A Conversation with the CEO of Ionis Pharmaceuticals about Spinraza

James Radke

The past couple of weeks have been incredibly busy for Ionis Pharmaceuticals. Last week, the company, alongside Biogen, was awarded the Prix Galien Best Biotechnology Product Award for the drug Spinraza (nusinersen).

This week, the clinical trial that led to Spinraza’s December approval was published in in the New England Journal of Medicine. That news, however, was soon overshadowed by the announcement that the company’s phase 3 clinical study testing inotersen in hereditary ATTR amyloidosis patients met its primary co-endpoints and that they expect to file a New Drug Application (NDA) as early as next week with the US Food and Drug Administration (FDA).

With all of this, it comes as no surprise that when Rare Disease Report caught up with the President and Chief Executive Officer (CEO) of Ionis, Stanley Crooke, M.D., Ph.D, he was happy to discuss the current events. The conversation focused on Spinraza, its development, and the transformative affect the antisense drug has had on children with spinal muscular atrophy.

Rare Disease Report: Can you provide a brief overview of how Spinraza was developed and came to market?

Dr. Stanley Crooke: Spinraza is a product of a technology called antisense technology.  It's a new platform for drug discovery that we've pioneered and I have led the development of the science and medicine around that. Spinraza is a remarkable drug in many ways. Mostly, the drug could not exist without the technology that we at Ionis invented; we discovered it and developed it through all of clinical trials. We were partners with Biogen in the development process but we ran all the programs and the clinical trials. Then Biogen exercised the option to license the drug and managed the regulatory process and were responsible for the launch.

RDR: What is antisense technology?

Crooke: As I'm sure you know, most drugs are small molecules that are designed to bind to proteins or molecules in the cell within the body. Similarly, antibodies are another category of drugs also designed to bind to specific proteins. Antisense technology is entirely different. It's a new chemical class that never existed before we created the medicinal chemistry of all of the nucleotides. Antisense drugs are small segments of genetic-like material that is chemically modified to interact with RNA.

Antisense is called antisense because it uses the same basic information that makes genetics so specific, that is Watson-Crick hybridization, to support very specific interactions. Antisense oligonucleotides, or what we call ASOs, bind with great specificities to their targets. (An ASO is synthesized nucleic acids that has a base sequence complimentary to mRNA’s base sequence or the ‘sense’ sequence).  We can now design these ASOs to take advantage of a number of different cellular mechanisms.

Antisense drugs typically prevent the production of disease-causing proteins. So, they do not wait for the protein to be made but rather they prevent the production of the protein.

RDR: What makes Spinraza unique?

Crooke: Spinraza is a little different; it uses a different mechanism. To understand that, I need to give a brief history lesson: about 15 years ago, it was determined that spinal muscular atrophy is caused by homozygous loss of function of a gene called SMN which produces the protein, SMN (survival motor neuron). That protein is necessary for the formation and maintenance of normal myo-neuro junctions, which are the junctions between nerves and muscles. So, if you don't make the SMN protein, then what happens is you are biochemically denervating all the muscles in the body. And just like if you were to denervate muscles because of a trauma, those muscles would then just wither away. The problem in spinal muscular atrophy is that they are basically not making a protein that is essential for life.

At the same time that we learned about the SMN gene being responsible for spinal muscular atrophy, it was discovered that humans – and only humans, it seems – have another gene called SMN2. It is the same gene as the SMN gene but along the way it acquired a small number of mutations. One of the mutations is in a region called a splicing enhancer sequence. 

When you want to make a protein, you have a machinery in your cells to read the information in your genes and make something called pre-messenger RNA. That pre-messenger RNA has the sequence that will make the protein but it also has a lot of other ancillary information. It is very essential information but not necessary to be decoded by the machinery that makes proteins.  

That ancillary information is essential but it has to be removed before the messenger RNA is ready to make the protein. And the systematic removal of the ancillary sections in the pre-messenger RNA to create a functioning messenger RNA is done by a process called splicing.

A splicer enhancer sequence makes sure that certain portions of the pre-messenger RNA make it to the final messenger RNA product. In the SMN2 gene, one of the mutations is in a splice enhancer segment and as a consequence, the correct messenger RNA is not made nor is the protein. More specifically, segment that does not get made is called exon 7.

Spinraza is an antisense agent designed to bind to that site and encourage the inclusion of exon 7 so that you get a full-length messenger RNA from the SMN2 gene and therefore you can make this protein that you need to be alive.  

RDR: What was the outlook for spinal muscular atrophy patients without treatment?

Crooke: About 50% of the babies born every year with spinal muscular atrophy have the worst form (type 1). For those babies, before Spinraza, they had on average about 6 months before the either would be dead or require permanent ventilation. There has never been, before Spinraza, a type 1 baby living to be 2 years of age.

The less severe form of the disease, and that's using the term very loosely, is type 2 or childhood onset spinal muscular atrophy. These patients never walk and as they age and get bigger, they get weaker.  A few of them may be able to crawl as toddlers but most lose the ability to even raise their arms. And as they grow, the muscles will grow at different rates so they often have all kinds of skeletal deformities. It is a terrible disease and for many decades the physicians who've taken care of these families have really had nothing bout solace to offer these families.

Spinraza is administered intrathecally about every 4 months. It has been proven to work extraordinarily well and the mechanism has been proven in animals and in humans.

RDR: And with treatment?

Crooke: Babies we treated with Spinraza produced the SMN protein and it was produced in the in cells where it is needed to be produced; motor neuron cells. In the initial experiments that we did on the infants, we showed dramatic, or what I have called extraordinary or miraculous, benefit with the babies. They are living well past the age of 2 and are achieving motor milestones that have never been observed for a type 1 baby.  Today, we've treated some for 4 years and we have not yet seen a plateau in the benefit.  If you go on youtube or other sites, you can probably see some of the videos that parents have posted showing the progression of their babies. It’s quite remarkable.

For type 2 children, those with a lot of scoliosis, the benefit is a little less because a lot of their problems they have are mechanical but again, we are seeing incredible benefit with Spinraza. And the longer we treat it, the better.

One interesting study we are currently doing is starting Spinraza right at birth. In the past, spinal muscular atrophy was not diagnosed into a couple months after birth but with screening, we can now diagnose these babies at birth. So we are administering Spinraza before they become symptomatic and the remarkable results that study, so far, are that these babies, most of these babies, appear to be developing like healthy babies with no disease at all.

I’ve been in drug discovery development for about 40 years. Normally, we see incremental advances in a disease with a new drug. Spinraza is different. Drug discovery developments usually don’t give us these type of profound events. All of us involved in getting this drug developed feel incredibly privileged to be associated with it.

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