Tirasemtiv Update - Final

[Ed340hp]

I finished the Tirasemtiv Clinical Trial.
Two weeks open label, to test reactions.
48 weeks double-blind trial.
An extra two weeks due to scheduling.

My breathing numbers have not dropped for the past 24 weeks, and my leg and arm strength improved over the past 18 weeks (slightly). My small muscles that have more atrophy (hand & foot paralysis in one or more direction of movement) do not feel to have improved on the muscles with the most paralysis, but where I can initiate movement the range of motion and strength feels not much worse than 24 weeks ago. The clinical trial instruments that measure force in kg verify the slightly improved strength in the larger arm & leg muscles.

I felt good enough the past month to use my recumbent indoor bicycle, starting a quarter-mile at the easiest #1 effort, in mid-March. I can now handle #3 for a half-mile, and another half-mile (or more) cool down easy spin at #1 (yes, #3 of #1-#27 effort). Not an everyday thing, and nothing like my 50 miles a week three years ago, but it is something to keep my spirits up. I pay with sore and uneasy muscles over the next few days of rest, if I push too much, but climbing steps is easier and knee-locking pain is less over these past weeks (as is some reduced uneasiness). I can push my wheelchair or a shopping cart further between rests.

Balance remains poor and I still have the occasional unexpected random delay or failure in muscle response, or dragging a foot/toe (the unchanged asymmetric paralysis of small muscles that does not seem to improve). Any trip or fall reinforces the need to be careful because the neuron death symptoms and progression remain unchanged. This is what is hard to communicate, the muscles sometimes simply don't move when called upon, and the small muscle movements that coordinate balance and dexterity are not reliable. There is no conscious feedback to warn you that the coordinated muscle did not get a signal, before a leg, foot, or arm buckles (and you go down, or hug a wall, or hang off the shopping cart handle). Late day fatigue just makes everything worse, but the presence of soreness does not seem to be much of a factor (fatigue comes every afternoon: exercising, lazy, or somewhere in between).

I apparently suffer slow progress with neuron death, and symptoms progress slow enough to notice a failure in neuron communication as the muscles atrophy. The neuron mortality progress remains relentless. Being sporadic, with my DNA not matching a familial sequence, I am unlikely to see a Clinical Trail for gene therapy as they rightfully target and trial one of the known familial gene sequences for splicing as the science matures. A symptom treatment may be the only option for my time, unless funding and research accelerates to include a shotgun gene splice effort for sporadic PALS (unlikely with current FDA protocols).

I now have four weeks of detox, to empty any residual Tirasemtiv from my system, before I start being assured I get the drug. They say the drug's muscle effects may last the four weeks. I hope so, because I prefer the stability of the past 20-odd weeks.

After detox they will start with the minimum 125mg dose for two weeks, and add an extra 125mg to the dose every two weeks moving forward until I reach the full maximum dose of 500mg/day (or level out, where & if I have an adverse reaction).

Tirasemtiv is not a neuron treatment, but as a muscle treatment it may have promise to keep some of us breathing without aids for more than a few extra months as we progress.

 

[AKNate]

Thank you for updating us! I hope this treatment is still doing you well & that it'll offer help to everyone soon enough.

 

[Ed340hp]

I return Friday to begin the next Vigor-ALS phase. I will be given the treatment drug, without guessing, as opposed to the earlier double-blind clinical trial where we never knew what was in the tablets.

In the past three weeks of detox with no drug, my frequency of muscle cramps and spasms have increased. Fatigue, strength, and coordination do not appear to have changed, but some of the irritating symptoms have returned. I forgot what the severity of the thin muscle section cramps inside the larger muscle groups were like (ouch), and the toe and finger cramps are worse than weeks back (irritating).

Thanks for the encouragement.

 

[KimT]

It really sounds like you got the real thing. I'm so glad you are getting the drug Friday. If the cramps and spasms decline, that will be a very good sign. I'm hoping and praying.

 

[AKNate]

Hey Ed,

It does sound like you got the real thing, please keep us posted in the coming weeks.

Can you also let us know how you were pre trial in terms of progression/strength etc? How were you going into the trial with stairs and other things - you mentioned climbing stairs was easier.

 

[don ng]

please update us thanks for this tirasemtiv thank you

 

[frankb]

Not to have ALS progression for 24 weeks is a big deal. Congrats.

 

[Ed340hp]

Two weeks into the guaranteed dosing at the 250/day level.

In the blind trial I did not know if symptoms were progression, or the drug. Knowing now that I am on the drug helps review the past year symptoms.

The past two weeks required adjustment. Muscle stiffness and heavy resistance returned, and some of the dizziness, as the drug changes how the muscles react to requests from the brain. The muscles move differently, with more muscle contraction tension on joints. The brain now has to add amplitude to get the muscle to contract on one side of the joint, and overcome some added muscle tension on the other side of the joint. The result is stiffness that is taking some major adjustments to get used to, and reprogramming of how to balance and coordinate movement (as before during parts of the blind trial). The first week on the drug was very difficult to adjust and predict movement, and to trust coordinated movement. This second week is getting much better. I am not back to where I was six weeks ago, but I am slowing trying to trust more predictable coordinated movement (it's been difficult).

I am still slow, stiff, weak, and at times need to mentally coordinate movement, but my knees are not as loose. I was walking with more locked knees two weeks ago, not trusting quads and leg muscles, and I feel less pressure and less pain on the knees this week.

Hand and finger strength is poor from atrophy, and I lost noticeable coordination strength in the detox weeks. Foot and toe, and ankle, strength & coordination loss is similar. Too early to tell if it will return.

My progression of atrophy is evident, and has been evident throughout the blind trial. A year ago, in June, I was walking with my stick and could handle a half-mile stretch with muscle fatigue recovery before a similar walk. I can maybe get fifty yards now, and foot and leg muscle fatigue is as bad as after the longer distance before, and recovery now is very difficult. My atrophied muscles swell up, but the big difference is lack of trust that the muscles will move as intended, as trust is severely diminished. Conscious feedback is needed now, as opposed to the unconscious expectation of coordination before. The experience affirms that this drug does not address neuron mortality, nor neuron coordination, it just enhances muscle function.

I just hope I can gain back some strength and range of motion, and trust to move as intended. The goal is quality of life, and in that context anything that offers stability is a win. I hope the blind trial results show quantified promise, because comparing the speed of progression was difficult (and is difficult, with a new challenge everyday).

 

[Ed340hp]

This is a brief update. The first two weeks at 250mg were rough as described before. The third and forth week were better as far as mind and body coordination. The edgy feeling subsided some, although anxiety from general progression and stiffness made sleep difficult. I am trying a drop of CBD oil before bed and it appears to help.

Week five was a jump to 375mg. Difficult adjustment, again, stiffness and poor coordination that is subsiding after six days. Strength is better on steps up curbs, when coordination is good. Endurance is OK. No substantial improvement tested, with the adjustment hindering motivation and trust of coordination. I stopped the CBD oil before the increase dosage, and anxiety got worse. Returned to the CBD oil drop before bed, and it is slowly getting better.

The jump to 500mg, and my normal clinic visit are scheduled next week. Hopefully the bumpy ride will smooth out.

 

[Ed340hp]

I want to update what the rough edge feeling is like. It is much like the nervous feeling after drinking way too much coffee or caffeine, combined with weather when you get a dry wind that is charged with a lot of free negative ions. The overall jittery feeling.

This jittery feeling, and the compromised balance, has subsided a lot.

The other thing is that I am moving some fingers and toes in motions that were near impossible eight weeks ago. The motion comes with the risk of cramps in muscle that has been quiet for months.

Hopefully, this description of what to expect can reduce the anxiety if the trial is conclusive in its benefit, and other PALS are feeling similar jitters and unease as they get dosed.

 

[AKNate]

Thanks so much for your constant updates Ed. It's so helpful and really gives hope to us all.

Do you know when this phase is due to finish? I'm strongly hoping for another ALS win this year!

 

[Ed340hp]

The phase 3 Vitality-ALS clinical trial for FDA review ends in July. My 50 weeks ended in March, and the last participants finish in July. The trial was tracked on a computer database from the start, so initial reports may be complete as soon as late October. If it proves valid the rest is up to the FDA.

The follow up non-FDA trial is Vigor-ALS. The Vitality-ALS participants like me are offered Tirasemtiv for free if we choose to continue. The difference is we are not in a double-blind trial. We are guaranteed to get the real drug. We know we get the drug, and our Doctors know, so we can work together to test what works to optimize the benefit. The plan is to follow PALS who choose to continue with the drug until the FDA approves or fails the Phase 3 trial result (hopefully with approval, and forever until a cure is found).

The Vigor-ALS testing is less often, and limited to SVC, but they are teamed with a software company who is testing a program to predict progression. The software goal is to speed predictive models of progression, to help Physicians and PALS optimize the benefit, and to speed up FDA Clinical Trials (use models to cut trials from 50 weeks to a shorter period).

A big problem with ALS Trials has been the 50 weeks, and the washout rate. Too many PALS do not finish the long 50 week trials. The pool of PALS for trials is small, so with the current 50 week protocol PALS get only one shot at a trial. With predictive modeling we might get 24 week FDA Trials, and two or three shots at trials, expediting a cure.

I am moving better today. The difficulty with the dose stabilization delay is that any layoff is a opportunity for this disease to kill neurons. Building and maintaining muscle tone suffers from any delay, so the unease and delay raises anxiety (and you just have to reinforce the delay is still better than the do-nothing alternative).

 

[Ed340hp]

My quarterly clinic visit was Tuesday, and everything is stable. No bad changes.

We talked about the rough edges and the tirasemtiv. The suspect is a caffeine reaction. It is subsiding. We will see.

 

[AKNate]

Hey Ed,

How is this med administered? Is it a pill?

 

[Ed340hp]

Hey Ed,

How is this med administered? Is it a pill?

Yes.

Each pill is 125mg.

Two pills in AM (250mg)
Two pills in PM (250mg)
Total dose for each day 500mg.

The pills are best absorbed on a stomach with minimal solid food, providing the reason for no food two hours before taking the pills, and no food for one hour after taking the pills.

The pills can be crushed and taken with a liquid.

I have been on the full 500mg dose for ten days. I also cut caffeine out ten days ago. The dose increase side effects are nearly gone. The caffeine withdrawal is slowly going away too.

The full dose is effecting a better muscle range of motion. I am still working out the coordination. My phone says I have upped my step count to about 1500 per day. I have been feeling the muscle twitching, but also more controlled movement, so more fatigue. It seems to be a benefit.