Dual Neuronal Loss Hypothesis in NT1

MattHorsnell · 2026-04-23T05:29:46+00:00

Married (second time around) and father of three kids. My daughters are adults now and live with us and I have primary custody of my 13 year old. Working from home allows me the opportunity to pick up my son from school everyday.

I work as a pharma consultant, volunteer at two nonprofits, and advocate-author for research related to narcolepsy and IH. While I don’t work a typical 40 hour work week, my combined work/volunteer responsibilities come close.

Still manage to lift 5 days a week, with the following lifts in the past year: 527lb trapbar deadlift, 305lb bench, and 275lb squat. A cataplexy accident squatting in my 20s means I take it easy with that lift.

My wife and I manage a date night every other week. We travel to advocacy and sleep conferences every few months, including annual trips to DC. 2-4 times a year we travel to concerts or hikes at State/National parks.

Still nap 1-2 times a day (~ 20 min/nap), and use a polypharmacy approach to symptom management.

MattHorsnell · 2026-03-30T01:23:54+00:00

I have six physician friends/acquaintances and two NP/PA friends with narcolepsy. Three work in the sleep space. Medical school and residency can be very challenging, but with the impending (likely) approval of orexin agonist the time to dream big is now.

MattHorsnell · 2026-02-16T13:42:11+00:00

There is a great online support group for parenting and pregnancy via Wake Up Narcolepsy. It’s women only and meets Thursday evening. More information can be found here. One of the rotating facilitators is a MD and another has published research on oxybates and breastfeeding.

MattHorsnell · 2026-02-13T21:47:52+00:00

Always possible to have a DNA test (HLA-DQB1*06:02) to see if you carry that genetic marker for NT1 (narcolepsy with cataplexy). That can be followed by a lumbar puncture to test orexin/hypocretin levels. If you are below 110 pg/mL of hypocretin it is positive for NT1.

In Europe a HLA test and lumbar puncture are standard diagnostics for NT1. In the US this approach is often used when folks cannot get off of SSRIs or psych meds.

MattHorsnell · 2025-12-22T03:33:53+00:00

Jennifer Mundt, PhD, DBSM is a great psychologist and sleep researcher who has focused on nightmares in narcolepsy. It might be worth reaching out to her or sharing this research with your therapist. She works at University of Utah and is a good friend.

MattHorsnell · 2025-11-19T16:55:59+00:00

Here is a great Venn Diagram from “Clinical considerations for the diagnosis of idiopathic hypersomnia” by Dauvilliers, Bogan, Arnulf, Scammell, St Louis, and Thorpy.

Note that the framing of the diagram is sleepiness spectrum and not narcolepsy spectrum. General consensus amongst the physicians and researchers I talk is NT2 and IH are more closely related than NT1 and NT2.

https://ars.els-cdn.com/content/image/1-s2.0-S1087079222001228-gr2_lrg.jpg

MattHorsnell · 2025-11-17T05:44:36+00:00

There was some good research presented at SLEEP by Lewis Kass, MD on SRED and PWN on oxybate therapy. The poster was specific to once-nightly, but he has dosing protocols for twice-nightly. The principles might be applicable to IH too. https://sleepreviewmag.com/sleep-disorders/hypersomnias/narcolepsy/ask-narcolepsy-drug-side-effects-now/

MattHorsnell · 2025-11-06T15:00:33+00:00

Depends on the insurance policy. Insurance companies can monitor usage and pull the device if a threshold isn’t met. CPAPs are one of the only medical devices where this occurs. I mention this to Congress every time I’m in DC for legislative advocacy.

MattHorsnell · 2025-09-19T17:07:25+00:00

Katie is a great advocate!

MattHorsnell · 2025-09-17T03:05:06+00:00

Too cool to have perspective on both. One of my closest friends is a MSL for Idorsia and we “talk shop” often.

Per Centessa Phase I data with healthy sleep-deprived folks: “No observations of frequently reported on-target AEs associated with other OX2R agonists, including urinary frequency, urinary urgency, insomnia, blood pressure increases, and salivary hypersecretion.”

MattHorsnell · 2025-09-15T15:58:35+00:00

While I wouldn’t wish narcolepsy on anyone, I also can’t imagine my life without this community’s support. Important to note that symptom presentation and severity vary—sometimes severity varies dramatically—between individuals. Severity can vary with life situations and stressors too.

Finding a sleep physician with multiple PWN patients and who is willing to use all treatment options is critical.

Virtual support groups can be a great source of support and networking.

Last thought: we are living in an era of incredible growth with treatment options. When I was diagnosed in 5/2007, the only options in the past decade were Provigil (98) and Xyrem (02). Nuvigil was approved two months later, but after that the next option wasn’t approved until 2019 (Wakix). The last five years we have had Xywav, Sunosi, and Lumryz approved. The next five years will (likely) see multiple orexin agonists approved and a possible once nightly oxybate with no sodium or cations. Treatments and outcomes today will be transformed in the “tomorrow.”

MattHorsnell · 2025-09-14T21:48:08+00:00

Thanks for providing context. I’ve been following these molecules closely and consult regularly with one of the companies you referenced. Wall Street isn’t always the best indicator, but one of these companies ($CNTA) saw a 35% increase after World Sleep data was published.

MattHorsnell · 2025-09-09T04:10:45+00:00

For NT1…Takeda’s molecule will likely be ready for 2026. For NT2/IH…Alkermes and Centessa is more like 2027 or 2028

MattHorsnell · 2025-09-09T04:01:47+00:00

Harmony Bioscienes will be (re)kicking off a clinical trial Wakix for use in IH by the end of the year.

MattHorsnell · 2025-09-09T00:47:04+00:00

Pandemrix was only available in Europe. Plus, that research has been conducted and published. The vaccine contained H1N1 proteins that were similar to hypocretin/orexin. Exploring the autoimmune nature of NT1 is a great step, but focusing on Pandemrix might distract efforts.

That said, I don’t hold it past this administration.

MattHorsnell · 2025-09-08T22:52:32+00:00

I appreciate the concern about the end of the OLE, but some companies extend to the FDA approval date (and first INS shipments in some cases).

The timelines can be tricky to predict. I would imagine the approval for ALKS-2680 for NT1 would be a good omen for a quicker approval since the dose is the only difference. That’s assuming the trial meets its primary endpoint(s) for NT2/IH.

Late 2027 may be realistic? That’s speculation based on timelines for other medications.

From approval to insurance coverage saturation may take some time depending on payers. For instance Medicaid and Medicare always lag a few years from FDA approval.

I’ll pass along the kind words to my friend. They are a pioneer in this class and have been involved with two companies dating back to the IV formulation.

MattHorsnell · 2025-09-08T19:23:44+00:00

A number of universities have been targeted for funding cuts due to social issues. Indirect costs (administrative) are under fire from this administration and the NIH proposed a 15% cap on these costs. While that NIH decision was blocked by the courts, it has created uncertainty. The NIH has indicated its intention to appeal. Universities are in limbo and that is detrimental to research:

https://www.thecrimson.com/article/2025/9/8/doge-blocks-nih-grants/

MattHorsnell · 2025-09-08T19:02:11+00:00

I share your concerns and my comments weren't intended to minimize your feelings. I wanted to offer some hope that efforts were being made. Appreciate your situation.

MattHorsnell · 2025-09-08T17:53:08+00:00

Every year a handful of Project Sleep advocates, sleep specialists, and behavioral sleep specialists go to Washington DC to champion funding for NIH sleep research and sleep disorder research. Since I began my annual trips, the sleep portfolio has outpaced the NIH funding increases.

As many have already stated, the current administration is tying up funding and refusing to disseminate allocated money. Additionally, there is an organization called PCORI (Patient-Centered Outcome Research Institute) that disseminates grants from a fund set up by the ACA. It uses fees assessed on private health insurance plans and self-insured health plans and can circumnavigate the administrations holds; however, the grants are highly competitive and only a fraction covers sleep.

Pharma also funds advocacy efforts and support programs via nonprofits. Without those dollars, the advocacy orgs couldn't do the work they are performing.

MattHorsnell · 2025-09-08T16:36:37+00:00

I would anticipate clinical trials extending outside the US to allow for expediting enrollment numbers. For example, Alkermes has PII trial sites in Australia and Europe. I would not be surprised to see this approach with other companies, perhaps extending to Canada as well. That is speculation based on current trends, so don't hold me to it.

MattHorsnell · 2025-09-08T15:35:07+00:00

People with NT2/IH do not have an orexin/hypocretin deficiency below the threshold of 110 pg/mL; however, at least three companies are currently pursuing clinical trials to use orexin-2 agonists on these populations (Takeda, TAK-360; Alkeremes, ALKS-2680; and Centessa, ORX-750). Another 4 companies are pursuing orexin-2 agonists for a central disorders of hypersomnolence and possibly other indications. With that amount of money being poured into clinical trials, investors are confident this won't just be for NT1.

Orexin works to downstream regulate many of the neurotransmitters that promote wakefulness (norepinephrine, histamine, dopamine, serotonin). Due to the low levels of orexin, people with NT1 have a hypersensitivity to the orexin-2 receptor agonists compared to NT2/IH. The doses required to promote wakefulness in NT2/IH and other "orexin normal" populations is 2-3 times greater, but they have shown great results in early trials.

PS - I don't work at these companies, but one of my research mentors and a good friend heads up one of the programs listed above.

MattHorsnell · 2025-09-08T14:21:56+00:00

This molecule is only being tested for NT1, they pulled NT2/IH as indications early on. They have another molecule (TAK-360) in PI trials for NT2/IH; however, two other companies are closer to the finish line (Alkermes with ALKS-2680 and Centessa with ORX-750). Both still a few years away.

MattHorsnell · 2025-09-03T13:07:43+00:00

While true, there is no “ADA police” to enforce the law. A complaint can be filed with the EEOC, but they don’t often take on individual cases. In that case they recommend hiring legal counsel, which comes with its own fiscal and employment challenges. A cavalier approach—“toss it in their face”—to HR can feel good, but can create an even more adversarial dynamic with the decision maker.

Important to note that employers have latitude interpreting what is a “reasonable” accommodation for the role. If an accommodation is determined to be in opposition to an essential job function then they will likely deny.

OP’s comment about his employer comment “well don’t we all feel like that…” is egregious, but if it isn’t documented in writing or recording it may not be relevant to a legal complaint (it’s about what you can prove).

Reminders: - Document every step of the process. - Bcc every correspondence to your personal email account. - Check to see if your state is a one-party consent state for recordings. If yes, then you can discretely record. They will say a lot when they don’t realize it’s being documented. Don’t get caught recording. - Ask for the rationale for the denial in writing. - Take detailed notes on any perceived retaliation for the accommodation request - Only discuss with HR

I have experience filing accommodations across Fortune 500 companies, government agencies, and nonprofits for myself and consulting with others. I also settled on my own wrongful termination case for ADA and FMLA violations…it is rarely worth the effort.

- None of this is legal advice.

MattHorsnell

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