Tag Archives: NIO752

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. 

A report from the ASO front

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The Comments section just received a trial participant’s personal report and some good questions about the anti-sense oligonucleotide (AS0) trial sponsored by Novartis.  As explained in my last post, all the patients in that trial have completed their participation and the data are being analyzed.  First, here’s the comment unedited (except for correcting the location of the PSP conference and my bracketed clarification in the fourth line), followed by my response.

IT WORKS! My husband was in the trial. No cure but a great year – his condition was improved in so many ways. I have been waiting for someone at Cure PSP to put out the word. I assumed they were going to present at the Toronto conference but they did not.

We are so sad they [Novartis] refuse to continue to give it to us. Novartis has a published policy to keep giving people in a trial drugs that provide help but denied us with the excuse it was phase 1. Even if it is too expensive when administered through the spine it provides evidence that this horrible disease can be managed and greatly improves life. We would love to go to Novartis and show them how it works. Hopefully they are not just proceeding on using it for Alzheimers. We have been watching and waiting to see if they release results. They need to publish them. HOPE MATTERS! Kathy and Steve from San Diego, California.

Kathy and Steve:

I’m so glad that you, Steve, had symptomatic benefit from NIO752.  You raise several good points deserving separate responses:

  • The known molecular mechanism of the drug would merely slow down, or hopefully halt, the future worsening of the disease, not improve it in absolute terms.  People entering clinical trials may start paying new attention to their health and changing their habits regarding diet, hydration, exercise, physical and other types of therapy, compliance with concomitant medication, and discontinuation of unnecessary concomitant medication that might have been producing side effects.  There’s also the possibility of a placebo effect.  All this, of course, could make someone entering the trial feel better and is why establishing true drug efficacy requires a control group. 
  • The reason not to provide the drug post-trial to Phase 1 trial completers is that the purpose of Phase 1 is to establish safety, and until that trial is over and the data analyzed, the drug’s safety remains unknown in people with PSP.  Even if the trial is over and the drug found to be safe, that applies only to the duration of the trial.  So, allowing a trial completer to continue to receive the drug for longer would be taking a safety risk, and there would no longer be a placebo group to use in assessing the magnitude of that risk.
  • That said, there’s a slight theoretical possibility that the reduction in tau production caused by NIO752 could actually allow recovery of normal function by some brain cells that were malfunctioning but still salvageable, producing an immediate symptomatic improvement.  But that might have no relationship to any long-term neuroprotective benefit.
  • I do have some good news in response to your hope that Novartis is still pursuing PSP rather than just Alzheimer’s.  I’ve heard that the company has been seeking information useful for the design of an efficacy PSP trial.  That suggests that such a trial is being at least provisionally planned. 
  • The results of Phase 1 trials are not always be published in journals, but they are often presented as posters at conferences and are announced by the company in the form of press releases.
  • Yes, HOPE DEFINITELY MATTERS!

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

Anti-sense oligo update

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CurePSP asked me to write up something on ASOs for their website (www.curepsp.org). Thought I’d give my loyal blog readers a sneak peak:

Probably the single biggest story in the world of PSP right now is NIO752.  That’s an antisense oligonucleotide (ASO) being tested for safety and tolerability in people with PSP.

ASOs interrupt the process by which a specific gene’s DNA is transcribed into RNA, thereby reducing the production of the encoded offending protein.  The ASO itself is a short stretch of RNA whose genetic code is a mirror-image of part of the DNA whose translation is to be suppressed.  The ASO’s genetic sequence and that of the offending DNA recognize each other and stick together, preventing the corresponding protein from being produced. In this case, the targeted DNA is the MAPT gene, which encodes the tau protein. Other ASOs operate by targeting slightly different stages of the transcription/translation process.

In the US, the FDA has approved several kinds of ASO, the best-known being nusinersin (brand name “Spinraza”) for spinal muscular atrophy, a progressive and usually fatal condition that typically starts in infancy but in mild forms can start at any age.  In the pivotal trial of nusinersen, 21 of 51 infants receiving the drug were improved after 6 months, while that was true for none of the 27 infants receiving sham treatment.  If we can achieve similar results for NIO752, it would be by far the best news ever for PSP.

ASO molecules are too large to cross the blood-brain barrier, which means that for a brain disease, they must be administered by injection directly into the spinal fluid.  This is performed as for a diagnostic spinal tap.  In the current trial, NIO752 is given once monthly over a period of 3 months and the participants are examined periodically for an additional 9 months.  The 64 participants are at 4 sites in the US (La Jolla, CA; Boca Raton, FL; Rochester, MN and Nashville TN), 2 in Canada (both in Montreal), 5 in Germany and 1 in the UK. This safety and tolerability trial is expected to end in May 2024.  Its sponsor is Novartis Pharmaceuticals, co-headquartered in Basel, Switzerland and Cambridge, MA. For more information: 1-888-669-6682 or novartis.email@novartis.com

A trial can detect important safety issues with only 64 participants but detecting actual benefit requires more.  The standard “primary outcome measure” for clinical treatment trials in PSP is the PSP Rating Scale.  Assuming that is still the case in 2024, when a treatment trial would begin, and half of the participants receive placebo, the minimum number of participants needed would be 276.  That number also assumes that the study is designed to detect at least a 30% difference between the two groups’ rates of progression.  Detecting less of a difference would require more participants and detecting a greater difference would require fewer.  A new outcome measure with less variability than the PSPRS would reduce the number of participants required.

From the standpoint of those with PSP and their families hoping to enter a trial of NIO752, the most important number isn’t a number, but a date: A trial starting in mid-2024 would probably end in 2027. Another important number is the eventual price of the drug.  NIO752 would have to be injected every month, lifelong. Nusinersen’s price is $125,000 per injection.  So, if the price of NIO752 is anything like that, the cost to Medicare, Medicaid and private insurors would present an impossible situation.  CurePSP estimates that about 20,000 people in the US have PSP at any given time.  If even half of them received a $125,000-per-month drug, the total annual cost would be $15 billion plus the doctors’ fees for the monthly injection procedure.  Clearly, something would have to give. 

But first, let’s hope that NIO752 actually works.