Investigational Treatment IPL344 Safely Slows ALS Progression in Small Phase 1/2a Trial

IPL344, Immunity Pharma‘s investigational therapy for amyotrophic lateral sclerosis (ALS), has a positive safety and tolerability profile and slows disease progression by about 50%, according to interim results from a small Phase 1/2a clinical trial.

The company said it now is planning a placebo-controlled trial to evaluate IPL344 in a larger ALS population. Pending positive results, the pivotal trial may support applications to regulatory agencies asking for IPL344’s approval.

“We are encouraged by the sizable magnitude (about 50%) of the disease-slowing effect observed in this small study. Our goal is to establish this large effect in the pivotal trial, especially as even drugs with smaller magnitudes of effect are considered a great step forward,” Eran Ovadia, Immunity Pharma’s CEO, said in a press release.

IPL344 is an investigational molecule designed to activate the Akt signaling pathway. Akt is important in protecting nerve cells from the processes that drive ALS progression, such as cell death, inflammation, and the buildup of misfolded proteins.

But this signaling pathway often is deactivated in ALS, leaving cells vulnerable to those destructive processes.

By directly activating Akt within cells, IPL344 is considered a disease-modifying therapy, or one that targets the disorder’s root cause. It is given intravenously (directly into a vein) once per day.

IPL344 received orphan drug designations from both the U.S. Food and Drug Administration and the European Medicines Agency earlier this year.

The open-label Phase 1/2a trial (NCT03652805) is designed to determine the safety and maximum tolerated dose of IPL344 in up to 15 ALS patients. It is ongoing at the Hadassah Medical Center, in Jerusalem, Israel, and is still recruiting.

Participants first undergo a 28-day Phase 1 safety study. After this, they may choose, at the investigator’s discretion, to continue in the long-term Phase 2 efficacy study (NCT03755167), and receive treatment for up to three years.

Treatment begins at 1.7 mg/kg and increases by 0.5 mg/kg every three to four days to the maximum dose of 3.2 mg/kg.

So far, eight patients have completed the 28 day safety study. No drug-related adverse events (side effects) have been reported.

Researchers also reported changes in functional impairment and respiratory function in the first six patients who received treatment for more than four months (range four to 13 months, average eight months).

During that period, patients experienced a 49% slower decline in existing abilities — as measured by ALS Functional Rating Scale-Revised (ALSFRS-R) scores that cover speech, swallowing, dressing and hygiene, among other daily functions — compared to their decline before treatment.

In advanced stages of disease, ALSFRS-R scores decline in a linear manner, meaning that physicians can predict a patient’s progression over a given period of time. During the average eight months of treatment, patients lost an average of 4.7 fewer ALSFRS-R points than that projected based on their pre-treatment progression.

Notably, the benefits started mainly after the first two months of treatment. Beyond that two-month mark, IPL344 slowed disease progression even further, by 61%.

Lung function was measured using the slow vital capacity (SVC), which measures the maximum volume of gas expired during a slow expiration. The six patients lost 1.3% SVC per month, on average, compared to an average of 3.1% among in the general ALS population.

This amounted to a 57% decline, or improvement, in the rate of lung function deterioration.

Both measures of functional impairment and lung function are well-established predictors of survival and the results so far indicate positive impacts on patients’ quality of life.

These interim results are in line with those from a patient treated earlier under a compassionate treatment protocol.

This rapidly-progressing patient began treatment at an advanced stage (ALSFRS-R=15), and survived under treatment for 26 months, losing only one ALSFRS-R point during the first 22 months.

“The results presented so far, in Immunity Pharma’s clinical trial and the preceding compassionate treatment with IPL344, are encouraging,” said Marc Gotkine, the study’s principal investigator and head of the Hadassah Medical Center’ ALS clinic in Jerusalem.

In the trial, IPL344 also was found to restore patients’ Akt activation levels to normal ranges, the company said.

“We have shown that our drug engages the Akt pathway, which is rapidly gaining recognition as a key pathway in ALS,” said Ovadia, Immunity Pharma’s CEO.