There have been a number of interesting developments in CMT research in the past few weeks. Here are three:

Update 1:

Pharnext recently announced topline results of its pivotal phase 3 (PREMIER trial) of PXT3003, its drug candidate for Charcot-Marie-Tooth 1A (CMT1A) concluding that it was a failure. CMTRF did not fund this project but was hopeful for a positive result.

Researchers design phase 3 studies to demonstrate whether a product offers a treatment benefit to a specific population. Sometimes known as pivotal studies, these studies involve 300 to 3,000 participants. Phase 3 studies provide most of the safety data. In previous studies, it is possible that less common side effects might have gone undetected. Because these studies are larger and longer in duration, the results are more likely to show long-term or rare side effects.

In this specific trial, the Overall Neuropathy Limitation Scale (ONLS), which measures functional motor disability, did not confirm findings from their previous clinical trial. Patients with mild-to-moderate CMT1A experienced improvement on both treatment and placebo, rather than the slow deterioration typical of CMT1A’s natural progression. This unexpected improvement in the placebo group complicates the interpretation of the results based on this endpoint. It also confirms what the medical literature as a whole has been saying for many years, namely that ONLS is undoubtedly a relevant endpoint over the long term, but not over such a short period of time as a clinical study.

Other data from the trial suggest no deterioration in the condition of patients under treatment, which is a positive sign in the context of a degenerative disease such as CMT1A. This suggests that PXT3003 might stabilize the condition of patients, which is an important consideration for a disease where progression is generally inevitable. The trial reaffirmed the high safety profile of the treatment, already established in previous studies, crucial for treatments of chronic diseases such as CMT1A.

“Considering these initial results, Pharnext plans to continue analyzing the data, particularly in collaboration with potential partners for licensing or acquisition of PXT3003. This analysis will help determine the next steps toward potential marketing authorization,” said the company.

Although the results we are sharing today are not exactly what we had hoped for, they are nonetheless very promising,” Pharnext’s Manager Hugo Brugière said. “We are now going to make the most of all the data we have accumulated over the last 10 years, including our two phase 3 studies and our 6-year extension study, which tend to demonstrate a beneficial effect on patients.”

Regulators usually leave it up to the company to make their case for approval even if outcomes aren’t what was expected – recently, some drug trial results for other indications were not overwhelming and many thought they wouldn’t be approved, yet they were. The company will likely be meeting with the agencies to explain the data and get insight. They will be pursuing approval in the hope that it can have a stabilizing effect on some patients.


Update 2: 

South Korean genome editing developer ToolGen Inc. announced in December that its application for orphan drug designation of the gene correction therapy (TGT-001) for CMT1A, submitted to the US Food and Drug Administration in September has been approved. This designation offers benefits such as tax deductions for clinical expenses, exemption from new drug application fees, and market exclusivity for seven years after approval.

ToolGen’s gene correction therapy TGT-001 aims at the root cause of CMT1A, protein overexpression due to the duplication of the PMP22 gene. The company says that it has completed validation of the treatment strategy through animal experiments.

In this video from 2020, Susan Ruediger CMTRF’s CMO interviews Dr. Jae young Lee of ToolGen:


Update 3:

In Japan a number of researchers report development of a method to delete the additional copy of PMP22 gene by 20–40% to prevent overproduction. Their results show that this method can reduce PMP22 protein production, leading to near normal production in patient’s nerve cells. Further safety assessments will be undertaken. If the treatment is safe for patients, it could become a therapeutic option for CMT1A patients.