Tag Archives: GV-1001

My bob-tail nag

Posted on by

One of this blog’s frequent commenters — OK, it’s my pal Jack Phillips, CurePSP’s Board Chair — prompted by my 3/8 26 post, has asked which of the three PSP Trial Platform drugs to bet on.  That’s a tough one, partly because unlike racehorses, each has a different mechanism of action, so it’s an apples/oranges/peaches comparison.  But as long as I don’t have to worry about peer review of my blog posts, here’s what I’m thinking at this point:

  • The AADvac anti-tau vaccine induces one’s immune system to make anti-tau antibodies, so one might expect it to do no better than the two failed passive (i.e., directly infused) monoclonal antibodies from a few years ago.  But the antibodies formed in response to AADvac recognize the middle part of the tau protein, while the monoclonals recognized the initial (i.e., N-terminal) end.  There’s good evidence now that the toxic part of abnormal tau is in AADvac’s middle-domain wheelhouse. So, the questions now are:
    • Has tau already done its dirty work before reaching the form or location susceptible to the antibody?
    • Most of the damage done by tau happens inside the brain cells, where antibodies can’t reach.  The hope is to pick off the abnormal tau in transition from one brain cell to another.  That works in mice with an abnormal version of the tau gene that causes a familial form of frontotemporal dementia with Parkinsonism.  But FTDP isn’t quite PSP and mice aren’t quite people.
  • LM11A-31 is very different.  It enhances the brain’s ability to repair existing damage.  It has shown benefit in a number of different animals models of different diseases with different aggregating proteins (or with none).  In humans with neurodegenerative diseases, the only published experience is in Alzheimer’s disease, where the benefit was modest, though the study was too small to assess efficacy in a valid way.  My concerns are that:
    • The drug’s modulation of the cells’ compensatory mechanisms might be too subtle to stand up to the onslaught of misfolded tau and other perturbations present in PSP.
    • Starting from an early stage of involvement in PSP, brain cells transmit misfolded tau to other cells.  It’s possible that this happens before the cells have lost much of their functional abilities, perhaps before the mechanisms that LM11A-31 modulates become relevant.
  • AZP-2006 improves lysosomal function, thereby helping the cells dispose of tau that’s overabundant, misfolded, aggregated or excessively phosphorylated. I personally favor that idea for three main reasons:
    • The high frequency of co-pathology (where the tauopathies have mild levels of other aggregating proteins) suggests that specific defects in a shared garbage disposal system affect specific combinations of proteins.  This in turn implies that if the predominantly affected protein is tau, then a tauopathy develops, with a few aggregates of other proteins such as α-synuclein, TDP-43 and others. I’d done research on the PSP cluster in a group of towns in northern France with severe ground contamination by multiple industrial metals. Lab experiments (performed in collaboration with a team under Drs. Aimee Kao and Carolina Alquezar at UCSF) have suggested that some of the metals in that environment can damage the disposal mechanism without affecting the production of tau itself.  That suggests that a treatment like AZP-2006 aimed at that mechanism could work.

So, my analysis gives AZP-2006 a slight edge among these three. But that’s based partly on results of my own research, so I have a sentimental bias.  Then there are other drugs in the pipeline, like:

  • NIO-752 (a tau-directed anti-sense oligonucleotide to reduce tau production)
  • FNP-223 (an inhibitor of an enzyme that allows phosphate group to attach to tau)
  • GV-1001 (mostly an anti-inflammatory to quell one important step in the disease process)
  • Bepranemab (passive, mid-domain antibody infusions)

Besides, much smarter people than I have been crashingly wrong in predicting clinical efficacy of drugs. But it’s a good mental exercise to think about it.

GV-1001: unclear news is good news

Posted on by

In July 2023, I posted a guardedly optimistic report on the launch of a small, Phase 2a trial in South Korea of the drug GV-1001, with the generic name “tertomotide.”  Three weeks ago (sorry for my delayed vigilance on your behalf), the company released some of the results.  The headline was that the drug failed to show benefit in slowing the rate of progression on the PSP Rating Scale.  Nevertheless, the company, GemVax, said they remained optimistic and would proceed with plans for a Phase 3 trial in North America and elsewhere.

Here’s the deal in a bit more detail.  I say “a bit” because it’s not as much detail as I’d want to see.  The trial was only 6 months long and the plan was for only 25 patients in each of the three groups: higher dose, lower dose and placebo.  That’s too brief and too small to demonstrate a realistic degree of slowing of progression.  The best longitudinal analysis of PSP to date calculated that to demonstrate a 30% slowing in a 12-month trial would require 86 patients per group.  Shorter trials and more modest slowing would require even more patients than that.  But early-phase trials like this are mostly about safety, not efficacy.

The results for the low-dose and placebo groups appears below, just for the PSP-Richardson patients: 

The vertical axis is the average improvement (downward) or worsening (upward) in the total PSP Rating Scale relative to the patient’s own baseline score.  (On the PSPRS, 0 is the best and 100 the worst possible score, and the average patient accepted into a drug trial has a score in the mid-30s.)  At 3 months, neither group showed much change.  But at 6 months, the placebo group had deteriorated by 4 points but the active drug group had remained close to its baseline.  So, that looks like a benefit, but the wide standard deviation (the vertical “whiskers” at 3 and 6 months) were too large to support statistical significance (i.e., to rule out the possibility of a fluke result).  Hence the negative headline, but you can see why the drug company felt encouraged by the result.

A more complicated but statistically more valid way to look at the same results appears below. This graph applies to both PSP-Richardson and PSP-Parkinson patients, hence the larger Ns:

This time the vertical axis is “least square mean change from baseline.”  That uses a statistical technique called “mixed-model repeated measures” to compensate for statistical noise in the results.  The basic shapes of the active drug and placebo curves look similar to the raw score graph.  But now, the two lines have the same slope between 3 and 6 months, suggesting that their rates of progression over that period were the same.  The interval from baseline to 3 months did have different slopes, favoring active drug.  So, this could mean one of 3 things:

  1. There’s a neuroprotective effect (i.e., a slowing of the progression rate) that lasts only 3 months, at which point the two groups proceed to progress at the same rate;
  2. There’s a symptomatic improvement by the 3-month point that persists to the 6-month point, but no protective effect at any point; or
  3. The trial’s small size, wide standard deviations, paucity of evaluations and short duration make it impossible to draw any conclusions about symptomatic or neuroprotective efficacy.

I’ll vote for Option 3.

The data for the high-dose group, which received twice the lower dose, is not presented in the company’s press release.  However, the high-dose group was included in the poster at the Neuro2024 conference (CurePSP’s annual international scientific meeting) in Toronto in October.  It did not show the possible benefit that the low-dose group showed.  So, that’s a little discouraging, but it’s not unheard-of in pharmacology for a higher dosage regimen to do something extra via a different chemical mechanism that counteracts some of the benefit of a lower dosage. So, that doesn’t worry me much.

    Now, the issue is just how safe and tolerable the drug was.  The press release only says, “The safety profile of GV1001 in the Phase 2a PSP Clinical Trial was consistent with prior safety data. GV1001 was generally well-tolerated with no serious adverse events related to the drug reported.” I’ve seen the actual numbers, and the press release is right. All of the adverse events, and there were very few, were things common in this age group or complications of PSP itself.

    So, that’s probably more information than you wanted about GV-1001, or maybe it’s a lot less than you’d have liked. (I’m in the latter category.)  Bottom line is that the results were good enough to justify a Phase 3 trial, which is slated to start in 2025, and that’s really good news.

    Note: The text in italics explaining the two graphs and detailing the drug side effects are corrections or additions to my originally posted version. I thank Roger Moon, Chief Scientific Officer of GemVax, for supplying this information after he saw the original post. These changes do not alter my conclusions.

    Four reasons to hope

    Posted on by

    It’s high time I updated you on currently – or imminently – recruiting PSP clinical trials.

    Here are the four in chronological order. All these are for “neuroprotection,” meaning slowing of the underlying disease process. They don’t attempt to improve the existing symptoms, however. That’s called “symptomatic” treatment and I’ll get around to that soon.

    More details:

    Sodium selenate provides supplemental selenium, which is critical for the function of 25 human enzymes with a wide range of functions. Two are relevant to PSP: glutathione peroxidase 4 and protein phosphatase 2A. The first regulates one type of programmed cell death and the second removes phosphate groups abnormally attached to the tau protein. The trial is happening only in Australia. See here for details, including contact information.

    FNP-223 inhibits an enzyme called 0-GlcNAcase (pronounced “oh-GLIK-nuh-kaze”), which removes an unusual sugar molecule from its attachment to tau. The sugar is called N-acetyl-glucosamine and it prevents abnormal tau from attaching at the same spots on the tau molecule. It’s an oral tablet and the trial, which has just started, will be in both Europe and North America. Click here for details and contact info.

    AMX-0035 is a mixture of two drugs in an oral solution. Both are currently marketed for conditions unrelated to neurodegeneration. The PSP trial has started in North America and will do so in Europe and probably Japan in the next few months. One of the two drugs, called sodium phenylbutyrate (marked as Buphenyl), addresses the brain cells’ management of abnormal proteins. The other, taurursodeoxycholic acid, marketed as TUDCA, helps maintain the mitochondria. Click here for details and contact info.

    Finally, GV-1001 is an enzyme with anti-inflammatory action in the brain. But it’s not like a steroid or non-steroidal anti-inflammatory drug. It acts by an mechanism that the drug company is keeping close to its chest and has something to do with DNA transcription into proteins. The drug has to be injected subcutaneously every day, like insulin. A small trial is in progress in South Korea and in you live there, here’s enrollment info. There are plans to start a trial in the US in 2025, but that could depend on the current trial’s outcome.

    Soon, I’ll post something on neuroprotection trials in which the double-blind recruitment is over but the results are pending. After that will be symptomatic trials.

    With all these trials in progress, CurePSP’s “Hope Matters” tagline is truer than ever.