Tag Archives: antisense oligonucleotide

A good problem to have

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Now, this is progress.  Novartis just yesterday announced in clinicaltrials.gov that its Phase 3 trial of NIO752 is ready to accept volunteers for screening. The name of the trial is PRESERVE.  Good name.  No, it’s not an acronym for anything.

So far, the company has only announced three trial sites (Rochester, MN; Englewood, CO; and Ulm, Germany) but dozens more will follow, with a total recruitment goal of 300.  Here are some details of probable interest to potential volunteers:

  • The drug is an antisense oligonucleotide, which as you’ve learned from this blog, interferes with the brain cells’ ability to translate the RNA from a specific gene into its protein.  In this case, the protein is tau, which lies at the heart of PSP.
  • As a very large molecule, NIO752 cannot pass the blood-brain barrier, so it has to be injected directly into the cerebrospinal fluid in the lower spine, using the same procedure as a diagnostic spinal tap (lumbar puncture).  This will be given every three months, assuming it follows the plan of the Phase 1 study.
  • A trial of the drug for safety in 45 people with PSP showed no important or permanent adverse effects from the procedure – just harmless and transient headaches or back pain in some.  Some transient confusion or lethargy occurred in three of the 45 – an effect of the drug, not the injection procedure.
  • The trial will enroll 300 participants overall, of whom 100 will be randomly chosen to receive a placebo injection.  That treatment assignment will be double-blind — not revealed to participant or neurological staff until the whole trial is over.
  • The duration of the double-blind period will be 72 weeks – about a year and a half.  After that, all the patients will be offered the opportunity to continue receiving the drug at no cost, as long as it has not been found to be harmful, and as long as Novartis is still manufacturing it.  That “open-label extension” program may end if and when the drug works and is on the market (let us pray).

Your big question right now should be this: Should I volunteer for the PSP Trial Platform (PTP) or PRESERVE?  The scheduled start for PTP is next month (June 2026), and those sites will roll out gradually, just like the PRESERVE sites.  So, in theory, there’s no overall difference in the timing, though a site near you might open for one study well before the other, or there may be an accessible site for one and not the other.  All the PTP drugs and NIO752 are similarly and acceptably safe, in my view.

Right now, I’d say volunteer for PRESERVE, though by a slim margin.  Two reasons, each minor:

  • Like any large, complicated project requiring approvals from government, private companies and academic institutions, the PSP Trial Platform has been subject to unforeseen delays.  (All major drug trials require collaboration among these three, but the PTP is more complicated than most.) In fact, the company sponsoring one of the three drugs planned for the PTP has still not finalized the arrangements, according to clinicaltrials.org. If that can’t be accomplished soon, the trial will start with only two drugs.  So, a bird in the hand . . .
  • The PRESERVE trial will have an open-label extension (see the caveats above), while the PTP has not yet decided on that, and it may differ across the different drugs.  Without an open-label extension, someone completing the Phase 2 trial would have to wait until the Phase 3 is finished and the drug approved before gaining access to it.  On the other hand, the FDA has been known to approve drugs for general use after only a Phase 2 if the need is great, and for PSP, it surely is. The PTP double-blind trials are 12 months long and the PRESERVE double-blind is nearly 18 months, so assuming both offer open-label extensions, someone on placebo in PRESERVE would have to wait six months longer to receive their active drug than someone in the PTP.

Yes, there are other drugs whose sponsors are optimistic that trials will start within the next year or so.  Those include bepranemab (a monoclonal anti-tau antibody), GV1001 (an anti-inflammatory), ARV-102 (an enhancer of abnormal tau degradation) and TPN-101 (an inhibitor of a toxic protein called LINE-1).  But the timelines there are just too uncertain for someone with PSP to consider right now.

Maybe the most important consideration is which drug is mostly likely to work.  I honestly don’t know, and the Phase 1 data don’t answer that question.  So that simplifies things a bit.

A difficult choice, I know, but a good problem to have. 

ASOs: sci-fi takes a step closer to reality

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Great news from Biogen about an antisense oligonucleotide (ASO) designed to reduce production of the tau protein. 

First, some background: Most of you have heard about ASOs, but for a refresher, see these posts of mine from 2022 and 2026.  Here’s a slightly more technical but cutely animated explanation of ASOs from Harvard Medical School:

The elevator version is that an ASO is a short length of RNA that binds and inactivates the brain’s messenger RNA for a specific protein – or an abnormal version thereof – to prevent it from carrying the protein’s genetic code from the DNA to the protein-manufacturing machinery.  In theory, the production of any protein involved in the cause of a disease can be reduced by designing an appropriate ASO to bind to a segment of that protein’s messenger RNA.

The FDA has approved only one ASO so far – for a childhood muscle disorder called spinal muscular atrophy – but dozens of other ASOs are in the development pipeline for other conditions, including tauopathies. Biogen is currently testing its anti-tau ASO, called diranersen (formerly BIIB-080) against Alzheimer’s, by far the most common tauopathy.  A few days ago, they announced the results of a Phase 2 study of its safety and tolerability.  Here’s Biogen’s press release and here’s the description of the trial (without results) in clinicaltrials.gov. 

Diranersen was well-tolerated in people with Alzheimer’s, as expected based on the Phase 1 results.  The big news was that the rate of accumulation of abnormal tau protein aggregation actually did slow down, as measured by levels of tau in the spinal fluid and by positron emission tomographic (PET) images of the tau protein’s distribution in the brain. The press release didn’t say how much slowing occurred, but it was apparently enough to convince Biogen to proceed to a Phase 3 trial and to convince the FDA to let them do so. More details will be presented at the Alzheimer’s Association International Conference in London in July 2026.

The trial was not primarily designed to assess slowing of progression of the participants’ actual cognitive loss, but it gathered that information anyway in various forms.  The primary such test, called the “Clinical Dementia Rating Scale Sum of Boxes,” measures memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. It did not show a statistically significant slowing of progression for diranersen in Alzheimer’s, but the press release hints that there was some slight, statistically non-significant, degree of slowing.  

That’s all about Alzheimer’s. For PSP, a different company, Novartis, is testing a different anti-tau ASO (NIO-752).  It is also well tolerated, as demonstrated by a recently-completed Phase 1 trial.  If the brain’s accumulation of abnormal tau can be slowed down in Alzheimer’s disease, as the Biogen press release claims, then presumably PSP can achieve the same result.  Novartis says it’s still (as of May 15, 2026) analyzing its Phase 1 PSP efficacy results, but those would have to be spectacular to show statistical significance in so small a study.  That company will soon start testing NIO-752 in a Phase 2 PSP trial in the US and other countries, so keep an eye on clinicaltrials.gov for enrollment instructions.

Given these new results of one anti-tau ASO in one tauopathy, what are the prospects for a different anti-tau ASO in a different tauopathy?  I’ll duck the issue and call them promising but far from a slam dunk. That will be the topic of a future post, but what I can say right now is even these modest, preliminary signs of success with ASOs in tauopathies would have been science fiction back when I was in med school 50 years ago.

Anti-sense makes sense

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Today’s New York Times had a human interest story about people with a rare, genetic form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) who are benefiting from a drug called tofersen (brand name, Qalsody). It was approved for clinical use in the US in 2023 and in Europe in 2024.  The drug slows the progression of that rare form of ALS by about two-thirds, a phenomenal degree of efficacy.  Today’s story was not news, just a heart-warming a review of the experiences of a few of the people benefiting.

Tofersen is a member of a drug class called “anti-sense oligonucleotides” (ASOs).  If that sounds familiar, it’s because several other drugs with the same mechanism are being developed for PSP.  ASO’s interfere with the ability of one’s cells to manufacture a specific protein.  In the case of PSP, that protein is tau, and for ALS, it’s superoxide dismutase-1 (SOD-1).  The FDA approval and the NY Times story pertain only to the 1-2% of ALS sufferers with an inherited mutation in the SOD-1 gene.  However, a 30-subject, non-blinded trial of tofersen in people with ALS without an SOD-1 mutation (that is, the vast majority) is in progress at Washington University in St. Louis, under the direction of Dr. Timothy Miller and colleagues, the drug’s original discoverers.   That trial is scheduled to end in 2028.

As far as PSP is concerned, the ASO furthest along the pipeline is NIO-752, from Novartis.That Phase 3 trial is scheduled to start this month (May 2026) with 300 patients with non-familial PSP (as for ALS, the vast majority). 

Should we expect a two-thirds slowing of progression, as in ALS with SOD-1 mutations?  Probably not, for two reasons:

  1. There’s no single mutation producing abnormal tau protein in the vast majority of people with PSP. 
  2. ASOs are large molecules – to large to cross the blood-brain barrier.  So, they are injected directly into the spinal fluid using the same procedure a diagnostic spinal tap.  ALS is a disease mostly of the spinal cord, which is close to the injection site and only a fraction of an inch in diameter, so tofersen can easily soak into the cord’s full thickness. PSP, on the other hand, is mostly a disease of the brain, where a drug must penetrate a longer distance and into a much larger mass of tissue.  It has been shown to do so in monkeys, but our large human brains may be a different story.

Despite those caveats, I’m optimistic because even if PSP derives only half of the benefit enjoyed by this genetic form of ALS, it will be a huge advance. Scientists call this “proof of principle.” That means that the general idea has been found to make sense in a similar situation.

The list of centers slated to participate in the NIO-752 trial has not been announced, so if you’re interested, keep an eye on www.clinicaltrials.gov, www.curepsp.org or this blog. Before you volunteer, keep in mind that several other promising trials for PSP will be starting over the next few months. Check those same three sources for info on those.

(Disclosure: I’ve done consulting for Novartis, but none since 2023, and I have no financial interest in the company.)

Proof of principle and cause for hope

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The gene therapy company uniQure announced today that its has succeeded in slowing the rate of progression of early-stage Huntington’s disease (HD) by 75 percent.  Although the specific treatment would not work for PSP, the general principle successful in HD could be relevant to all neurodegenerative diseases.

The new research is not yet peer-reviewed nor published.  In writing this post, I used information from the company’s press release,  a news article from the BBC, and Old Reliable, ClinicalTrials.gov.

Unlike PSP, HD is a purely genetic disease.  It works on an autosomal dominant mechanism with full penetrance, which means that anyone inheriting one copy of the disease-causing version of the relevant gene from either parent will develop the disease.  The gene’s technical name is IT15 and it encodes a protein called huntingtin or HTT (notice the “-in” ending indicating a protein).  The gene defect is extra copies of a span of the three nucleotides C, A, and G. This “CAG repeat expansion” directs the cell’s protein factories (the ribosomes) to build into the HTT protein an excessively long string of the amino acid glutamine.  The normal span is 7 to 35 CAG repeats, but in people with HD, one of the person’s IT15 genes has at least 36 repeats. In people with HD, the normal version of the IT15 gene continues to make normal HTT, which means that half of their HTT is normal and half isn’t. The new treatment suppresses the brain’s production of the abnormal half.

Here’s how the trial worked: The researchers started with a kind of virus routinely used in research called AAV, which readily enters brain cells but by itself causes no harm.  They made short stretches of DNA designed to encode a type of micro-RNA corresponding to the abnormal HTT protein.  They inserted that DNA into the viruses and dubbed the result, “AMT-130.” In a 12-18-hour neurosurgical procedure, they injected the AMT-130 viruses into the caudate and putamen, the parts of the brain where HD does its main damage. The viruses released their DNA into the brain cells, which started transcribing it into RNA.  In this case the RNA was actually a “microRNA” designed to bind and disable the cells’ own abnormal RNA that would have gone on to be translated into abnormal HTT protein.   

In that way, the researchers hoped to reduce the cells’ production of abnormal HTT protein.

The trial included 29 people with HD at four study sites (Two in Warsaw, Poland and one each in London, UK and Cardiff, Wales.) Seventeen of the participants received a high dose of the virus, 12 received a low dose and all were observed for 3 years.  They were examined using the standard Unified Huntington’s Rating Scale (UHRS) and other measures of neurological function as well as spinal fluid sampling to measure levels of proteins associated with neurodegeneration.  As a control group, the trial used records of people with HD from an unrelated study of the natural history of the disease called “Enroll-HD.”

The result in the high-dose group was far better than anyone dreamed of. 

The “primary outcome measure,” the rate of worsening in the UHRS, was only 25 percent of that of similar patients from the control group.  Subsidiary measures of clinical efficacy gave similar or even better results.  Levels of neurofilament light chain (NfL), a protein released into the spinal fluid by degenerating brain cells, actually declined, while increasing in the control population. 

The low-dose group gave much less impressive results, which in a way is good because it suggests that the improvement was actually from the treatment rather than from some statistical fluke.

So, is this relevant to PSP?  Yes and no.

It’s relevant to PSP because:

  1. PSP and HD are both neurodegenerative diseases with an abnormally aggregating protein playing a critical but incompletely understood role in the loss of brain cells: tau for PSP, huntingtin (HTT) for HD.
  2. The anti-sense oligonucleotide treatment presently under development in PSP, NIO-752, works by the same principle as the AMT-130 virus.  But it’s injected into the spinal fluid and engages the tau messenger RNA directly, whereas AMT-130 releases DNA, which encodes RNA acting as the equivalent of an anti-sense oligonucleotide.

It’s not so relevant to PSP because:

  1. The tau protein aggregating in PSP is not defective from a genetic standpoint.  Yes, it’s misbehaving, but as far as we know, PSP has no common, specific, mutated form of the tau gene that could make its RNA susceptible to a targeted attack like that provided by AMT-130.  Rather, the misbehavior of tau in PSP is caused by other abnormalities in the brain cells resulting from the cumulative effect of multiple mild genetic mutations, probably along with some sort of toxic environmental exposure. 
  2. The ASO under development for PSP simply reduces the production of normal tau, and since tau has essential functions in the healthy brain, we would not want to completely eliminate its production as AMT-130 could potentially do for HTT in HD.  This means that any benefit provided by the ASO in PSP would have to be moderate at best.
  3. The damage in early HD (the stage recruited by this trial) is almost entirely in the caudate and putamen, the targets of the injections.  But in PSP, by the time a patient is diagnosed, the damage has involved many more than just two areas on each side of the brain.  This would make injecting all the involved areas extremely difficult.

Despite these reservations, the news is good for PSP because like the monoclonal anti-beta-amyloid antibodies for Alzheimer’s disease, AMT-130 sets a precedent for slowing the course of a neurodegenerative disease by attacking an aggregating protein.  But unlike the AD results, the patients receiving AMT-130 for HD suffered only mild side effects and enjoyed a dramatic benefit.

Even if this technique can’t help PSP because its tau is not genetically defective, other proteins are likely to be mutated in at least a few people with PSP.  We do know of 22 genes with some sort of genetically-related defect, but we don’t know if any are encoded into defective proteins like the HD mutation is. 

But we can hope that before too long, there will be diagnostic markers to detect PSP before it spreads beyond two or three small brain areas; and the results of genetic testing in a lone individual with PSP will allow their neurologist to order up a cocktail of injectable gene therapies to fit their own combination of mild gene mutations.  We can dream.

NIO752 update

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Today reader RW posted a comment asking about the status of the NIO752 trial. I thought my answer was so, SO well-crafted and informative that I just had to promote it from a comment response to a full blog post, and here it is:


RW:

First, for the benefit of your fellow readers, NIO752 is the anti-sense oligonucleotide from Novartis. An ASO is a short span of RNA injected into the spinal fluid space. In this case, the injections are given four times: every three months for a year. The drug reduces production of tau at its source — where its gene is transcribed into protein. In my opinion, it’s more likely to work against PSP than any other past or current experimental drug. However, the need for the spinal injections could limit its appeal, especially if one or more of the oral (i.e., more convenient) drugs currently in more advanced stages of clinical testing reach the market first.
The Phase 1 NIO752 trial ended a month or so ago and Novartis, apparently, is still crunching the numbers. It’s typical for that to take 2 or 3 months, so I wouldn’t infer anything from it. Keep in mind that this was only a Phase 1 trial, powered to assess safety, not efficacy. I haven’t heard anything through the grapevine about major safety problems during the trial, but you never know what the actual data might show or how the company might react in terms of continuing to advance the drug into a Phase 2 trial.
LG