Tag Archives: symptomatic

GV-1001: unclear news is good news

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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.

    Current treatment trials

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    My last post was a nerdy list of pathogenetic mechanisms in PSP along with the statement that treatments to address most of those mechanisms are in the clinical pipeline. One of you wrote in to kick me out of my lofty, scientific detachment, asking just what those treatment candidates are. So here’s a list.

    The first four panels are active trials and the last is future trials.

    The first two and last panels show neuroprotection trials (i.e., to slow disease progression).

    The third and fourth show symptomatic trials (i.e., to help the symptoms without affecting the underlying disease process).

    For current information on how to enroll, visit clinicaltrials.gov and search on the drug and/or sponsor and/or “progressive supranuclear palsy.”

    A how-to guide for doctors

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    Educating health care providers about PSP and CBD has long been a goal of mine and of CurePSP.  Most of my patients relate unfortunate stories of bothersome or even disabling symptoms for years before any physician suspected the correct diagnosis.  During those years, they may have endured futile, expensive, and potentially harmful diagnostic tests and treatments.  Even after PSP or CBD is correctly diagnosed, attempts to manage the symptoms are often unsupported by evidence, prescribed at an inappropriate dosage, or continued after any benefit has disappeared — while their side effects continue.

    All too often, the neurologist tersely informs the patient that no treatment is available for PSP or CBD and that they should just go home, do the best they can and maybe get some physical therapy.  While it’s true that there’s no “specific” treatment or way to slow the underlying disease process, there are treatments that ease most of the symptoms as symptoms.  This is called “palliative” or “symptomatic” management and it’s up to the neurologist and other clinicians to understand and offer it.

    These management measures are not unique to PSP or CBD – they are standard drugs and therapies used for symptoms regardless of their underlying cause.  Having said that, it’s also true that patients with PSP may differ from others in their reactions to common medications. 

    You may recall that in 2018 a brief single-author book appeared that described management of PSP for clinicians.  For better or worse, the author (that would be me) relied heavily on his own experience, his own reading of the literature and his own philosophical point of view to recommend diagnostic and therapeutic approaches.  That was great as far as it went, but it didn’t reach much of an audience.  The book’s cover price — $75 for the paperback or digital editions – deterred many, and the publisher didn’t advertise it at all.

    But now we have a new resource – the CurePSP Centers of Care.  In 2017, when CurePSP organized this network of highly-qualified academic centers in the US and Canada, the mission was to have a list of geographically well-distributed centers providing first-rate care for PSP and CBD.  The network has now grown to 30 sites with plans for 10 more in the next few years.  But besides providing care, the CoC’s are also uniquely positioned to work collaboratively to improve care.  

    So in 2019, I and the other three members of the CoC Steering Committee (Drs. Irene Litvan, Brent Bluett and Alexander Pantelyat) organized the other 21 (at the time) CoC site directors to write a “best practices” document on the symptomatic management of PSP and CBD.  We divided the topic into 12 section and for each, created a writing committee from the list of site directors and any institutional colleagues whom they chose to recruit as collaborators.  Each committee submitted a 2- or 3-page draft that the Steering Committee edited and stitched together into a coherent article.  We returned that to the whole group so that every co-author could have some input into the whole document and then submitted the result for publication.

    We chose Frontiers in Neurology, an “open-access,” on-line journal, meaning that viewing and downloading articles does not require a subscription or a per-article fee.  Such journals cover their expenses by having advertising and by charging a fee to the authors; in our case CurePSP paid the $2,950 bill.

    Here’s the link to the article and here’s the URL: https://www.frontiersin.org/articles/10.3389/fneur.2021.694872/full

    Please consider sending the link (or a hard copy) to any clinician you know who takes care of people with PSP or CBD.  That’s not only neurologists, but also primary care physicians and nurse practitioners, ophthalmologists, optometrists, rehabilitation medicine specialists, neuropsychologists, physical therapists, speech/swallowing therapists, and occupational therapists.  Maybe keep a copy in your “go-bag” to provide to your doctors and nurses in a hospital or emergency room.  CurePSP will soon start a North America-wide campaign to distribute the link along with a series of videos of experts discussing and enlarging on points raised in the publication.

    I think the authors of the paper did a great job, if I do say so myself.  But now begins the real work of broadcasting our advice so that clinicians can be competent and comfortable taking care of people with PSP and CBD.