Monday, November 11, 2013

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.

9 comments:

jetmanbash said...

I don't believe you are giving an accurate report in regards to what has really transpired and what is to be looked for in the future. The IV formulation with the ALNY TTR-amyloidosis medication has several caveats IMO. The rebound effect is one, but only minor. The real albatross is the fact that the medication is given/has to be given in the IV form with decadron before and after. The so-called minor side-effects hint at the possibility of anaphylated reactions with prolonged use even with the decadron to help aid in cutting down side-effects. The ISIS drug does not have to be given with decadron and in that form it IMO actually outperforms the ALNY sq form. Time will tell, but the media for now is being manipulated by hearing about the 95% knock down rate without all of the details. Those being that the 95% knock down rate only occurs with the IV formulation. That IV formulation has to be given with fairly large doses of decadron. Even with those fairly large doses of decadron that are strong hints that with prolonged use the IV formulation may cause anaphylactic reactions. The IV form will have to be given in a hospital setting because of this. Both ALNY drugs will cost more that ISIS version. ISIS still has about an 18 month head start in the marketplace, and ISIS doesn't have that rebound effect as noted. The rebound effect may relate to the steroid...the decadron wearing off. It is still an open opportunity for both companies, but my money is on ISIS. t

Anonymous said...

Dirk,
I don't know what you mean by "lead". I assume you mean getting an effective treatment to market the soonest? I'm invested in Isis but not married to it. Some people say Isis has an 18 month lead. What part of the process will Alnylam shave down to get to market first? Will P3 be greatly compressed because of the orphan status? Will the trial just be better designed and more compact? Is the product so superior that testing doesn't have to be so long? Is the 18 month lead mentioned simply an illusion of false hope? Or do some combination of all of the above lead to the whittling away of the 18 month figure?
TIA

Anonymous said...

Jetman,

How did you come up with ISIS having a lead of 18 months over Alnylam? Is that the number that you pulled out of your hat or what? According to CTA filing as listed on clinicaltrials.gov, both ISIS and Alnylam are expected to complete their P3 trial at about the same time. In addition to P3 data, Alnylam will have long term safety data in about 30 patients from their open label extension study in P2 to support their NDA. It seems to me Alnylam has much more robust clinical trial design than ISIS has. And by the way, don't count too much on what ISIS says about having solved their draconian ISR problem.

Anonymous said...

Hi Dirk,

This is quite encouraging indeed. I am quite intrigue to know your thoughts about how Anylam will manage to advance without licensing the "Zamore design rules" technology in the next years. They have lost their opposition to these patents in US and they just withdrawn their opposition for the European ones. Are those patents really essential?

Anonymous said...

Dirk,

Minor rebound seen at the end of 21 days was also seen in NHP study which came down substantially over next few weeks as dosing continued. So there is nothing to be concerned about. What is nice here is dose response is very prolonged. So frequency of dosing could be reduced to only once every six weeks or even once every two months in patients with very mild disease. This could be a very competitive advantage for Alnylam over ISIS.

Dirk Haussecker said...

ISIS/GSK haven't publicized their ISFAP presentation yet. Must be real exciting progress there. According to Jetman, they are about to submit NDA at the end of next year.

Who is in the lead with submitting NDA may come down to which treatment is perceived as more effective in the patient/physician community. Based on the knockdown data, it is clearly ALN-TTR02, not ISIS-TTRRx. ~18% remaining insulting protein versus ~30%, an almost 50% increase with the antisense. If ISIS/GSK were to get slightly earlier approval, the commercial windfall might not last long.

Zamore patents...I can see how one might argue around them, but it is a threat, esp. following discovery of how Alnylam actually conducts their trigger design/selection.

Anonymous said...

My reading is that Isis started their trial a year before Alnylam and the study period is about 3 months less than Alnylam's (65 weeks versus 18 months). Add those together and you get a 15 month lead.

BUT the completion dates are only separated by one month (April 2017)

Some questions come to mind:
How could ISIS blow a 12 month head start?
Is Alnylam being foolishly optimistic to think they can enroll the trial in a few months when ISIS has taken a couple of years?
Is ISIS once again playing the pastie similar to the mipo situation where we did "real" trials and the competition breezed in with the bare minimum?

Nothing like a good horse race!


From clinicaltrials.gov
NCT01960348--Not yet recruiting
ALN-TTR02
First received: October 9, 2013
Phase 3
The difference between the ALN TTR02 and placebo groups in the change
from baseline of modified Neuropathy Impairment Score+7 (mNIS+7)
[ Time Frame: 18 months ]

Estimated Enrollment:
200
Study Start Date:
December 2013
Estimated Study Completion Date:
May 2017
Estimated Primary Completion Date:
January 2017 (Final data collection date for primary outcome measure)



NCT01737398
ISIS TTR Rx--Recruiting
First received: November 27, 2012

A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study
Efficacy of ISIS TTR Rx as measured by change from baseline in the modified Neuropathy Impairment Score +7
[ Time Frame: 65 weeks ]
Efficacy of ISIS TTR Rx as measured by change from baseline in the
Norfolk Quality of Life Diabetic Neuropathy questionnaire [ Time Frame: 65 weeks ]


Estimated Enrollment:
195
Study Start Date:
December 2012
Estimated Study Completion Date:
March 2017
Estimated Primary Completion Date:
November 2016 (Final data collection date for primary outcome measure)

Anonymous said...

Dirk,

How many products have been approved by the FDA using RNAi? the only one I know of is Marqibo from Talon using the Tekmira LNP delivery.. Are there others and can you list them ?

Dirk Haussecker said...

Marqibo isn't an RNAi Rx, so zero FDA marketing approvals.

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