Thursday, May 20, 2010

ALN-VSP02 Interim Safety and Early Signs of Activity Supporting Continuation of Trial

[This entry has been updated on May 21, 2010]

At precisely 6pm tonight, ASCO released the much-awaited abstracts for presentations at the upcoming cancer meeting. This included one on the interim analysis of Alnylam’s ALN-VSP02for the treatment of liver cancers (my review with Tobias Wolfram on VSP02) targeting both VEGF (antiangiogenic) and KSP (anti-proliferative) and delivered by first-generation SNALP technology*. Importantly, the drug showed an encouraging safety profile with no cases of flu-like hypersensitivity reactions up to the highest dose tested so far (0.7mg/kg, dose-escalation ongoing) and signs of hepatotoxicity up to 0.4mg/kg, the two most important expected potential toxicities for SNALP delivery-based drugs.

There was one death possibly related to the study drug in a patient with a pancreatic neuroendocrine tumor (most others had colorectal cancers) at the 0.7mg/kg dose level. This patient died of hepatic failure after receiving the 2nd of the 4 bi-weekly 15-minute infusions. While liver patients do often die from hepatic failure and patients in the trial probably have a relatively short 1-2 year life expectancy which means that deaths are to be expected in such a trial just by chance, because of the temporal association of the treatment with the death, a contribution of the drug cannot be excluded. A general hepatotoxicity of the drug or delivery technology, however, is unlikely because, unlike flu-like reactions to liposomal siRNAs, hepatotoxicities should be more uniform, at least in 'average' persons, but were otherwise absent in the 0.4mg/kg cohort as well as in the two other patients dosed at 0.7mg/kg. Similarly, except for a minor grade 2 infusion reaction that responded to slowing of the infusion, there were otherwise no significant adverse events, quite remarkable for such a cancer trial, which supports that the death was an isolated case of which the exact cause remains to be fully determined.

Interestingly, in the deceased patient there was extensive tumor necrosis following drug treatment and this was correlated with decreased blood flow as measured by DCE-MRI, consistent with successful VEGF inhibition. Although it cannot be excluded at this point, it is probably too early to say whether the death may have even had to do with too rapid tumor necrosis due to VEGF and/or KSP inhibition by affecting already impaired liver function in liver cancer patients. Altogether, blood flow was measured in 8 of the 12 patients treated as of December 2009 with 80% of the tumors showing a remarkable >40% decline [in blood flow].

Eyes are now on the more detailed data presentation at the ASCO meeting in June that will include further safety, tolerability and also pharmacodynamic data, possibly at even higher dose levels**. More information on the exact distribution of the declines in blood flow and the neuroendocrine patient history will be of particular interest.

* Second generation SNALP formulation have potencies that are about 10-50 increased compared to the one used in the present trial that had a predicted 50% knockdown potency at around 1mg/kg. This means that at therapeutically relevant doses for future SNALP-based drugs of around 0.05-0.2mg/kg, no significant toxicities have been observed so far in both Tekmira's SNALP-ApoB and Alnylam's ALN-VSP02 trials.

Putting the ALN-VSP02 Adverse Event into Context (update May 21, 2010)

It has come to my attention that there is considerable angst, especially among investors, about the one death in the trial. While every such case is unfortunate and has to be studied in detail whether it is linked to treatment with the investigational drug, let me emphasize that the reason why liver metastases are specifically treated for most cancers, including in this trial, is because they turn out to be rate-limiting for many of these late-stage patients. As such, more deaths are to be expected in this trial, also and especially due to liver failure. One caveat, however, is that the patient died after the 2nd infusion, that is between 2-4 weeks after dosing had been initiated and one of the enrollment criteria for the trial was a life expectancy of >12 weeks, so a contribution of the drug is likely.

A good indication about the seriousness of these adverse events as it relates to drug safety and risk:benefit is how regulators react to such reports that by the way have to be made in a timely manner, meaning that if there had been more such reports they must not have been deemed sufficient to stop the trial. Related to this, it will be important to learn whether the regulators allowed further dose escalation or whether the patients that have been recruited since the December 2009 abstract deadline were treated largely at the 0.4 and 0.7mg/kg dosages to further study the drug safety around these dose levels, although the company did say in their press release that the maximum tolerated dose has not been 'reached' yet [update: the company has since confirmed that dose escalation has continued since December 2009, meaning that at the very least there should now be data for the 1.0mg/kg cohort if not higher which reflects favorably on the safety profile thus far].

It is surprising that Alnylam did not comment generally much about the detailed data in the press release about the abstract. It is possible that they consider doing so at this point as being of little value since much more comprehensive and informative data will be presented soon at the ASCO.

In the meantime, unlike drugs developed maybe for restless legs syndrome or ED, deaths are a frequent occurrence of cancer drug development and investors have to live with that without assuming the worst.


Anonymous said...

Do you know what % reduction in tumor size ALN-VSP showed in early animal model studies?

Is the currently reported 40% reduction in tumor size better or worse than expected based on previous studies?

Dirk Haussecker said...

Not to be confused, the 40% number in the abstract refers to the reduction in blood flow as measured by DCE-MRI, and not a reduction in tumor size per se. An 'average' reduction of tumor size would certainly be considered a breakthrough for many types of liver cancers and in some of those cases Alnylam would probably skip phase II studies altogether.

The animal data question again is difficult to answer because the model systems differ. In some cases VSP02 totally eradicated the tumors.

Anonymous said...

Alnylam would never consider skipping Phase II studies and jump to a Phase III. To suggest so is silly, and without being rude, this shows an academic versus industry background.....

Dirk Haussecker said...

I believe you are twisting my words here. I was just responding to the theoretical scenario where there was '40% tumor size reduction' in a phase I liver cancer study. Depending on the exact data and the subpopulation of liver cancer, such a decision would not be unprecedented.

Just have a look at the history Delcath's liver cancer drug-device combo for melanoma metastatic to the liver. Following similarly encouraging phase I studies, Delcath skipped phase II and now everything looks as if it will be a home-run success.

I'm curious about your response.

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