Antisense Technology Produces Huntington’s Disease Breakthrough

Huntington’s Disease (HD) is one of the most prevalent severe, ultimately fatal genetic neurological diseases of our times for which impactful treatments are desperately lacking.  Based on results from a clinical study aiming to knockdown the disease-causing gene using RNaseH antisense technology, this is about to change over the next 3 years.

IONIS-HTTRx study results presented at CHDI

At the major annual HD gathering this week, lead investigator Tabrizi from the University College London presented data from a phase I-II study of antisense drug candidate IONIS-HTTRx in patients with early symptoms of the disease.

IONIS-HTTRx (aka RG6042), developed by Ionis and partnered with Roche, targets both wild-type and mutant huntingtin protein to provide all patients with the most potent and safest sequence possible.  While mutant allele-specific approaches have been discussed and are being pursued by antisense rival Wave Life Sciences, the concern that suppressing wildtype huntingtin in adults seems to me a far-fetched theoretical discussion, if not wishful thinking given that antisense is unlikely to completely eliminate wildtype huntingtin and that the drug is being given to adults.  

To wit, the concern is based on genetic mouse models where complete huntingtin knockout causes embryonic lethality. Importantly, this is not recapitulated in mouse model where knockout is delayed until adulthood.

Call me cynical, but the choice of an allele-specific approach by Wave Life Sciences has likely been primarily motivated by allowing for some follower differentiation.  Ironically, by limiting themselves to a much reduced sequence space around co-segregating single nucleotide polymorphisms, the sequences may not only lack the potency, but also the apparent safety of IONS-HTTRx.

Good safety profile maintained until highest dose tested

In this study, IONIS-HTTRx was given monthly over 3 months.  Speaking to the safety of the approach, apart from transient side effects due to the intrathecal mode of administration, no adverse events of note were reported and all 46 subjects have subsequently rolled over into the open-label extension study.

Importantly, doses as high as 120mg monthly were well tolerated at which dose the knockdown effect seems to have plateaued.  This not only bodes well for IONIS-HTTRx, but for the entire neurological disease franchise of Ionis Pharmaceuticals. 

The human safety and tolerability results are consistent with a range of small and large animal models (including dogs, pigs, non-human primates), some of which were a year or longer in duration.

Robust huntingtin lowering

It is widely thought that mutant huntingtin protein is harmful to the cell expressing it, ultimately resulting in neuronal death throughout the brain.  This can be visualized by considerable, 30%-level atrophy of the brain over the course of the disease.

Although it is not possible to assess huntingtin levels directly in brain tissue in humans from biopsies, the experience in the preclinical animal models and human data from spinal muscular atrophy drug SPINRAZA allows one to model the correlation between ASO-dependent protein changes in the cerebrospinal fluid (CSF) and the various areas of the CNS quite well.

Since SPINRAZA is based on chemistry that is highly similar to that of IONIS-HTTRx, they behave identically in terms of biodistribution for all intents and purposes.

In the two highest cohorts, 90mg and 120mg, mean 40% mutant huntingtin reductions in the CSF were observed shortly after the last dose with further reductions (50%+) seen thereafter.  Such levels are predicted to reflect 55 to up to 85% reductions in the cortex and 20-50% in the caudate.

This degree of knockdown exceeds that necessary to see changes in HD animal models, some of which with manifest disease symptoms at treatment onset.

The future is bright

The study results therefore raise hopes that  IONIS-HTTRx may halt or even reverse disease in manifest HD patients.  As exciting and medically likely with the biggest bang for the buck is the prospect that the drug candidate may prevent disease symptoms to emerge in the first place when given early to those at risk of developing the disease (~1 in 2 with a parent having HD, 200,000 in the US alone). 

The companies and clinical investigators are now busy designing a pivotal outcomes study which I would guess will ultimately involve 150-250 early-stage patients over a period of 16-24 months.  The size and extent of the trial will depend on which endpoints are chosen.  A pre-planned interim look at ~12 months may also make sense to look at brain size as a potential way to obtain accelerated approval.  Accelerated approval under the new FDA may also be possible based on functional analyses the investigators are currently conducting using data from the present study and the open-label extension with dosing well beyond 3 months..

In drug development, sometimes you can tell early on whether a drug candidate is destined to breeze through to approval. In this regard, IONIS-HTTRx certainly feels like Spinraza.

Wave Rides Coattails of Ionis, Strikes CNS Deal with Takeda

Today, Wave announced the licensing of their (stereopure) antisense technology to Japanese Big Pharma Takeda for their application in the central nervous system (CNS).  In return for $110M in upfront cash, a $60M equity investment and other biobuck goodies, Takeda receives an option to co-develop/commercialize ASO candidates for the treatment of Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and type III Spinocerebellar Ataxia (SCA3).  Takeda also receives opt-in right to additional preclinical programs.

This deal has clearly been driven by the outstanding data gathered by rival Ionis and its corporate partner Biogen in applying phosphorothioate antisense chemistry for diseases of the CNS.  This not only includes the remarkable efficacy and commercial success seen with splice-skipping oligo Spinraza for spinal muscular atrophy (SMA), but also preclinical knockdown and biodistribution data from many other CNS programs. 

Also of note, Ionis and Roche disclosed last December statistically significant knockdown of huntingtin in people with HD, the same indication as Wave’s lead neurology program which has entered clinical development.  Important additional color for the Ionis HD candidate, especially relating to the actual depth of target knockdown is to be presented  at the upcoming CHDI conference at the end of this month.

To wit, the efficacy of exon skipper Spinraza relied on gain-of-function where minor (say 20%) target engagement may already translate into significant clinical benefit.  Most other programs, however, aim at inhibiting a disease-causing molecule from being made.  Here, you may want more like something of the order of 50%+ target engagement. 

Another wrinkle is that the target cells in the CNS will differ from indication to indication whilst antisense efficacy is not homogeneous throughout the CNS, so the SMA and HD program data will not have de-risked all the indications.   

Nevertheless, it is crystal clear that phoshorothioate oligos hold tremendous value for the many diseases of the CNS of high unmet medical need for which the industry is more and more relying on gene-targeted approaches after years of failures with small molecules.  And kudos to Wave for retaining substantial commercial value to the licensed programs.  

So thank you, Ionis, for making it exceptionally easy for them!

Alnylam Green Shoots After Corporate Restructuring

The latest quarter must have been the best quarterly performance by Alnylam in the last 3 years. After going through a rough patch that culminated in Novartis not adopting a widely expected $100M platform license with the attendant lay-off of a third of its staff, the results and also tone of the conference call struck me as if the company had re-discovered its old enthusiasm for RNAi Therapeutics drug development and is intensely focused on creating value by providing additional clinical proof-of-concept data over the coming months.

There is reason to be cautiously optimistic about the upcoming clinical data. For one, dose escalation for the liver cancer candidate ALN-VSP02 seems to have progressed beyond the magic 1mg/kg mark and is still ongoing! First generation or not, the fact that patients have now received and tolerated this kind of dosage, and on a repeat basis, is major de-risking for all of Alnylam’s, but also Tekmira’s pipeline candidates which involve LNP delivery (almost all of them). Similarly encouraging, ALN-TTR01 dosing is also ongoing and with 3 centers in Europe recruiting now, results may not be that far off (28 patients anticipated in this phase I study).

Although the first generation LNPs appear to be well tolerated, Alnylam seems to be even more excited about a potential quantum leap in LNP delivery: LNPs containing the next-generation MC3 lipid which not only silence in the unprecedented single micro-gram per kg range for gene targets in the liver, but also appear to be very well tolerated in animals. The MC3 lipids are derived from the DLin-KC2-DMA ionizable lipids developed by Tekmira, results from which were published earlier this year in Nature Biotech.

Besides the science, financials seem to be in better-than-expected shape, and I believe is what underlies today’s jump in share price (you can assume that the stock market wouldn't pay much attention to MC3). With over $370M cash/equivalents on the balance sheet, Alnylam is poised to close the year with well over the previously guided $325M cash/equivalents. Having slashed the work force, albeit probably at considerable personal cost, thus buys the company strategically valuable breathing room. In addition, there were a number of positive one-offs this quarter, including $2M for the successful award of 8 federal grants, a Quark milestone, and increased activities related to Novartis finalizing its 31 target picks. And with Novartis' relationship with Alnylam settled now, it should become easier to talk to other companies about partnerships and further add to the strong financial position.

Alnylam and Medtronic also stand to receive very significant funding from the Huntington’s Disease Foundation (CHDI), likely totaling over $10M, some of which has already been earned (agreement is retro-active). Somewhat dampening the excitement around that program was news that ALN-HTT is now a 2012 goal for entering the clinic, while LNP-delivered ALN-TTR02 and PCSK9 (both probably MC3) are poised to be the Company’s 2011 new clinical candidates.

An interesting tidbit on PCSK9 is that, faced with numerous competition from mainly monoclonal antibody candidates against the same target, some of which have already entered the clinic, it appears to be now Alnylam’s strategy to emphasize the fact that with RNAi you down-regulate both intra- and extracellular PCSK9 levels, which therefore is closest to recapitulating human genetics which has been driving the adoption of PCSK9 as a drug target for hypercholesterolemia in the first place. A good argument indeed.

Overall, my most important take-home was that this seems to be a re-energized company, and with some of the right clinical news, there may soon be a second honeymoon between Alnylam and its shareholders (of whom I’m btw not one of…yet).