This week, newly public RNAi Therapeutics company
Dicerna
initiated its first phase I study of a Dicer-substrate-based RNAi
Therapeutic. DCR-MYC targets the
well-known Myc oncogene utilizing a liposomal delivery formulation (EnCore) for targeting
a variety of cancers, solid and hematological (
à
Myc and lymphoma) malignancies alike, but with a planned focus on primary liver cancer in future studies.
The cancer trial start coincides with Novartis’ bitter, brake-slamming exit
from internal RNAi Therapeutics development,
largely blaming lack of suitable delivery technologies. In particular, in classic Big Pharma style, Novartis
seems to have selected its 31 RNAi trigger
picks under the 2005 Alnylam license not based on where delivery is most advanced,
but based on where it wished to strengthen its disease franchises.
It is this putting the cart-in-front-the-horse attitude that is at the
root of Big Pharma’s miserable failure with an emerging platform technology
that has its own mind of where it wants to go first.
According to
commentary by Alnylam, cancer appears to have
been a focus of Novartis’ target selection.
With regard to delivery to cancers, I would agree with Novartis to the
extent that it is not as far developed as for example for the liver. A problem with it is the inter- and intra-cancer heterogeneity
of the EPR effect that most current cancer delivery approaches rely on. You therefore have to be quite careful as to which cancers you select. The same heterogeneity applies to target
receptor expression (e.g. LDL-receptor, folate receptor) and Tekmira will have
its good, not necessarily publicized reasons for why it chose neuroendocrine (NET) and adrenocortical
carcinoma (ACC) for its ongoing phase II trial with TKM-PLK1, preliminary results
from which are expected this year.
I’ve had the pleasure of attending the
European Symposium of Controlled Drug Delivery in the Netherlands this week and presentation
after presentation showed that for most liposomal formulations, tumor
penetration is a major issue. The good
news is that EPR is very real, but the field has come to a point where it needs
to establish the rules for which cancers are amenable and which strategies
(size, lipophilicity) can be employed to aid in tumor penetration.
Imaging studies presented at the conference and the
recent (conditional) European marketing approval of the companion-diagnostic/folate receptor-targeted
cancer drug pair by Endocyte (
Vintafolide)
strongly suggest that patients should be pre-selected
based on whether they have cancers amenable to EPR. For example, pre-treatment with a small dose
of the drug co-formulated with a diagnostic contrast reagent would both
visualize amenable tumors as well as have the side benefit of de-sensitizing
the patient to hypersensitivity reactions that are typically observed for
infused drugs during the first administration.
So while I remain uncertain about the specific prospects of
DCR-MYC partly due to concerns around the target and partly due to the relative inexperience of Dicerna in liposomal delivery, RNAi
Therapeutics will become a reality in
the treatment of cancers. Just don’t
expect clumsy Big Pharma R&D to rise to the challenge.
2 comments:
I think Novartis will take a very good look at what Marina Biotech can do based on the success Marina has demonstrated with Mirna and ProNAi.
remind me again, what is "EPR effect"?
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