"It has been one of the greatest and most difficult years of my life. I learned everything is temporary. Moments. Feelings. People. Flowers. I learned love is about giving- everything- and letting it hurt. I learned vulnerability is always the right choice because it is easy to be cold in a world that makes it so very difficult to remain soft. I learned all things come in twos: life and death, pain and joy, sugar and salt, me and you. It is the balance of the universe.
It has been the year of hurting so bad but living so good, making friends out of strangers, making strangers out of friends. We must learn to focus on warm energy, always. Soak our limbs in it and become better lovers to the world, for if we can't learn to be kinder to each other how will we ever learn to be kinder to the most desperate parts of ourselves."

— Rupi Kaur

This poem is for the many GNE Myopathy (aka HIBM) patients who had a bad week last week due to the disappointing update on treatment. I didn't make a formal public announcement but last October I joined Ultragenyx's Phase III human study on Sialic Acid extended release (Ace-ER). This substrate's extended release Ace-ER was in part licensed by ARM funded HIBM Research Group Lab (I used to be an ARM representative for 7-8 years but have since taken a break and more of an independent advocate) as well as Nobelpharma and AAIPharma. Ultragenyx, like many of us, had hoped this Sialic trial would demonstrate positive results but alas could not meet primary and secondary endpoints.

I didn't formerly announce my enrollment in the trial because I wanted to see how the trial progressed before raising the hopes of the many who have supported my numerous fundraising efforts over the past 11 years...BUT last week Ultragenyx announced their trial failed and they would abandon all development of the drug and move on from GNE Myopathy (HIBM).

*It's important to note that just because the trial failed does not mean sialic substrate doesn't work but alas we don't have the data to know either way.

For the past few years there have been TWO substrate trials happening at the same time. Ultragenyx's Sialic was one, NIH's ManNAc was the other. NIH began working on ManNAc in 2003 after they hosted an HIBM workshop in collaboration with Dr. Daniel Darvish, founder of HIBM Research Group, and in 2005 NIH proved ManNAc to be beneficial in HIBM mouse model. NIH finally began a ManNac trial in 2012. Ultragenyx began their sialic trial in 2011. 

I did my best to keep walking, waiting for either trial to begin but in 2011 I went into a full-time wheelchair...RIGHT before Ultragenyx announced the start of Phase I trial. The Ultragenyx sialic trial began in 2011 and neither Sialic nor ManNac trials were open to non-walking patients. The logistical reasons in terms of data collection for this make sense but it was still a bummer, after all I had made fundraising and advocating a near (free) full-time job for 5 years. But I was still happy some form of human trials were beginning for our condition and watched the progress with caution.

Last year I attended the RAREArtist ceremony as an awardee on DC's Capitol Hill. Ultragenyx's CEO, Emil Kakkis was there and he and I got to talking about the sialic trial. I told him I was an HIBM patient (aka GNE Myopathy) and asked why this trial wasn't open to wheelchair patients. I understand a lot about the trial process and that non-walking patients can't complete a lot of the physical tests required for pertinent data collection. But as a wheelchair-bound patient I explained to him how much more devastating it is to lose your upper extremities than lower extremities. He shared my sentiment and understood, explaining the team doesn't always think of that, "they're always thinking about saving the legs", he said. But he felt the same and assured me that admitting wheelchair patients would be topic they would discuss.

Now, like I said I get the clinical trial data collection process and my inability to even chart in many of the strength tests necessary to collect data (to decipher if the therapy is working or not) but I explained in 5-10 years (the realistic projection for a substrate to come to market) the number of wheelchair customers will be even higher than today. We are a big market for whatever future therapy is approved. Now I'm not even sure if this discussion influenced open enrollment of wheelchair bound patients but as soon as Ultragenyx announced opening the trial to non -ambulatory patients later that year, I joined.

So why do GNE patients' muscle degrade? In short it's thought the primary reason is we don't produce sialic acid. 

What is sialic? The following is quoted from NIH: "Sialic acid is a negatively charged sugar localized at the end of glycoconjugate chains on glycoproteins and glycolipids. These chains are present on the cell surface and are crucial for many biological processes, including cell adhesion and signal transduction. Sialic acid synthesis is tightly regulated; defects in this pathway cause a variety of disorders, including hereditary inclusion body myopathy (HIBM), sialuria, infantile sialic acid storage disease (ISSD), and Salla disease.

HIBM is caused by mutations in the gene encoding the key enzyme in sialic acid synthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase, which in turn leads to sialic acid deficiency. Without adequate supplies of sialic acid, progressive muscle degeneration (or myopathy) sets in."

So what's left? What's the future? Well, NIH's ManNAc trial is still happening and had Osiris results for their Phase II trial, and a couple different organizations either have a gene therapy proposal or are starting gene therapy development, and perhaps in the near future we will go even beyond these proposed therapies...

I've been an advocate for so long, 11 years, that I'm almost numb to bad news but the devastating news was crushing to many and appears to be a major setback. I cried some but in a way I wasn't completely surprised, but it was still disappointing. It's frustrating for those who keep getting worse and I don't think anyone can understand this feeling unless they've experienced constant mobility loss.

Many are fretting the dreadful chair, a major milestone, just as I did a few years ago. My new dreaded milestone is the fear of losing upper extremity capacity...BUT I'm trying to live for today and within my personal passions and goals in order to remain focused. It isn't always easy but I don't have many other options. 

I feel bad for everyone but to everyone I would say keep going and keep sharing. Don't lose hope, it may still be a very long road or maybe not, who knows. The point is every effort from those involved is another step to perhaps another door. Perhaps in the not so distant future, despite my own potential increased frailty, we will have prevented a newly diagnosed patient from getting worse and that has to mean something. I'm not saying I've given up but I'm aware of the reality that maybe I won't make it this time around or maybe I will...I guess we won't know unless we keep trying. That's all we can do. Today there are more patients, more organizations and more scientists involved, all we can do is help grow the noise of GNE Myopathy. If you need a break, take one. If you have the energy, be loud.

Much love to all the patients XO.