Oligonucleotide Therapeutics for Spinal Muscular Atrophy Impresses in Clinical Study

In addition to the continued validation of RNAi in Man, the other big winner of 2013 in the field of oligonucleotide therapeutics was single-strand phosphorothioate chemistry in the CNS.  Today, ISIS Pharmaceuticals announced clinical data from the most prominent candidate in that effort, namely ISIS-SMNRx for spinal muscular atrophy (SMA), a genetic muscle-wasting disease.  Following intrathecal administration of the splice modulating oligonucleotide, time- and dose-dependent improvements were observed not only in muscle function, but also in SMN protein production (biomarker), thus laying the foundation for an accelerated approval pathway.

In the open-label phase Ib/IIa study in ~30 children with the ‘less severe’ form of type II and III SMA, functional improvements of 1.5, 2.3, and 3.7 points on the HFMSE scale were seen at the 3mg (3 doses), 6mg (3 doses), and 9mg (2 doses) cohorts, respectively.  The changes were thus largely consistent with results from a previous similar, but single-dose phase I study where a 3.1 point increase could be observed at the 9mg dose.

Despite the generally positive news, the data raise a number of questions.  For example, optimal dosing frequency remains uncertain as there were similar functional improvements regardless of whether a single dose had been given or 2-3 doses.  This could have been due to the  long half-life of the drug and the time it takes from SMN protein production (as a  result of the splice modulation) to impacting motor neuron function.  Similarly, in the prior phase I study no positive changes in HFMSE scores were observed at the 3mg and 6mg doses whereas in the present study, improvements were reported.  Clearly, larger patient numbers are required  to settle on the optimal dose, and in fact this dose may not have been reached yet (note: a 12mg cohort has been initiated and children from the phase Ib/IIa trial are allowed to roll over to an additional dose of 12mg).

Case for accelerated approval?

Possibly foreseeing such issues due to small patient numbers, ISIS Pharmaceuticals and BiogenIdec recently developed an assay that allows them to measure SMN protein abundance in the cerebral spinal fluid (CSF).  It is the results from these measurements that provide a strong case for why ISIS-SMNRx should be made available (pending the 12mg results) before a larger phase III study will have been completed.  This is because the functional improvements were accompanied by increases in the SMN protein which also were dose-dependent with a more than doubling of SMN protein at 9mg.

In SMA, the SMN1 protein is missing due to mutations.  The therapeutic approach of ISIS-SMNRx takes advantage of the fact that humans have a pretty much identical gene to SMN1, SMN2.  The problem with SMN2, however, is that only ~10% of its precursor messenger RNAs is spliced into a functional SMN protein due to a difference in essentially just one nucleotide in exon 7.  The severity of the disease, i.e. whether somebody belongs to type I (most severe), type II, type III, or type IV of the disease depends on the copy number of SMN2 genes: 2 copies in type I, ~3 copies in type II and III, and at least 4 copies in type IV.

Therefore, doubling the protein output for type II and III patients (the patient population in the present phase Ib/IIa study) would appear to put the children into the type IV category in terms of protein output (correponding to ~6 SMN2 copies).  In contrast to type I-III, type IV results in no differences in life-expectancy and only in rare cases causes patients to be wheelchair-bound late in life.  

Severe disease of high unmet need, strong biomarker data with highly suggestive functional results, all dose-proportional…the ingredients for an accelerated approval. 

Just in: ISISis reporting preliminary data from a parallel multi-dose phase II study in the most severe, infant form of SMA (type I).  Although small in numbers, the fact that the 4 babies at the starting 6mg dose are still alive and without permanent respiratory support at an average age of 12.5 months appears to be much better than expected.  According to natural history data, you would have expected 2 babies either dead or on permanent ventilation by month 10.  

And finally...the ISIS-SMNRx results increase the value of Marina Biotech's CRN chemistry.  This chemistry competes with the ISIS 2'MOE chemistry employed in ISIS-SMNRx and appears to be of higher potency/affinity, but much less defined safety.

Next Stop: ISIS-SMNRx for Spinal Muscular Atrophy

In case you were wondering why RNA Therapeutics stocks have been going up and up regardless of the overall markets, it is because it is happening right now: RNA Therapeutics are claiming the role of the 3^rd major drug discovery engine, the most vibrant at that, following small molecules (withering) and recombinant proteins/monoclonal antibodies (running out of target space).  It therefore becomes important to anticipate the next major event on that road which are the results from two separate multi-dose phase II studies of ISIS-SMNRx to be reported sometime over the coming 6 weeks.

ISIS-SMNRx for the treatment of severe, orphan disease spinal muscular atrophy (SMA), a muscle wasting disease, is yet another powerful example of how RNA Therapeutics typically target the root causes of diseases rather than merely covering up their symptoms as drugs so often are designed to do, especially drugs for chronic illnesses. 

In SMA, the SMN1 gene is inactivated due to a mutation.  Luckily, there is another SMN1-like gene, SMN2, and this differs from SMN1 by one nucleotide.  As a result, splicing of SMN2 predominantly generates transcripts lacking an exon which in turn results in inactive SMN proteins.  Only a small fraction of SMN2 is spliced functionally.  By antagonizing a splice silencer element on the SMN2 precursor mRNA, phosphorothioate 2’MOE antisense ISIS-SMNRx redirects splicing towards the active form of SMN thereby rescuing the deficiency underlying SMA.  It is insights like these why you want your kids to study biology.  

Following intriguing phase Ib/IIa results from a small, open-label single-dose study in kids with type II and III SMA (‘moderate’ and ‘less severe’ forms of the disease) which showed dose-related continual functional improvements over 9-14 months, consistent with the long half-life of the oligonucleotide in the CNS, the multi-dose phase II studies aim to confirm that in a larger patient population.  In addition, a second phase II study is conducted in infants with the very severe type I form of the disease which results in nightmarish life expectancies of less than 2 years. 

   

It is the compelling scientific rationale, the 12mg dose, the preclinical efficacy and PK results at even smaller dosages and the tantalizing phase Ib/IIa results described above that you would think that the outcome from these two studies should be positive. 

If they are, expect them to be all over the news and RNA Therapeutics stocks continue their march upwards.

ISIS-SMNRx was discovered by ISIS Pharmaceuticals and is partnered with BiogenIdec.

  

Big Pharma Panic over Nucleic Acid Therapeutics

News this week of Roche licensing antisense technology from Santaris 3 years after having written down a related $500M+ investment in RNAi Therapeutics, is symptomatic for the apparent panic and resulting schizophrenic behavior that grips Big Pharma when it comes to Nucleic Acid Therapeutics (NATs).  Can NATs help rekindle their flagging discovery efforts or will NAT companies leave them in the dust as they advance to the top of the Pharma food chain?   

Meanwhile, Big Biotech in the form of BiogenIdec has also recognized that NATs are critical for their growth in the form of a partnership with Zinc Finger Nuclease specialist Sangamo Biosciences for the treatment of red blood cell disorders (sickle cell and beta-thalassemia).  This follows significant (~$150-200M) recent investments in ISIS’ antisense technology for diseases of the CNS and a deal with microRNA Rx company Regulus Therapeutics.

If you sit back and consider the clinical and preclinical developments in the space (look out for the upcoming RNAi Therapeutics Investment Guide 2014), there can be no doubt that nucleic acid therapeutics (including oligonucleotide therapeutics) are about to materialize as the 3^rd major chemical class of drugs following small molecules and recombinant proteins.  In fact, their mechanistic versatility (gene up- and down-regulation, modulation of RNA processing etc) means that in a few decades, there will be many more NAT-based new molecular entities than small molecules and recombinant proteins combined, in many cases for genetically defined patient populations.  

Interestingly, in 2013, only 2 monoclonal antibody new molecular entities (NMEs) received marketing authorization by the FDA (see here).

Investors do not have to take such a very long view as a number of commercially attractive Oligonucleotide Therapeutics are gearing up to enter the market, including for TTR amyloidosis, Hepatitis B infection, spinal muscular atrophy, and hypertriglyceridemia.

For those interested in the more particular relevance of yesterday’s deals to RNAi Therapeutics stocks, the Roche-Santaris deal ($10M in upfront plus the usual biobucks and royalties) represents another blow to ISIS’ claim that it owns the IP in the space, especially in light of the ongoing litigations and patent battles between the companies and the fact that not long ago, Roche partnered with ISIS on Huntington’s Disease.  This should provide further comfort to those, including myself, speculating that Marina Biotech’s CRN chemistry is a valid equivalent, if not superior alternative to the ISIS and Santaris antisense chemistries.  Regarding the deal between Sangamo and BiogenIdec ($20M upfront plus the usual biobucks and royalties), it is a validation of the attractiveness of the hemoglobinopathy market that forms an important part of Alnylam’s pipeline options.

In additional RNAi Therapeutics developments...

Bad news for Benitec

In a recent paper by Lisowski et al. from Stanford (Kay lab) which appeared in Nature, very strong evidence was presented that the AAV8 serotype is far from ideal when it comes to transducing human hepatocytes.  This is in contrast to preclinical results mainly in mice that have shown highly efficient, almost 100% transduction of hepatocytes, the transduction level probably needed to achieve an RNAi cure of HepC.

Based on the preclinical work, the AAV8 serotype was readily embraced by gene therapists and adopted for various liver-related clinical studies. Surprisingly, however, the data so far in hemophilia did not support a significant advantage of AAV8 over the old AAV2 workhorse.

The study by Lisowski et al. shows that this is very likely the result of poor AAV8 transduction of human hepatocytes.  Among the multiple striking results, in mice with chimeric human/mouse livers, basically only the murine hepatocytes could be transduced whereas the adjacent human hepatocytes were not.

This is an unfortunate development that Benitec cannot be held responsible for.  It could be a double-whammy though for the company as in addition to the commercial concerns about the HepC indication for TT-034, results from the ongoing phase I study may not even support the delivery technology for other liver applications.  There is, however, light at the end of the tunnel as there are plenty new AAV serotype that appear to be as good in transducing human hepatocytes as AAV8 is in transducing murine hepatocytes.

BiogenIdec Obtains Exclusive Rights to Most Attractive Application of ISIS Technology

It is official.  With BiogenIdec obtaining 6 years of exclusive rights to ISIS’ antisense technology (ASO) for the evaluation of potential drug targets in the CNS and the treatment of neurological disease with ASOs, ISIS has essentially given up on the homerun potential that single-stranded antisense technology could have had in this therapeutic area.  Instead, the company continues to cap its upside and distract its attention by partnering with multiple companies in various disease areas.  What is more, in the one area where it likes to retain most ownership, targeting genes expressed in the liver for cardiovascular disease, it is likely to be eclipsed by best-in-class solutions from RNAi Therapeutics.

Deal Recognizes Unparalleled Druggability of Oligonucleotide Therapeutics

Neurological disease is arguably the most attractive application of antisense technology because of the surprisingly deep tissue penetration of the CNS following local delivery and the multitude of severe diseases of very high unmet medical need such as SMA, Huntingon’s, myotonic dystrophy and ALS.  These diseases are often genetically well-defined and thus ideal targets for the entire repertoire of antisense functionalities (gene knockdown in- and outside of the nucleus, boosting and redirecting gene expression through splice modulation).  Indeed, the fact that BiogenIdec commits so much attention to Antisense Therapeutics speaks volumes to the great competitive advantage of Oligonucleotide Therapeutics: the vastly superior drug target space versus small molecules and monoclonal antibodies, including the ability to go after the root cause of diseases.

Compared to RNAi Therapeutics, I view the deep tissue penetration following local administration of phosphorothioate-based oligos as the key competitive advantage.  This is especially the case when the target cells have a broad distribution in the CNS.  For more localized target areas, virally delivered DNA-directed RNAi Therapeutics should be competitive.

  

Flawed Business Model Based On Old Times

If you follow biotechnology, you will know that keeping commercialization rights to successful drugs rather than wholesale partnering and collecting royalties here and there is the ultimate path to shareholder value creation.

ISIS’ aversion to commercializing drugs itself can be traced back to the experience of its CEO, Dr. Stan Crooke, at Big Pharma GSK.  In his mind, it is the commercialization focus and large sales forces of Big Pharma that have been killing innovation and is wasting capital. 

The flaw in this reasoning is that times have changed and the specialty/orphan drug business model, the sweet spot of Oligonucleotide Therapeutics at that, has become a huge success in the industry.  Witness the likes of Aegerion and Alexion, but also Alnylam where retaining essentially the full rights to the TTR amyloidosis franchise alone is valued by the market at close to the entire market cap of ISIS with its dozens of clinical programs.  Accordingly, the ISIS TTR program that has been licensed to GSK is an also-ran in the valuations of ISIS Pharmaceuticals.

Apparently realizing the problems with this business model, the company has been making contortions trying to accommodate what must be hefty investor criticism with business development gimmicks such as ‘preferred partnerships’ and keeping drugs longer before licensing.  The BiogenIdec relationship obviously violates the latter principle.

With most other companies, I would not be as harsh when it comes to a $100M plus X biodollars deal. But for a $3.5B market cap company and the reasons stated above, it is difficult to find even a financial rationale for capping the value in the most attractive disease area for its technology.