Dicerna Admits Defeat, Licenses LNP Tech from Tekmira

Show me the non-human primate data.  Robust evidence of gene knockdown in monkeys is a key requirement to gain confidence in a company’s liposomal delivery claims.  Dicerna has never done that and yet been able to pull off an IPO and make claims about clinical development timelines without actually being in possession of a realistic delivery technology.

In retrospect, it is not surprising that they eventually had to come hat in hand to the liposomal delivery powerhouse, aka Tekmira- after claiming that its liposomal delivery technology (EnCore) was superior to Tekmira’s…  After all, Dicerna is under pressure to get its first proper development candidate in the clinic for Primary Hyperoxaluria Type I (PH1), especially after Alnylam had publicly announcedtheir intention to go after PH1, too.

According to the agreement announced today, Dicerna will use Tekmira’s 3^rd generation LNP technology and manufacturing to get DCR-PH1 into the clinic sometime in 2015.  In return, Tekmira will get $2.5M upfront, $22M in potential development milestones and single-digit royalties- in other words, nothing to write home about other than the satisfaction that they were proven right scientifically.

You may interject that Dicerna already has a clinical program using EnCore technology, DCR-MYC for cancer.  Unfortunately, there are many ways to curing cancer in mice and I am yet to be convinced that they have been primarily the result of RNAi mechanism of action.

In summary, a moral victory for Tekmira, a deal that made sense for Dicerna and which could and should have happened a long time ago.  In a final twist of irony, Dicerna has given Tekmira a back-handed compliment in issuing another press release today where it announces that future development programs will be based on Dicerna’s conjugate delivery technology.

Now that makes actually sense for a Dicer-substrate-based company.  Expect Alnylam to increase its saber-rattling vis-a-vis Dicerna.

.

Disclosure: Long Dicerna, no position in Tekmira

Dicerna Trying to Succeed Where Novartis Has Admitted Defeat

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.