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The U.S. Food and Drug Administration (FDA) has lifted a partial clinical hold that limited the use of certain dose levels of prosetin being tested in <a href="https://projenx.com/">ProJenX</a>’s Phase 1 trial.
The <a href="https://clinicaltrials.gov/study/NCT05279755">PRO-101 trial (NCT05279755)</a> is a three-part study designed to test the oral medication in healthy volunteers and people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The first two parts in healthy volunteers have been completed, and the company has received the green light to launch the final portion of the study, which will investigate the experimental therapy in people with ALS, in <a href="https://alsnewstoday.com/news/phase-1-trial-testing-prosetin-als-patients/">Canada</a> and <a href="https://alsnewstoday.com/news/projenx-phase-1-trial-testing-prosetin-als-expands-eu-countries/">Europe</a>.
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<h3>ALS patients in US will also be recruited for the trial&#8217;s final Part 1c</h3>
With the removal of the partial hold, ALS patients in the U.S. will also be recruited for the trial&#8217;s final Part 1c. ProJenX didn’t disclose when the hold was applied or the reasons for the FDA’s concerns.
&#8220;Following recent Clinical Trial Application authorizations in Canada and Europe, we are very pleased that FDA has lifted this partial clinical hold, which previously limited prosetin dose levels in Study PRO-101 in the United States,&#8221; Erin Fleming, ProJenX’s co-founder and chief operating officer, said in a <a href="https://www.prnewswire.com/news-releases/projenx-announces-removal-of-partial-clinical-hold-for-prosetin-program-by-fda-302101883.html">company press release</a>.
&#8220;The FDA&#8217;s decision allows us to fully pursue a global strategy to bring this promising investigational treatment to people with ALS and other neurodegenerative diseases,&#8221; Fleming added.
In ALS, some proteins acquire an abnormal structure and clump together, forming toxic structures that are believed to contribute to nerve cell damage and disease progression. A cellular organelle called the endoplasmic reticulum (ER) has some ability to reduce these abnormal proteins, either by promoting their correct folding, or by targeting them for degradation.
However, when too much of these proteins are present and ER demand largely surpasses its capacity, a condition known as ER stress may be triggered, which can lead to cell death.
Prosetin, developed by ProJenX co-founders at Columbia University, is a first-in-class oral therapy designed to reduce ER stress in nerve cells, easing damage and reducing cell death. It works by blocking a protein called mitogen-activated protein kinase kinase kinase kinase, or MAP4K.
After promising findings in patient-derived cells and animal models, ProJenX launched the first-in-human PRO-101 trial to investigate the experimental oral therapy in healthy volunteers and ALS patients.
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<h3>Prosetin found safe in volunteers without ALS</h3>
Results from the first two parts, in which healthy volunteers received single or multiple ascending doses of prosetin or a placebo, indicated the treatment was generally safe and well tolerated.
&#8220;There is an immense unmet need for safe and effective treatment options for ALS, and prosetin is an exciting investigational therapy option in the current clinical trial landscape,&#8221; said Jinsy Andrews, MD, associate professor of neurology and director of neuromuscular clinical trials at Columbia University.
&#8220;I am encouraged by prosetin&#8217;s compelling preclinical efficacy data and by its consistent safety and tolerability profile in healthy volunteers and chronic toxicology studies, and look forward to working with the ProJenX team to bring Study PRO-101 to people <a href="https://alsnewstoday.com/living-with-als-2/">living with ALS</a> in the United States,&#8221; Andrews added.
The trial will now evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of prosetin oral solution in people with ALS. Pharmacokinetics refers to the movement of a medicine into, through, and out of the body, while pharmacodynamics looks at a compound’s effects on the body.
More than two decades of research have shown &#8220;a critical role for MAP4K inhibition on ALS motor neuron survival, and we are thrilled to be advancing prosetin to people living with ALS in the coming months,&#8221; said Stan Abel, president and CEO at ProJenX.

Partial clinical hold lifted in US for Phase 1 trial of ProJenX’s prosetin

Health Canada has cleared <a href="https://projenx.com/">ProJenX</a> to open the third part of its ongoing Phase 1 clinical trial and begin testing the experimental therapy <a href="https://projenx.com/our-science/">prosetin</a> in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The first two parts of the <a href="https://clinicaltrials.gov/study/NCT05279755">PRO-101 trial (NCT05279755)</a> involved healthy participants and showed that the therapy has a good safety and tolerability profile. This final portion now will continue to evaluate prosetin’s safety, tolerability, and pharmacological properties in ALS patients.
&#8220;Following Health Canada&#8217;s [clinical trial application] authorization, we will be able for the first time to evaluate prosetin in people living with ALS,” Erin Fleming, ProJenX’s co-founder and chief operating officer, said in a <a href="https://www.prnewswire.com/news-releases/projenx-receives-health-canada-clinical-trial-application-authorization-for-first-study-of-prosetin-in-people-living-with-als-301999912.html">press release</a>.
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“We are encouraged by the safety and tolerability profile that has emerged from completed healthy volunteer studies of prosetin, and we are laser-focused on initiating ALS patient enrollment in Canada as quickly as possible,&#8221; Fleming added.
In ALS, certain proteins are folded abnormally and more prone to form clumps, which is known to contribute to nerve cell damage and death. One way these clumps affect cells is by causing stress in certain cellular organelles, including the endoplasmic reticulum (ER).
This cellular compartment normally works to produce, fold, and transport proteins, but when it becomes overwhelmed with too much unfolded proteins, it can trigger cell death.
&#8220;Despite scientific advances, ALS remains a fatal, devastating neurodegenerative disease that demands more meaningful treatment options,&#8221; said Angela Genge, MD, associate professor at the Neurology and Neurosurgery Department at McGill University. Genge also is director of the ALS Centre of Excellence for Research and Patient Care at the Montreal Neurological Institute (The Neuro).
<h3>How prosetin works</h3>
ProJenX’s lead candidate, prosetin, is a first-in-class oral therapy designed to revert ER stress and reduce damage to motor neurons — the nerve cells that are affected in ALS. It works by blocking a protein called mitogen-activated protein kinase kinase kinase kinase (MAP4K).
Based on the discovery that blocking MAP4K protected motor neurons in several patient-derived cell models, ProJenX’s co-founders at Columbia University optimized prosetin to reach the brain and potently inhibit MAP4K in nerve cells. Their studies showed that prosetin reduced inflammation and <a href="https://www.projectals.org/wp-content/uploads/2019/10/Development-of-MAP4-Kinase-Inhibitors-as-Motor-Neuron-Protecting-Agents.pdf">improved nerve cell survival</a> in an animal model of ALS.
ProJenX was created in 2022 out of a research collaboration between <a href="https://projectals.org/">Project ALS</a> and Columbia University in New York City to rapidly develop and commercialize prosetin for people living with ALS. Following its launch, the first-in-human PRO-101 trial began <a href="https://alsnewstoday.com/news/dosing-begins-phase-1-clinical-trial-prosetin-als/">evaluating the candidate therapy</a> in healthy volunteers and ALS patients.
The trial is divided in three parts. In parts 1a and 1b, a number of healthy volunteers received single or multiple ascending doses of prosetin or a placebo. Now, Part 1c will evaluate the treatment in people with ALS.
&#8220;ProJenX has generated compelling preclinical data showing that prosetin may protect motor neurons against well-established pathological [disease-causing] mechanisms in ALS,” said Genge, who also is an investigator in the PRO-101 trial.
Prosetin was granted <a href="https://alsnewstoday.com/news/prosetin-granted-orphan-drug-designation-for-als/">orphan drug designation</a> for ALS by the U.S. Food and Drug Administration in 2020. The status grants several incentives to companies developing medications for rare disorders, including financial benefits and seven years of market exclusivity if the therapy is ultimately approved.

Tag: ProJenX

Partial clinical hold lifted in US for Phase 1 trial of ProJenX’s prosetin

Final part of Phase 1 trial to test prosetin in ALS patients