Wednesday, December 28, 2011

Gradalis Swiftly Moves ddRNAi-Enhanced Cancer Vaccine Candidate through Clinic

I’ve been reminded a number of times by the staunch Benitec-supporters here that Texas-based biotech company Gradalis has been moving a ddRNAi-enhanced cancer vaccine candidate (‘FANG’) aggressively through clinical development. Virtually out of nowhere, Gradalis initiated clinical trials two years ago and there are now two active phase II trials, one in ovarian cancer and one for advanced melanoma. A peer-reviewed publication on the phase I trial was also just published (Senzer et al.) arguably making FANG the lead RNAi candidate in oncology.

The phase I study involved over 40 patients with advanced solid tumors and demonstrated the safety and logistic feasibility of the approach. Although evidence of suggestive of efficacy was presented such as a clear correlation between an immune response and survival, it would be premature to conclude anything with regard to efficacy. Having now followed a number of cancer vaccines, most of which have eventually failed, it seems to me that correlations such as this could be just as well as a reflection of the fact that those with more responsive immune systems will do better anyway.

FANG’ comprises of plasmid DNA from which a single RNA polymerase II promoter drives the expression of an upstream GM-CSF open-reading-frame followed by a pair of downstream RNAi hairpins. This plasmid is introduced by electroporation in a petri dish into the patients’ own cancer cells which have been obtained from a tumor resection. After allowing some time for the expression of the transgenes, the cells are irradiated so as to kill off their proliferative potential and are then re-introduced like many other vaccines by intradermal injection.

The GM-CSF component, wildly popular in the cancer vaccine field and also part of Dendreon’s famous prostate cancer vaccine PROVENGE, is supposed to serve as an attractant, proliferation and maturation factor for dendritic cells which are supposed to ingest, present and thereby stimulate an immune response against the antigens unique to a tumor; the pair of ‘bifunctional’ hairpins meanwhile both target furin which is thought to be an important protease for the maturation of the various isoforms of TGF-beta, a well-known immunosuppressant often overexpressed in cancer.

‘Bifunctional’ here means that one hairpin is perfectly matched and therefore mostly relies on the so-called Ago2/cleavage-dependent mode of RISC activation, whereas the other hairpin contains a central bulge due to mismatching changes introduced in the passenger strand arm of the hairpin thus relying on the non-cleavage pathway of RISC activation which can be facilitated by all four human Argonautes (both predicted to yield the identical guide strand). This strategy of distributing the RNAi between the various Argonaute proteins is certainly an interesting idea, but I’m not sure whether even Gradalis knows what consequences of this is both in terms of efficacy and safety.

A general lack of detailed molecular mechanistic studies is probably my biggest concern with this candidate and when thinking about Gradalis in general. It also at least partly explains why FANG has been moving so rapidly through the clinic. I find it particularly troubling that I have seen no detailed studies by Gradalis looking at the relationship between furin knockdown and TGFbeta inhibition which is key for Gradalis' strategy. This already has caused difficulties in interpreting some of the phase I data where possible assay problems complicated reconciling apparently only modest reductions in furin with much more pronounced down-regulations of TGFbeta. This not only makes it more difficult to make the right development decisions, but also when it comes to finding a partner for the program. On the other hand, you could argue that a cancer vaccine candidate involving both GM-CSF expression and TGFbeta inhibition already has a good chance at succeeding, and sweating out the technical details would only cause delays without making us much the wiser.

As I had mentioned, the Benitec supporters are following Gradalis’ development with much interest as such an advanced ddRNAi candidate may be a prime licensing opportunity for Benitec which controls an important part of the ddRNAi patent landscape. I’ve certainly looked at the hairpin structures involved in light of Benitec’s patent claims (esp. the ‘099 Graham patents) and there is a good chance that Gradalis ought to take a license as it further monetizes this candidate, although their structures may give them a bit of wiggle room.

Mirna Therapeutics selects Marina Biotech’s SMARTICLE delivery tech

In another notable development last week, cancer microRNA Therapeutics company Mirna Therapeutics said that it would use Marina Bio’s SMARTICLE liposomal delivery technology for the development of microRNA replacement therapy for cancer. Based on conference presentations, the two companies had been collaborating on the delivery of microRNA mimics before announcing the deal. An attraction of the SMARTICLE delivery technology, which Marina had acquired from Novosom, is certainly the fact that there is already clinical experience after SMARTICLE-enabled ‘DNAi’ compound by ProNAi has begun dosing a year ago. Similar to related agreements between Mirna and Silence, and InteRNA and Silence, insightful details about the financials were not disclosed. For Marina, which have diluted shareholders by what seems like a 100-fold over the last 3 years (unreal, really), it is good news as its extensive technology offering is finally getting takers.


Anonymous said...

The boys down in wall street better start making those phone calls there is much needed money to be gathered .On the other hand, Texasians can pretend they have struck oil and a donation to Benitec would definitely place them in GOD'S good book.

Anonymous said...

Well, if Gradalis are going to take advance of Benitec's patented technology by using the lack of transparency created by Merck v. Integra, I hope they won't be complaining when Big Pharma return the favour by getting FDA clearance in record time for a similar drug based on 'their' technology.

Anonymous said...

While Gradalis have two new patent applications involving this technology it is worth noting that the original claims made in 2008 (application 11/983,482) have been rejected twice by the USPTO. The application is still under review as Gradalis provide more information but you would have to think that their patent position is on shaky ground and a deal with Benitec would be in everybody's best interest.

Dirk Haussecker said...

Remember...a patent gives you only the right to exclude, NOT the freedom-to-operate. Gradalis may get dozens of patents, yet this does not change anything whether Benitec patent claims apply to what they are doing.

Anonymous said...

Sorry Dirk but we dont quite understand what you mean mate, an explanation for the lesser social class would be greatly appreciated.

Dirk Haussecker said...

In even simpler terms: When considering whether Benitec has claims on Gradalis products, you can essentially ignore whether Gradalis has patents or not.

Gene Genie said...

Gradalis has approached Benitec for a licence , the Pfizer Hep C preclinical data was outstanding the ducks seem to be lining up fro ddRNAi.

Ozymandius said...

Gradalis has approached Benetec for a licence? Is this info that Benetec has released to the Australian Stock Exchange? Can't seem to find it as of now. Would appreciate further information.

Anonymous said...

Gradalis asked the FDA to consider a breakthrough therapy designation for its personalized cancer vaccine known as FANG on the back of preliminary data from their PII ovarian cancer trial. They presented this preliminary data and historical data from PI FANG for advanced cancer at today's ASGST. Looks promising.

Anonymous said...

"Gradalis asked the FDA to consider a breakthrough therapy designation"

If the FDA granted this request, I wonder if that would start an IP war as FANG would be the first approved RNAi drug and others may want a piece of the action. ddRNAi, RNAi triggers and other patent holders will probably lining up to stake a claim.

Anonymous said...

Gradalis 9 presentations at ASGCT meeting. Here are the links to the abstracts. This represents a high degree of confidence in the technology and the results they are achieving.

Phase II Study of FANG™ (Autologous Tumor Cell – GMCSF/pbi-shRNA™ Furin DNA Plasmid) Vaccine in Advanced Melanoma

Phase I Study of the "Triad" Autologous (FANG™) Vaccine, Incorporating Bifunctional shRNAfurin and GMCSF Transgene Expression, in Advanced Ewing's Sarcoma: Preliminary Data in Pediatrics Patients

Clinical Development of "Bifunctional" shRNA Knockdown of Acid Ceramidase

Detection of RNA Interference (RNAi) Mediated mRNA Cleavage in Fresh Injected Tumor Tissue from Patients a Phase I Trial of an Intratumoral pbi-shRNA™ Lipoplex Targeting Stathmin-1

Multiplex Bi-Functional Short-Hairpin RNA (shRNA) Targeting Single-Nucleotide KRAS Mutations in Pancreatic Cancer

Short Hairpin RNAs (shRNA) Against Steroid Receptor Coactivator-3/Amplified in Breast Cancer 1 (SRC-3) and Steroid Receptor Coactivator-1 (SRC-1) as Breast Cancer Therapeutic Agents

Circulating Plasmid Detection in a Phase I Clinical Trial of Intratumoral Injection of pbi-shRNA™ Nanoplex

Long Term F/U – Phase I Study of the "Triad" Autologous (FANG™) Vaccine, Incorporating Bifunctional shRNAfurin and GMCSF Transgene Expression, in Advanced Cancer Patients

Phase I Study Results of pbi-shRNA™ STMN1 Nanoplex Via Intratumoral Injection in Advanced Cancer

Anonymous said...

Thanks for the links. If their breakthrough therapy application with the FDA gets approved is there any indication from Gradalis when they'd expect to have it commercial?

Anonymous said...

"any indication from Gradalis when they'd expect to have it commercial?"

Gradalis is a private company that play its business cards very close to its chest. It is also an integrated company which mean it can do its own research, trials and manufacturing. When the FDA finally does give approval for one or more of its treatments the company could gear up quite quickly but when it would advertise this fact would probably depend on when it needed the extra funds from investors to support the expansion.

Anonymous said...

Great work Gradalis:

Anonymous said...

Can anyone advise if Gradalis is listed on a stock exchange and what their code is?

Anonymous said...

They are a private Co.

Anonymous said...

Is this still part of the running gag against Benetic?

What is it with Dirk and the BLT supporters?

Anonymous said...

Who mentioned Benitec you muppet? It's about Gradalis, FFS.

Anonymous said...

Looks like Dirk is about to be fully vindicated for his derision of Benitec in the near future.

Smart money in volume heading for the doors last night on BTEBY collapsing the price.

Anonymous said...

Great Post above Plastic.

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