so far there is only 1 really good combination. I am still optimistic about IMGN853 despite the toxicity issues.
    I plan on waiting for a better price, maybe around $11. At that level, the price reflects predominantly the T-DM1 royalty stake.

    Andre – No doubt ADCs are not as clean as people had hoped but they are still a promising approach and in some cases there will be ADCs with optimal combination of target/disease/linker/payload, of that I am certain.
    Don’t see any meaningful readthrough for SGEN, if anything it is pssible because SGEN has been claiming IMGN’s linkers are less stable which can lead to toxicity. Important to note that SGEN have also encountered toxicity issues and their therapeutic window is not as wide as expected.

    Ohad

    Like

  11. Thanks, Kirk, very interesting! Did they mention activity on T315I mutation? If so, another reason to be concerned about ARIA’s long term prospects.

    Chris – Yes, irreversible liver toxicity is a major issue.

    Ohad

    Like

  12. Ohad, per CC CRIS believes they can address the hold rather quickly (even said in CC that timeline for future 427 trials hasn’t been pushed back). I guess we’ll see. Regardless, I’ve been long for 907 and will continue to hold. I have long thought that is the most important drug for CRIS.

    Like

  13. Chris – It is becoming very hard to find good biotech companies with reasonable valuations. There are a couple of names I am looking into.
    With respect to existing portfolio holdings – I don’t plan any massive changes. I think INFI is attractive at these levels, bought some yesterday but if the ASH abstracts disappoint, it will take a hit tomorrow.

    mcbio – I hope they are right. I actually don’t like 907 – looks too broad of a spectrum with safety implications.

    Ohad

    Ohad

    Like

  14. Ohad!
    what about this morning’s press relase on CDX-1127… one CR and various PR. No toxicities. Sounds very good to me… They will go ahead an test it in combination with other immuno drugs.. PDL-1, etc
    Can you put a number on market potential? I know this is just P1, which isn’t even complete… Thanks
    Dan

    Like

  15. Ohad, can you expand on your CRIS comments on 907 with too broad spectrum and safety implications? The early issue was daily dosing was causing PI3K metabolite to build up because it has over 24 hour half-life. The hope is that the new P1 dosing regimen (2x/week or 3x/week) will alleviate these issues and still allow ability to dose escalate for better efficacy.

    Like

  16. Roy, I did the same. Sold 1/5 two weeks ago and then anothe 1/5 yesterday at the opening. It is already down $3 from them. I am thinking o buying back some when it settles. I am not sure what is next. Perhaps a partnership announcement or acquisition, since the compoany has zero debt, no pipeline, and Scarlet has a history of selling companies. Any other thoughts?

    Like

  17. Hey Ohad ….do you have any explanation for why Genmab has taken such a hammering over the last few weeks ? Whatever I have seen from the abstracts for ASH looks quite decent. Thanks !

    Like

  18. regarding genmab, it looks like some folks are concerned about bad results, which will be presented @ ash. so they decided to take the money. but reading the last announcement, i don’t find something to worry about.
    only my view.

    other ideas?

    Like

  19. mcbio – My concern is more general regarding inhibiting 2 very broad class of targets. To date, targeting each family (pan-PI3K and pan-DAC) proved tricky due to narrow therapeutic window. In other words, inhibiting both PI3K and HDAC will cause so much toxicity that an safe an effective dose would be impossible to establish. Like always, let’s wait for actual data.

    Neo – I agree re AMBI, results look good in terms of CRc for both 30 and 60 mg. About a third of patients were bridged to transplant, which is a clinically meaningful endpoint. quizrtinib also appears combinable with chemo regimens and one of the abstracts mentions a p3 starting next year. Perhaps people are worried about QTc prolongation, but that’s not new with this drug.

    Christian and Martin – imo it’s mostly the GA101 CLL data that appears numerically better to ofatumumab’s. Didn’t see anything meaningful on daratumumab’s safety profile. The abstract for dara+revlimid combination is scarce in details.

    Ohad

    Martin

    Like

  20. Ohad
    AMBI did not say anything about a possibility for an accelerated approval.
    If they give up on the AA it could explain the drop in the pps. They have two catalysis in the following 3-4 weeks – FDA meeting and ASH. It looks that the market does not expect good news from the both events. Your thoughts?.
    –andre–

    Like

  21. Thanks Ohad ! Also if anything the Qt prolongation is also improved at the lower doses. The following is from the conference call-

    “At the same time, I think we said before that with the exception of QT, says follow up we know today, the safety profile for this drug is very consistent and with regards to QT, I think we can say now with our 2B study that there is a clear dose response here or we materially lower the incidence at the proposed dose of 60.”

    Like

  22. Ohad,

    What on your thoughts on Tefferi’s abstract on Imetelstat for ASH? Have you seen the critiques by Feuerstein and Herper? An oncologist that I know describer the results as “sensational.” The media types and the pundits on the Biotech Values board do not agree. They are arguing that there were no “true” CR’s reported in the abstract.

    Like

  23. Ohad, fair enough of CRIS and CUDC-907. I would just add that 907 isn’t a true pan-PI3K as it barely hits gamma and hits alpha and delta most potently. Also, it’s not a true pan-HDAC as it doesn’t hit all of the HDAC isoforms. But, you’re right, we need to wait for more data to see if what the drug does hit ultimately allows for safe administration.

    Like

  24. Hi Ohad

    How du you see the Gazyva data compared to the Arzerra data in first line CLL in combination with Chlorambucil, when they are not head to head and the Gazyva is Investigator assessment data and Arzerra is Independent Review Committee data. Its hard to compare – right ?

    How do you see the data from Sanofi/ImmunoGen with SAR650984 compared to Daratumumab data ? No abstacts released from MOR202 from MorphoSys/Celgene – maybe their Q3 CC tomorrow will explain.

    Thanks for your nice blog Ohad
    Sukkeralf

    Like

  25. hi Sukkeralf, we will most probably not hear anything from morphosys/celgene before their 2013 annual conference call.

    A data presentation will probably be available at ASCO 2014 end of may/beginning June.

    Like

  26. Ohad, love to hear your opinions on $GERN data. I shorted it based on Adam’s story, which probably was a regurgitation of a short hedge fund.

    Also what do you think of $AGIO and $EXEL. I am long both.

    Go Maple Leafs!

    Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s