LOS ANGELES — The novel agent soticlestat flopped in a pair of phase III trials for rare seizure disorders, researchers reported here.
Among Dravet syndrome patients in the SKYLINE trial, the median change from baseline in convulsive seizure frequency over the full treatment period was -22.16% with soticlestat and -8.64% with placebo, a nonsignificant difference (P=0.061), reported Venkatesha Murthy, MD, of drug developer Takeda Development Center Americas in Cambridge, Massachusetts.
In addition, among Lennox-Gastaut syndrome patients in the SKYWAY trial, the drug did not significantly reduce the frequency of major motor drop seizures during the treatment period, with a percentage change difference of -1.17% from baseline compared with placebo (P=0.785).
Results likewise came out neutral for seizure frequency during the maintenance period and for all secondary endpoints. Both trials were presented by Murthy’s group at the American Epilepsy Society annual meeting.
Soticlestat had raised hopes as a first-in-class selective inhibitor of cholesterol 24-hydroxylase, which is a brain-specific enzyme that reduces glutamatergic hyperexcitability.
However, Takeda announced in June that the trials had missed their primary endpoints for Dravet syndrome and Lennox-Gastaut syndrome. The company worked with regulators to determine whether positive outcomes on secondary endpoints for certain patients might be enough to move forward.
In a prespecified exploratory analysis in the Dravet syndrome population, soticlestat did significantly reduce convulsive seizures in the subgroup of patients with the SCN1A gene mutation thought to be causative in the condition (difference of -17.38 percentage points vs placebo, P=0.045).
Most patients do have this mutation, which perhaps meant that this group had confirmed Dravet cases, Murthy suggested.
Caregiver- and clinician-rated improvement, as well as responder rates, also significantly improved with the investigational agent, although disability-related quality of life and non-seizure symptoms were unchanged.
However, Murthy told MedPage Today that the future looks dim for soticlestat. “Recently, we’ve heard [the FDA does] not see this evidence as providing substantial evidence of effectiveness,” he said.
SKYLINE included 144 patients ages 2-21 years (mean age 10.5) with a Dravet syndrome diagnosis adjudicated independently by the Epilepsy Study Consortium. The trial enrolled patients with at least 12 convulsive seizures over 12 weeks before screening and at least four per 28 days during the baseline period. They had failure of at least one antiseizure medication before enrollment and could be taking up to four antiseizure medications at a stable dose.
SKYWAY included 270 patients ages 2-55 years (mean age 12.5) with a Lennox-Gastaut syndrome diagnosis, also adjudicated independently by the Epilepsy Study Consortium. They had to have failure of at least one antiseizure medication at baseline and at least eight major motor drop seizures per 28 days during the 4-week minimum prospective baseline period.
Both trials randomized patients to twice-daily doses of 300-mg soticlestat or placebo, both in addition to standard-of-care treatment, with a 4-week titration period and 12-week maintenance period.
Murthy noted that the trials were adequately powered, with SKYLINE being the largest trial to date in Dravet syndrome.
There are other drug candidates moving forward in the field, he noted, “so this is not going to be seen as disappointing news. But for us, it’s really disappointing.”

Disclosures
The trials were funded by Takeda Development Center Americas.Murthy and other authors disclosed employment by Takeda.

Primary Source
American Epilepsy Society
Source Reference: Murthy V “Soticlestat as adjunctive therapy in children and young adults with Dravet syndrome: The phase 3 SKYLINE clinical trial” AES 2024; Abstract 2.375.

Secondary Source
American Epilepsy Society
Source Reference: Guerrini R “Soticlestat vs placebo as adjunctive therapy for Lennox-Gastaut syndrome: Results from the phase 3, randomized SKYWAY clinical trial” AES 2024; Abstract 1.489.

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December 9th, 2024
To Members of the United States Senate:
We, the undersigned Nobel Laureates, are writing to ask you to
oppose the confirmation of Robert F. Kennedy, Jr. as Secretary of the
Department of Health and Human Services (DHHS).
The proposal to place Mr. Kennedy in charge of the federal agencies
responsible for protecting the health of American citizens and for
conducting the medical research that benefits our country and the
rest of humanity has been widely criticized on multiple grounds. In
addition to his lack of credentials or relevant experience in
medicine, science, public health, or administration, Mr. Kennedy has
been an opponent of many health-protecting and life-saving
vaccines, such as those that prevent measles and polio; a critic of
the well-established positive effects of fluoridation of drinking
water; a promoter of conspiracy theories about remarkably
successful treatments for AIDS and other diseases; and a belligerent
critic of respected agencies (especially the Food and Drug
Administration, the Centers for Disease Control, and the National
Institutes of Health). The leader of DHHS should continue to nurture
and improve— not threaten—these important and highly respected
institutions and their employees.
In view of his record, placing Mr. Kennedy in charge of DHHS would
put the public’s health in jeopardy and undermine America’s global
leadership in the health sciences, in both the public and commercial
sectors.

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Many patients are confused about what their surgeons are planning. Here’s how to get the details.The most common reason for a hysterectomy, the removal of the uterus, is to address chronic sources of pain and bleeding that can disrupt daily life — including fibroids, endometriosis, menstrual disorders and pelvic organ prolapse. A rising reason is a patient’s desire to align anatomy with lived gender.Despite being called “elective” by doctors, the procedure can be life-changing, and in some cases, even lifesaving. But hysterectomies are typically not emergency surgeries — meaning patients have time to ask questions and weigh all their options. To make sure you know exactly what you’re agreeing to, here are five questions to ask your doctor.Can you go over the reproductive organs and explain which ones you will be removing?Dr. Karen Tang, who is a gynecological surgeon and the author of the book “It’s Not Hysteria,” about reproductive health, begins her consultations by sketching the reproductive system out on a whiteboard.Then, she explains which organs she plans to remove and why. When she and a patient go over a surgical consent form, she translates any technical terms into lay language. For instance, “total laparoscopic hysterectomy with bilateral salpingectomy” becomes “removal of the uterus, cervix, and fallopian tubes, leaving the ovaries behind.”If a visual helps you understand, bring in a diagram yourself and ask your doctor to refer to it. If your consent form does not include plain language, have your doctor define unfamiliar terms or write nonmedical definitions on the form. Your surgeon should be able to explain why each organ is to be removed, and the risks and benefits of each option.If the words “partial” or “total” come up, ask your doctor to slow down and explain exactly what they mean. In general, surgeons should avoid these terms, because they are used inconsistently, Dr. Tang said.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

The health secretary pick and his organization have worked around the world to undermine longstanding policies on measles, AIDS and more.Robert F. Kennedy Jr., who is in line to lead the Department of Health and Human Services in the next Trump administration, is well-known for promoting conspiracy theories and vaccine skepticism in the United States.But Mr. Kennedy, an environmental lawyer, has also spent years working abroad to undermine policies that have been pillars of global health policy for a half-century, records show.He has done this by lending his celebrity, and the name of his nonprofit group, Children’s Health Defense, to a network of overseas chapters that sow distrust in vaccine safety and spread misinformation far and wide.He, his organizations and their officials have interfered with vaccination efforts, undermined sex education campaigns meant to stem the spread of AIDS in Africa, and railed against global organizations like the World Health Organization that are in charge of health initiatives.How Robert F. Kennedy Jr. Fights Health Policy Abroad:He undermined confidence in the measles vaccine ahead of a deadly outbreak in Samoa.He and his organization promote AIDS falsehoods.He aligned himself with fringe figures, including people who ended up on German security watch lists.His European chapter paid a British lawmaker to speak at a conference promoting vaccine skepticism.His Africa chapter pushes measles misinformation and risky remedies.Along the way, Mr. Kennedy has partnered with, financed or promoted fringe figures — people who claim that 5G cellphone towers cause cancer, that homosexuality and contraceptive education are part of a global conspiracy to reduce African fertility and that the World Health Organization is trying to steal countries’ sovereignty.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

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