Praxis FDA Clinical Trial Phase 3 - Upcoming Interim Results Q1 2025
- rspace2
- Apr 15
- 8 min read
Updated: Apr 20
Executive Summary - Praxis is a short going into interim results.
Praxis Precision Medicines is developing Ulixacaltamide, a small molecule intended to treat essential tremor. Ulixacaltamide is in Phase 3 development, and Praxis has announced an interim readout in Q1 2025.
In Phase 2 studies, Ulixacaltamide failed to reach statistical significance for its primary endpoint. Although there was a trend towards significance, the Ulixacaltamide treatment arm failed to reach statistical significance (p = 0.125). There are minor differences in the Phase 3 study, but these adjustments are superficial in nature. We therefore believe the Phase 3 study results will mirror those seen in Phase 2.
Additionally, a similar molecule, Suvecaltamide, failed its phase 2 study using the same primary endpoint. Echoing the Phase 2 results introduced above, the manufacturer of Suvecaltamide (Jazz Pharmaceuticals) noted a “numerical difference” between treatment and placebo that did not reach statistical significance.
The trick here is timing. The near-term catalyst is an interim readout, which means the company can kick the proverbial can down the road. Puts are a bit expensive, but it may be worth purchasing a few out of the money puts in case the trial burns down. I favor way out of the money puts - around $40 strike price or synthetic puts to your risk tolerance.
Background Information
Essential Tremor
Essential tremor (ET) is a neurological disorder that causes involuntary, rhythmic shaking—most commonly of the hands, but can also affect other parts of the body. While everyone has some level of physiologic tremor (for example, a slight shake in the hands when held outstretched), essential tremor is more pronounced and persistent, and can interfere with daily activities. Please note this condition is separate from Parkinson’s Disease (PD).
Symptoms:
· The tremor often appears when the muscles are active (unlike PD, which is a resting tremor).
· It is most noticeable in the hands and forearms, but can also affect the head and voice.
· Any activity requiring fine motor skills can become challenging.
This video demonstrates the disease:
Causes:
The etiology of the disease is poorly understood. It is believed to involve abnormal communication between the cerebellum and the thalamus.
Some researchers have hypothesized ET is a neurodegenerative disease centered in the cerebellum. Purkinje cell loss has been observed in post-mortem analyses.
Genetics play a significant role; approximately half of all people with essential tremor have a family history of the disease.
The age of onset varies. For people with familial essential tremor, it tends to present earlier, usually in young adulthood. However, the most common age of onset is after 40.
Prevalence:
Prevalence estimates vary widely (0.5% to 5%) depending on the definition and how it is diagnosed. A general estimate would be about 1% of the population worldwide.
It becomes much more prevalent in older populations. After age 60, the prevalence rises to about 5% and after 80, it rises to 10%.
It is much more common than PD.
Prognosis:
ET is not life-threatening. However, it worsens over time and can cause functional impairment.
Treatments:
Lifestyle
Reducing stress, caffeine, maximizing sleep, and minimizing temperature fluctuations
Drugs
Propanolol (beta-blocker)
Primidone (Anti-seizure medication with poorly understood mechanism of action (MOA) regarding its targeting of ET)
Devices/Interventions
Focused Ultrasound (FUS)
Deep Brain Stimulation (DBS)
Propanol has been used in the treatment of ET since the 1980s. Several studies have found that tremors are reduced by around 50% in half of patients. However, propranolol does little to affect tremors in the neck, head, or voice.
Primidone is slightly more effective than propranolol in treating ET. The response rate is 60-80%, and the tremor reduction is 50-70%. Because the two have differebt MOAs, they are often used in combination when monotherapy fails. Side effects of these drugs are common, as they are older drugs and have relatively non-specific MOAs.
Focused Ultrasound (FUS) uses powerful, targeted ultrasound waves to destroy a small section in the brain responsible for the tremors. It is non-invasive and uses an MRI to guide the waves. The waves converge in the ventral intermediate nucleus (VIM) of the thalamus, generating heat and ablating the tissue. A 2016 NEJM study found a 50% reduction in tremor severity after 3 months that increased to 70% at 12 months. 75-90% of patients experience significant tremor improvement; most see major functional improvement. However, it is only approved for treating one side of the body, typically the dominant side. It is less effective in head, neck, and voice tremors. Possible side effects include balance, swallowing, and mild speech issues, which typically resolve several weeks or months after the procedure.
Deep Brain Stimulation (DBS) modulates brain activity by implanting electrodes at the VIM that connect to a battery-powered neurostimulator placed around the collarbone. The procedure is typically done when the patient is awake to monitor tremor activity. DBS reduces tremor severity by 80-90% in 90+ % of patients. It is the gold standard of ET treatment. It works bilaterally and typically does not lose treatment effect. The main issues with the procedure are the risks involved with neurosurgery and the high cost of the procedure.
Development History in Essential Tremor
Sage-324 Kinetic 2 Study
Sage-324 is a neuroactive steroid GABAa receptor positive allosteric modulator (PAM). It was tested in the treatment of essential tremor during a phase 2 study, dubbed Kinetic 2.
The KINETIC 2 Study was designed to evaluate the dose-response relationship of different doses of SAGE-324 on upper limb tremor. The study also evaluated the safety and tolerability of SAGE-324. The primary outcome measure was the TETRAS PS Item 4 Total Score (which rates upper limb tremor severity from 0 to 4 based on action or posture) at Day 91, with the primary analysis evaluating how this score changed across different SAGE-324 doses.
Patients were randomized to three dosing regimens, 15, 30, and 60mg. There was a period of up titration in the three-month study. It did not exhibit a statistically significant treatment effect at any dose. However, there was a dose-dependent response in adverse effects, such as somnolence, dizziness, fatigue, and headache. Further development on the drug was halted after the negative clinical trial.
Suvecaltamide (JZP385)
Suvecaltamide (mentioned in the executive summary) is a modulator of T-type calcium channels. It was tested in a phase 2b trial in which the primary outcome was the mADL TETRAS score (rates tremor-related interference with daily activities like eating or writing). It did not achieve statistical significance in this metric or the secondary outcome, the CGI-S (clinician-rated scale of overall illness severity, from 1 to 7) scale at the highest dose.
The company did note, however, that there were “numeric improvements” in both the mADL TETRAS score and the CGI-S score. Further development in ET has not occurred. An upcoming phase 2 readout in Parkinson’s Disease will determine the drug's future.
Octanol and Octanoic Acid
Several studies were conducted on 1-octanol and its active metabolite, octanoic acid. The thesis behind this drug is that some people’s tremors were reduced upon ingesting alcohol. Octanol was proposed to mimic alcohol’s effects on the tremors without intoxication. Two studies were conducted, and both had positive results, but lacked power and rigor. Frankly, the results from these small studies seem about as good, if not better, than other medications. Our supposition is further trials were not conducted due to the lack of funding; there is no impetus to develop a non-patentable molecule. Additionally, there were concerns with the frequency of administration and duration of effect.
As a sidebar, I would give octanol and/or octanoic acid a try if you or someone you know suffers from ET.
Praxis Medicines
Now that we have laid the groundwork around the clinical pipeline for ET treatment, let’s explore our company of interest, Praxis Medicines.
Ulixacaltamide
Ulixacaltamide (Prax-944) is a selective inhibitor of T-type calcium channels. The drug is dosed at 60mg daily in the morning. Does this sound familiar? The MOA is similar to that of Suvecaltamide, which failed its phase 2b trial. Two ongoing P3 studies are testing Prax-944 in ET (ESSENTIAL 3). A Q1 2025 interim readout is scheduled. This is the short-term catalyst we are focusing on.
Vormatrigine
It is important to note Praxis is also developing Vormatrigine, a sodium channel inhibitor that is being investigated in focal onset seizures and generalized epilepsy. Vormatrigine trial results are unlikely to interfere with the Q1 2025 Ulixacaltamide readout, as it is anticipated the readout for Vormatrigine will be in latter half of 1H 2025.
Clinical Trials – Ulixacaltamide
Phase 3 Study Design
There are two ongoing P3 trials involving Ulixacaltamide in ET – under the banner of ESSENTIAL3. Study one of ESSENTIAL3 is a randomized, parallel design, double-blind, placebo-controlled study (N = 400) and Study two is a randomized withdrawal (RW) study (N = 200). Of note, a parallel study is a study in which patients are randomized to the treatment groups, and there is no crossover between the groups. The groups of patients are compared at the end to assess the efficacy of the treatment as compared to placebo. A randomized withdrawal study is a study in which patients who initially respond to the treatment are randomly assigned to either continue the treatment or withdraw from the treatment onto a placebo. The study is designed to test the durability of treatment and whether symptoms return upon cessation of treatment.
“Primary endpoints will be change from baseline to Day 84 in mADL11 (TETRAS-ADL items 1–11 with modified score), and the proportion of participants maintaining response following RW. Secondary endpoints will include responder rates and mADL11 change after 12 weeks, as well as change in TETRAS-ADL, clinician and patient measures of severity, Archimedes Spiral, and safety assessments.” A link to the trial announcement is below.
Phase 2 Study Results
It is important to consider the P3 interim readout in the context of previously released P2 data. In Praxis’s P2b readout:
“Ulixacaltamide demonstrated improvement in modified Activities of Daily Living (mADL) primary efficacy endpoint relative to placebo that did not reach statistical significance (p=0.126), and achieved nominal statistical significance in TETRAS-ADL secondary endpoint (p=0.026)”
Simply put, the trial failed phase 2b. They tested dosages at both 60 and 100mg. There were no differences noted between the dosages in the study. The only reason the FDA likely allowed the program to continue onto P3 is the lack of available drug treatments in ET.
Phase 1 and 2 Study Results – Dose Titration
This dose-finding trial tested quite a few dosages, ranging from 20-120 mg. Most of the results did not meet statistical significance compared to their baseline values. Higher doses actually seemed to be less effective than lower doses, which is normally a red flag. There is nothing in this trial that indicates this drug works. Even in the accelerometry study (a quantification of tremor amplitude), the results were not significant. It is possible that in some people it may work, but clinical significance of any benefit is doubfult.
Conclusion
This is cut and dry from a clinical standpoint. There is scant data that indicates Ulixacaltamide is effective as compared to placebo. The targeting of T-type calcium channels as the etiology of ET is dubious at best. There is possible efficacy in secondary endpoints, but it is highly unlikely the drug will pass P3 by meeting the same primary endpoint that it failed in P2.
However, it is hard to know if the company will kill the trial with the interim analysis. Like in P2, there may be some trend toward a positive result with the secondary endpoints, and some degree of improvement compared to placebo, albeit without reaching statistical significance. If this were to occur, it is unlikely the company would outright halt the trial. Will this cause the stock to drop enough to be worth paying the high premium on puts? Will a mixed result actually cause the market to react positively? These are the main factors I am concerned about in this readout.
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