Monday, August 13, 2018

RNAi Therapeutics Now a Commercial Reality


Last Friday, Alnylam received notification from the US Food and Drug Administration (FDA) that ONPATTRO (aka Patisiran) has been approved for the treatment of hATTR-related polyneuropathy.  This marks the culmination of an almost picture-book translation of a brand-new biotechnology into therapeutic reality.  20 years from worms to patients is nothing.

ONPATTRO development path

Much has been made in the press about the great uncertainty, reflected in supposedly unusually long timelines, of whether RNAi can be a therapeutic modality at all.  Of course, the challenges of delivering RNAi triggers in WoMan, staving off unwanted innate immune responses, and the question of how the transcriptional noise stemming from slightly modulating dozens of unrelated targets will affect safety were all daunting at the beginning.

But looking back, with the exception of a 2-3 year delay due to having to change from an insufficiently potent LNP chemistry to the MC3 lipid-based LNP underlying ONPATTRO and having to institute steroid pretreatment to minimize ‘infusion reactions’, all these challenges more or less dissolved in the development path of ONPATTRO.

A special shout-out here to Ian MacLachlan and his team at formerly Tekmira for solving the critical delivery challenge first.

A best-case scenario would therefore have seen an approval in 2015-6.  2018 is therefore not that bad at all.  Here a quick run-down of the milestones leading up to the approval:

1998: discovery of double-strand RNAs (dsRNAs) being the trigger for RNAi in worms

2001: finding that RNAi can be triggered in WoMan by short dsRNAs

2002: first demonstration of RNAi in mice

2005: first therapeutically relevant demonstration of RNAi in monkeys

2009: initiation of first clinical trial of first-generation LNP-RNA (SNALP-ApoB, aka PRO-040201; ALN-VSP02)

2012: start of ONPATTRO clinical development

2012: first solid clinical proof-of-concept for RNAi in WoMan from ONPATTRO phase I study

2012: start of ONPATTRO phase II study

2013: start of ONPATTRO phase III study (APOLLO)

2017: positive data read-out from APOLLO

2018: EU and US marketing approvals for ONPATTRO  


ONPATTRO is just the beginning

Since ONPATTRO had been conceived starting about a decade ago, there has been, of course, considerable progress in RNAi trigger design (safety, efficacy) and (conjugate) delivery technologies.  As a result, a slew of other RNAi drug candidates by Alnylam, including Givosiran for Acute Intermittent Porphyria (likely 2019 approval), Inclisiran for cardiovascular disease (likely 2020 approval), and Lumasiran for primary hyperoxaluria (likely 2020 approval), are about to be approved.  Especially with the adoption of off-target-minimizing chemical modifications, I am confident that the success rate of RNAi drug candidates for tissue types for which delivery is robust will only increase.

After the liver, for which the current crop of marketing candidates is the target organ, the CNS should be the next huge opportunity as Alnylam gears up to bring a first candidate into that organ over the next year.  In addition, Arrowhead Pharmaceuticals and Alnylam have also started to talk about opportunities in the lung and cancer, although here I am still hesitant about whether these are near-term clinical opportunities or something that will have to wait another 3 years or so.

RNAi shatters antisense competition

As the world is abuzz about the first full-blown marketing approval of an RNAi Therapeutic (note: formal marketing authorization in the EU is still pending), I would be remiss not to display a key graph illustrating the power of RNAi gene silencing versus competing approaches such as gene silencing by mass action RNaseH antisense (TEGSEDI by Akcea Therapeutics) and trying to keep bad proteins from acting out with small molecules (generic tetramer stabilizer diflusinal):  






If you were diagnosed with TTR amyloidosis and had an average life-expectancy of 2-5 years, which treatment would you like to be on?

Stock market reaction

When Alnylam opens for trading today, it will likely be down due to disappointment that the FDA label, unlike the anticipated case in the EU, will only specify TTR-related polyneuropathy for which the APOLLO study had been designed, and not cardiomyopathy with none of the exploratory cardiomyopathy data from APOLLO included.  While this is somewhat disappointing in light of biomarker-based accelerated approvals of Eteplirsen in DMD where target modulation and therapeutic hypothesis were enough to win the day, this should only be a minor hiccup in the overall history of RNAi Therapeutic.  In light of the recent Pfizer small molecule Tafamidis cardiomyopathy data, it is very likely that RNAi trials will show a benefit for cardiomyopathy symptoms as well in a dedicated study (à ALN-TTRsc02). 

Until then, it is possible that the cardiomyopathy data are being withheld until Alnylam and the FDA can come up with a way to include those in an amendment, or as part of an accelerated approval submission.  It is also likely that TTR patients will now more readily be referred from cardiologists to neurologist for an intense neuro check-up such that primary cardiomyopathy patients can access ONPATTRO (and get paid for it) at the slightest signs of polyneuropathy.

Thursday, August 9, 2018

TEGSEDI worse than tetramer stabilizer according to newly released EMA document


When Ionis presented data from the phase III NEURO-TTR study last year in Paris, they clung to numbers close to ‘zero’ to make the point that its TTR-lowering antisense drug TEGSEDI (aka inotersen) was 'stabilizing' and ‘halting’ disease progression.  According to a newly released document by the European Medicines Agency (EMA), this, however, does not seem to be truthful: TEGSEDI only delayed the progression of polyneuropathy compared to placebo, but patients on placebo still got worse over the 15 month study period.   

This not only widens the apparent distance in therapeutic efficacy between TEGSEDI and RNAi competitor ONPATTRO (which improved on disease parameters), but even puts it apparently behind generic tetramer stabilizer diflusinal.  Diflusinal also happens to be much better tolerated than TEGSEDI which has been plagued by platelet and renal issues.

EMA document suggests numbers were inflated

According to the ‘Summary of Product Characteristics’ document issued by EMA following its approval of antisense drug TEGSEDI for the treatment of TTR-related polyneuropathy, mNIS+7 after 15 months increased by +11 points vs 25 points for placebo.  By contrast, Ionis Pharmaceuticals (which has now licensed the drug to subsidiary Akcea Therapeutics) claimed a mere +5 point progression.  Curiously the placebo values haven’t changed.

This compares to an increase of +9.2 for diflusinal over 24 months and -6 for ONPATTRO over 18 months.

Similarly, on another measure of disease progression, the Norfolk Quality of Life questionnaire increased by only +0.99 per the Paris presentation last year, but by +4.38 per the EMA document.  Once again, the placebo numbers remained essentially the same.

Finally, what had been heralded as a TTR knockdown close to that of ONPATTRO, a median 75-79% TTR reduction vs 82% for ONPATTRO, now looks much different when considering that mean knockdown was only 68-74%, possibly reflecting the poor tolerability profile of TEGSEDI and missed doses.

I am sure that Akcea and Ionis will have eloquent explanations for the discrepancies which just so happens to  conveniently and selectively favor their drug when analyzed by them.  These new numbers, however, are not just minor adjustments, but represent substantial changes to the TEGSEDI narrative.

It should be noted that it is likely that tetramer stabilizers and TTR-lowering agents will be taken together by many patients.  The relative efficacy and tolerability numbers, however, put TEGSEDI in a very weak position with regard to direct competitor ONPATTRO, also as it comes to reimbursement decisions. 

ONPATTRO heart aches

In the phase III APOLLO study, patients treated with ONPATTRO were numerically less likely to die compared to those on placebo (~50% reduction in death rate).  Following the Paris meeting, I came away with the impression that the deaths in the ONPATTRO arm were largely due to cardiac failure and infection.

According tothe New England Journal of Medicine publication on the study, this seems to be a misunderstanding as infection was a main cause of death in the placebo arm while all deaths in the ONPATTRO arm were cardiac.  As has been pointed out by others on Twitter (@ionisdisrupts and @artkrieg), this could raise questions in the minds of regulatory bodies whether to include TTR cardiomyopathy applications on the label despite of ONPATTRO improving on related secondary endpoints.

In fact, considering that the recent study design agreement with the FDA for follow-up drug ALN-TTRsc02 also focuses on polyneuropathy endpoints, it is all but official that the label for the upcoming approval of ONPATTRO will be targeted at the polyneuropathy population only and that separate trials will have to address the patients mainly suffering from cardiomyopathy symptoms.

Disclosure: short AKCA, long ALNY.

Friday, August 3, 2018

Taking Stock of RNAi Therapeutics


Though currently vacationing, this summer is starting to get quite busy for the RNAi Therapeutics space, so I thought a quick update summary might be warranted.

RNAi Therapeutics on the eve of commercialization

Following a positive opinion by the CHMP in the EU and an upcoming US decision next week, preparations for the first commercialization of an RNAi Therapeutics, ONPATTRA (aka Patisiran) are in full swing.

The financial markets are full of worry that the label could be a narrow one for ONPATTRO, mainly focusing on the polyneuropathy manifestation of TTR amyloidosis that has been the primary focus of the phase III APOLLO study.  While this is to be taken for granted given the trial design, since many TTR patients have overlapping polyneuropathy and cardiomyopathy symptoms and given the strong cardiomyopathy secondary endpoint data in APOLLO, it has been voiced again and again by physicians at last years European ATTR meeting that patients will be put on an TTR lowering therapy at the slightest indication of cardiomyopathy.

Interestingly, this label worry has had no impact on Akcea’s stock marching to a $3B market cap despite the antisense competitor TEGSEDI clearly having inferior efficacy and a worrisome safety profile.  The choice is: ‘for the convenience of an at-home needle injection (mind you, you'd still have to go to the doctor's office frequently for safety check-ups), do you want to have something that is likely to only delay disease progression instead of reversing it and that might even shorten your life expectancy versus prolonging it if you did nothing?  To help you make this decision, be reminded that your life expectancy from diagnosis is around 5 years.’

Market uptake among cardiologists should also be a catalyzed by the Pfizer tetramer stabilizer Tafamidis data later this month.  Following news that Tafamidis had a positive impact in a phase III trial geared towards the cardiomyopathy symptoms, Alnylam's share price took a hit.  By contrast, the impact on ONPATTRO commercialization should be positive if the upcoming data presentation shows a mere disease stabilization for Tafamidis given that ONPATTRO has clearly beaten Tafamidis in polyneuropathy (there is no reason to believe a priori why cardiomyopathy should respond differently to tetramer stabilizer vs TTR knockdown).  Ultimately, increased awareness of TTR-targeting medicines in the cardiology community by players like Pfizer should only help ONPATTRO commercialization there.

Importantly, the star medicine among this new crop of TTR drugs, GalNAc-based TTRsc02, is on track to start a 9-month pivotal phase III study by the end of year and a cardiology-focused trial shouldn’t be far behind.  

Onwards and upwards RNAi.

Disclosure: long Alnylam as the clear value play in Oligonucleotide Therapeutics these days with a number of significant catalysts in the back half of the year, especially over the next month; short Akcea since not only do their most important medicines, TEGSEDI and WAYLIVRA, s.ck in terms of safety/efficacy, the revenues of their medicines has to be shared with Ionis, Novartis, and now also PTC Therapeutics.  One would therefore have to multiply their market cap by a factor of 3 or so (--> ~$9B) for comparison purposes with more typical biotech market caps.

Amgen misleading secrecy around AMG-890

Not only would Akcea have to share revenues for its most exciting drug candidate, a GalNAc-targeted Lp(a)-antisense in phase II, with Novartis, it now has serious and likely superior RNAi competition in the guise of AMG-890.  To wit, the rights to GalNAc-RNAi AMG-890 were licensed 2 years ago from Arrowhead Pharmaceuticals to Amgen and despite it having been the lead GalNAc-RNAi candidate at Arrowhead until then, HBV and AAT candidates by Arrowhead seem to have beaten AMG-890 to the clinic by a year or so.  This and the early trial termination of the ARO-AAT trial in my mind raised serious concerns that Arrowhead was willing to take far more risks with its current technology than Amgen wanted to, raising questions over the general quality of the Arrowhead pipeline in light of their otherwise amazing execution speed.

Now that Amgen has disclosed that they must have filed the AMG-890 IND/CTA-equivalent months ago, but already dosed their first subject with it, more positive interpretations are warranted.

Disclosure: Since the Arrowhead cult has attacked me on my stock trading potentially influencing my view of their technology, here a more detailed summary of my trading strategy: I started pursuing a ‘covered short’ strategy following the strong run-up in the wake of the ARO-AAT early termination and first knockdown data news releases (July puts expiring worthless, then writing new puts for August and September largely in the $14-16 range) and consider myself lucky to have covered my short on the stock route from $17 to $12.5 last Friday and this Monday leaving me short a bunch of puts.  As Arrowhead has strongly rebounded from the sell-off, I have been gradually re-shorting it starting from the ~$14.5 level to lock in some of the windfall profits; by now, the short covers ~1/3 of my puts (note: ‘covered short’ is actually a misnomer as the short portion of the trade could still bankrupt you).

RXi biting the dust no matter the (ocular) data

Self-delivering RNAi Therapeutics company RXi Pharmaceuticals reported encouraging data this week from a small study of anti-scarring candidate RXI-109 for retinal scarring.   In important news to the RNAi Therapeutics space at large, no serious drug-related adverse events were seen with these highly modified oligonucleotides.  On the efficacy side, numerical improvements were seen over placebo, but clearly need to be regarded as preliminary.

For a sub-$10M market cap company, such news should have strongly propelled the stock under normal management.  In this case, the clinical results look like a mere note on their way to impending bankruptcy.  It is a timely reminder that the number 1 job of a CEO is actually investor relations and making sure adequate capital is available when needed.  It seems like RXi’s CEO has believed that operational execution is all that was needed and that investment funds will start knocking on their door.  This was a serious miscalculation, especially since after the split from CytRx, a biotech that many would consider a scam, the entire pre-existing financing mechanics (I spare you the gory mechanics) of RXi fell away.

Disclosure: I hold a small long position in RXII (<1 a="" and="" be="" been="" believe="" bit="" company="" course="" different="" it="" management.="" more="" much="" of="" portfolio="" s="" should="" span="" style="mso-spacerun: yes;" technology="" the="" under="" value="" valued="">  I cannot, in good conscience, recommend this stock as a buy under current circumstances.

 Note: a proof-read version with links will follow as time permits.

Monday, July 9, 2018

Regulus Therapeutics Declares MicroRNA Therapeutics Bankrupt


Once considered a new star on the biotech firmament, the most prominent microRNA Therapeutics company is going from bad to worse fast.  

Last week, Regulus Therapeutics announced that both of its clinical programs in Alport’s Syndrome and autosomal dominant polycystic kidney disease (AKPKD) had been voluntarily halted for financial and preclinical reasons. Instead, the company will now try to renegotiate the Alport deal with Sanofi and use its remaining resources to focus on a preclinical program for HBV.

Management not in control

The program pauses follow a string of other setbacks over the last 3 or so years. Most prominently, it discontinued a highly promising candidate for the treatment of HCV due to safety questions and having been a few years too late to a highly competitive game.  A slow early advancement of that miR-122 program was partly to blame for this.

After that, it has been one delay after another for various programs.  Partner AstraZeneca e.g. returned a liver-targeted metabolic program and the Alport's program has been hit by multiple delays and trial reconfigurations.

If this was not sufficient proof that managing a biotech company has been well above the paygrades of the multiple executive teams that have come and gone over the years, running out of cash in this genetically-focused biotech bull environment is simply unacceptable.  Even if microRNAs may have lost its early luster as targets for particularly complex diseases, I had thought that having exclusive access to the huge IP portfolios of parent companies Ionis and Alnylam for microRNA Therapeutics purposes would provide a powerful backstop when it came to accessing fresh capital.

With a market cap of less than $40M and last week’s ‘we’ve-run-out-of-cash news’ I was obviously wrong…

Chasing a 'safe' target

Since microRNAs which typically have a range of biologically meaningful targets are thus promising for treating particularly diseases of complex causes and manifestations, I would have thought that with the genetics gold-rush that we are now witnessing in neurology, not least because of antisense drug SPINRAZA, there would be much interest in Regulus Therapeutics there.

I understand that HBV is becoming a hot area again, with the skyrocketing valuations of Arrowhead, Dicerna, and Arbutus suggesting that high rates of functional cures are just around the corner.  Going after HBV with a microRNA, however, would seem like a surprising choice though given that in terms of direct antiviral activity, a microRNA approach should pale in comparison to the RNAi competition.  You would therefore think that Regulus is considering a immune reactivation-related microRNA target for HBV, but it is not clear to me which model they would be basing this on.  

Hey, management, at least show us some data to hang our hats on when you sell a preclinical concept as your future.

Or does choosing HBV betray that they have lost all confidence in their ability to deal with the biological complexity of microRNAs, instead seeking safety in just measuring simple viral knockdowns?

After the quasi-demise of microRNA diagnostics leader Rosetta Genomics, there is now the real prospect that the therapeutics counterpart will equally go belly-up soon.  In order to avoid that, Regulus needs new, confident management first and foremost as the main task now is to make the case for microRNAs as therapeutic targets.  Where are all the boastful biotech executives when you need them?

Monday, July 2, 2018

Arrowhead Achieves Robust Alpha-1 Antitrypsin Lowering As Grounds for Trial Termination Still Shrouded in Mystery


Last Friday, Arrowhead Pharmaceuticals presented first data from its phase I study of ARO-AAT being developed for addressing liver disease in people with certain mutations in the alpha-1 antitrypsin gene.  Based on the selective data release, Arrowhead has assumed the lead in this indication as Alnylam struggles to regain its footing following apparent off-target-related liver toxicity almost 2 years ago.

The press release can be found here, the actual presentation here

With a mean maximal target gene knockdown of -87% between 6 to 8 weeks following a single subcutaneous injection of 100mg dose of the GalNAc-enabled ARO-AAT, Arrowhead has shattered the previous AAT knockdown record by Alnylam’s ALN-AAT of -80% at a ~4x dose of ARO-AAT.  The dynamics of the knockdown also suggests that infrequent dosing should be feasible with ARO-AAT, although without seeing the multi-dose data from this study, it is difficult to predict whether we are talking about quarterly or semi-annual dosing here.

It will also be interesting to find out whether the variation of knockdown in the 4 patients- ~-70% knockdown at 4 weeks for the 2 weaker responders and ~-90% for the 2 better responders- had to do the polymorphism issues similar to those encountered by Alnylam before.

Safety mystery remains

When Arrowhead announced on June 18 that it would terminate the healthy volunteer trial prematurely given that it had escalated above doses at which maximal knockdown can be observed, I was hesitant in taking it at face value or whether this decision also had something to do with the safety profile of ARO-AAT.

The Alpha-1 National Education Conference update only added to the impression.  Firstly, because Arrowhead must already know the knockdown from the 200mg and perhaps also the 300mg open-label cohorts since at least June 18, why didn’t the company simply show the data?   

Regarding safety, the company chose a cut-off date of June 11, that is a week before the June 18 decision.  By June 11, there were only 2 drug-related injection site reactions among the 32 subjects that had received at least 1 dose of either ARO-AAT (n=20) or placebo (n=12) per slide 17 of the presentation.  Those happened to be in the 2 of 4 100mg open-label subjects, the only subjects for which the knockdown had been reported.  

Confusingly, the company also reported that 44 subjects had received at least 1 dose (at least as of the trial termination decision date of 18/6), meaning that 8 subjects had further received 300mg of ARO-AAT (4 open-label, 4 blinded) and 4 placebo (all blinded).  Adding to the confusion, a company representative emailed me in a response to a tweet of mine on the ISR frequency that the safety update referred to those 40 subjects that had received at least 1 injection as of 11/6, but- as I said- contrary to this statement the table on slide 17 only included 32 subjects.  For all those others, the safety data were missing entirely.

The question now is whether the omission was intended as a teaser for the Liver Meeting presentation in November, a minor math issue, or whether there was something more nefarious to it.  The speed with which the company will move into patients (which already have or are at risk for liver disease) will be an important indication whether liver toxicity or the like has been observed subsequent to June 11.

Wednesday, June 20, 2018

Small Molecules and Gene Therapy Muscle Out Oligonucleotide Therapeutics


Over the last two days, breathtaking data were reported for the treatment of two severe, inherited muscle-wasting diseases affecting children.  The investigative agents were a small molecule splicing modulator and a gene therapy both of which appear to achieve superior results compared to approved Oligonucleotide Therapeutics agents. 

The developments highlight the risk that while gain-of-function changes (here by splice modulation) may have proved to be low-hanging fruits for Oligonucleotide Therapeutics, they, unlike gene knockdown approaches, face increased challenges from other technology platforms.

Small molecule splicing modulation for Spinal Muscular Atrophy (SMA)

In 2011, Roche started collaborating with PTC Therapeutics on small molecule splice modulators for the treatment of SMA.  The idea is to screen small molecules for their ability to bring about changes in RNA processing that would hopefully be gene-specific enough so as not to cause widespread off-targeting.

I had always considered this to be a monumental, if not insurmountable task.  This is because a given splicing event brings together a set of proteins that each in turn also function at other genes.  So surely a small molecule that may bias splicing from SMN1 to SMN2, as does antisense oligonucleotide SPINRAZA from Ionis and Biogen through highly specific base pairing, would also affect a range of other genes.

If that were not enough of a challenge, a small molecule carries the extra baggage of being more widely available across tissue types such that off-targeting is a risk to not just the CNS as with SPINRAZA, but many other cell types where there may be no benefit from SMN upregulation.

Accordingly, the first compound in the PTC-Roche collaboration to enter clinical development, RG7800, had to be discarded last year due to retinal tox concerns.  Another small molecule competitor, branaplam from Novartis, had similarly been put on hold due to tox concerns although this compound has resumed development late last year.

It was therefore amazing to see updated results from the FIREFISH study of the follow-on compound RG7916 in type I SMA infants.  They show that 90% of children had an improvement in the CHOP-INTEND measure of physical functioning after 6 months on the drug.  The results are particularly impressive considering that treatment had been initiated relatively late compared to the new standard of care with SPINRAZA and the soon-to-be-approved gene therapy by Novartis (àAvexis).   

Not only that, there had been no treatment discontinuations due to safety issues with RG7916.

Given that SPINRAZA has to be given intrathecally while RG7916 can be given orally, and given that both the gene therapy and the orally available RG7916 appear to be somewhat more efficacious than the oligonucleotide, the focus of Biogen and Ionis should now be on testing combinations of SPINRAZA with both modalities.  Ideally, there is added efficacy from using the agents together either because due to higher achievable SMN protein levels and/or due to complementary biodistribution (note: the value of SMN increases outside motor neurons is debated).  If not, the SPINRAZA franchise may have a limited shelf-life.

Fake-it-‘til-you-make-it Sarepta with gene therapy breakthrough

The other piece of great news for families dealing with neuromuscular disease came yesterday at the Sarepta Therapeutics R&D Day. 

To wit, Sarepta had used dubious data and a lot of political lobbying to get the controversial exon skipper eteplirsen approved under accelerated approval.  While delaying the confirmatory study that is supposed to be part-and-parcel of an accelerated approval, Sarepta has been raking in billions in sales and added market capitalization.  This has allowed the company to build a veritable DMD powerhouse with a number of candidates that look much more promising than ordinary PMO-based eteplirsen.  They include peptide-conjugated PMOs and especially gene therapies.

If you are involved in drug development, better get used to the dubious morals of the industry.  If things go well, you behave like the paragon of virtue, if things don’t go so well you fake it until you get another chance at succeeding.  I digress…

Before the initial gene therapy data were to be presented by Jerry Mendell from Children’s Nationwide of SMA fame, I had dreaded the thought of having a hyped-up R&D Day being about divining the meaning of a biopsy slide or two on the barely-above-background expression of the microdystrophin transgene.

However, what was presented was anything but borderline.  Unlike with eteplirsen where we were dealing with debatable 1%-type absolute expression levels, there was robust microdystrophin expression: ~75% of cells expressed the transgene (by IF) with roughly 30% absolute expression of microdystrophin relative dystrophin from a normal person (by Western blot).

Not only this, the microdystrophin was functional at the molecular level as judged by restoring dystrophin-related protein complexes serving to protect the muscle from damage by acting as shock absorbers.  Accordingly, CK levels in the blood, a marker of muscle damage and elevated in children with DMD, were robustly (9x) and uniformly lowered in all 4 boys between the ages of 4 and 7.  Add to this the obligatory before-and-after videos and there is little doubt already at this relatively early stage already (~1-3 months after gene transfer) that AAVrh74.MHCK7.microdystrophin is a powerful agent applicable to essentially all types of DMD.

On the safety side, there were considerable, but transient and manageable increases in liver enzymes.  This was to be expected, however, considering the very high doses of AAVRh74 needed to achieve widespread transgene expression in muscles throughout the body and treating physicians know to look for it.

If the safety holds up and expression continues to be long-lived, AAVrh74.MHCK7.microdystrophin could render many exon-specific oligonucleotide splice modulators obsolete. The duration of action is the most concerning issue to me at this point given the attendant cell turnover and attendant risk of losing episomal gene therapies in patients with muscle damage.    

Tuesday, June 19, 2018

Arrowhead Cuts Trial Short And The Market Loves It


Yesterday, Arrowhead Pharmaceuticals announced that it is cutting short its phase I study of ARO-AAT as it had observed what appeared to be maximal drug activities at lower than predicted doses.  ARO-AAT is the GalNAc-targeted investigational RNAi agent for the treatment of alpha-1-antitrypsin-related liver disease.  This just 3 months after it had initiated dosing in the (healthy volunteer) study.  

The stock market greeted the announcement, sending shares up another 24% turning it into a 10-bagger in the span of one year!

Interpretation of AAT program status

This is what was said to describe the general results seen so far:

We have escalated above a dose that we believe achieves maximal activity, and all doses to date appear to be generally well-tolerated.”

And this was the trial design:

AROAAT1001 (NCT03362242) is a Phase 1 single- and multiple-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and effect of ARO-AAT on serum alpha-1 antitrypsin levels in healthy adult volunteers. The study includes 7 cohorts in which 16 subjects receive placebo and 28 subjects receive single or multiple doses of ARO-AAT at doses of 35, 100, 200, or 300 mg. Additional cohorts were planned at a dose of 400 mg, but were deemed unnecessary based on observed activity at lower doses.

The company said that data from the study would be presented at AASLD late this fall.  However, based on the original study design involving single and multiple dose cohorts of 35, 100, 200, 300, and 400mg, we can roughly infer the following from the press statements: single and multiple dose cohorts of the first 3 doses up to 200mg had been completed (= 6 cohorts) and the 300mg single-dose cohort had started when they determined that 300mg is already above where maximal activity is reached.  Although the statement does not exclude the possibility that maximal activity appeared to have been seen already at 100mg, we can conservatively 200mg (~3mg/kg) as the dose with which the company plans to move into patients.

In monkeys, the company reported that AAT expression in the liver was almost completely abolished following 2 doses of 3mg/kg spaced 28 days apart based on last year's AASLD poster.

Moving pipeline and technology speedily along

This fast-tracking of the program is consistent with Arrowhead’s overall rapid-fire execution in bringing new programs into the clinic and then use modern, parallel-cohort trial designs and disease experts to move them rapidly along in the clinical development bowel. 

Its goal- and there is every indication they will make good on it- is to bring around half a dozen clinical candidates into the clinic in just over year.  If that weren’t challenging enough for a small biotech company like Arrowhead, these programs are not limited to being targeted to a single tissue (the liver), but could also involve the lung and cancer.

In a way, the liver pipeline is being moved along in a similar fashion to when Alnylam selected its current late-stage clinical crop of candidates 5 or so years ago in a cook-off between different target genes.  Once the technology is ready for a certain tissue, you focus on populating the pipeline with related candidates.  This allows you to grow your market cap and become an established biotech player.  With a market cap now well above $1B, Arrowhead certainly is close to reaching that dream.  It only needs to add to balance sheet cushion.

Overpromising

On the other hand, claimed breakthroughs not in just one (lung), but two (à cancer) additional tissue types, make me wonder whether Arrowhead has started to overpromise again in a fashion similar to the DPC experience when it and investors chose to whistle over safety signals ('DPC has no side effects').  It is understandable if RNAi companies dangle the carrot of additional tissue types in front of the investor community- investors need dreams to hang their hats on- but the speed in light of the size of the company make me wonder if they are taking a short-cut or two too many and investors choose to ignore red flags again.

How times have changed: a year ago, still overly punished by the markets for the DPC fiasco, an cutting-a-trial-short announcement like yesterday’s would have sent shares down further.  Now, Arrowhead is getting the benefit of the doubt.

Knowing that a statement like ‘all doses to date appear to be generally well-tolerated’ can mean pretty much anything bar a drug-related patient death, I choose to remain neutral with regard to the news and will await the AASLD data until further judgement on the quality of Arrowhead’s approach.

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.