Alnylam Escalates Liver Cancer Drug Candidate to Dose Levels Predicted to Yield Meaningful Knockdown

Alnylam provided an update on the ongoing phase I clinical studies for their RNAi Therapeutics candidate ALN-VSP02 for liver cancer. Clinical data such as these are widely anticipated by investors and potential partners alike, and Alnylam with recent comments have left themselves little choice but to be measured against the quality of the data.

The presentation provided at the Chemotherapy Foundation Symposium held this week in New York City follows a June 2010 presentation at the prestigious ASCO meeting at which point 19 patients had received the liposomal formulation containing siRNAs directed against VEGF and kinesin spindle protein (KSP) up to a dose level of 0.7mg/kg. The importance of the new data is that the trial has now reached a dose of 1.25mg/kg, a dose that based on pre-clinical studies for VSP02 is predicted to start to yield meaningful and widely distributed gene knockdown in the liver (compare ASCO pharmacokinetic data with AACR 2009 animal data). However, for VSP02 to reach a dose of at least 1.5mg/kg would be even better.

The ASCO data included preliminary data from 19 patients and strongly suggested that VSP02 has anti-angiogenic activity as measured by reduced blood-flow in the tumors and as might be expected from reduced VEGF activity. This response, however, was not dose proportional which could be due to small numbers. As to safety in this quite sick and heavily pre-treated patient population as of ASCO, the one patient death was remarkable, an event that was deemed possibly due to study drug. Since this patient had an extensive liver tumor burden it had been decided to exclude patients of comparable or worse cancer burden for the remainder of the studies.

Achieved dose bodes well for the entire LNP pipeline

The good news is that the 0.7mg/kg dose has been overcome and that there have been no dose-related elevations in liver enzymes, the expected dose-limiting toxicity for most LNP applications. If we assume that such general liver toxicity and potency of LNPs are independent parameters, in the case of the ionizable LNPs I believe a valid assumption, then the fact that 1.25mg/kg has been achieved in this challenging patient population, challenging especially in terms of liver health, this should bode well not only for VSP02, but also for the other D-Lin-DMA-based LNP drug candidates currently in clinical trials or close (ALN-TTR01, TKM-PLK1, and TKM-EBOLA), and even more so for the 2^nd gen LNP formulations with up to 100x increased potency for liver gene knockdown.

Among the 9 patients recruited since ASCO, one patient experienced transient grade 3 thrombocytopenia at 1.25mg/kg, a dose-limiting toxicity that necessitated a confirmation of the safety of 1.25mg/kg. Again, given the nature of the patient population and the importance of the liver also for platelet function, I would not read too much into this adverse event. With 6 patients in this cohort having been initiated on the drug, it looks like 1.5mg/kg is realistic.

Some patients have now received quite a number of LNP administrations, up to 13 (up to 5 at ASCO), and 3 with stable disease have entered the extension phase of the study. A trend towards increased disease stabilization with dose was noted. While this is promising, I would again caution that we are dealing here with very limited number of patients in an uncontrolled trial, and also the fact that some of this analysis could be confounded by the fact that a slightly different patient population is now being recruited at the higher dosages following the 0.7mg/kg adverse event. No tumor responses were reported.

In summary, the update is very encouraging for the success of VSP02, and even more so for the entire LNP pipeline. The next major milestone will be the presentation of biopsy data, possibly at ASCO 2011, which should critically tell us whether the drug is doing what it’s supposed to do (RNAi cleavage assay; mono-aster formation; RNA/protein knockdown etc). Beyond that, it will be interesting to speculate on the nature of the next clinical studies. A combination of VSP02 with a microtubule-targeting chemotherapeutic could be promising with VSP02 functioning as a sensitizer, thereby opening up MT cancer drugs also for liver cancer. Combinations trials with DNA-damaging agents often used for liver cancer would also appear to be reasonable to investigate.

Next stop for the clinical data-flow: Results from the ongoing ALN-TTR01 studies- this time hopefully with knockdown data.

Update on Silence Therapeutics

Yesterday seemed to be RNAi Cancer Therapeutics Awareness Day, with Silence Therapeutics highlighting a publication related to their lead candidate Atu-027, also in phase I studies for solid cancers. The publication concerns the activity and potential mechanism of action of the PKN3-targeting lipoplex formulation in mouse models for (hematogenous) lung metastases.

I would categorize these studies as being consistent with the previous scientific reports by Silence Therapeutics that suggest pleiotropic mechanisms to be responsible for the observed pre-clinical activity of Atu-027. Importantly, the results further seem to indicate that we may not see a response in the form of existing tumor shrinkage in the phase I studies as Atu-027's main activity appears to be in preventing the spread and seeding of new metastases. Similar to ALN-VSP02 the maximum tolerated dose will be the primary focus of the phase I trial with Atu-027.

Shareholders, albeit apparently pleased by the publication of these studies, will be even more interested in a Calando or Alnylam-like clinical update for Atu-027. And even more than that (!), they will want to know whether a takeover offer is finally forthcoming. In any case, it may be advisable to become more concrete about short-term financial plans in order to avoid a situation like last year when Silence Therapeutics was forced to merge with Intradigm as it was running out of funds.

This includes reporting milestones it is currently receiving, such as from Quark. Alnylam reported a Q3 increase in InterfeRx revenues of about $2M which I speculate largely comprises the Quark payment related to Quark granting Novartis an option on their kidney drug candidate. I speculate that Silence received a similar amount from Quark.