Wednesday, April 10, 2013

RNAi Therapeutics Arriving in Oncology


Yesterday, Tekmira presented data from the dose escalation portion of the phase I trial with TKM-PLK1 for the treatment of solid tumors.  I agree with the company that the fact the drug candidate was associated with clinical benefit in 4 out of 9 evaluable patients receiving 0.6mg/kg or more versus no such association at dosages below is 'highly suggestive' that TKM-PLK1 has anti-tumor activity indeed.  I also agree with their decision to pursue the neuroendocrine tumor indication for their first phase II study later this year based on the present data.

What I would like to focus on today, however, is much more exciting data contained in the TKM-PLK1 data as it relates to RNAi delivery to oncology…the key obstacle in making RNAi Therapeutics work for cancer.  Specifically, the long-circulating 2nd gen SNALP formulation employed in TKM-PLK1 exhibited vastly improved pharmacokinetics over the short-circulating 1st gen SNALP formulation employed in Alnylam’s ALN-VSP02.  Whether cancer in the liver or not, long circulation times are critical in order to take advantage of the Enhanced Permeability and Retention (EPR) effect that is at the heart of nanoparticle-based approaches in oncology.

It is for this fact that I am optimistic that the ‘highly suggestive’ data (which you invariably will hear about in phase I cancer studies involving a mix of late-stage cancer patients such as this one) are for real.

10-Fold More siRNA at 24 hours

Slide 13 of the AACR presentation shows that at 24 hours, around 1500 nanograms siRNA was present in 1ml of serum at the maximally tolerated dose of 0.75mg/kg.  This compares to around 150 nanograms of combined KSP and VEGF siRNA per ml at this time point for ALN-VSP02 as presented at ASCO2011.  If you’ve ever been at the bench and performed siRNA transfections in tissue culture cells, 1.5 microgram siRNA in a ml of media is overkill, and in this case it is real tumors that are served by blood containing such large siRNA concentrations- for days.

Considering the PK profile, it is not surprising that the one paired tumor biopsy obtained so far showed RNAi activity according to 5’ RACE, whereas such detection was rare in the ALN-VSP02 trial.  Clearly, more tumor biopsies have to be taken in the dose extension phase of the study (which apparently is recruiting quite well).  This will also be important for assessing siRNA concentrations in the tumors themselves.

Selecting the Right Patients

A heterogeneous patient population as in this trial alone obviously makes it very difficult to select the right cancer types for future clinical development.  There are a number of biomarker strategies that Tekmira could, and in my opinion, should employ in their future development.

Based on target biology, the KRAS mutation status should be given high priority.  KRAS-driven cancers are thought to be highly dependent on PLK1 expression.  Related to this, PLK1 expression itself could be used as a guide in patient selection.

A more unusual strategy would be to use imaging technologies based on nanoparticles which presumably rely on the same EPR effect in order to assess whether the tumors are amenable to EPR effect (alternatively, a simpler perfusion test may provide similar insights).  I could imagine that the fact that neuroendocrine tumors seem to respond to TKM-PLK1 is a result of such a favored effect.  Finally, another (admittedly less likely) selection strategy considering delivery would be to target tumors with high expression levels of LDLR-like receptors which are thought to be important in the cellular uptake of SNALP particles.

And last but not least, for those that like to think of comparative values, with a much better target and PK profile over ALN-VSP02, TKM-PLK1 may now be considered the lead RNAi Therapeutics oncology candidate. 

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14 comments:

Anonymous said...

Why is TKMR down big in a raging bull market???

Dirk Haussecker said...

I guess the market hoped to see the 'tumors melt away' as my friend XMan would say ;) I guess I will bequeath my Tekmira shares to my grandchildren. Maybe share price will have caught up to underlying value by then.

Anonymous said...

Looks more like smoke and mirrors to me.Il-6 data is weird and Race conclusions joke at best.Are you sure you're notsmoking someone's socks Dirk?Isnt there a suggestion they're just trying to make the most out of it?And there w eare within minutes you're got an entire bullish report out about it;are you sure about all this.Presumably you'll be doing the same for Arrowhead ow you own them.

Anonymous said...

The problem is the long timelines, expense, and low odds associated with cancer drug development. The Phase I for this program was started over 2 years ago! I am praying their 3rd drug target is some orphan disease and not oncology. It is painful being a shareholder, right now.

Dirk Haussecker said...

With regard to newsflow,Tekmira will be reporting data from the expansion phase later this year. After the settlement with Alnylam, recruitment seems to be picking up for the dose expansion part (as of AsiaTides end of Feb, 5/10 already enrolled). Once in phase II, the finish line is in sight.

But I agree, an orphan indication for pediatric indication where they can push for accelerated approval based on biomarker and suggestive clinical efficacy alone and no placebo control is the type of indication that is currently favored. Enrol 12 kids in a phase II and your market cap can be $1.3B.

kpeter778 said...
This comment has been removed by a blog administrator.
Anonymous said...

"Enrol 12 kids in a phase II and your market cap can be $1.3B".......what a sloppy,ridicilous and awful comment (sounds to me like your were proposing 12 mice for treating in an in vivo experiment); you are obviously clueless about ethical principles in clinical trials

Anonymous said...

@ "...the long-circulating 2nd gen SNALP formulation employed in TKM-PLK1 exhibited vastly improved pharmacokinetics over the short-circulating 1st gen SNALP formulation employed in Alnylam’s ALN-VSP02..."
Dirk,
why do you emphasize / distinguish between 2nd gen (PLK1) and 1st gen (VSP02)and what is (your)thechnical criterion? Both formulations are made from DLinDMA and the combination with C12, C14, C16 or C18 PEG-DAA conjugates (e.g. PEG-c-DMA or PEG-c-DSA) as well as the differences regarding PK etc. have already been described e.g. back in 2005 in the same patent(US7,807,815).
Regards, V.

Dirk Haussecker said...

VSP02 employs a short PEG-lipid anchor, PLK1 a long one.

Dirk Haussecker said...

PS: I'm also surprised that Alnylam employed a short anchor despite of the fact that the short/long anchor PK differences had been known and that liver cancer is not equal to delivery to the liver.

Anonymous said...

Dirk,

in contrast to your argumentation TEKMIRA describes in this paper from 2009 that the PEG-lipid chain length (and circulation time) does not make a difference in LNPs for liver cancer... K.D. in liver cancer is almost equal (PLK1,ca. 80 %)and survival (51/53 days, control 33 days). But they found differences for s.c. tumor models...

Judge AD, Robbins M, Tavakoli I, Levi J, Hu L, Fronda A, Ambegia E, McClintock K, MacLachlan I., Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J. Clin. Invest., 119, 3 (2009) 661-73.

“…For vehicles containing poly(ethylene)glycol-conjugated lipids (PEG-lipids) such as SNALP, increased blood residency time and tumor accumulation can be achieved by incorporating PEG-lipids with longer alkyl chains that associate more strongly with the lipid particle and provide greater shielding in the blood compartment (49). Replacing the C14 PEG-lipid [PEGcDMA] with the C18 analogue [PEG-cDSA](50) had the predicted effect of significantly increasing the blood circulation time of PLK1424-2/A SNALP in mice without altering its therapeutic efficacy in hepatic tumors (Supplemental Figure 8; median survival: PLK PEG-cDMA, 51 days; PLK PEG-cDSA, 53 days versus LUC; PEG-cDMA, 33 days; P < 0.05). Despite a relatively short blood-circulation time and rapid distribution to the liver, repeat administration of PEG-cDMA SNALP containing PLK1424-2/A caused significant inhibition of s.c. Hep3B tumor growth compared with LUC-U/U siRNA treatment controls (Figure 9A)..."

Regards,
V.

Dirk Haussecker said...

V.,

Excellent observation.

The basis for my comment regarding liver cancer is that the blood supply of normal hepatocytes (largely portal venous) is different from that of 'liver cancer'. At least for hepatocellular carcinoma, it is thought that it is arterial blood from which the cancer draws (ask Delcath investors).

Supporting my view is also presentation by the CSO of Dicerna (Bob Brown) at the recent AsiaTides meeting who showed data illustrating that the PK requirements for 'liver cancer' and non-liver cancer are essentially the same- at least in their animal models.

I just would handwavingly explain Supp Fig 8 of Tekmira's paper as a setting that could not differentiate between the PK requirements.

Dirk Haussecker said...

Furthermore, even IF there were no benefits of prolonged circulation times for primary liver cancer, what about the metastatic lesions present in the target population for ALN-VSP02?

Valentin said...

This is cool!

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