Tekmira Enters 2015 a Different Company

Today is the last official day for Chief Technology Officer Ian MacLachlan at Tekmira.   While scientifically a great loss to Tekmira, the change marks the end of Tekmira as a technology development company and the official beginning as a commercially focused clinical product development company.  From the clinical pipeline, it is TKM-HBV, Tekmira’s gene silencing candidate for the finite treatment of HBV infection, which stands out as the most important, if not existential asset to be watched in 2015.

After generation 1, 2, 3, and now even 4 SNALP LNP, and 10, 100, 1000x fold improvements in the potency and therapeutic window, the time has come to stop telling us that ‘next time will be better’ after yet another immunostimulatory setback.  In both cases (TKM-ApoB, TKM-EBOLAold), I was willing to take the bait as the company and Dr MacLachlan explained the basis for their continued confidence with scientific authority.  For TKM-EBOLA, the plausible explanation for the immunostimulation seen in the healthy volunteer study was particle heterogeneity following resuspension of the lyophilized liposomes (note: a lyophilized formulation was used in that case because Ebola may have to be used in areas with unreliable cold chains; other SNALP LNP products are provided as 'wet' formulations).

However, with the recent initiation of phase I studies of generations 3 and 4 formulation of TKM-HBV and the departure of Dr MacLachlan, the company seems comfortable with taking their last two shots at proving that SNALP LNPs can enable potent gene knockdown in the absence of transient immune suppression at comfortable safety margins and with profiles that are competitive with the emerging conjugate platforms in RNAi and RNaseH antisense.

Although a bit under the radar for the moment, the new studies with non-lyophilized 3^rd generation TKM-Ebola Guinea should be informative as to whether the lyophilization hypothesis holds water.  As these studies should likely be of shorter duration than the TKM-HBV phase I studies, the safety results from those studies should be a harbinger for the safety for at least TKM-HBVgen3, if not TKM-HBVgen4.  

The changes at the company will be welcome by some investors which might have grown tired of holding shares in a lab experiment.  On the other hand, they dampen my outlook for other liposomal delivery opportunities not only in RNAi for oncology (see today's ho-hum update on TKM-PLK1), but also in the sizzling hot fields of mRNA and CRISPR Therapeutics.

So good luck Ian and thanks for leaving the company in good order. Yours is also a great loss to the field of RNAi Therapeutics.  Hope you will come back to Nucleic Acid Therapeutics with renewed motivation.

Hello 2015

Lastly, a Happy New Year to all my readers.  2015 should be a year that will be marked by clinical RNA Therapeutics data of ever higher quality which will make it crystal clear that RNA Therapeutics has become the 3^rd major drug discovery engine of the pharmaceutical industry. 

First up: Regulus end of January/February 4mg/kg RG-101 in HCV.

A Defining Month for Tekmira

As if Ebola has not showered Tekmira with enough attention, Tekmira will be front and center in the RNA Therapeutics industry in October.  It will be clinical results from two other drug candidates utilizing Tekmira’s RNAi delivery technology (TKM-PLK1 and ALN-TTR02) and pre-clinical data for TKM-HBV that will define Tekmira's trajectory as a 'normal' biotech company.  'Normal' as I have little idea how Ebola will change all this.

Accordingly, depending on the dataflow, Tekmira could finally be transformed into an established biotech company.  If there are serious disappointments, Tekmira risks being delegated to being 'the Ebola company'.

Event 1 (October 10-11): Do GI-NET patients respond to TKM-PLK1?

The first upcoming data event is the phase IIa update for TKM-PLK1 in gastrointestinal neuroendocrine tumor (GI-NET) and adrenocortical carcinoma (ACC) patients.  This one can be considered a bonus event for Tekmira as barely anybody has been paying attention to the potential of this first-generation SNALP-based product candidate.

 

Results from a  multi-dose escalating phase I study suggested a dose-dependent benefit with patients receiving 0.6mg/kg or more having an increased likelihood of showing ‘clinical benefit’ (stable disease or partial response) than those receiving less of the drug.  In particular, almost all (5/6) GI-NET and ACC patients in that trial with otherwise enrolled across a wide range of cancer types exhibited at least stable disease, with a partial response by RECIST and a 19.3% reduction in tumor size.

One aspect that I found particularly encouraging in these results was that TKM-PLK1 which involves a long-circulating form of SNALP achieved ‘several fold’ increased target tumor concentrations compared to an earlier, short-circulating SNALP product (ALN-VSP02 from Alnylam).   Unfortunately, the precise differences were not disclosed.

The factor that makes me most optimistic about a positive update (--> multiple tumor responses) at the upcoming 7^th Annual NET Conference in Nashville is that there is evidence that SNALP LNP delivery should work particularly well in the GI-NET and ACC settings.  Not only did GI-NET and ACC patients seem to perform well in the phase I study, there have historically been apparent biological effects of other nanoparticulate cancer RNAi Therapeutics in neuroendocrine tumor patients, including cases of extended stable disease with Atu027 by Silence Therapeutics.  

Moreover, the adrenal cortex, and possibly other endocrine structures, seems to be a preferred target organ (next to liver) for SNALP LNP delivery.

What makes me less excited about this program is that TKM-PLK1 is based on fairly old SNALP LNP delivery technology, and wouldn’t it be nice to see the potent PLK1 RNAi trigger being utilized in the latest delivery formulation.

Event 2 (October 13): Does ALN-TTR02 show a therapeutic benefit in TTR amyloidosis?

At the upcoming American Neurological Association’s 2014 Annual Meeting, Alnylam will present first data from its high-profile ALN-TTR02 product candidate that will look not just at target gene knockdown (expected to be in the 80% range), but also whether this translates into an apparent therapeutic benefit.

ALN-TTR02 is an RNAi Therapeutic for the treatment of the FAP form of TTR amyloidosis and uses Tekmira’s delivery technology.  As a result, Tekmira stands to financially benefit from it in the form of development milestone payments and royalties (in the low to mid single-digit percent of revenues) which may reach ~$50-100M annually for this $500M market cap company if analyst projections as to the FAP market prove correct.

The data to be presented comes from the open-label extension (OLE) of the relatively short phase II study.  In this OLE study, Alnylam will look every 6 months how patients are doing according to the mNIS+7 functional score which will then be compared to data gathered from a Natural History study of the disease. 

It is expected that 20 patients that had been rolled over from the phase II study will now have reached the first 6 month time-point.  The phase II study was too short (2 doses spaced apart 3-4 weeks) to reasonably expect an obvious therapeutic benefit from the knockdown of the disease-causing transthyretin gene.

It is important to remember that a failure to see a therapeutic improvement after 6 months with ALN-TTR02 does not necessarily reflect badly on SNALP LNP delivery technology as long as the knockdown remains in the 80% range and is well tolerated.  In that scenario, target risk and an insufficient period of knockdown may be responsible instead and this is where each RNAi Therapeutic has its unique development risk.

My prognosis is that first divergences from the Natural History will be seen if the preclinical experiences and those from other amyloidotic diseases such as AA amyoloidosis are any guide (~50% knockdown and beyond should lead to a benefit).  From a Tekmira technology point-of-view, I will pay close attention as to the safety and tolerability of longer-term dosing, which so far looks quite good.

  

                Event 3 (October 15): Coming out for TKM-HBV

Possibly the dataset with the most impact on Tekmira is the revelation of the company’s RNAi candidate for HBV infection.  Based on data revealed earlier this year by Alnylam which showed a SNALP LNP-based RNAi compound to have multi-log viral knockdown and 2 log HBsAg knockdown in the challenging chimpanzee model with moderate amounts of drug, TKM-HBV is set to become most-potent and therefore hopefully best-in-class among the knockdown approaches by Arrowhead Research (ARC520, first-mover), ISIS/GSK, and Alnylam.

To facilitate cross-comparisons, Tekmira may wish to directly compare its candidate with Arrowhead’s ARC520 for which the structural identity is known.

One aspect that I will be paying particular attention to is whether the data support dosing without transient immune suppression.  This is because I am concerned that such a regimen, especially if it involved steroid use, would not be acceptable in the HBV setting. As you may remember, the company attempted to get away without immune suppression with TKM-EBOLA in a trial in healthy volunteers, but at moderate-to-high dose levels immune stimulations were seen prompting the FDA to put that program on Clinical Hold for the volunteer population. 

Having said that, TKM-Ebola is now being used in much more fragile patients actually infected with Ebola, and anecdotally even the most stringent dosing regimens such as 7x daily appear to be tolerated here, presumably without pre-medication.

As per the last quarterly conference call, Tekmira management seemed confident that TKM-HBV would not require pre-medication.  Since such immune stimulation is thought to be highly sequence-dependent, I do not fully understand their confidence, but maybe a little bit of immune stimulation is not that bad in the Ebola setting after all.

An IND for TKM-HBV is planned by the end of the year with first dosing starting in early 2015.

Buckle up for an exciting month with Tekmira, and if all that weren’t enough, it unfortunately looks like we are still in the early innings with Ebola as being ahead of the curve is a concept foreign to the governing authorities.

Disclosure: long Tekmira.

Oligonucleotide Therapeutics Need to Embrace New Genomic Era in Cancer Medicine

With ASCO 2014 behind us, I am left with the impression that oligonucleotide therapeutics have failed to keep pace with important developments in cancer drug development.  Most importantly, cancer oligonucleotide therapeutics need to take advantage of the latest genomic tools and insights in cancer biology to select the patient populations most likely to respond treatment to both increase success rates and to save development dollars.  After all, this is what you would expect from a platform most suited to personalized medicine.

In some cases, drugs are being developed a priori with specific mutations in mind such as the selective EGFR-mutant inhibitors by Clovis Oncology and AstraZeneca which have caused quite a stir amongst clinicians and investors at ASCO.  In other cases, and this is something spearheaded by companies like Foundation Medicine and their pharmaceutical partners, comprehensive next-gen sequencing is employed as trials progress to identify often complex signatures that render a cancer susceptible to a treatment. 

And particularly relevant for delivery aspects, other companies such as Endocyte are using imaging diagnostics to identify those cancers that either express the right surface receptors for a ligand-targeted agent or those amenable to the EPR effect relevant for nanoparticle-based delivery.

Although I believe that Tekmira has also a delivery-related rationale in selecting adrenocortical carcinoma and neuroendocrine cancers for TKM-PLK1 based on their insights in liposomal delivery, the oligonucleotide field at large is failing to take advantage of delivery-related cancer selection strategies.

In terms of tumor response related to hitting the right targets and pathways, I would like to see the field embrace the personalized genetics approach.  Prospectively targeting KRAS mutant colorectal cancers with a PLK1-RNAi therapeutic would be one example.  Going one step further, a development strategy that looks at the genomic profiles of various cancers and then pull out the formulation with the right RNAi trigger or antisense oligo against critically activated pathways would play into the strength of the technology: every signature is ‘actionable’ as the technology leaves no target behind.

Especially for delivery approaches that can penetrate tumors well, innovative cancer development could unlock the considerable potential that oligonucleotide therapeutics have for oncology.  Beyond TKM-PLK1, the androgen receptor antisense compound by ISIS/AstraZeneca could be an important first test case for this concept in oligonucleotide therapeutics.

RNAi Therapeutics Companies Cashed Up and Ready to Strike

With the $36M fund-raising last night, Arrowhead Research has become the 4^th publicly traded RNAi Therapeutics company in short succession to cash up for a real shot at drug development success.  The other companies are Tekmira, RXi Pharmaceuticals, and as it was made official this morning, Silence Therapeutics.

The money will be spent on promising drug candidates in the cancer field (TKM-PLK1, Atu027), chronic HBV (ARC520), and scarless wound healing (RXI-109) without having to take dangerous short-cuts or partner the crown jewels prematurely.  Moreover, it will help to advance critical delivery technologies such as DPC, SNALP, and self-delivering RNAi triggers which should provide for non-dilutive partnering opportunities without having to entertain low-ball offers.   

It is notable (and not surprising) that unlike Marina Biotech and Benitec which so far have failed to similarly escape the financing maelstro, Tekmira, Arrowhead and Silence all sport healthy in-house R&D operations.  RXi does not have such operations- yet.  However, they were critical for bringing RXI109 into the clinic on which the company’s ~$80-90M market cap rests.   

The cash infusions should also give the companies, which among them own most of the leading platform technologies, the opportunity to make up for the 20-30 fold gap in valuation to the likes of ISIS Pharmaceuticals (2.3B market cap in antisense), Alnylam (1.5B market cap in RNAi), and Sarepta (1B market cap for a phase II orphan indication).  If monoclonal antibodies are any guide, this will not play out as the winner-takes-all the public markets have it right now.

Below is a quick rundown of the newly cashed-up crop of RNAi Therapeutics companies for those new to the field.

Disclosure: I am long Tekmira and Arrowhead Research. 

Disclaimer: Investments in RNAi Therapeutics carry more risks than you want to know and think about.  The following can only be a very brief teaser for you to start your own due diligence.

Arrowhead Research: In the pursuit of a cure for chronic HBV

Market cap: ~60-70M (of which ~$35M in cash)

Unless Arrowhead Research comes up with a compelling orphan drug application of its technology when it will disclose its second development program in H1 2014, investment success will hinge on the fate of ARC520.  ARC520 is Arrowhead's unique attempt at a functional cure for chronic HBV that will enter clinical development shortly.  I interpret last night’s fund raising in that the IND-enabling tox studies were positive.  The results of these will be critical in determining whether ARC520 can be dosed high enough to safely achieve the type of 90% HBsAg reductions that will be required for that lofty goal.

With cash of around $35M, Arrowhead can now retain full rights to that program at least after value-inflecting phase I proof-of-concept knockdowns have been achieved.  To extend the cash runway beyond the predicted ~2 years, Arrowhead owns the exciting Dynamic PolyConjugate delivery technology, particularly the subcutaneous version and potential new developments for cancer applications.  DPC offers an obvious non-dilutive funding opportunity.

Having slept over the announcement of the PIPE financing which doubles the share count near multi-year lows, I believe it still was a good one in a difficult situation.  Potential partners would have liked to exploit the financial weakness of Arrowhead and the fast-money crowd (think Dawson and Rodman) would have liked to reap risk-free gains from trading around a public offering.  Instead, Arrowhead seems to have found one or more significant investors that share the vision with management.  It is comforting that besides the sweet entry price, no special gifts in the form of warrants and otherwise seemed to have been handed out.  No wonder Arrowhead closed up 13% the day after the financing.

Upcoming catalysts:

  - Determination of maximally tolerated dose in volunteer study with ARC520;

-          - DPC partnering (always on the table);

-          - Modest ALN-TTRsc results would emphasize value of DPC (mid-2013) and may get Alnylam into  play;  

-          - DPC data on cancer (probably H1 2013);

-          - Nominating new development candidate (Q2 2014);

-          - ARC520 viral knockdown results in the Hong Kong trial (H1 2014).

Tekmira Pharmaceuticals: Quality Technology, Quality Financial Management

Market cap: ~$70M (of which ~$40M in cash)

If you are looking for relative stability in RNAi Therapeutics, Tekmira could be attractive.  It was its SNALP technology that enabled the current revival (with well over $300M capital inflows in the industry in the first 4 months of this year) and remains one of the two leading systemic delivery technologies with the value possibly shifting towards oncology indications.  Its leading development candidate, TKM-PLK1 for solid cancers, is about to enter phase II studies and has yielded promising dose-related evidenceof efficacy in phase I. 

The company’s aerosolized LNPs could be an unanticipated windfall for investors, although I have yet to see the all-important safety data.  Its Ebola biodefense program is not valued much by the market, but has been an important stabilizing factor for the company in terms of funding and represents an attractive commercial opportunity in its own right.  

Upcoming catalysts:

-          - TKM-PLK1 data from the expansion cohort (H2 2013);

-          - Design and initiation of phase II studies for TKM-PLK1 (H2 2013);

-          - Follow-up candidate and potentially data for TKM-EBOLA (H2 2013);

-          - Nomination of new development candidate;

-          - $5M milestones each if ALN-TTR02 by Alnylam enters phase III development and Ascletis   initiates a trial in China with ALN-VSP02 for primary liver cancer (both H2 2013/H1 2014);

-          - Partnering of SNALP delivery technology, also for non-RNAi, non-therapeutic applications (always on the table);

       - Monetization of Talon royalties (uncertain timing if at all) 

Silence Therapeutics: A novel cancer approach and strong purchasing power

Market cap: ~150M (of which $30-35M in cash)

Following a remarkable financial turnaround and management reshuffle, Silence Therapeutics has become a force to be reckoned with once again.  Unlike in the early days, it is the product candidates, and not RNAi trigger IP, that is the focus of the New Silence.

First and foremost is Atu027, an endothelially targeted RNAi Therapeutics aimed at preventing cancer metastasis.  The company believes that Atu027 will be most useful in combination with small molecules that aim at killing primary tumor cells and consequently is about to initiate phase Ib/phase II combination trials.

According to the information in the latest financing (which was approved today), a significant investment will be made in building a broader pipeline.  This will take advantage of the company’s three lipid-based delivery technologies: Atuplex (broad endothelial cells), DACC (lung endothelial cells), and DBTC (cells in the liver).  In general, the market cap and cash infusion position the company well to pick up some distressed RNAi and other assets.

Upcoming catalysts:

-          - Initiation of pancreatic cancer combination trial with Atu027 (H2 2013);

-          - Nominating new development candidate(s) (H2 2013);

-          - Pre-clinical data on liver delivery technology (2013);

-          - Partnering, also for non-RNAi, non-therapeutic applications

RXi Pharmaceuticals: Just dermal anti-scarring no more  

Market cap: $80-90M (of which ~$20M in cash)

RXi Pharmaceuticals is the company that popularized the self-delivering RNAi trigger concept.  Unfortunately for the company, it made a critical IP mistake of staying clear of the most potent versions it could have created with its ideas (à dsRNA length).  Furthermore, it seemed that it never was able to get anything into the clinic.

This changed last year with phase I initiation for RXI-109, a potentially superior alternative to Pfizer’s antisense-based dermal anti-scarring candidate.  However, as part of a reorganization, it essentially got rid of its R&D to focus all resources on RXI-109.

As you know, getting rid of in-house R&D is a mortal mistake if you want to be a platform-based company.  With the recent $16.4M cash infusion by OpkoHealth it will be interesting to watch whether they can become a self-delivering RNAi trigger platform-based candidate again, or whether the claimed company growth will largely be around expanding the indications of RXI-109 to other anti-fibrotic indications, especially ocular ones.

Upcoming catalyst:

-          Presentation of phase I data from RXI-109 (any day).

RNAi Therapeutics Arriving in Oncology

Yesterday, Tekmira presented data from the dose escalation portion of the phase I trial with TKM-PLK1 for the treatment of solid tumors.  I agree with the company that the fact the drug candidate was associated with clinical benefit in 4 out of 9 evaluable patients receiving 0.6mg/kg or more versus no such association at dosages below is 'highly suggestive' that TKM-PLK1 has anti-tumor activity indeed.  I also agree with their decision to pursue the neuroendocrine tumor indication for their first phase II study later this year based on the present data.

What I would like to focus on today, however, is much more exciting data contained in the TKM-PLK1 data as it relates to RNAi delivery to oncology…the key obstacle in making RNAi Therapeutics work for cancer.  Specifically, the long-circulating 2^nd gen SNALP formulation employed in TKM-PLK1 exhibited vastly improved pharmacokinetics over the short-circulating 1^st gen SNALP formulation employed in Alnylam’s ALN-VSP02.  Whether cancer in the liver or not, long circulation times are critical in order to take advantage of the Enhanced Permeability and Retention (EPR) effect that is at the heart of nanoparticle-based approaches in oncology.

It is for this fact that I am optimistic that the ‘highly suggestive’ data (which you invariably will hear about in phase I cancer studies involving a mix of late-stage cancer patients such as this one) are for real.

10-Fold More siRNA at 24 hours

Slide 13 of the AACR presentation shows that at 24 hours, around 1500 nanograms siRNA was present in 1ml of serum at the maximally tolerated dose of 0.75mg/kg.  This compares to around 150 nanograms of combined KSP and VEGF siRNA per ml at this time point for ALN-VSP02 as presented at ASCO2011.  If you’ve ever been at the bench and performed siRNA transfections in tissue culture cells, 1.5 microgram siRNA in a ml of media is overkill, and in this case it is real tumors that are served by blood containing such large siRNA concentrations- for days.

Considering the PK profile, it is not surprising that the one paired tumor biopsy obtained so far showed RNAi activity according to 5’ RACE, whereas such detection was rare in the ALN-VSP02 trial.  Clearly, more tumor biopsies have to be taken in the dose extension phase of the study (which apparently is recruiting quite well).  This will also be important for assessing siRNA concentrations in the tumors themselves.

Selecting the Right Patients

A heterogeneous patient population as in this trial alone obviously makes it very difficult to select the right cancer types for future clinical development.  There are a number of biomarker strategies that Tekmira could, and in my opinion, should employ in their future development.

Based on target biology, the KRAS mutation status should be given high priority.  KRAS-driven cancers are thought to be highly dependent on PLK1 expression.  Related to this, PLK1 expression itself could be used as a guide in patient selection.

A more unusual strategy would be to use imaging technologies based on nanoparticles which presumably rely on the same EPR effect in order to assess whether the tumors are amenable to EPR effect (alternatively, a simpler perfusion test may provide similar insights).  I could imagine that the fact that neuroendocrine tumors seem to respond to TKM-PLK1 is a result of such a favored effect.  Finally, another (admittedly less likely) selection strategy considering delivery would be to target tumors with high expression levels of LDLR-like receptors which are thought to be important in the cellular uptake of SNALP particles.

And last but not least, for those that like to think of comparative values, with a much better target and PK profile over ALN-VSP02, TKM-PLK1 may now be considered the lead RNAi Therapeutics oncology candidate. 

Register for the GTC RNAi Research and Therapeutics meeting in San Francisco today (June 20-21).  Get a free RNAi Therapeutics blog T-shirt and 20% discount on registration by entering discount code 'RNABLG13'.

Cancer RNAi Therapeutics Moving On

As RNAi Therapeutics targeting genes expressed in the liver, especially for orphan indications, have captured much of the recent interest in the technology, it is time to once again pay closer attention to RNAi Therapeutics in the oncology space.

Atu027 and TKM-PLK1 Moving into Phase II

Silence Therapeutics have just announced that they got the green light from the German regulators to test Atu027 in combination with small molecule gemcitabine in pancreatic cancer.  Following a short phase Ib to establish the safety of the combination (note: the original phase I was a monotherapy trial), the plan is to rapidly move into phase II which will aim at establishing proof of concept for efficacy.  Depending on the funding situation, it is possible that the company will expand Atu027 into other indications in phase II, possibly in collaboration with private investigators in the UK.

Clearly, the strength of Atu027 is its safety profile so far, one that has surpassed my own expectation for this positively charged lipoplex formulation.  The clinical attraction meanwhile is that Atu027 aims at a quite novel anti-cancer mechanistic approach by inhibiting metastatic spread by fortifying the vascular endothelia. 

The challenge with Atu027, however, is that the gene target, PKN3, remains a relative black box.  This not only demands a certain leap of faith in mechanistic terms, but also complicates the clinical development as biomarkers and other tools are not readily available.

This is quite different from TKM-PLK1, the cancer RNAi Therapeutics by Tekmira.  Polo-like kinase 1 is a hot target, but specificity/safety issues have so far dogged drug development efforts with small molecules, most notably represented by Boehringer-Ingelheim.  By contrast, the SNALP RNAi delivery approach promises to be more cancer tissue targeted and consequently should avoid some of the dose-limiting toxicity observed so far, especially the hematologic ones.

TKM-PLK1 has flown a bit under the radar and the phase I update late last year did not capture much attention.  This is probably because the response rate did not seem too much to get excited about.  However, as Ian MacLachlan, the CSO of Tekmira, pointed out at the AsiaTides meeting last week, it was a small dose-escalating phase I trial (20-30 patients) in advanced solid cancer patients and only four patients actually received TKM-PLK1 for two or more cycles (6 infusions over 2 months) at 0.6 mg/kg or above, dose and durations you would think would be required for advanced cancer patients to get a chance to respond in the first place. Notably, two out of those four showed signs of efficacy: one partial response and one with stable disease after more than 6 months on study drug.

In light of that, the phase I profile of TKM-PLK1 supports my view that it could be the foundation for an exciting PLK1-related cancer franchise for Tekmira and I look forward to seeing the full results presented at the upcoming AACR meeting.  My attention will be particularly focused at any direct measures of target knockdown.  Beyond that, with the company’s healthy financial situation, I look forward to a rich phase II strategy involving a number of solid cancers and innovative study designs such as patient selection based on genetic criteria.  As good as Tekmira's science is, they now also need to be as proactive and innovative on the clinical front.

ALN-VSP02 and CALAA01 Falling Behind

As TKM-PLK1 and Atu027 are moving into phase II, fellow early movers in oncology RNAi ALN-VSP02 and CALAA01 are falling behind. 

The next step for ALN-VSP02 will be a phase I in hepatocellular carcinoma (‘real’ liver cancer) in China under a license by Alnylam to Ascletis.  As noted by Patrick Lu of Sirnaomics at AsiaTides though, it would be a mistake to believe that the Chinese regulatory environment is any less demanding than in the West.  Au contraire, it seems that much more paperwork is required to file an RNAi-realted IND as the authorities there are keen on building their expertise in this new technology.  Expect a delay of at least 6 months from IND application to the green light to go ahead, after all the paperwork has been submitted.  For Tekmira watchers, I expect the $5M milestone thus in 2014, not in 2013.

While ALN-VSP02 still has a pulse, despite of the fact that it lacks the long circulation thought to be necessary for cancer uptake (note: delivery to liver cancer is a very different animal from delivery to normal liver; TKM-PLK1 is a long circulating SNALP), RIP CALAA-01 by Arrowhead Research.  Having said that, the value of CALAA-01 to Arrowhead Research has not been lost entirely as the company has filed for a patent covering a low/high dose strategy of minimizing immune stimulation.  

As the recent high-profile pulling from the market of a pegylated peptide (Omontys by Affymax) due to hypersensitivity, even anaphylactic reactions demonstrate (and also the infusion reactions reported by Alnylam in their SNALP RNAi Therapeutics trials), administration-related hypersensitivity reactions are an issue for the entire drug development arena.  In order to rescue the value of a number of blockbuster franchises, I expect that changing administration schedules could be one area attracting increased attention.  A patent here could have unexpected value.   

A New Crop of Cancer RNAi Therapeutics

Behind TKM-PLK1 and Atu027, a new crop of cancer RNAi Therapeutics is emerging.   Dicerna has signaled that it will finally move into clinical development (Q1 2014) with a liposomal Dicer-substrate formulation with a focus on liver cancer.  Of note, the liposomal formulation process is quite distinct from that of SNALP involving sequential core and envelope formation steps, potentially amenable to ligand-directed targeted delivery.

Another program worth following is another one for liver cancer, the subject of a collaboration of Korean company Bioneer andSanofi-Aventis.  The attraction of that program is that the nanoparticle here, SAMiRNA, comprises a single molecule, even to the extent that the RNAi trigger and delivery components can be manufactured on a single column.  Although I’m opposed to the fundamental notion that the ease of route of administration and the manufacturing process should drive drug development, don’t underestimate the attraction of meeting idealistic product profile when it comes to partnering with Big Pharma.    

The efforts above are a reminder that cancer could be an even bigger commercial opportunity for RNAi Therapeutics than liver-related indications.  The genome-wide targeting opportunity with RNAi Therapeutics has not been lost.  The pharmaceutical industry is watching.

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ALN-VSP02 Was a Good Start, but Directs Focus Towards Improved Formulations

Alnylam recently published detailed phase I results from its RNAi Therapeutic candidate to treat liver cancer, ALN-VSP02.   Although results from this study had already been reported, the new paper by Tabernero and colleagues provides an insightful warts-and-all view of Tekmira's SNALP generation 1.0 (short-circulating DLinDMA particles) in a solid cancer.  The results show that while ALN-VSP02 did achieve a number of important goals, including evidence of tumor response and RNAi activity, it will be necessary to turn to the newer SNALP formulations for more robust efficacy and improved safety.

New Insights on ALN-VSP02 Activity

Previously, Alnylam provided clear evidence of RNAi activity using the 5' RACE assay.  It is now clear, however, that this was only based on 3 positive biopsies out of 15 investigated in this regard, and only for the VEGF, but not the KSP target gene.  Consistent with this less than robust RNAi activity, there was no convincing evidence of target gene knockdown and no spindle abnormalities as would have been expected from KSP knockdown.

New Insights on ALN-VSP02 Safety  

The present paper also provides valuable insights into the safety of a SNALP 1.0.  As was reported before, infusion reactions were seen in a minority of patients and this was readily addressed in practical terms by slowing the rate of infusion.  Interestingly, the infusion reactions appear to be related to complement activation, not cytokine activation.

Some cytokines were also upregulated (rarely TNF-alpha, however), especially above 0.4mg/kg, despite the use of modified siRNAs.  The evidence thus increasingly points towards the DLinDMA lipid itself to be the culprit.

Finally, ALN-VSP02 caused considerable spleen toxicity, especially with prolonged dosing.  In the one complete responder in the study, 90% of the spleen was reduced after receiving 50 doses of ALN-VSP02.  This is consistent with the preclinical monkey data.  Somewhat reassuringly for SNALP 1.0, this effect might be due to on-target efficacy, as the same lipid formulation with a luciferase siRNA did not have this effect in monkeys (note: the spleen is not an essential organ in humans, and I’d much rather have my spleen removed than cancer).

SNALP-based Cancer RNAi Therapeutics in the Future

Based on the above limitations, it is important that future SNALP-based cancer RNAi Therapeutics include the following improvements, essentially all of which have been achieved over the last 6-7 years since ALN-VSP02 had been selected as a development candidate: firstly, a more potent and less immunogenic lipid is required (there should be multiple to choose from now); secondly, the SNALP particles should be less than the 80-100nm with ALN-VSP02 and include more stable PEG-lipids for improved, i.e. prolonged circulation times to better take advantage of the EPR effect of solid tumors (TKM-PLK1 includes such stable PEG-lipids); and finally, as spleen safety might also be affected by lipid accumulation along the endosomal-lysosomal pathway, enhanced lipid biodegradability may be desirable.

ALN-VSP02 has been put on hold by Alnylam for development in the Western markets.  Last year, however, Alnylam licensed development and commercialization rights to Ascletis for the Greater China market where liver cancer (hepatocellular carcinoma, HCC) is prevalent.  The next clinical study by Ascletis is expected to involve more HCC patients who, unfortunately, have been almost entirely missing in the phase I study of ALN-VSP02.  Despite the challenges that ALN-VSP02 will face in HCC, innovative RNAi Therapeutics have an important role to play in the future treatment of HCC, a disease that is proving again and again hard to manage by more conventional approaches as Celsion’s disappointing results (radiofrequency ablation with liposomal doxorubicin) today showed. 

What to Expect from RNAi Therapeutics in 2013

2012 was the most exciting year in the ~12-year history of RNAi Therapeutics- both from a scientific and financial perspective.  Left for dead by most, unambiguous gene knockdown results in Man have allowed the technology to regain much-needed respectability.  With the start of 2013, the industry is looking to build on these successes with additional clinical trial results, interesting new therapeutic candidates and product-specific and platform-related deals, particularly in the area of delivery.  With appetite for innovation increasing in a low interest rate economy and with the orphan drug tsunami, 2013 could be a quite rewarding year for the discerning investor.

Clinical results to look out for

Clinical results in 2013 that will continue to shape perceptions of the technology include phase II study results for ALN-TTR02 in TTR-FAP by Alnylam, phase I results from its GalNAc conjugate version ALN-TTRsc, and phase I results from a number of other programs, foremost from oncology drug candidate TKM-PLK1 by Tekmira, ALN-AT3 for hemophilia by Alnylam, and finally RXI-109 for dermal scarring by RXi Pharmaceuticals.  

For ALN-TTR02, it will be important to confirm the impressive knockdown results from the phase I study, but over longer periods of time and with still acceptable safety.  ALN-TTRsc will be an important proof-of-concept for the subcutaneous delivery of RNAi Therapeutics and should provide a good idea of what to expect for ALN-AT3 which is based on the same GalNAc siRNA conjugate technology.  The success or lack thereof of Alnylam’s GalNAc technology will also affect the perception of Arrowhead’s DPC technology as either a competing or necessary subQ alternative to GalNAcs.

Tekmira’s TKM-PLK1 has not gotten much credit so far.  This, however, could change with the presentation of the full phase I results, possibly at this year’s ASCO.  I consider PLK1 as the single most attractive target for cancer RNAi and I am bullish that the molecular analyses will show molecular, if not clinical efficacy at this early stage.  And while TKM-PLK1 could overcome the safety-efficacy hurdle for some indications, the importance of PLK1 as a target demands that Tekmira will continuously work on improved follow-on versions.

Finally, RXi’s second phase into RNAi for skin applications.  I also consider dermal scarring as an interesting differentiated, because cosmeceutical RNAi product opportunity.  

Cool pipeline additions

As detailed in my last blog entry, there are two exciting infectious disease drug candidates for which clinical development will ramp up in 2013: Arrowhead’s ARC520 aiming to achieve for HBV what has recently been achieved in HCV (dramatically increased cure rates and less suffering from the side effects of interferons), and Calimmune’s ddRNAi-based HIV drug candidate aiming to keep the virus out of immune cells.

It looks like we will have to wait for clinical efficacy results from these programs for a while (2014-2015), either due to the nature of the cell competition approach involved in the HIV program or because of the use of healthy volunteers.  I believe the latter is what Arrowhead has guided for ARC520, but from an investor perspective this would be highly unforunate as this would delay the demonstration of gene knockdown with the DPC platform.  And from a medical perspective, I am struggling to see what the value or necessity of a volunteer trial would be.  

Deals and Big Pharma

In addition to clinical trial results, RNAi Therapeutics investors will be getting up each morning to check the internet for whether a deal has been announced.  Alnylam’s ALN-PCSK9 is the most imminent partnering candidate and will be an indicator of the mere differentiation value of RNAi Therapeutics.  While clinically more advanced monoclonal antibody-based programs for the industry’s most desired target, PCSK9, exist, should monoclonal antibody stumble as a class, RNAi Therapeutics and ALN-PCS could suddenly have the market for itself.  Considering the multi-billion $$$ potential of PCSK9, a gamble worth taking for a Big Pharma in my opinion.

Similarly to ALN-PCS in the hypercholesterolemia market, the size and complexity of the clinical program that would be required to turn ARC520 into a major HBV drug well exceeds Arrowhead capacities, and this could mean that we will see an early licensing deal around that asset, too.  While proof-of-concept clinical knockdown data would greatly increase the partnering value of ARC520, from a financial perspective (--> di-lu-tion!) early partnering may be prudent if no alternative non-dilutive capital alternative presented itself.

As delivery is gating for all of the above RNAi Therapeutics product opportunities, delivery naturally should be the subject of a few more platform-type relationships.  Tekmira’s SNALP technology for addressing diseases of the liver, lung, and cancer tops the list for a meaningful partnership (>$10M upfront), and also Arrowhead’s DPCs for liver-targeted gene knockdown ought to see some interest.  

Delivery-related deals should also reveal which Big Pharma company is still committed to the RNAi Therapeutics platform.  For the efforts at Takeda, Merck, and Novartis (the three most significant ones in terms of investment to-date), it could be a make-or-break year.  I cannot imagine that these groups are allowed to exist in their current forms for much longer before they get anything into the clinic.  For this, they probably need to swallow their own pride and accept that expert outside help is necessary for their delivery needs (rather than attempting home-brew versions).  Given the recent clinical and late preclinical results for SNALPs and DPCs, chances that they will finally do something have certainly increased.

A Happy New Year everybody.

Eventful Months for Tekmira

Last week, Tekmira reported its quarterly results and provided a corporate update.  With interim phase I results for its lead clinical candidate TKM-PLK1, well received clinical results by its licensee Alnylam, the Stop-Work Order from the Department of Defense, milestone payments from Talon and Alnylam, and the prospect of a jury trial following a key decision by the judge in the litigation with Alnylam, these certainly must have been one of Tekmira’s busiest 4 months ever.

TKM-PLK1 Results

20 months after trial start, Tekmira finally reported first data from its lead clinical program, TKM-PLK1 for advanced solid cancers.  The most informative data from this early-stage trial, as expected, related to safety/tolerability and pharmacokinetics. 

Accordingly, it appears that the maximally tolerated dose using an aggressive once-weekly dosing regime is 0.75mg/kg after encountering dose-limiting toxicities in the form of a case of transient thrombocytopenia and hypoxia/dyspnea each at 0.9mg/kg.  These data are in line with the clinical safety/tolerability data from other DlinDMA-based SNALP formulations (ALN-VSP02, ALN-TTR01) where the maximally tolerated dose was slightly higher, but which were dosed in in less aggressive schedules.  Although there seems to be a trade-off between dosing frequency and safety/tolerability, I would agree that for cancer applications where gene knockdown is targeted in rapidly dividing cells, more frequent dosing vs higher, but less frequent dosing may be desirable.  This is because the duration of gene knockdown is known to be largely inversely correlated with cell division frequency.   

Looking back at the overall DLinDMA results (ALN-VSP02, ALN-TTR01, TKM-PLK1), given the fairly uniform maximally tolerated doses, it is possible that lipid-specific toxicity can be as dose-limiting as siRNA sequence-specific immune stimulations.  It will therefore be interesting to see whether there will be a general shift in the maximally tolerated dose with SNALP formulations comprising different lipids.

While, as in many of these small, dose escalation trials, there were encouraging signs of therapeutic efficacy, here in the form of one partial response by RECIST and one stable disease, what excited me most about the released data was that this particular SNALP formulation achieved ‘several fold’ higher drug exposure levels than previous formulations (aka ALN-VSP02).  High/long exposure levels, of course, are thought to be critical for efficient drug delivery via the EPR effect.  The advance can be attributed to Tekmira’s rational SNALP design approach involving the use of a long-chain lipid-anchored PEG such that the cloak of invisibility is shed only after longer circulation times.  This is unlike in ALN-VSP02 (short chain anchor SNALP formulation) which exhibited short circulation times suitable for RNAi trigger delivery into various hepatic cell types.  Similar to ALN-VSP02 this time, further important pharmacokinetic data showed that the PK profile did not change upon repeat administration.  It is therefore unlikely that neutralizing antibodies are generated to the PEG component.  In certain old preclinical studies this had been shown to be an obstacle to repeat administration.

I look forward to learning about the more detailed clinical results.  In particular, I’d like to see not only the blood PK data, but possibly also the drug accumulations in tumor biopsies which could be compared to the ALN-VSP02 biopsy data.  By this, one would be able to model how exactly the higher blood exposure levels translate into tumor delivery benefits.  

Ebola Stop-Work Order

Earlier this month, Tekmira and competitor Sarepta received Stop-Work Orders from the US Department of Defense relating to their Ebola biodefense programs.  Tekmira has greatly benefitted from the DoD contract- not so much in terms of making a direct profit from the contract, but in that it also provided funding for progressing its technology platform.  A significant number of employees would have to be laid off if the final decision on whether to continue with the program, expected by September 1, were negative.  Although the impact on Tekmira’s science would not be immediate, it would definitely impact the speed of Tekmira’s technology advances if no substitute funding was found soon (see litigation section).  What is particularly frustrating about this Order is that it comes in the middle of an ongoing phase I clinical trial (at least wait for the results before making a final decision) and because budgetary uncertainties, not scientific deficiencies apparently being the reason for it.  Ironically, therehave been two recent outbreaks of Ebola in Africa highlighting that Ebola is not just a bioterrorist, but also persistent public health threat.

Tekmira Partners Celebrate Successes, Company Collects Milestones

The recent past were particularly exciting for Tekmira’s technology licensees Alnylam and Talon Therapeutics.  As discussed on this blog before, the ALN-TTR02 knockdown results, critically enabled by Tekmira’s delivery technology, were very positively received by the biotech community, including investors.  These results also paved the way for the initiation of a phase II trial of ALN-TTR02 triggering a $1M milestone to Tekmira.  As important as the milestone is to Tekmira on the eve of the jury trial, once the company has fully recovered possession of its technology, the liver knockdown results should allow the company to turn many of those companies on the sidelines into willing customers once there is a resolution to the litigation.

A somewhat unexpected $1M milestone came from Talon Therapeutics, a small biotech company that had licensed early Tekmira small molecule liposomal drug candidates.  The milestone was triggered by the FDA approval of one of the licensed product candidates, Marqibo (liposomal vincristine), for the treatment of advanced Ph- ALL.  In addition, the company is entitled to receive sales milestones.   

All Set for a Jury Trial

Despite all the important events above, the most important news regarding the financial viability of the company came when the judge made the important decision to reject the delay and cost-intensifying tactic (here: Motion for Summary Judgment) by Alnylam paving the way for a jury trial at the end of October.  As the case will be tried on all counts and, according to Alnylam’s regulatory disclosure, could cost the company in excess of $1 billion, you would think that Alnylam has no choice but to settle the matter (or buy Tekmira).  The longer Alnylam waits, the more dearly it is likely to cost them.

In that light, the next 2-3 months should be even more exciting for Tekmira shareholders and hard-working employees.

Tekmira and Arrowhead Advance Cancer RNAi Therapeutics

This week, important developments for two of the most advanced cancer RNAi Therapeutic candidates were announced. Arrowhead reported that it has now completed enrolment of the phase I CALAA-01 study and is initiating a dose-optimizing phase Ib study, while Tekmira disclosed that it has received the green light from the FDA to go ahead with an additional phase I study of TKM-PLK1, this time using Hepatic Arterial Infusion to complement an ongoing effort involving intravenous administration. This study will be conducted in collaboration with the National Cancer Institute (NCI).

CALAA-01: Optimizing dosing schedule

CALAA-01 is a targeted cyclodextrin-based nanoparticle formulation (RONDEL) of unmodified siRNA against RRM2, a gene involved in DNA synthesis (more background on CALAA-01 here). Enrolment in the phase I clinical trial commenced 3 years ago. Interim data were presented last year in a Nature paper and the ASCO annual meeting. At that time, about 15 patients with various forms of advanced solid cancers had been treated. Encouraging qualitative biopsy results showed that at least some of the RNAi Therapeutic reached its physical target and was able to mediate RNAi target cleavage there.

Until then, no dose-limiting toxicities had been seen. The ASCO presentation, however, revealed that there were fairly widespread, albeit low-grade (g1-2) immune stimulations (‘flu-like symptoms’). The reason why immune stimulation with this candidate was fairly common is likely related to the fact that unmodified siRNAs were used. Judging from Arrowhead’s quarterly conference call this week, it seems as if the immune stimulation warranted a discontinuation of further dose escalation. The company stated, and I certainly agree, that it should use modified siRNAs in the future to mitigate this side effect.

Interestingly, what the company apparently found in the study is that in some patients the immune stimulation subsided following repeat-administration of the drug, as if they became desensitized to the immunostimulatory potential. It is therefore the goal of the newly announced phase Ib study to find dosing regimes that take advantage of this preliminary finding to achieve higher doses, e.g. by first giving a lower dose in order to desensitize before continuing with the predicted higher, hopefully efficacious dose. If this hypothesis can be confirmed, it would not only be positive for CALAA-01, but a valuable insight for the entire field of RNAi Therapeutics.

Having said that, in light of the clinical findings so far and reservations about the chosen gene target, I do not find CALAA-01 to be a compelling candidate. While I can agree with the phase Ib study, it is more because it will allow the company to gather further information about the RONDEL delivery system without much further delay as it continues its efforts to partner and monetize the delivery technology.

Situations like these highlight the risk of RNAi Therapeutics platform companies like Arrowhead/Calando and Benitec that refuse to have in-house R&D. In this case, in-house R&D could have already readied a modified RRM2 siRNA formulation, or even a formulation targeting a more exciting cancer gene target, without too much additional effort. Instead, more needs to be invested in a candidate that is difficult to partner already and may never make it into phase II, leaving Arrowhead to hope that their argument that the CALAA-01 studies are a way of de-risking the RONDEL delivery platform will convince potential partners and investors.

In my opinion, virtual drug development may be possible for one-in-a-kind therapeutic candidates, but is not compatible with building a platform.

Tekmira and NCI to Begin Hepatic Arterial Infusion (HAI) Study of PLK-1

The clinical development of TKM-PLK1 began earlier this year with a phase I dose escalation study using intravenous administration. Similar to ALN-VSP02, TKM-PLK1 is a SNALP-based formulation, but should be more widely applicable because its pharmacology was tailored so that it can also reach tumor tissues outside the liver. What makes TKM-PLK1 particularly exciting is that its gene target is probably the most potent one in the cancer field, having emerged many times as a top hit in genome- and kinome-wide RNAi screens for rapidly killing cancer cells without affecting normal cells.

The new phase I study of TKM-PLK1 that was announced this week will not only allow the company to more quickly gather important pharmacologic information on the drug, but should also be a viable alternative route of administering TKM-PLK1 for treating primary liver cancer and cancers with liver involvement by using Hepatic Artery Infusion to expose tumors to very high concentrations of the drug which would otherwise not be possible by simple intravenous administration.

Black box less black

One challenge in the development of novel cancer therapeutics is that it can take a long time before their true potential becomes clear. Biomarkers are therefore highly sought after, with RECIST tumor response criteria being a popular way of determining anti-tumor efficacy. Unfortunately, merely measuring immediate tumor responses is not always predictive of therapeutic success as sometimes you see such responses, but without concomitant increases in life expectancies (e.g. Avastin in advanced breast cancer, and many chemotherapeutic settings), and sometimes you don’t see them, yet you do get increases in life expectancies, an issue particularly relevant for targeted therapeutics (e.g. Provenge in prostate cancer).

Access to tumor biopsies is therefore very valuable in determining at an early stage whether your drug functions as expected on a molecular level and what tissue concentrations you need to achieve to trigger these responses. It is therefore an attraction of the new study that it will allow for biopsy collection. Through this, Tekmira should further learn more about which tumors types may be most suitable (e.g. primary/metastatic, genotype, pH).

Aside from the scientific value of the study, this study has the added benefit in that it could help validate Tekmira's platform technology for cancer in a controlled and timely manner, at a time when Alnylam evaluates Tekmira’s technology mainly for knocking down genes in ‘normal’ liver. Clinical data from both these approaches are expected in coming months and should serve as catalysts.

A treatment in its own right

Liver tumors almost exclusively derive their blood supply from the arterial circulation, whereas 75% of the blood flow in normal liver comes from the portal vein. Because of SNALP pharmacokinetics, this means that directly infusing TKM-PLK1 should have the benefit of increasing the drug exposure of liver tumors while at the same time greatly reducing potentially dose limiting exposures of the normal liver(***see correction and clarification below), the predicted dose-limiting organ for SNALP technology. This therefore should make it possible to achieve higher maximally tolerated doses, an important goal in most cancer drug developments.

It is for this reason that Hepatic Artery Infusion (HAI) has become an accepted and frequently used drug delivery modality in the treatment of unresectable liver tumors. Therefore, should the results suggest therapeutic efficacy in this setting, it could well pave the way towards studying HAI of TKM-PLK1 directly in phase III studies.

****Correction and clarification: I have received justified criticism of my statement that HAI would ‘greatly reduce potentially dose limiting exposures of the normal liver’.

The criticism was based on the notion that the normal liver in patients with liver tumors would still go on and be supplied by blood from the hepatic artery in addition to the blood supplied by the portal vein. Consequently, a good chunk of what you provide by HAI would also end up in the normal liver parenchyma. On the other hand, the critique was based on the assumption that the liver tumors would not compete for blood from the hepatic artery. My take on that is that this is probably a good assumption especially for smaller tumors, but in cases where liver tumors make up the bulk of the total liver mass, at least based on high-school physics (pressure and diameter of a tube determining the flow of liquids), there should be at least some quantitative shunting of hepatic arterial blood away from the normal liver.

Moreover, the criticism raised another factor determining whether direct HAI of SNALP will enhance SNALP uptake by cancer cells relative to intravenous infusion, namely whether the SNALP particles get taken up efficiently during the first pass of SNALP through the liver tumor. SNALP uptake is determined by various factors such as time, ionization behavior, active targeting, LDL-receptor status, so that’s probably a more complicated discussion.

Overall, the point is well taken, and while SNALP administration by HAI should have a positive effect on the ratio of drug concentration in Tumor relative to Normal Liver and therefore should increase the therapeutic index, I will have to partially retract my statement in that this is mainly due to optimized exposure of liver tumors during first pass and may vary significantly from tumor to tumor, and that another reason for choosing the hepatic artery vs portal vein may be just the relative surgical ease of accessing these structures.