Thursday, June 11, 2015

There is No Doubt: Splice Modulator Drug for Spinal Muscular Atrophy Works

The fairy-tale story of the splice modulation for spinal muscular atrophy (SMA) continues.  This morning, Isis Pharmaceuticals provided an update on the phase II study of ISIS-SMNRx in type I SMA infants.  The data built on already highly promising data as of last September, showing that a doubling (~9 to ~18 months) of the median ‘event-free survival’ compared to the Natural History has now been reached with numbers still increasing as more than half the infants remain event-free.

Only one out of 12 infants still on study suffered an event (permanent ventilation) over the last 9 months.  This one in 108 month event rate compares to 6 events in ~200 months in the prior phase of the study, suggesting that if babies can be diagnosed and treated early enough so that they are covered during a critical period of development (e.g. maturation of the neuromuscular synapse) chances are that they will enjoy a very significant treatment benefit from ISIS-SMNRx.

This is thus consistent with the biomarker data showing that ISIS-SMNRx increases the missing functional full-length SMN protein by 2-3 times essentially turning a type I SMA infant (usually 2 copies of SMN2) with an 80% chance of dying or going on permanent ventilation by 18 months into a much milder form of the disease where patients have 4 or more copies of SMN2 and have an almost normal life expectancy (note: those with 3 copies, usually type II SMA, live into teens/early adulthood). 

While as a parent, I would almost do anything for my child to get access to the drug and I do understand there to be calls for immediate (à once diagnosed, the window of treatment opportunity may be quite narrow) regulatory action, the first consequence of today’s data should be getting SMA on mandatory genetic panels for newborn screening.  Only then will there be maximal benefit once the ongoing blinded phase III study reads out in late 2016/early 2017.


Anonymous said...

With an $8B current market cap do you think there's potential for gains to reflect the risk here? Lots of treatments fail at this stage, let alone those for infants.

Dirk Haussecker said...

Err, you talking about Isis Pharmaceuticals? ISIS-SMNRx is 'just' 1 of their ~40 drugs in the pipeline.

Anonymous said...

Did you write a recent post about Sarepta? Apparently they are doing well.

Anonymous said...

The market is reacting in a strange way to seemingly excellent Isis data/updates of late. Be very careful here. Could this be a sign that there is trouble with the platform that has not been made public yet?

Anonymous said...

Not so much trouble with the platform, more like a leap frog of the technology by the new kid on the block rendering ISIS obsolete.

Even Dirk seems to think so. When he asks the following question, I would've thought he'd be suggesting his always hold, never sell all time favourite and bigger than Apple stock ISIS for contender. But nope, he's touting ARWR now.

who else but $ARWR for broad strategic $ALNY-Genzyme-type partnership- or BIGGER?

Anonymous said...

Not so sure it's a tech leap by someone else. The market doesn't think that strategic in the time frame where this will play out. Just noise.

Anonymous said...

Pioneering gene therapy may save babies’ lives

Researchers in Columbus seek to aid development of children born with spinal muscular atrophy

Tenley, in December, became one of eight babies who’ve so far had the one-time, one-hour infusion of experimental gene therapy that researchers are beginning to let themselves believe might rescue babies from this disease.
Some had a low-dose infusion, others a dose that Dr. Jerry Mendell calls “intermediate.” The goal is to find a sweet spot, where you reap optimal benefit but don’t deliver a deadly dose.
Mendell, who has devoted nearly five decades to neuromuscular disease, is not a boastful guy. He’s mindful of pitfalls and rooted by dashed hopes.
But a smile crept across his face last week as he pulled out his cellphone to share video of a baby in the study. She could sit up on her own.
So far, the babies who’ve had the heftier dose have done significantly better, which was expected. And it appears that delivering the treatment as early as possible is critical, said Mendell, who directs the Children’s Center for Gene Therapy.
On a graph that plots their developmental progress over time, every baby is either not getting worse or is improving. If you looked at a similar graph of untreated SMA babies, the lines would all go down.
“No one in this trial has succumbed to the disease, which is really exceptional,” Mendell said, pointing to one baby’s chart. The measures have hit a normal range.
If the babies continue to do well and the Food and Drug Administration eventually OKs the treatment for any baby with SMA, routine testing after birth could find newborns with the disease and prompt immediate treatment, Mendell said.
Before he goes to the FDA with results, he’d like to test the therapy in 12 babies, including newborns identified in utero because their parents had a previous child with SMA.
Mendell said it’s unlikely that motor neurons already lost to the disease can be recovered, so speeding the treatment is critical.
If the project continues to generate good results, this work could propel gene-therapy development for other diseases, including Lou Gehrig’s disease and muscular dystrophy, Kaspar said.

Dirk Haussecker said...

Let's hope the gene therapy is working. It would also be a nice complement to ISIS-SMNRx. The more SMN protein in more cells (note: biodistribution of viral vector and ASO will not be identical) the better!

gene genie said...

Dear Dirk what is your view on the TMK Ebola study reaching the predetermined end point.

Anonymous said...

Cure SMA ‏@CureSMA 21h21 hours ago
Dr. Finkel: limited supply of drug may also be an issue in open access. #SMAconference

Cure SMA ‏@CureSMA 22h22 hours ago
Dr. Finkel: FDA are not the "bad guys." They fulfill a key role in helping us design safe & effective trials. #cureSMA #SMAconference

so what does it take to get accelerated access.....?...or is that just a pipe dream to get families to keep sending their money like a carrot on a stick?

does it work? are there improvements? yes or no

Anonymous said...

when it comes to the dull ISIS stock action recently, it must be kept in mind after Friday June 26 ISIS is kicked out of the Russell 2000 and indexers have been and will continue to be dumping massive quantities until end of trading 6/26. It doesn't matter it is being kicked upstairs to the Russell 1K. All the real action is in the R2K, about $500B indexed to it and ISIS is the largest component at .5%, well to be precise now the second largest after a semi merger put a semi stock ahead of ISIS. The numbers may not be precise but .5% of $500B is an awful lot of selling pressure on ISIS.

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