Threshold Scores Big With Pancreatic Cancer Data

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Phase II data

Based on top line results from a large randomized phase II, adding TH-302 (two different doses) to standard chemotherapy led a statistically significant difference in progression-free survival (PFS). PFS is the time patients live without experiencing disease progression. Patients who received TH-302 with Gemzar had a median PFS of 5.6 months compared to 3.6 months in patients who received Gemzar alone (p = 0.005).

The response rate in the combination arms was also superior to that in the Gemzar arm (22% vs. 12%). Interestingly, patients who received the higher dose of TH-302 appeared to do better than those receiving the lower dose, which is an important indication of the drug’s activity. According to the press release, TH-302’s safety profile was consistent with a previous phase I trial for TH-302 and Gemzar, where skin and mucosal toxicities were the most significant side effects.

To put things in perspective, a statistically difference in PFS in pancreatic cancer is a very rare event. Even Amgen’s (AMGN) ganitumab (AMG-479), currently  in phase III in pancreatic cancer, could not demonstrate a statistically significant PFS or OS benefit in its randomized phase II. Ganitumab+Gemzar had a PFS of 5.1 vs. 2.1 months with Gemzar alone in an 80-patient trial.  Unlike Amgen, Threshold evaluated TH-302 in a very large trial (214 patients), enabling the drug to reach statistical significance and making it more predictable of future phase III studies.

The most impressive results to date in pancreatic cancer were generated using the aggressive chemotherapy regimen FOLFIRINOX. In a recently published phase III trial, FOLFIRINOX was superior to Gemzar in both PFS (6.4 vs. 3.3 months) and overall survival (11.1 vs. 6.8 months), with both differences being  highly statistically significant. Despite the clear benefit, FOLFIRINOX is associated with severe side effects, which preclude its use in the broad patient population. If proven effective, TH-302+ Gemzar could be widely used due to a favorable safety profile.

Open issues   

There are still several open questions pertaining TH-302’s data. As a general comment, available information is based on a short press release, so caution is obviously needed when evaluating the data. Three main issues are physician’s bias, the cross over protocol chosen for the trial and potential safety issues.   

The trial’s biggest issue was the fact it was an open label study, so physicians knew which patient was assigned to each arm. This is problematic since PFS was assessed by the treating physician, which might create a bias favoring the TH-302 arms. Bearing in mind that PFS was assessed every 8 weeks, identifying progression one scan later could have a major impact of almost 2 months, which is the alleged benefit for TH-302 in the trial. Still, it is hard to believe the highly statistical difference is driven purely by this investigator-bias. Pancreatic cancer is a very aggressive disease where progression in the form of tumor growth or new metastases is often associated with clinical symptoms physicians cannot ignore.

A second issue has to do with TH-302’s effect on overall survival, the most important clinical endpoint that will probably be required for approval. The company did not provide any overall survival data, probably because the data set is not mature enough. Even when survival results are reported, they might be confounded by the trial’s cross-over design that allows patients on the Gemzar arm to receive Gemzar+TH-302 upon progression on Gemzar alone. If TH-302 is indeed efficacious, any benefit in the active groups might be masked by giving the drug to patients on the control group.

In fact, the cross-over design creates two control arms:  (i) patients who receive Gemzar alone followed by Gemzar+TH-302 upon progression (ii) patients who receive Gemzar alone and get off the trial upon progression. Ideally, the first group should do better, however, these two groups are not likely to be balanced as patients who are too frail and sick will not be kept on a regimen of active chemotherapy. As a result, patients who cross over have better prognosis inherently. It will also be interesting to see whether patients who cross over from Gemzar alone to Gemzar+TH-302 experience tumor shrinkage or prolonged disease stabilization.

Lastly, there is the issue of side effects, which could be crucial when two agents have overlapping toxicities. Side effects could be a major barrier even for an effective regimen in a deadly indication such as pancreatic cancer (see FOLFIRINOX’s case). Therefore, the incidence and degree of side effects could have a major impact on TH-302’s ultimate market share. According to the press release, the safety profile of TH-302 is consistent with that observed in an earlier phase I trial- primarily rash and mucosal toxicities. These groups of toxicities are not common with Gemzar, which is encouraging.  It is also encouraging that no hematologic or GI toxicities were mentioned in the PR, since these are toxicities frequently associated with Gemzar.

Commercial potential

Although pancreatic cancer is not one of the most common it still has an annual incidence of ~100 thousand cases in US and Western Europe. Since the disease is often diagnosed at an advanced stage with such dismal prognosis, a drug with a survival benefit and a reasonable safety profile could attain a substantial market share. Using other next-gen chemotherapy drugs such as Abraxane and Doxil as benchmarks and assuming 5-6 month of treatment duration, TH-302 could generate $35k-$45k per patient. Even with a conservative penetration of 30%, TH-302 could generate $1B in sales every year in the US and Western Europe alone.

Earlier this year, Threshold sold worldwide rights for TH-302 to Merck-Serono for $25M upfront, $525M in milestones and double digit royalties on sales. Merck will pay 70% of worldwide development costs for TH-302 and will have marketing rights outside of the US. In the US, Threshold has the right to co-promote TH-302 with its own sales force.

Needless to say, had Threshold waited for the pancreatic cancer data, it could have gotten a much more lucrative deal. Therefore, the deal is a great achievement for Merck-Serono, which now has a promising asset with high chances of success in its pipeline.

Biotech portfolio updates

We are initiating a position in Threshold based on the positive pancreatic cancer data in anticipation for full data and initiation of a phase III trial later this year. TH-302 is being evaluated in additional indications including a phase III trial in soft-tissue sarcoma and several other phase II studies. Even when assuming Threshold will not co-market TH-302 in the US, it could still generate peak royalties of ~$150 every year assuming a 10-15% royalty rate and limited market penetration in pancreatic cancer alone.

We are selling all of three Micromet (MITI) positions at a profit of 270%, 194% and 81%, respectively, following its acquisition by Amgen. Micromet was not only the largest holding in the portfolio but also one of my favorite companies. All that is left is congratulate the company and its management team for a remarkable achievement and hope that blinatumomab finds its way to the market as soon as possible.

We are also selling our position in Pharmacyclics (PCYC) at a profit of 413%. Pharmacyclics has one of the best drugs in development with high likelihood of being a multi-billion dollar franchise. Nevertheless, with a market cap of $1.8B and no substantial near term catalysts except initiation of phase III trials, the company looks fairly priced.

Lastly, we are initiating a position in ONYX (ONXX) and adding additional positions in YM Biosciences (YMI) and Array Biopharma (ARRY).

                                               Portfolio Holdings as Of March 4th, 2012

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33 thoughts on “Threshold Scores Big With Pancreatic Cancer Data

  1. Glad to see additional YMI, the offering has seemed to put a floor at 2. Hope to here partnership and phase II results soon. Thanks again for the updates and congrats on locking in profits.

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  2. PFS of 5.6 months, impressive only because of the lack of any god news in this cancer.

    Also watching Celegen’s Abraxane

    Celgene Abraxane phase II results. ((Abraxane is now in phase III trials.))

    In Phase II, almost half of the patients responded (overall response rate was 48% (21/44)) and two-thirds experienced disease control (disease control rate was 68% (30/44)). The median progression-free survival was 7.9 months (95% CI: 5.8, 11.0) and the median overall survival (OS) was 12.2 months (95% CI: 8.9, 17.9). The one-year survival rate for patients was 48%.

    http://ir.celgene.com/phoenix.zhtml?c=11

    Competition, with some serious side effects. Abraxane is also a targeted via ligands towards that “hard to penetrate” tumor. Wondering what folks in the pancreatic field are saying about Abraxane?

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  3. RR- Abraxane is definitely the favorite runner up in panc cancer right now. Data look impressive but they are from a non-randomized trial. Unfortunately, there are a lot of examples of agents that performed well in p2 pancreatic cancer studies but failed miserably in p3 (Avastin, Erbitux). What will be interesting with Abraxane is whether there will be a correlation between their suggested predictive biomarker (SPARC) and survival.

    Lauren – as an antisense drug, there are inherent challenges with this agent that make me skeptic about the ongoing p3 program despite the impressive survival benefit observed in p2. Combining the drug with Taxotere is also not the best positioning given progrses with other agents for HRPC.

    Ohad

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  4. Newlink has a pivotal pancreatic cancer trial under SPA as well with data due early next year I believe. Any opinions? I was wondering how long you would hold PCYC. Im considering entering a short position as I believe it is highly over valued even though p2 data is good.

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  5. >as an antisense drug, there are inherent challenges with this agent that make me skeptic about [OGXI’s] ongoing p3 program.

    Can you elaborate this?
    Thanks
    -summer.

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  6. Don’t know the Newlink program that well. I wouldn’t short PCYC, they still have a spectacular drug.

    Summer – Antisense drugs are thought to have delivery problems, primarily reaching the tumors and entering cells (assuming you have stability in the bloodstream).

    Ohad

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  7. Back to Threshold and Th-302 versus Abraxane

    Found a single arm study for TH-302 that were just as impressive as the Abraxane single arm study:

    Median overall survival (OS), based upon data for all 43 patients regardless of TH-302 dose, was 11.4 months (95% CI: 6.0 to 15.8 months) and median progression-free survival (PFS) was 6.4 months (95% CI: 4.7 months to 7.7 months).

    http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=517518

    With a far better side effect profile

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  8. >Antisense drugs are thought to have delivery problems, primarily reaching the tumors and entering cells (assuming you have stability in the bloodstream).

    I agree with the above for gen 1 antisense drugs. Do you also believe this to be the case for gen 2 antisense drugs? Or do you simply prefer to hold antisense drugs in penalty box for previous spectacular failures until proven otherwise?

    Thanks
    -summer

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  9. RR- we’re gonna have to wait to AACR next month to say anything definitive about TH-302’s safety profile.

    Summer – until proven otherwise, I don’t consider antisense drugs as suitable for treating systemic diseases.

    jh – Our position speaks for itself although it’s hard to predict. FWIW, I heard AZN plans to start p3 with AZD6244 this year, couldn’t find anything formal.

    Ohad

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  10. A SPARC role in metastasivity of pancreatic cancer, found an interesting article:

    Lack of host endogenous SPARC results in (a) enhanced growth of implanted pancreatic tumors, (b) alteration in the deposition of ECM constituents within the tumor, (c) reduced rates of tumor cell apoptosis, (d) a decrease in the percentage of blood vessels that maintain pericyte support, and (e) altered distribution of macrophages within the tumor.

    http://mcr.aacrjournals.org/content/2/4/215.full

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  11. Ohad,

    Can you give an update on THLD following Monday’s AACR presentation and their CC? Seems like a lot of volatility lately. Thx.

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  12. PLX has a PDUFA in May for a drug that the FDA allowed to be used for Gaucher’s disease in the United States even though it was not yet approved because of Genzyme’s drug shortage. Thus, it appears that it will be approved, however, its difficult to put a valuation on plx. What do you believe is fair value for plx on approval? Thanks.

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  13. Dan and Mike- the TH-302 data set was positive, no syrprises to any direction. Overall survival data is expected later this year, could have a major impact, acknowledging the confounding effect of the crossover.

    Sam- sorry cant comment on PLX

    Heymang- we need to wait for the actual data but GIST represents a small but significant market.

    Ohad

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  14. Very interesting stock blog. Perhaps we should all explore a stock a month and share thoughts. Targeted chemo is my interest too. Also, I have begun to follow dementia treatment prospects. This should see explosive growth as well. For now I will just mention two thoughts about snta. HSP90 inhibition looks promising. I think management is looking at all tumors so they can find the best response rates, then select among those cancers for a phase 3 registration trial. They may be going overboard a bit but they were burned in the past and seem quite circumspect now. Secondly, they have competition from infinity pharmaceuticals.
    What is your favorite Biotec co?

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  15. Hello Ohad,
    Has the synta mangement have an estimated timeline of the no/go decision where they will decide to terminate the study or continue it?

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  16. Do you believe that management is choosing not to partner to get better terms on a positive trial or that they are unable to get a partner due to unfavorable terms?

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  17. I assume they’ll have preliminary data in the coming year to decide whether to continue or abadon the lung cancer trial.

    Regarding the underlying cause of not doing a licensing deal – hard to say but I would go with not being able to get the terms they had wanted.

    Ohad

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  18. Thanks, there are some interesting points there, still imo there’s clearly a signal that warrants p3. From what I recall, not all imbalances were in favor of both TH-302 arms.

    Ohad

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  19. Did you listen to SNTA’s web cast today (5/3/2012) and if so, can you provide some feedback of your impression? Thx. Dan

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  20. Somewhat vague remarks but all in all sounds quite good. At least now we know the GLAXY trial generated some sort of an efficacy signal. This is a major de-risking event, no doubt.

    Ohad

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  21. Hi Chris,

    I wouldn’t interpret not presenting at ASCO as positive or negative. We’ll have to wait for the data to decide.

    Re EXEL- Some of the issues he brings up are good points, prostate cancer is getting very crowded and there is no survival data for cabo. He fails to address the main point with cabo, which is the bone effect. This has never been observed with other drugs, including the new ones, so cabo if the effect is real, cabo is in excellent position IF the effect is real and translates to survival benefit.

    Ohad

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  22. Thermodox, heat sensistive liposomes that target tumors via HIFU heating of tumor area. Trial soon to start on relief of bone metastasis pain that is so common in late/end stage cancer. Partnered with Philips, stage II
    Also has a stage III fully enrolled metastatic liver trial with Thermodox used with RFA in hopes of being able to treat larger lesions than current RFA only treatment.

    Second half of 2012 could be critical and rewarding.

    Possible leaks may be showing in price and news.

    May 1, 2012 – New research will assess FUS and ThermoDox as a combined treatment for pancreatic cancer

    , Jun 7, 2012 – Celsion Announces Collaboration With the University of Oxford to Design and Execute a Clinical Trial Using Ultrasound-Guided High Intensity Focused Ultrasound and ThermoDox(R) for Metastatic Liver Cancer

    Like

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