It is 6 o’clock in the morning in my part of the world, have not slept all night, but am more awake now than I have been for a long time: The ASCO abstracts on Silence Therapeutics’ Atu027 (for advanced solid cancers) and Alnylam’s ALN-VSP02 (for cancers with liver involvement) have just been released and both surpassed my already optimistic expectations (copies of abstracts, see below).
For one, I fully expected to learn about additional warts with regards to the safety profile of the drug candidates, aspects that the companies may have chosen to ignore until now for obvious reasons. This, however, was not the case. Atu027 seems to be remarkably innocuous and well tolerated at doses where we can expect to see anti-tumor activity based on the pharmacological evidence. No dose-limiting toxicities (DLTs) and no cytokine inductions with this positively charged lipid-siRNA formulation! ALN-VSP02 also did very well in that only one additional DLT at the very high 1.5mg/kg dose (a case of hypokalemia, i.e. too little potassium) was disclosed that we had not heard of before. Together, Atu027 and ALN-VSP02 demonstrate that lipid-siRNA/nucleic acid formulations are clinically viable indeed.
On the efficacy front, Atu027 exceeded my expectations considerably. Keeping in mind that this has been a small phase I study (abstract relates to the first 21 patients and dose escalation still ongoing), the fact that one patient with highly advanced (an enrolment criteria) neuroendocrine cancer had disease stabilization for 9 months and another had a partial regression of pulmonary metastases sounds very encouraging already and would seem to justify a more targeted phase I study in this patient population, but considering that there was still another breast cancer patient that had regression of liver metastases (breast cancer patients die from such metastases, not the primary cancer) makes it even more impressive and almost more than just ‘anecdotal’ evidence of anti-tumor efficacy.
The clinical investigators of Alnylam’s ALN-VSP02 also had some new intriguing data to report with regard to efficacy: while only 1 of 12 patients up to 0.4mg/kg had stable disease for at least 2 months, 7 of 15 had stable disease for that time period if given more than 0.4mg/kg. This does not look like chance at all and maybe these mouse experiments tell us something about the potential of RNAi Therapeutics for cancers after all. The only clarification that I hope to get is whether some of that difference might be explained by a difference in baseline characteristics, especially in light of the fact that the enrolment criteria had been adjusted at 0.7mg/kg to limit the extent of liver metastases a trial participant could have.
With the abstracts released, all eyes are now on the data presentation at the actual Meeting in 2-3 weeks’ time. We should then learn of more details related to the data contained in today’s abstracts, and with the appetite thus wetted….updates from the more recent patients in the higher dose groups for Atu027 (every additional cohort is a significant plus) and the dose expansion phase of ALN-VSP02.
The sleep is finally over, lots more RNAi Therapeutics clinical data to come.
First-in-human phase I study of Atu027, a liposomal small interfering RNA formulation, targeting protein kinase N3 (PKN3) in patients with advanced solid tumors.Background: Atu027 is a novel RNAi therapeutic based on cationic lipoplexes containing chemically stabilized siRNAs, which targets PKN3 gene expression in the vascular endothelium. PKN3 acts as a downstream effector of PI3K-signaling pathway and is implicated in controlling cellular morphology and locomotion in endothelial and cancer cells. Preclinical data obtained in various cancer mouse models revealed target-specific, RNAi-mediated silencing of PKN3 expression and significant inhibition of tumor progression and metastasis formation. Methods: Patients (pts) (ECOG PS 0-2) received Atu027 as a single 4h-infusion with 3wks follow-up, and were thereafter treated twice weekly over another four week period. Upon SD, pts were given the opportunity to continue until PD. Dose escalation was accompanied by assessment of data related to toxicity and pharmacokinetics (PK). Results: The study design comprises 11 escalating doses. To date, 21 pts have received Atu027 of seven dose levels up to 0.120 mg/kg. Mean age = 62.4 years (range 29-81), 12 female, 9 male. No premedication was required. No cytokine activation (TNF-α, IL-1β, IFN-γ, IL-6) was observed. In some subjects transient activation of the complement system (C3a, Bb, sC5b-9) was found, but without any clinical relevance. Preliminary PK-data showed dose-dependent increase in plasma siRNA as well as lipid levels. Across the dose levels tested, Atu027 was generally well-tolerated. Adverse events possibly related to Atu027 were fatigue grade (G)1 (4pts), hair loss G1 (2pts), sweating G1 (1pt), and abdominal pain G2 (1pt). G3 AEs not considered as DLTs were elevated lipase (1 pt, DL2) and diarrhea (1 pt, DL5). No dose limiting toxicities (DLTs) were seen so far. Stable disease after 3 months was observed in 6 pts. Two pts with neuroendocrine cancer had disease stabilization for 9 months, and partial regression of pulmonary metastases, respectively. Another patient with breast cancer had regression of liver metastases.Conclusions: Atu027 is well-tolerated and antitumor activity has been observed. Accrual is ongoing to determine the MTD of Atu027. |
Thanks Dirk. Very useful. Hope you can talk to them at ASCO and provide further updates. Looks like Silence is successful in raising close to 10 M US with their recent offer.
ReplyDeleteI have a general and perhaps ignorant question.
ReplyDeleteWe know that Alnylam has the rights to the Tuchl II patent which covers siRNA with 3’ overhangs. We also know that others (Silence) use blunt end siRNA’s that don’t seam to have any issues with incorporation into RISC and subsequent silencing of the gene target. Despite this, Alnylam still is considered by many to be the gate-keeper in RNAi trigger ip. So I’m curious as to why Alnylam’s ip is more attractive than that surrounding blunt ended RNAi triggers?
Thanks!
It's a good question. Tuschl-II can certainly considered to be Alnylam's crown jewel in its IP portfolio as 3'overhangs allow for the most potent RNAi triggers- on average. Nevertheless, it is also clear that you can make RNAi triggers that get around Alnylam's IP estate, so 'gate-keeper' would not be the appropriate expression any more. Alnylam was close to becoming the gate-keeper 4-6 years ago, when T-I and Kreutzer-Limmer were still a real threat. The irony is that Silence, as of today, has currently more freedom-to-operate in RNAi triggers than Alnylam. Alnylam would currently infringe Silence's Zamore patent in Europe, and possibly also the US for most of their RNAi triggers.
ReplyDelete"The irony is that Silence, as of today, has currently more freedom-to-operate in RNAi triggers than Alnylam." If that were true, you'd think Alnylam (or someone else) would have made an offer for SLN by now. Their current market cap is under $US 9 million.
ReplyDeleteWell, freedom-to-operate does not automatically mean that the RNAi triggers you are using are necessarily the best ones. In that regard, I would say that Alnylam's Tuschl-type triggers are, on average, certainly more potent and flexible. Nevertheless, Silence has certainly demonstrated that they can make potent RNAi triggers within their IP space, too, and again, they probably have a better claim to freedom-to-operate now than Alnylam (Zamore in Europe, and depending on the interpretation also in the US). Price may play a role in the end. Alnylam is asking for hundreds of millions for a limited platform license, not so Silence.
ReplyDeleteAs to a takeover of Silence by Alnylam: yes, it may make sense to take off the market a competitor with a profile very close to Alnylam for a pittance. On the other hand, it seems to be Alnylam's policy to remove competitors by driving them into bankruptcy, and Silence, with prudent mgmt, may do well on its own. At 2 pence a share, $10M in cash and improving expense structure, you'd think it can only go up from here.
and they'd have to grab benitec whilst they were at it for another pittance, just as an insurance bet for anything ddrnai might do that sirna can't. then it'd be a true category killing one stop shop.
ReplyDeleteIf I am reading abstracts correctly it looks like Silence formulation is more effective than Alnylam and at lower doses (few stable disease with .12 mg/kg with no premeds and major adverse effects vs. many with progressive disease even at higher doses of 1.25 mg/kg, needs premed and two major adverse events). Of course, this is Phase I safety trial but the sign already indicate who has a better formulation. Wouldn't that be threatening for Alnylam?
ReplyDeleteWe have to wait for more details, but it's also my first reading that Atu027 is almost stealing the show here. Safety and preliminary efficacy look intriguing. The dosages though are not directly comparable, as Atu027 works on the endothelia, VSP02 on the tumor cells, therefore different pharmacological demands.
ReplyDeleteWe should get more insights into the safety of VSP02 at ASCO. Aside from the death, the other 2 DLTs were at quite high dosages where you expect to see some tox with the VSP-like SNALP formulations. The death, as discussed, was in a patient where the liver had taken over the liver. There are now more potent SNALP formulations, also with better tox profile at comparable dosages according to a recent patent app by Tekmira (actually assigned to 'Protiva').
It will be important which tumors Silence will choose to focus on and in which combinations with other modalities. The formulation seems to do something to the tumor, and if done right should have a good chance in improving cancer outcomes. Some of the highest profile studies at ASCO may prolong lives by maybe 2-4 months, with a differentiated and well tolerated modality, there is no reason why RNAi Therapeutics can't do as well or better. The differentiation factor in particular adds a lot of the value.
PS: I favor TKM-PLK1 over ALN-VSP02 for a SNALP-formulated solid tumor candidate. It's been better characterized, also with regards to immune stimulation, and it targets my favorite RNAi cancer gene target: polo-like kinase 1.
Hi Dirk, I agree with your analysis, however at the end of the day the public sees only the result not how you get there. Silence seems to have an upper hand. I guess we will hear more from you later.
ReplyDeleteI did not realize Silence formulation works on endothelia. Is that because charged lipids compare with SNALP? Their target is PI3K pathway which is key cancer pathway. Can you elaborate? Thanks.
Yes, the charge has something to do with the endothelial uptake of the Silence formulation.
ReplyDeleteCancer cells are acidotic , what does this mean for selective delivery? On the abstracts very good news all round , does this mean the sector is bottoming out like monoclonals in 1994 ? 500 million US would buy the whole listed sector , less than what Roche spent on its short ( 4 year) now abandoned program . The IP space has changed a lot in the last 12 months and may change more. Has big Pharma jumped out just as the good data starts as they did in monoclonals? Is history repeating ? The old Chinese saying about living in interesting times is painful to those who have pursued this breakthrough technology . I think RNAI will stand the test of time , but will those who backed it will be around to enjoy it?
ReplyDeleteSilence and the other smaller RNAi players are doing a fine job of driving themselves into bankruptcy without Alnylam's help.
ReplyDeleteWow. Can you make some projection as how that could happen so we know where to put our investments?
ReplyDeleteYou don't have to look much further than Tekmira to understand that it is Alnylam's active strategy to interfere with the business prospects of competitors, marginalize and bankrupt them.
ReplyDeleteAnother example, this time relating to Silence is Alnylam's opposition to the issued PKN3 'gene patent' in Europe. Unlike the AtuRNAi, this particular patent directed at a gene that Silence had discovered and essentially done all of the heavy lifting shouldn't really be of interest to Alnylam, unlike e.g. Zamore or AtuRNAi trigger designs. Nevertheless, Alnylam opposes this patent and the only reason I can see is that Alnylam uses its deeper pockets to frivolously involve Silence in legal proceedings and deter potential partners from partnering Atu207.
It is then also a bit hypocritical for Alnylam to at the same time extol the importance of 'gene patents' e.g. by writing an Amicus Brief on the Myriad case.
I wonder if the company that bought Nucleonics IP in their bankrupcy proceedings is the same one that brought the 'third party' challenge against Benitec's primary patent in the UK only weeks after the USPTO had reissued it? Given your comments Dirk, it would seem highly possible.
ReplyDeleteNice series of discussions. I thought there was a comment before from this blog that Alnylam bought the Nucleonic IP.
ReplyDeleteIn regard to Dirk's comment, I agree Alnylam is very aggressive in trying to corner the market segment, perhaps because of Maraganore's experience with Millennium. Would they succeed though? Their legal expenses is extremely high and they are fighting many fronts. Is that a good strategy? Millennium certainly could not continue to fly high and now is a Takeda company. There appears Merck is able to operate in the domain after the settlement. Is Alnylam playing with fire hurting others also burning themselves? With positive ASCO publicity, investors are still hesitating; that should send a message.
Hi Dirk,
ReplyDeleteno word for Marina and Calando?
Best
fms