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Saturday, March 22, 2014

Endocyte Success to Catalyze Interest in Folate-Targeted RNAi Therapeutics

One of the big stories on Wall Street this Friday was Endocyte and their folate-targeted drug vintafolide. All on the same day, Endocyte received a positive opinion by the CHMP in the EU, paving the way towards marketing authorizations of vintafolid in ovarian cancer in this important market.  Simultaneously, it announced encouraging phase II data in non-small cell lung cancer (NSCLC) in which the drug, in combination with chemotherapy agent docetaxel, met the primary endpoint in extending progression-free survival (PFS).

I hope I got all of that right.  What is more important in the context of RNAi Therapeutics and this blog is that folates have been considered by the field as a promising targeting agent in the past and the successes by Endocyte and progress in RNAi delivery could lead to a new push in that direction.

The idea behind vintafolide is simple.  Since non-targeted small molecule chemotherapeutics inhibiting basic cell division processes cause widespread toxicity in normally proliferating tissues (e.g. GI tract, bone marrow), often times preventing their use at therapeutic dosages, targeting such agents specifically to cancer cells should greatly increase their therapeutic window and utility.  In the case of vintafolide, the chemotherapeutic agent (DAVLBH) is targeted towards the folate receptor that is overexpressed in many tumors as tumors have an increased demand for folates to support their growth.

Following binding of the folate drug-conjugate to the folate receptor, the conjugate is taken up by the cancer cell through endocytosis.  Once in the endosome, the folate falls off the drug which in turn is then free to diffuse into the cytoplasm to inhibit cell division by binding to tubulin. Meanwhile, the folate receptor recycles back to the cell surface.  All analogous to ASGPR and galactose in the liver.

One challenge with folate-targeted RNAi Therapeutics that I have heard a number of times, is the concern that folate receptor expression is not sufficiently uniform to get at all/most the cancer cells.  This assumes that in order to be successful, a cancer RNAi Therapeutics would have to reach the majority of cancer cells.

Interestingly, vintafolide is used in combination with a companion diagnostic comprising folate with a molecule that can be imaged.  By first running the imaging test, Endocyte has been able to focus their studies on those patients which express folate receptor on all their tumor masses.  Importantly, apparent anti-tumor activity correlated with folate receptor expression.  Such enrichment strategies could obviously also be applied to folate-targeted RNAi Therapeutics.

Imaging tests, however, would not be able to address folate receptor expression heterogeneity within a tumor mass.  It would be interesting to know to what degree vintafolide activity was restricted to the cell that has taken it up or whether it could also act on by-stander cells.

RNAi Therapeutics companies that could take an interest

I can remember Alnylam-related OTS presentations before 2009 that looked at simple folate-siRNA conjugate delivery with promising localization data.  Knockdown efficacy, however, seemed limited. 

This is not surprising given the absence of endosomal release chemistries in those molecules.  Endosomal release of receptor-targeted RNAi Therapeutics could obviously be addressed by Arrowhead’s DPC technology.  A folate-targeted single molecule DPC would be my front-runner in realizing the potential of folate receptor-targeting for RNAi Therapeutics. 

Curiously, Merck has partnered with Endocyte on vintafolide and as we know had been busy copying delivery technologies by Arrowhead and Tekmira.   It would therefore greatly surprise me if Merck had not looked at folate-targeted RNAi Therapeutics, which might strengthen Alnylam’s effort in developing folate-targeted DPCs following their acquisition of Merck's RNAi assets in January.

In addition to the conjugate companies, liposomal players such as Tekmira and Dicerna could get in on the folate action as well.  This is because receptor-mediated endocytosis is believed to play an important role in the cellular uptake of liposomes that are not constitutively positively charged (àApoE-LDL receptor).  By adding folate to the mix, one could a) extend the utility of a liposomal cancer RNAi Therapeutic to cancers overexpressing either receptor, and/or b) enhance cellular uptake by interacting with 2 receptors simultaneously on cancer cells that express both receptors.

6 comments:

  1. Look at TapImmune's (TPIVD ticker) March 19 press release about a clinical
    trial with Mayo Clinic on a cancer vaccine targeting Folate Receptor Alpha for breast and ovarian cancer. TapImmune has technology that can stimulate killer and helper T cells. Check out their PolyStart delivery vehicle. Very impressive and will give RNAi a real challenge.

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  2. Two references:
    Zheng, Y.; Song, X.; Darby, M.; Liang, Y.; He, L.; Cai, Z.; Chen, Q.; Bi, Y.; Yang, X.;
    Xu, J. Preparation and characterization of folate-poly(ethylene glycol)-grafted-trimethylchitosan
    for intracellular transport of protein through folate receptor-mediated endocytosis. J. Biotechnol.
    2010, 145, 47-53.

    Dohmen, C.; Frohlich, T.; Lachelt, U.; Rohl, I.; Vornlocher, H. P.; Hadwiger, P.;
    Wagner, E. Mol. Ther. Nucleic Acids 2012, 1, e7.

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  3. Thanks, Marc, will check those publications out. Wagner used to collaborate with Roche/ARWR, so this supports ARWR's evaluation of folate as a targeting ligand.

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  4. Am hearing stories MRK is about to be bought out by a grouping of companies led out of Australia. Possibly by BLT. More likely ALNY and ensuing minnows.

    HBV is central to the cause.

    Is this the motivation for dissing on ARWR? Quickly short then go long.

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  5. Arrggh! Serial Benitec botherer now pretending to be Benitec pumper on Dirk's blog.

    Reverse takeover and keiretsu conspiracy theories up next no doubt.

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