First RNAi Therapeutic Nearing Finish Line

ALN-TTR02 for the treatment of TTR amyloidosis is the most advanced RNAi Therapeutic in clinical development and has been carrying the torch for the field as whole. Expectations are therefore high and a stumble in this program as a result of the therapeutic hypothesis underlying the program not panning out would likely trigger a temporary*, but steep sector-wide sell-off.  

* it should be clear, however, that with the current ability to robustly knock down genes in the liver, RNAi Therapeutics will result in a number of successful treatments.

It therefore came as a relief yesterday when Alnylam presented (press release here, data slides here) 12-month data from an open-label extension phase II study of ALN-TTR02 in the polyneuropathy form of the disease (FAP) showing

a)      continued robust gene knockdowns for more than a year (88-80% reductions peak/trough in 3-week cycle);

b)      disease stabilization (if not improvement) when the Natural History of the disease would have predicted marked deterioration (predicted mNIS+7 at 12 months of +18 in Natural History vs ~-2.5 on ALN-TTR02).

Furthermore, the safety of this liposomal formulation enabled by Tekmira seemed more than sufficient for a disease as severe as FAP TTR amyloidosis (5-15 year survival following diagnosis) with the most significant adverse events being related to the intravenous route of administration meaning that ALN-TTR02 should be given under trained medical surveillance.

There are some questions that remain open, some of which should be answered by the ongoing phase III APOLLO study which should complete sometime in 2016 (with an 18 month primary endpoint).

Firstly, it will be important to show disease stabilization to be strictly related to ALN-TTR02.  In the phase II study, most patients (20 of 27) were on tetramer stabilizers which have previously shown to result in very modest (tafamidis) to moderate (diflusinal) therapeutic benefits.  While neither tafamidis nor diflusinal have shown disease stabilization after 12 months, the concern remains that they could have contributed to the apparent therapeutic benefit seen in the phase II study.

To my surprise, the 7 patients not taking tetramer stabilizers on top of ALN-TTR02 seemed to do even better, at least numerically than those taking them (-6.5+/-9.2 vs -1.1+/2.5).  Although the number was quite small, the fact that this is the opposite result from what one might have expected, it is possible that a slight placebo effect may have played a role in this open-label study: those for which ALN-TTR02 was the only medical intervention might have had a greater ALN-TTR02-driven placebo effect.

Other more complicated explanations based on TTR lowering affecting the PK/PD relationship of tetramer stabilizers are also possible if this phenomenon is for real.

Fortunately, the blinded phase III APOLLO study will compare ALN-TTR02 to patients taking no tetramer stabilizers to treat their FAP.  Finally, it would be of interest to look at the effect of ALN-TTR02 on the spleen in the APOLLO study as spleen toxicity due to lipid stability might be the most important safety parameter with chronic dosing.    

In summary, yesterday’s 12-month data removed important overhangs over the RNAi sector and we are on track for the first commercial RNAi drug in 2017. Seeing is believing.

Extended Use of SNALP Delivery Technology Well Tolerated

On Monday, Alnylam revealed an update on their lead ALN-TTR02 drug candidate for the treatment of the FAP form of TTR amyloidosis. Given that this could be the first commercially meaningful RNAi Therapeutics to hit the market, a lot of attention is being paid to its progress in the clinic.  Success and failure of this program are expected to have widespread repercussions for the RNAi, if not Oligonucleotide Therapeutics field.

Importantly, the data from the phase II open-label extension study provided strong evidence that the underlying SNALP LNP delivery technology, licensed from Tekmira Pharmaceuticals, is safe and well tolerated with 19 of the 27 patients involved having now received ALN-TTR02 once every 3 weeks for at least 6 months.  After 282 doses administered, no drug-related serious adverse events were seen with infusion-related issues as expected the main source of adverse events.  Notwithstanding the 8 mild flushing events and infusion reactions, there have been no drop-outs in the study so far.

On the efficacy side, ALN-TTR02 continued to produce robust sustained 80-90% knockdowns with a trend towards increased knockdown efficacy with prolonged dosing.  This knockdown certainly puts ALN-TTR02 ahead of the competitor antisense drug from ISIS and GSK (ISIS-TTRRx) which is expected to be in the 70% range, but is probably ahead in terms of patient enrolment in their pivotal study.

The results presented at the ANA conference had been widely anticipated because it was the first time that Alnylam revealed measures of therapeutic efficacy beyond the gene knockdown.  Accordingly, at the 6-month time-point patients treated with ALN-TTR02 exhibited less neurological declines as would have been expected from the Natural History of the disease.  Unfortunately, in the absence of hard biomarker evidence indicating improved neurological and, for a subset of patients, cardiac functions, the apparent improvement in the well-being of the patients (mNIS+7) could easily be attributed to the open-label nature and the relatively early time-point of the study.

Therefore, despite of the fact that shares in Alnylam increased 20% on the results and the provider of the delivery technology, Tekmira, barely budged on the news, the most important take-home from the results was that SNALP LNP delivery technology and indeed extended robust RNAi has a remarkably good safety profile.

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.

Big De-Risking of ALN-TTR02 and SNALP Delivery Platform

Today, Alnylam reported (PR here, presentation here) first data from its phase II open-label extension study of ALN-TTR02.  ALN-TTR02 is developed for the treatment of TTR amyloidosis (FAP form) and with a phase III study underway is the industry’s lead blockbuster candidate.  There is no doubt that its results will have a big impact on the perception of the technology.   Importantly, the new data revealed at the International Symposium on Amyloidosis show that ALN-TT02 not only maintains consistent knockdown potency following multiple (>2) administrations, but even more importantly, indicate that the biggest risk, long-term safety, will not be a problem.    

Phase II promising, but with efficacy and safety questions

The new data follow on from a 2-dose phase II study (somewhat euphemistically labeled 'repeat administration) showing that ALN-TTR02 can achieve ~80% TTR knockdown levels not only following a first dose, but also following a second dose.  This was good to see because there was theoretical concern that SNALP LNPs could provoke generation of neutralizing antibodies to the PEG component which might compromise efficacy following repeat dosing.  Indeed, TTR levels seemed to return back to normal more quickly following the second compared to the first dose and was responsible for Alnylam switching from a 3-week to a 4-week dosing interval.

On the safety side, infusion-related hypersensitivity reactions are the major concern with SNALP LNP as with most other infused therapeutics, nucleic acids, protein, or small molecules alike.  While the steroid pre-treatment may have ensured that no major immune reaction was seen in the phase II study, infusion reactions had been recorded in 3 of 20 infusions at the key 0.3mg/kg dose.  Intriguingly, when a micro-dosing pre-treatment strategy was employed (increasing the length of infusion from 60 to 70 minutes) no such reactions were seen in the 18 infusions thus administered.  This is probably related to the fact that infusion reactions in general are essentially restricted to the first dose and are dose-related.

Phase II open-label extension data provide highly positive answers

In thinking about a headline for today’s blog entry ‘spectacular’ was on my mind a lot.  However, I refrained from using this term as the scientific results show very comforting consistency. 'Spectacular consistency' may be too oxymoronic.   In stock market terms, however, this consistency may very well be called ‘spectacular’ both for the much increased likelihood that ALN-TTR02 will make it across the finish line and for the safety demonstration of Tekmira’s SNALP delivery platform in general for which the major concern has always been safety, not efficacy.

Importantly, the results revealed today show that the ~80% knockdown potency is maintained following an aggregate of 119 doses of 0.3mg/kg ALN-TTR02 compared to an aggregate 38 doses before.  In the patient who has been on therapy the longest, this was the case following 9 doses over half a year.  The integrated knockdown level over time may have indeed been slightly higher than 80% since TTR levels were measured at their nadir, just before the next dose.  One can therefore conclude that the enhanced recovery from gene knockdown following the second dose did not intensify over time and that sustained and consistent knockdowns can be achieved over the long-term.

Regarding safety, just 3 instances of mild-moderate adverse events were reported in the extension phase that were deemed possibly treatment-related.  Probably only the 2 instances infusion reactions in a single subject call for attention.  Even so, none of them were deemed severe enough that the infusion rate had to be slowed as it is normally done.  The other mild-to-moderate AEs were an ‘increase of diarrhea’ and an 'impairment of taste'.  Maybe not all that bad in a disease like FAP.

Further indicative of the tolerability of ALN-TTR02, Alnylam projects 27 out of the initial 30 patients to participate in the open-label extension study.  First functional results from this OLE are expected to be reported by the end of 2014.

Disclosure: I could not resist but buy back some TKMR today based on the recognition that today’s data represent a great de-risking of the SNALP LNP delivery platform the company depends on.

Alnylam Solidifies Lead in TTR Amyloidosis Race

Over the weekend, Alnylam announced expanded data from the phase II study of ALN-TTR02 (aka PATISIRAN) in the FAP form of TTR amyloidosis at the ISFAP meeting being held in Brazil.  The data confirm the consistent knockdown potency of ALN-TTR02 and, most interestingly, suggest that a new dosing regimen can address the most rate-limiting safety issue encountered so far. 

Compared to the 19-patient dataset revealed at the Peripheral Nerve Society meeting at the end of June, the latest update includes data from 9 more FAP patients that received the highest dose (0.3mg/kg) in the once-every-3-week treatment regimen.  Previously only 3 patients received such dosing whereas the data from the 6 patients with the once-every-4-week dosing indicated an undesirable TTR rebound effect towards the end of the 28-day treatment cycle.

Data from the 12-patient once-every-3-week cohort now show that a ~80% persistent knockdown of TTR can be achieved although there still seemed to be a minor rebound effect at the end of the 21-day treatment cycle (down to ~75% knockdown).  It therefore needs to be watched whether the apparent rebound effect worsens or maybe gets better with dosing for more than the two infusions as performed in this study (open-label extension study ongoing).   

The most exciting revelation, however, from the new data was that there were no apparent infusion reactions in the 9 additional subjects.   Previously, 3 out of 7 in the once-every-4-week cohort of 0.3mg/kg experienced such reactions.  Infusion reactions thus far tends to rank as the rate-limiting safety issue in the development of SNALP-related RNAi Therapeutics and although they appear to be readily managed by slowing the rate of infusion, are dose-related, and generally occur only during the first infusion, it would put everybody at ease if there were no such risk.

Rather than being the result of a streak of luck, the absence of infusion reactions coincided with the institution of a 70-minute microdosing strategy which Alnylam labeled as ‘proprietary’.  If it holds up, it would definitely be good news for Alnylam and FAP patients.  Beyond that, Tekmira may actually be the major beneficiary of such progress as its pipeline rests on i.v.-administered SNALP RNAi Therapeutics such as ALN-TTR02.


By initiating a phase III study of Patirisan and further announcing fast-track designation for this product candidate, the company remains on track for an approval in 2016/7.  Data from the competing RNaseH antisense compound by ISIS and GSK at the same meeting remains to be publicized.

Alnylam Indicates that 80% Subcutaneous TTR Knockdown Achievable with Magic 2.5mg/kg Dose

This morning, Alnylam announced a milestone in the development of subcutaneously administered, systemically acting RNAi Therapeutics.  A ‘more than 80%’ knockdown was achieved in a phase I trial of ALN-TTRsc, the GalNAc-siRNA conjugate for the treatment of TTR amyloidosis.  It is the first time that a meaningful knockdown in Man was reported using the subcutaneous route of administration.

The key question as to the clinical attractiveness of the liver-specific GalNAc delivery platform versus intravenous alternatives such as SNALP (compare to just reported ALN-TTR02 clinical results) relates to injection volume and frequency of administration.  The hurdle to overcome here would seem a once weekly regimen with dosages of 2.5mg/kg or less.  2.5mg/kg is widely considered to be a threshold as this amount of drug can be accommodated in a 1ml syringe.  Higher injection volumes would likely be quite painful and possibly increase the risk of injection site reactions.  Higher dosing frequencies in order to stay within the 2.5mg/kg limitations would reduce the convenience factor.

Unfortunately, these data points were left undisclosed in today’s announcement.  Instead, we were given a riddle.  The company first stated that the results were in-line with observations in non-human primates.  At another point, they say that 80% knockdown with ALN-TTRsc were achieved in non-human primates with the magic 2.5mg/kg dose.  Logically, Alnylam stated that in humans 80%’ knockdowns were seen with the 2.5mg/kg dose. 

Curiously, the company also stated that dose escalation was continuing.  It makes, of course, sense to push the degree of knockdown.  The difference between an 70% knockdown (e.g. ISIS-TTRRx), an 80% knockdown (current ALN-TTRsc results), and 90% knockdowns (e.g. ALN-TTR02) is that compared to a 90% knockdown, the amount of remaining insulting protein (here: mutated TTR) is twice (80%) and 3x (70%) as high which could result in dramatic differences in the clinical outcome, or even whether a knockdown approach would even work for a disease like TTR amyloidosis.

Maybe we will get more clarity on dose and dose frequency at today’s R&D day.  If not, more detailed results are to be presented at the Annual Scientific Meeting of the Heart Failure Society of America (HFSA), September 22-25.

Alnylam Moves to Increased Dosing Frequency as Knockdown Duration Shortens

The ALN-TTR02 phase II results have finally been announced.  The results are consistent with the view that ALN-TTR02 is a strong candidate for becoming RNAi’s first marketed drug.  Having said that, the knockdown efficacy results came short of what one could have expected based on the phase I and non-human primate results and explain why the company has amended the protocol to test increased dosing frequencies.

Non-human primate studies show cumulative dosing

Alnylam had long telegraphed the results for the phase II studies.  They stated that we should expect the clinical results to be essentially the same as what they are seeing with the drug in non-human primates.  I understand that non-human primates are an immensely insightful model system in RNAi Therapeutics development.  Still, making such strong suggestions just weeks before clinical data release seemed a bit odd in that it risked stealing its own thunder.

Anyhow, the non-human primate studies showed the peak and the terminal knockdown (terminal knockdown defined as the knockdown just before repeat dosing) increased with each additional dose administration.  Whereas the peak/terminal knockdown in cycle 1 was ~85%/47% at 0.3mg/kg, they were ~90%/58% in cycle 2 and so on.  This is what Alnylam refers to as with ‘cumulative’ efficacy.

Unfortunately, this was only partially repeated in humans.

Knockdown not as sustained with repeat dosing

The ALN-TTR02 phase II study represented the first opportunity to rigorously test gene knockdown of a SNALP-delivered RNAi Therapeutic following repeat dosing.  Whereas the phase I study in healthy volunteers was a one-dose study, this phase II study was a 2-dose repeat-administration trial in European patients with TTR amyloidosis (FAP form).  In both studies, target gene knockdown could easily be determined by measuring TTR levels in the blood.

In my analysis of the data, I will stick with slide 10 of Alnylam’s slide set which seems to provide the clearest overview of the data.  At the critical 0.3mg/kg dose level, the peak knockdown either remained +/- the same (~80à80% for once-every-4-weeks) or showed evidence of cumulative activity (~80à88% for once-every-3-weeks) when comparing the first with the second dose administration.  While this looks quite good, albeit somewhat less than what was observed in the phase I study, slide 5), the downside surprise comes with the terminal knockdown values.  Here, the knockdown for cycle one (day 28; n=6) was around 75% with tight error bars, but dropped to 60% for cycle two (day 56; n=5) with much more considerable inter-patient variability.  The same was observed for the 0.15mg/kg dose level with ~53% and ~45% reductions after cycle one and two, respectively.

I have no idea where Alnylam is getting the 93% knockdown from that is so prominently mentioned in the press release.  Are they referring to a single patient that achieved such knockdown?    

Once-every-3-weeks to stay on top of competition

You can safely assume that reduced knockdown duration and the fact that the critical phosphorothioate antisense competitor by ISIS/GSK has a ~70% knockdown have driven Alnylam’s decision to amend the ongoing phase II study by including once-every-3-week regimens.

Data for the first such cohort was provided.  As noted above, once-every-3-weeks showed evidence of cumulative peak knockdown activity thus staying on top of the antisense competition.  It is a shame though that the data provided coincidentally ended on day 35, only a week before the important repeat terminal knockdown point.  It is thus not possible to tell whether diminished terminal knockdown is also an issue for the once-every-3-week regimen.

Safety findings largely related to route of administration  

Safety findings were only reported at the 0.3mg/kg level (4 events in 9 patients).  The infusion-related reaction and the 'nuisance' side effect of fever/chills are known for SNALP delivery, but do not appear to be prohibitive.   Unfortunately, there was a serious adverse event due to a misplacing of the infusion needle.  New to me is the finding of polyuria (peeing a lot). 

Based on this profile, Alnylam will try to lower the amount of immune suppression given with the drug.  Immune suppression is given as a precaution to avoid hypersensitivity reactions seen with SNALP-enabled TKM-ApoB.  It seems to me that in introducing the once-every-3-week regimen, Alnylam wants to dial up the product profile by lessening the burden of the immune suppression.

The future of ALN-TTR02

Given the high unmet medical need for FAP patients, ALN-TTR02 should remain on track of making it to the market provided reduced TTR levels indeed translate into a clinical benefit (a low risk at 80% knockdowns).  Some additional warts, however, have been added to the product profile and my main interest as to the future data will be how efficacy and safety is maintained not after just two, but after 3, 4, 5 doses and so on.  

It would also be good to find an explanation for the diminished knockdown duration (e.g. some neutralizing antibodies or a peculiarity of TTR gene regulation?).  Tekmira, the delivery partner which should receive a $5M milestone on the initiation of ALN-TTR02 phase III studies at the end of this year, would be an important ally in answering this question.  This could therefore be an important test of whether the two companies can put aside past differences.

  

The ALN-TTR02 Phase II Results...Abstract Today, Presentation Tomorrow

The abstracts for the Peripheral Nerve Society Meeting in France have been published.  The abstract on ALN-TTR02 does not reveal the results, but I post them anyway as a warm-up for tomorrow.  You can notice though that there is a relative shift towards the once-every-3-week regimen and the dose escalation started at the same point as the phase I study did (0.01mg/kg).  Check back for more tomorrow.

INTERIM RESULTS FROM PHASE II TRIAL OF ALN-TTR02, A NOVEL RNAi THERAPEUTIC FOR THE TREATMENT OF FAMILIAL AMYLOIDOTIC POLYNEUROPATHY

Adams D1, Coelho T 2, Suhr O3, Conceicao I4, Waddington-Cruz M5, Schmidt H 6, Campistol J7, Pouget J8, Buades J9, Falzone R10, Harrop J10, De Frutos R10, But- ler J10, Cehelsky J10, Nochur S10, Vaishnaw A10, Gollob J10. 1Centre Paris-Sud, APHP, Hopital de Bicetre, INSERM U788, Service de Neurologie, and Centre de Reference des Neuropathies Amyloides Familiales Le Kremlin-Bicetre, France; 2Unidade Clinica de Paramiloidose, Hospital de Santo Antonio, Porto, Portugal; 3Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden; 4Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Lisbon, Por- tugal; 5Hospital Universitario Clementino Fraga Filho, Rio de Janeiro,Brazil; 6TheUniversityHospitalofM¨unster,M¨unster, Germany; 7Hospital Clinic, Barcelona, Spain; 8Centre de Ref- erencedesMaladiesNaueromusculairesetdelaSLA,Hopital de la Timone, Marseille, France; 9Hospital Son Llatzer, Palma de Mallorca, Spain; 10) Alnylam Pharmaceuticals, Cambridge, MA, USA.

Familial amyloidotic polyneuropathy (FAP) is a fatal, autosomal dominant, multi-system disease caused by abnormal tissue deposition of mutant and wild-type transthyretin (TTR). Almost all circulating TTR is synthesized by hepatocytes, and in FAP this liver-derived TTR is responsible for amyloid accumulation in the main target organs, including peripheral nerves, gastrointestinal tract and heart. Treatment approaches have focused on reduction of amyloidogenic TTR monomer either through elimination of hepatic production of mutant TTR (liver transplantation) or stabilization of the TTR tetramer (tafamidis). While both of these approaches have been shown to slow neuropathy progression in a limited subset of FAP patients with the V30M mutation and early disease, there remains a significant unmet need for new therapies that can impact FAP patients with different TTR mutations across a broader range of disease severity. ALN-TTR02 is a systemically administered lipid nanoparticle (LNP) formulation of a small interfering RNA (siRNA) targeting wild-type and all mutant forms of TTR. This formulation predominantly delivers the siRNA to the liver, thereby inhibiting synthesis of TTR at the primary site of production. In non-human primates, repetitive dosing with ALN-TTR02 every 3–4 weeks at doses up to 0.3 mg/kg resulted in an average relative TTR suppression of up to 90% with no tachyphylaxis of the pharmacodynamic effect. In a randomized, placebo-controlled, Phase I dose-escalation trial in healthy volunteers, a single intravenous infusion of ALN-TTR02 administered over 60 minutes was shown to be safe and well-tolerated, and potently suppressed serum TTR levels by 82-94% at doses of 0.15–0.5 mg/kg. TTR reduction of up to 67% was observed out to 28 days post- dose, suggesting that sustained TTR knockdown could be achieved with a monthly dosing schedule. Based on these promising results, a multi-national Phase II trial of ALN-TTR02 in FAP patients was initiated in mid-2012 to evaluate the safety/tolerability and pharmacodynamic effect of multiple doses of ALN-TTR02. Patients receive two doses of ALN- TTR02 administered every 3–4 weeks at dose levels ranging from 0.01 to 0.3 mg/kg, with a total anticipated enrollment of approximately 27 patients. In this presentation, we will provide an update on the results of this ongoing clinical trial.

ALN-TTR02 Phase II Results Preview

Although the phase I results for ALN-TTR01 in late 2011 and ALN-PCS02 in first half of 2012 should have caught the attention of the diligent biotechnology investor, it was the highly potent knockdown (>90%) reported for ALN-TTR02 in July of last year that put the spotlight back on RNAi Therapeutics. The results for the TTR amyloidosis drug candidate not only benefited Alnylam, they were a blessing to the entire field of RNAi Therapeutics allowing it to raise ~$300M over the ensuing 12 months.  It is therefore an understatement that the phase II results for ALN-TTR02 to be disclosed in about two weeks will be closely watched across the industry and investors.

Possibly hoping to relieve some of the tension around the event, Alnylam has long telegraphed what we should expect the results from this open-label study to be: just look at the multi-dose non-human primate data and this is what you will see repeated in humans.  Nevertheless, I doubt that the generalists are buying the argument that non-human primates studies are highly predictive of clinical results, at least in terms of gene knockdown.   Just witness the valuations of other RNAi Therapeutics companies that have reported impressive non-human primate data (one could call that a buying opportunity).

Study primarily designed for safety…

The phase II study for ALN-TTR02 is primarily one of safety for repeat administration of ALN-TTR02.  The initial two-dose study design seems an overly cautious approach given that products enabled by Tekmira’s SNALP delivery technology have already been dosed for several months in patients with cancer.  This could be due to differences in how the different divisions within the FDA view the safety of SNALP and/or RNAi product candidates. 

With regard to hypersensitivity reactions, which are probably the most critical hurdle ALN-TTR02 needs to overcome, multi-dosing should actually the lower the incidence of infusion reactions (desensitization) which were the major safety issue in the phase I single-dose study.  With regard to spleen toxicity, multi-dosing is predicted to increase risk (cumulative).

Overall, given the dose (study geared towards the 0.3mg/kg dose) and history of ALN-TTR02, I am quite optimistic that no nasty surprises will emerge on the safety front.  This would also be consistent with plans by Alnylam to reduce the use of immune suppressants in the extension phase of the study.

…but efficacy could drive volatility

Although we have already been told what the efficacy results should look like and that Alnylam is aiming for an 80% knockdown, I expect analysts to pay close attention to efficacy given that Alnylam is in an arms race with ISIS/GSK.  As a reminder, in the 300mg/week regimen that has been chosen for the ongoing phase II/III study, a ~70% knockdown was reported with the ISIS/GSK antisense compound.  However, while a phosphorothioate antisense compound for liver-targeted gene knockdown given weekly has a sustained knockdown effect over time, there are wider fluctuations between peak and trough knockdowns for a SNALP-delivered RNAi Therapeutics administered only once a month.  In other words, watch the time-course of the knockdown, especially after Alnylam announced that it is considering a once-every-3-weeks regimen for the extension phase of the study.

Wall Street ascribes most of Alnylam’s value to TTR amyloidosis program

The reason, of course, why the TTR amyloidosis data is expected to cause major volatility is because two thirds if not more of Alnylam’s market value is based on a discounted cashflow analysis for ALN-TTR02 and ALN-TTRsc in the polyneuropathy and cardiomyopathy markets, respectively.  It is estimated that with premium orphan pricing (you will be surprised how precisely Alnylam’s pharmacoeconomic models will arrive at a fair price of $300,000 per patient year), peak sales revenues for Alnylam’s TTR products will be somewhere between $1.3-$2.0 billion.

I am optimistic that the TTR product candidates will make it to market and dominate over any phosphorothioate-based antisense competitor.  However, there remain important uncertainties as it relates to pricing and reimbursement, especially in some of the European markets where many of the FAP patients reside.  Furthermore, there is always an element of chance when it comes to avoiding prohibitive toxicities from sequence-specific off-targeting in a chronic treatment setting.

Over time, however, it does look like the rest of Alnylam’s pipeline is finally gathering steam.  With the porphyria and AAT deficiency candidates ALN-AS1 and ALN-AAT, respectively, and the intriguing complement inhibitor program, additional differentiated, high-value orphan opportunities are emerging.  It remains to be seen, however, whether the GalNAc-siRNAs are potent enough to exploit the potential of RNAi Therapeutics for these diseases or whether other delivery technologies enabling deeper knockdowns would have been appropriate.  This concern e.g. applies to the hemophilia program where my feeling is that only deep knockdowns will allow you to see clinically meaningful improvements in clotting times.  Unfortunately, I am still trying to find results from clotting assays (which are standard in the field) and not just the thrombin measurements that Alnylam is providing.

Trading the event

As Alnylam's share price has tripled since last year's announcement of phase I results and given that the two-dose design won't do that much for additional de-risking, I am speculating that only in a very bullish, confident biotech market that seizes on every news opportunity there is much upside from the phase II top-line results.  Because of the nervousness that has been creeping into the markets the last two weeks, I am taking a small bearish position ahead of the event, in a way hedged by much larger long positions in other RNAi Therapeutics companies (Arrowhead Research, Tekmira, RXi Pharmaceuticals) which are more attractively valued on a relative basis and should benefit from renewed RNAi Therapeutics investor interest as a result of the data release.

Last reminder that the GTC RNAi Therapeutics conference will start this week.  Don't forget to mention 'RNABLG13' for 20% discount on registration.

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.

Tekmira Regains Control over Leading Delivery Technology

When Tekmira filed its lawsuit against Alnylam in March 2011, it found itself in an impossible position: Alnylam’s apparent mis-use of SNALP-related trade secrets not only diminished their strategic value to Tekmira, including depriving it of potential pharmaceutical partnerships, Tekmira may even not have been able to use the technology it invented.  As a result, it might have been left to die in a little cage with ‘1^st generation’ technology as its technology was making rapid progress.    

Cash and Control

Based on the disclosed terms of last night’s settlement with Alnylam (Tekmira's version here, Alnylam's version here), Tekmira got essentially all that it needed: control over its leading systemic RNAi Therapeutics delivery technology, including the contested MC3 lipids of which the IP was assigned to Tekmira, and a $65-75M payment (~$16-18M of which will go to pay outstanding legal fees).  The payment, of course, will finally allow the otherwise financially conservative company to push forward their development pipeline with interesting therapeutic candidates such as TKM-PLK1.  Notably, as part of the settlement, Tekmira obtained full ownership over this candidate which I believe addresses one of the most exciting RNAi targets in oncology. According to the Q3 financial results, also released today, TKM-PLK1 has been making good progress, including showing signs of drug activity and will advance into phase II studies next year.

Beyond the cash, the new IP licensing arrangement between the companies is at least as valuable.  Importantly, Tekmira has regained exclusive sub-licensing rights to ‘LNP intellectual property’, an incredibly important part of the settlement as before that Alnylam enjoyed such control, mainly via its rights to the Semple-Wheeler IP covering important aspects of ionizable SNALP technology.  This should open the door for Tekmira to enter into the long-expected pharmaceutical partnerships. Novartis and Takeda are here the most obvious near-term candidates for platform-type relationships.

Assuming that the new relationship is not restricted to RNAi Therapeutics, an added bonus is that the settlement could similarly pave the way for relationships in the microRNA Therapeutics space, particularly for the delivery of microRNA mimics.  Only recently, privately-held Mirna Therapeutics made headlines by raising $34.5M to fund the development of a microRNA mimic into the clinic, indicating the significant interest in this area of drug development.

Value of the Trade Secrets

Less clear is the damage to the trade secrets that were at the center of the dispute and on which much of Tekmira’s strategic advantage rested.  Numerous groups and companies have attempted home-brew liposomal RNAi trigger delivery, but only Tekmira’s technology has made it into the clinic.  Especially the ability to formulate and manufacture the particles is what set Tekmira apart from the competition.  In their press release, however, Alnylam stated their intention to use its own LNP manufacturing capabilities.  Apparently, it has already established such GMP manufacturing capability over the last year (in a separate building apparently for added suspense).  Assuming that Tekmira did not assist them in establishing such manufacturing, this indicates that the number of people with critical knowledge to the trade secrets has grown.  This can be particularly a problem in the wake of lay-offs in a place like biotech world capital Cambridge, Mass. 

Still, I assume there to be significant hurdles for other companies to replicate Tekmira’s processes, and with its liposomal experts, Tekmira should continue to lead in advancing SNALP delivery, making it the liposomal delivery partner of choice.

With cash of around $50M (excluding the $10M which are contingent on likely 2013 development milestones for ALN-VSP02 and ALN-TTR02), partnerships likely to come in due to the clarified IP situation, the $141M DoD Ebola biodefense contract (a new more potent and safer formulation will be used) and the income stream from Talon Therapeutics, Tekmira has thus emerged as the vibrant RNAi Therapeutics company it should have become 3 years ago.  Nevertheless, today's terms underline the value of Tekmira and RNAi delivery in general.  Exciting times ahead.

Genzyme Taps RNAi Therapeutics for TTR Amyloidosis

Orphan disease gold miner Genzyme has just partnered Alnylam’s promising TTR amyloidosis drug candidate, giving it the right to commercialize resulting medicines in Japan and ‘other Asia-Pacific countries’.  In addition to a healthy $22.5M upfront, Alnylam stands to receive the customary development milestones and actually high royalties for a post-phase I program, plus Genzyme bears responsibility for the regulatory process in the licensed territories.

The basis for this deal, as also expressly stated in the press release, were the potent, ~90% knockdown efficacies obtained in the (single) dose-ranging ALN-TTR02 phase I study (for review, see 'Simply SNALP').  Critically, it was Tekmira’s SNALP delivery technology that made these results possible and catapulted Alnylam’s market cap by ~300M (50% increase in share price) at the time the phase I results were announced this summer.  I should add, however, that in addition to ALN-TTR02, the preclinical subcutaneously administered candidate ALN-TTRsc has been included in the deal. 

Clearly, if they are really serious about the competitiveness of the subcutaneously administered GalNAc-siRNA conjugate, Genzyme has got to be hoping that there won’t be a repeat of the mipomersen (antisense) injection site reaction fiasco which, in addition to the liver fat and immune stimulation issues, is endangering the approval for mipomersen even in the very high unmet medical need population of homozygous familial hypercholesterolemia.  In this case, the adverse event that could drastically lower the deal value soon after its close comes in the form of the Tekmira litigation risk (note: Genzyme is ISIS' partner on mipomersen and should know, also about the strength of the competing subQ ISIS-TTRRx program which is partnered with GSK).  

In case you are wondering what I am alluding to: less than a month after Genzyme invested more than $300M in ISIS and their hypercholesterolemia candidate mipomersen, the FDA issued a Partial Clinical Hold due to significant safety signals with the systemic phosphorothioate oligonucleotide, according to last week’s Briefing Documents for the mipomersen Advisory Committee meeting.   The risk in the TTR case, of course, is the pending litigation with Tekmira, involving the critical RNAi delivery technology enabling the ALN-TTR02 results, its manufacturing and other (e.g. 2’-O-methyl) IP associated with the TTR amyloidosis program.  You would expect that Genzyme would have at least waited for another month or so before closing the deal (trial date in November).  

I doubt that the deal value would have been much higher without the overhang given the size of the Asian TTR market.  But then, of course, nothing can surprise me here any more and a resolution to the Alnylam-Tekmira troubles may already have been hammered out.  A clue may be how Tekmira responds to the news.  If there is tonight a we-are-pleased-that-Genzyme-has-partnered-ALN-TTR02-for-which-we-provide-the-delivery-technology-PR, then it's probably nothing to get excited about.  But if there is silence, then maybe the real news may come with a slight delay.  

Talking of Tekmira, this company, as it is customary in biotech sub-licensing, is likely to receive a partial payment out of the $22.5M upfront (plus a cut of the future income stream related to ALN-TTR02).  Another partnership implication is that Alnylam has talked to Takeda, and Takeda declined on ALN-TTR.  As you remember, in 2008 Takeda forked over $150M to Alnylam, also for being the exclusive Asian partner for 5 years with a right of first refusal for Alnylam drug candidates in the Asian territories.   You’ve got to wonder how comfortable that conversation was, especially after handing over some of that for the ‘technology transfer’.  There might be even less room to hide from Genzyme, as I believe Genzyme and Alnylam may be sharing one building now.

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.

Simply SNALP: RNAi TTR Knockdown Data Impress

Clearly, RNAi Therapeutics is back in fashion.  Well, almost.

Alnylam’s announcement of profound gene knockdown in the ALN-TTR02 phase I study for the treatment of TTR amyloidosis was greeted with an over 50% jump in the stock price on very high volume.  Various observers pointed out that this might have been an over-reaction given the early nature of the data.  On the other hand, considering that the over 80% peak knockdowns achieved with only a single dose of 0.15mg/kg are representative of a widely applicable delivery strategy, namely Tekmira’s SNALP technology, and considering that an accelerated approval path  should be possible for this orphan disease, determining the fair value of a SNALP-based company like Alnylam becomes difficult.

Yes, this was a study that enrolled just 17 subjects, healthy volunteers at that.  But it may be this that makes the tight variability in the pharmacodynamic response (=TTR knockdown) even more remarkable so: less than 5% relative standard deviations in the 0.15mg/kg and 0.30 mg/kg 3-person dose cohorts, the relevant groups for this analysis.  

When I had mentally listed the technical risks of SNALP-mediated delivery several years ago when I did my fundamental research on SNALP delivery, intersubject knockdown variability was one of the major ones.  However, given the present results and those from the recent hypercholesterolemia study (ALN-PCS02), I am much less concerned about this now, also in patient groups where liver health may be affected.

Moreover, the dose-related TTR knockdown in humans was essentially what has been seen in non-human primates.  Although a number of analysts were apparently puzzled by the importance of this observation, its value to a scientist is obvious: you can essentially eliminate the risk that an SNALP program fails in phase I due to lack of knockdown efficacy (and if you are one of those scientists that also dabble in the stock markets, you can start investing in the stock based on the monkey data that you’ll see presented at an informal presentation).   

The safety profile with ALN-TTR02 in this study was good.  There was one infusion reaction seen in other SNALP studies before and that was managed by slowing the infusion rate.  This was said to be possibly related to the pre-treatment with corticosteroids, and not the liposomal formulation itself.  In any case, while corticosteroids and other transient immune suppressions will not be an issue for the initial patient populations in diseases like TTR amyloidosis, Tekmira and Alnylam should start to try and wean themselves of it.  The improved, more predictive immune stimulation assays may form a sound scientific basis for this.

The reason for why the study was limited to 17 healthy volunteers was mostly due to competitive concerns.  In particular, the ISIS/GSK TTR antisense compound is said to skip phase II studies altogether and go straight into a pivotal phase III.  In data presented in May of 2011, this antisense compound was reported to effect a 44% mean TTR reduction at the 200mg/week dose level when given for four weeks, and 81% knockdown at 400mg which was the next higher dose tested.  400mg/week, however, is a dose that I believe is too high for chronic phosphorothioate oligonucleotide administration.  Although ALN-TTR02 should thus be 100- to 200-fold more potent on a weight basis than the antisense drug candidate, being the first-to-market is seen by some as an important factor for the commercial success in this orphan market, especially since these compounds work by the same mechanism of action.

The value of SNALP delivery

Some readers of this blog may be tiring by now of reading me sing the praises of SNALP delivery technology and Tekmira.  Yes, I’m invested in the technology via my Tekmira shares.  In all fairness, however, it is the clinical data from the SNALP compounds, really starting last November with the ALN-TTR01 data (SNALP Works!) that are reviving the RNAi Therapeutics field: ALN-VSP, ALN-PCS, and ALN-TTR.  We have heard a lot about exciting new, revolutionary RNAi delivery technologies, often claiming to solve the putative problems with  SNALP technology.  However, in the end, it is SNALP that is set to unlock the first wave of RNAi Therapeutics value creation.

Even Arrowhead Research and Benitec which develop competing delivery and RNAi trigger technologies, respectively, admitted so much in congratulating Alnylam to the results.  Sadly, they missed the opportunity to also congratulate the real innovator behind SNALP technology, Tekmira.  It seems that since Alnylam is getting all the media attention, it was probably not a good PR strategy to do so.

RNAi delivery technologies are tough to develop and rare to find, but when they work, they open up a range of therapeutic opportunities.   

Preview: For my next post, I am planning to write something about last week’s MC3 paper and how it reveals that covering all the tracks is hopeless when a scheme is that elaborate (RE Tekmira-Alnylam litigation), and why Alnylam the stock may be a great short here. 

Phase I Study of ALN-TTR01 in Transthyretin Amyloidosis- A Preview

(For a discussion of the phase I results, see here).

Alnylam is about to reveal results from its phase I study with ALN-TTR01 for the treatment of transthyretin amyloidosis (ATTR) at the Nov20-22 FAP meeting in Kunamoto, Japan. This blog provides a brief overview of the rational for RNAi Therapeutics in this disease and the importance of this particular study for the field of RNAi Therapeutics.

ATTR is an autosomal dominant amyloidotic disease due to point mutations (>100 possible) in the TTR gene. These mutations cause protein misfolding and aggregation into fibrils that, depending on which tissues they accumulate in, can cause various organ dysfunctions, most notably polyneuropathy (FAP), cardiomyopathy (FAC), and gastrointestinal/nutritional defects. For those that develop the disease, death is common 5-15 years following the emergence of disease symptoms (usually between 30 and 50 years of age). Although there is genotype-disease phenotype overlap, the most common mutation, Val30Met, strongly predisposes to FAP, while the Val122 is associated with FAC. About 10,000 patients suffer from FAP and 40,000 from FAC. As a rare genetic disease, it occurs in clusters, with FAP cases for example concentrated in Portugal, Sweden, and Japan.

Until recently, the only accepted treatment has been liver transplantation for FAP where removing the source of the mutant TTR in blood serum can reverse the polyneuropathy. Pfizer just got European approval for FAP with its small molecule TTR conformational stabilizer Vyndaqel based on slowing the rate of peripheral neuropathic impairment.

There exists, however, great need for additional therapies as Vyndaqel actually missed the primary endpoint in its pivotal study (the FDA did not accept the NDA for review earlier this year), and because liver transplantation is ineffective for FAC. The latter seems to be due to wildtype TTR still being able to deposit into pre-existing plaques, for example in heart tissue, at a rate that is higher than the turnover of the amyloidotic plaque. In fact, the amyloidotic potential of wildtype TTR is illustrated by the fact that it frequently causes spontaneous amyloidosis in elderly people (senile ATTR).

RNAi Therapeutics Approach to ATTR

The contribution of both wildtype and mutant to disease pathology, the dynamic turnover of plaques, and the fact that TTR knockout mice have the same life expectancy and fertility as their wildtype littermates and are otherwise essentially asymptomatic, makes RNAi Therapeutics a highly attractive treatment approach for this disease. TTR is involved in the transport of vitamin A and thyroxine in the blood, but it appears that in the absence of TTR these carrier functions are compensated for by other carrier proteins in the serum. What is more, essentially all the life-limiting pathologies are caused by TTR that is expressed in the liver, and with Tekmira’s SNALP delivery technology, RNAi can address the relevant gene expression.

TTR01 vs TTR02

One source of confusion that I expect to affect the financial markets tomorrow stems from Alnylam developing two candidates for ATTR, ALN-TTR01 and ALN-TTR02, the difference between the two candidates being in the SNALP lipid composition. TTR01 is the subject of the present trial and is based on an early DLinDMA lipid-containing formulation. It was shown to be effective in knocking down TTR in non-human primates with an ED50 of around 0.3-0.4mg/kg. As the highest dose in the phase I study was 1mg/kg it is reasonable to expect there to be evidence for TTR knockdown in the ALN-TTR01 trial. I should warn, however, that because of the small patient number in each dose cohort and the natural intra- and inter-patient variability of TTR levels in the serum, the pharmacodynamic outcome measure in this trial, the pooled numbers may not give us a straightforward 'stat-significant' answer.

Because of the rapid developments in improving the efficacy and tolerability of SNALP technology, it is therefore almost assured that Alnylam will drop TTR01 and prioritize TTR02 which takes advantage of these developments and for which the filing of an IND is imminent.

Consequently, the importance of tomorrow’s results for the RNAi Therapeutics field lies in providing proof-of-concept for RNAi knockdown following systemic delivery at OKish tolerability. That’s it. It also sets up the results from the phase I studies with ALN-PCS02, the PCSK9-targeting hypercholesterolemia candidate, which are expected to be reported by the end of this year. As PCS02 uses one of the more recent SNALP formulations, this will be the SNALP candidate that has to shine both in terms of knockdown efficacy and safety/tolerability.

ATTR Economics

If you had any doubts as to the commercial potential of ATTR, it is worth noting that Vyndaqel, Pfizer's just-approved TTR drug, is expected to be priced at more than 100,000 Euros per patient year and that most (known) FAP patients are in healthcare systems that will still bear such costs. Pfizer last year paid $200M in upfront considerations for FoldRx, the original developer of Vyndaqel, with another $200M in contingent milestones. Although FoldRx has a mission of developing other protein folding-based drugs, this price tag was essentially for a drug with results from a pivotal trial that failed to meet the primary endpoint and for which approval was far from certain. Considering Alnylam’s cash position, this one registrational drug candidate valued FoldRx higher than all of Alnylam- although you might justify that with the mounting existential risks stemming from Alnylam's alleged theft and misuse of Tekmira's SNALP technology.

Given these economics, it is not surprising that other companies have similarly recognized the commercial potential of ATTR. Importantly, ISIS Pharmaceuticals will also present progress with its antisense candidate for ATTR (ISIS-TTRRx) at the meeting. This candidate entered clinical development in May and is financed by GSK which retains an option for its exclusive license.

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