233AS101 - Phase 1 Study in ALS
Research type
Research Study
Full title
A Phase 1, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis
IRAS ID
196244
Contact name
Pamela Shaw
Contact email
Sponsor organisation
Biogen Idec Research Limited
Eudract number
2015-004098-33
Duration of Study in the UK
2 years, 1 months, 0 days
Research summary
Summary of Research
Amyotrophic lateral sclerosis (ALS), is a rapidly progressive, invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles (muscle action we are able to control, such as those in the arms, legs, and face).
Although the majority of patients suffer from sporadic ALS (without family history), approximately 2%, have an inherited, or familial, form of ALS caused by a variety of genetic mutations known as superoxide dismutase 1 mutations (SOD1-ALS).BIIB067 is an investigational drug which reduces the levels of the toxic protein that causes the genetic mutation. The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics (PK) of BIIB067, in adults with SOD1-ALS.
The study is randomised (participants are randomly allocated to treatment), double-blind (neither the participant nor study team will know which treatment is being given) and placebo-controlled (the study drug will be compared with an inactive “placebo”). It consists of 2-parts, A (single ascending dose) and B (multiple ascending dose) and BIIB067 will be administered by intrathecal bolus injection (via an injection into the spinal canal) to up to approximately 72 adults with either sporadic ALS (Part A only) or SOD1-ALS (Parts A and B).
Approximately 17 sites are planned in the United States, Canada, and Western Europe.
This study is sponsored by Biogen Idec Research Limited.Summary of Results
: A Study to Learn About the Safety and Effects of Tofersen (BIIB067) in People with SOD1-ALS
Drug Studied: Tofersen (BIIB067)
Protocol #: 233AS101, Part A and Part B
Study Dates:
Start: January 20, 2016
End: January 16, 2019Thank you!
Thank you to the participants who took part in this study. The participants helped the researchers learn more about using tofersen in people with amyotrophic lateral sclerosis associated with the superoxide-dismutase 1 gene, also known as SOD1-ALS. Tofersen is not approved for use outside of clinical trials.Biogen sponsored this study and reviewed the results when this study ended. Biogen thinks it is important to share the results with the participants and the public.
We hope this helps the participants understand and feel proud of their important role in medical research. If you have questions, please speak with the doctor or staff at the study site.
What was the purpose of this study?
ALS is a disease that affects the motor nerve cells in the brain and spinal cord that help control movement. ALS causes weakness in muscles that leads to difficulty walking, speaking, eating, and breathing. It is a progressive disease, which means that it gets worse with time. In the case of ALS, this eventually leads to death most often due to individuals not being able to breathe.
In 1-2% of people with ALS, this disease is caused by a mutation in the superoxide dismutase 1 gene, also known as SOD1. The mutation of the SOD1 gene causes an abnormal SOD1 protein to be made. Researchers think this abnormal protein can cause the nerve cells in people with ALS to break down and die.
In this study, the researchers studied an investigational drug called tofersen. Researchers believe that tofersen can reduce the creation of SOD1 protein, including its abnormal forms. A decrease in levels of abnormal SOD1 protein might slow the worsening of ALS. This study was done to learn more about the safety of tofersen and how it works in people with SOD1-ALS.
This study consisted of 3 parts: Part A, Part B, and Part C. This is a summary of Part A and Part B. The results of Part C of this study will be provided in a separate summary.
The main questions researchers wanted to answer in Parts A and B of the study were:
• What adverse events did participants have during the study?
• How did tofersen move through the body?
• What abnormal lab tests and exams did participants have during the study?
• Did tofersen lower the amount of SOD1 protein in the fluid around the spinal cord?Who took part in the study?
Part A of the study included 20 participants at 10 research centers in 4 countries.
Part B of the study included 50 participants at 14 research centers in 6 countries.The study took place in the following countries: Belgium, Canada, France (Part B only), Germany, United Kingdom (Part B only), and the United States.
Participants took part in this study if they:
• Were 18 years of age or older
• For Part A, had ALS (some participants in Part A did not have SOD1-ALS)
• For Part B, had ALS and a SOD1 mutation
• Had at least 50% of their original lung strengthFor more information on who could take part in the study, please refer to the websites listed at the end of the summary.
What happened during the study?
The study started in January 2016 and ended in January 2019. When the study ended, the sponsor created a report of the results for Part A and Part B. This is a summary of that report. The results of Part C will be provided in a separate summary.
This was a double-blind study. This means none of the participants, doctors, or other study staff knew if each participant took tofersen or placebo. This was done to make sure that the study results were not influenced in any way.
A placebo looks like the study drug but does not contain any active drug. Using a placebo helps researchers learn if the results of the study are due to the study drug or other factors.
At the beginning of both Part A and Part B of the study, participants answered questions about their medical history. They were also physically examined by a doctor at their study clinic.
To join Part A of the study, participants could have any type of ALS. For Part B, only participants with a mutation in the SOD1 gene could take part.
Study participants could either be given tofersen or placebo. Tofersen or placebo were injected into the fluid around the spinal cord. The fluid around the spinal cord is called the cerebrospinal fluid, also known as CSF. This medical procedure is known as a lumbar puncture. The dose of tofersen was measured in milligrams, which is shortened to mg.
Part A
Each participant who was enrolled in Part A stayed in the study for up to about 15 weeks.
This included up to 7 weeks of screening, 1 day of treatment, and 8 weeks of follow-up.
During Part A of the study, 20 participants were randomly placed in 1 of 4 treatment groups depending on the time they joined the study. Each group was given a different dose of tofersen or placebo. All participants received only one dose of tofersen or placebo. The lowest dose group started first. The next higher dose group only began receiving tofersen if there were no adverse events that were serious enough to prevent an increase in dose. An adverse event is a new or worsening medical problem that may or may not be caused by a study drug. Participants in Part A could choose to enroll in Part B of the study.The list below shows how many participants took placebo or tofersen during Part A:
Placebo: 5 participants
Tofersen 10 mg: 3 participants
Tofersen 20 mg: 3 participants
Tofersen 40 mg: 3 participants
Tofersen 60 mg: 6 participantsPart B
Each participant who was enrolled in Part B stayed in the study for up to about 31 weeks.
This included up to 7 weeks of screening, 12 weeks of treatment, and 8 weeks of follow-up.
During Part B of the study, 50 participants were randomly placed in 1 of 4 treatment groups depending on the time they joined the study. Each group was given a different dose of tofersen or placebo. The lowest dose group started first. The next higher dose group only began receiving tofersen if there were no adverse events that were serious enough to prevent an increase in dose. Participants received 5 doses of either the placebo or tofersen over 12 weeks.The list below shows how many participants took placebo or tofersen during Part B:
Placebo: 12 participants
Tofersen 20 mg: 10 participants
Tofersen 40 mg: 9 participants
Tofersen 60 mg: 9 participants
Tofersen 100 mg: 10 participantsWhat were the study results?
When Part A and Part B of the study ended, Biogen reviewed the data and created a report of the results. This is a summary of that report. Below is an overall summary of the results and the key questions researchers asked during the study.
What adverse events happened during the study?
This section is a summary of the adverse events the participants had during the study. An adverse event is a new or worsening medical problem that may or may not be caused by a study drug. A lot of research is needed to know whether a study drug causes an adverse event. An adverse event is considered serious when it results in death, is life-threatening, causes lasting problems, or requires hospital care. These are called serious adverse events. When new drugs are being studied, researchers keep track of all adverse events that participants have during the study. Not everyone experiences the same adverse events.The main goal of this study was to learn more about the potential adverse events of tofersen.
Did any adverse events happen during this study?
A summary of the adverse events that happened in Part A is listed below.
Placebo – 5 participants
2 participants (40%) had adverse events.
No participants had serious adverse events.Tofersen 10 mg – 3 participants
2 participants (67%) had adverse events.
No participants had serious adverse events.Tofersen 20 mg – 3 participants
3 participants (100%) had adverse events.
No participants had serious adverse events.Tofersen 40 mg – 3 participants
3 participants (100%) had adverse events.
No participants had serious adverse events.Tofersen 60 mg – 6 participants
6 participants (100%) had adverse events.
No participants had serious adverse events.No participants stopped treatment because of an adverse event in Part A of the study.
No participants died because of an adverse event in Part A of the study.A summary of the adverse events that happened in Part B is listed below.
Placebo – 12 participants
12 participants (100%) had adverse events.
2 participants (17%) had serious adverse events.
1 participant (8%) stopped treatment because of adverse events.
1 participant (8%) died due to adverse events.Tofersen 20 mg – 10 participants
10 participants (100%) had adverse events.
2 participants (20%) had serious adverse events.
1 participant (10%) stopped treatment because of adverse events.
1 participant (10%) died due to adverse events.Tofersen 40 mg – 9 participants
9 participants (100%) had adverse events.
1 participant (11%) had serious adverse events.
No participants stopped treatment because of adverse events.
No participants died due to adverse events.Tofersen 60 mg – 9 participants
9 participants (100%) had adverse events.
2 participants (22%) had serious adverse events.
1 participant (11%) stopped treatment because of adverse events.
1 participant (11%) died due to adverse events.Tofersen 100 mg – 10 participants
10 participants (100%) had adverse events.
No participants had serious adverse events.
No participants stopped treatment because of adverse events.
No participants died due to adverse events.What serious adverse events happened during the study?
There were no serious adverse events in Part A of the study.
In Part B, 14% of the study participants had a serious adverse event. There were a total of 8 serious adverse events that were reported in 7 out of the 50 participants.
The serious adverse events that happened in Part B are listed below.
Placebo – 12 participants
1 participant (8%) had breathing failure because of ALS.
1 participant (8%) had sudden worsening of lung problems.Tofersen 20 mg – 10 participants
1 participant (10%) had a heart problem.
1 participant (10%) had difficulty breathing.Tofersen 40 mg – 9 participants
1 participant (11%) was not able to breathe well enough.Tofersen 60 mg – 9 participants
1 participant (11%) had breathing failure because of ALS.
1 participant (11%) had an increase in protein in the CSF and an increase in white blood cells in the CSF.Tofersen 100 mg – 10 participants
No participants had serious adverse events.There were 3 deaths in the study:
• 2 participants who received tofersen who died after they stopped treatment.
• 1 participant who received placebo during treatment.The treatment group and cause of death for each are listed below:
• Placebo - Death due to breathing failure caused by ALS
• Tofersen 20 mg - Death due to blood clot in the lung
• Tofersen 60 mg - Death due to breathing failure caused by ALSWhat common adverse events happened during the study?
In Part A, the most common adverse events were procedural pain, headache, back pain, muscle spasms, and limb pain. Muscle spasms, also known as muscle cramps, are forceful and painful contraction of muscles.
The 5 most common adverse events that happened in Part A are listed below.
Placebo – 5 participants
1 participant (20%) had procedural pain.Tofersen 10 mg – 3 participants
No participants had any of the most common adverse events.Tofersen 20 mg – 3 participants
1 participant (33%) had procedural pain.
2 participants (67%) had headache.Tofersen 40 mg – 3 participants
1 participant (33%) had headache.
1 participant (33%) had limb pain.Tofersen 60 mg – 6 participants
3 participants (50%) had procedural pain.
1 participant (17%) had headache.
2 participants (33%) had back pain.
2 participants (33%) had muscle spasms.
1 participant (17%) had limb pain.In Part B, the most common adverse events were related to the injection into the fluid around the spinal cord, including headache, procedural pain, and post-lumbar puncture syndrome. Post-lumbar puncture syndrome is a headache that some people experience after having a sample of their CSF taken.
The 5 most common adverse events that happened in Part B are listed below.
Placebo – 12 participants
7 participants (58%) had headache.
3 participants (25%) had falls.
5 participants (42%) had procedural pain.
3 participants (25%) had post-lumbar puncture syndrome.Tofersen 20 mg – 10 participants
4 participants (40%) had headache.
1 participant (10%) had back pain.
3 participants (30%) had falls.
4 participants (40%) had procedural pain.
4 participants (40%) had post-lumbar puncture syndrome.Tofersen 40 mg – 9 participants
2 participants (22%) had headache.
1 participant (11%) had back pain.
3 participants (33%) had falls.
1 participant (11%) had procedural pain.
3 participants (33%) had post-lumbar puncture syndrome.Tofersen 60 mg – 9 participants
4 participants (44%) had headache.
1 participant (11%) had back pain.
2 participants (22%) had falls.
4 participants (44%) had procedural pain.
3 participants (33%) had post-lumbar puncture syndrome.Tofersen 100 mg – 10 participants
6 participants (60%) had headache.
5 participants (50%) had back pain.
5 participants (50%) had falls.
7 participants (70%) had procedural pain.
3 participants (30%) had post-lumbar puncture syndrome.How did tofersen move through the body?
To answer this question, the researchers looked at the results of blood tests and samples of CSF. This is the fluid that is found around the brain and spinal cord. The researchers then measured the amount of tofersen in these samples. Researchers wanted to know how much tofersen stayed in the CSF and how it was removed from the body. They did this both before and after the participants received tofersen.
Overall, the researchers found that:
• Tofersen concentration in the CSF depended on the dose that participants received and did not accumulate in participant’s blood or CSF. The concentration of tofersen was highest in the 100 mg group.
• It took 3 doses of tofersen given 2 weeks apart for it to reach steady state. Steady state is reached when the amount of medication in the body remains constant.
• Tofersen levels peaked in the blood between 2 and 6 hours after each dose.What abnormal lab tests and exams did participants have?
To answer this question, the researchers looked at the results from the following:
• Blood and urine tests
• Physical exams
• Exams to check lung strength
• Exams to check how well the participants' brains were working
• Exams to check the heart’s rhythm and electrical activity
• Blood pressure and heart rateWhen checking participants’ heart activity during Part B, researchers found:
• 1 participant in the placebo group had an abnormally rapid heartbeat.
• 1 participant in the tofersen 20 mg group had a problem where the upper part of the heart beat too quicklyAlso, during Part B some participants had an increased number of white blood cells found in their CSF.
• 1 of 12 participants (8%) in the placebo group had a high white blood cell count.
• 16 of 38 participants (42%) in the tofersen groups had a high white blood cell count.For all the other tests, researchers found that there were no major changes in the test results after treatment in the study.
Did tofersen lower the amount of SOD1 protein in the fluid around the spinal cord?
To answer this question, the researchers measured the levels of SOD1 protein in the participants' CSF. The researchers did this both before the participants received treatment and throughout the study.
After 12 weeks of treatment, the following changes in SOD1 levels were observed for each treatment group:
• Tofersen 20 mg (10 participants): 2% increase in SOD1 levels in the CSF
• Tofersen 40 mg (9 participants): 25% decrease in SOD1 levels in the CSF
• Tofersen 60 mg (9 participants): 19% decrease in SOD1 levels in the CSF
• Tofersen 100 mg (10 participants): 33% decrease in SOD1 levels in the CSFOverall, the participants who received 40, 60, or 100 mg tofersen had less SOD1 protein in their CSF compared to those who received the placebo. The participants who received 100 mg tofersen had the greatest reduction in SOD1 levels compared to the placebo group.
Did any related adverse events happen during this study?
The researchers recorded all adverse events that the study doctor considered to be related to study treatment experienced by the participants in Part A and Part B of the study.
Only those adverse events that the study doctors believed to be related to treatment with tofersen or placebo are included in this section.A summary of the related adverse events that happened in Part A is listed below.
Placebo – 5 participants
No participants had related adverse events or related serious adverse events.Tofersen 10 mg – 3 participants
No participants had related adverse events or related serious adverse events.Tofersen 20 mg – 3 participants
No participants had related adverse events or related serious adverse events.Tofersen 40 mg – 3 participants
No participants had related adverse events or related serious adverse events.Tofersen 60 mg – 6 participants
2 participants (33%) had related adverse events.
No participants had related serious adverse events.No participants stopped treatment because of a related adverse event in Part A of the study.
No participants died because of a related adverse event in Part A of the study.A summary of the related adverse events that happened in Part B is listed below.
Placebo – 12 participants
No participants had related adverse events or related serious adverse events.Tofersen 20 mg – 10 participants
2 participants (20%) had related adverse events.
No participants had related serious adverse events.Tofersen 40 mg – 9 participants
2 participants (22%) had related adverse events.
No participants had related serious adverse events.Tofersen 60 mg – 9 participants
6 participants (67%) had related adverse events.
1 participant (11%) had related serious adverse events.Tofersen 100 mg – 10 participants
4 participants (40%) had related adverse events.
No participants had related serious adverse events.No participants stopped treatment because of a related adverse event in Part B of the study.
No participants died because of a related adverse event in Part B of the study.What related serious adverse events happened during the study?
There were no related serious adverse events in Part A of the study.
In Part B, 1 of the 50 study participants (2%) had 2 serious adverse events that were both considered related to treatment by the study doctor. This participant was in the tofersen 60 mg group, as listed below.
Tofersen 60 mg – 9 participants
1 participant (11%) had an increase in protein in the CSF and an increase in white blood cells in the CSF.What common related adverse events happened during the study?
In Part A, 2 of the 20 study participants (10%) had adverse events that were considered related to treatment by the study doctor. Both participants were in the tofersen 60 mg group, as listed below.
Tofersen 60 mg – 6 participants
1 participant (17%) had muscle cramps.
1 participant (17%) had reduced muscle reflexes.In Part B, many of the adverse events that were considered related to treatment by the study doctor only happened to 1 participant per treatment group. Listed below are those related adverse events that happened to more than 1 participant across all treatment groups.
Placebo – 12 participants
No participants had related adverse events.Tofersen 20 mg – 10 participants
2 participants (20%) had pleocytosis.Tofersen 40 mg – 9 participants
1 participant (11%) had an increase in white blood cells in the CSF.
1 participant (11%) had pleocytosis.Tofersen 60 mg – 9 participants
4 participants (44%) had an increase in protein in the CSF.
3 participants (33%) had an increase in white blood cells in the CSF.Tofersen 100 mg – 10 participants
2 participants (20%) had limb pain.
1 participant (10%) had an increase in protein in the CSF.In this study, pleocytosis was described as an abnormal increase in lymphocytes in the CSF. Lymphocytes are a type of white blood cell.
How has this study helped patients and researchers?
The results show that the most common adverse events included headache, falling, back pain, procedural pain, and post-lumbar puncture syndrome.
The study also showed that tofersen lowered the amount of SOD1 protein in the CSF.
The levels of SOD1 protein in the CSF were decreased the most in the participants who received 100 mg of tofersen. The results of Part B showed that 100 mg of tofersen should be used to test participants in Part C of the study.
Where can I learn more about the study?
You can find more information about the study online at https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C51dc66aeafaa430f547208dab018d0f6%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638015917872009984%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=NW2K9SaGHAZqdJpa%2FnNbxpwgZqbShgsxkWuqIemzTCc%3D&reserved=0. Once on the site, type NCT02623699 into the search box and click “Search”.
You can also find more information online at https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C51dc66aeafaa430f547208dab018d0f6%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638015917872009984%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=EAs7D7rNe0QxBookKb34M01pL0AjNYMRLCCY5v7%2F9As%3D&reserved=0. Once on the site, click “Home & Search”, then type 2015-004098-33 in the search box and click “Search”.
If you have questions about tofersen or the results of this study, please speak with the doctor or staff at the study research center.
Official study title: A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics and
Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 MutationBiogen, the sponsor of this study, has its headquarters in Cambridge, Massachusetts (USA).
The results presented here are from a single study. You should not make changes to your therapy based on these results without first consulting your doctor.
Thank you.
Biogen
225 Binney Street
Cambridge, MA 02142
USA
ClinicalTrials@Biogen.com----------------------------------------------
Title: A Study to Learn About the Effects and Safety of Tofersen (BIIB067) in People with SOD1-ALS
Drug Studied: Tofersen (BIIB067)
Protocol Number: 233AS101, Part C
Study Dates:
Start: March 27, 2019
End: July 16, 2021Thank you!
Thank you to the participants who took part in this study. All the participants helped the researchers learn more about tofersen in people with amyotrophic lateral sclerosis with a confirmed superoxide-dismutase 1 gene mutation, also known as SOD1-ALS. Tofersen is not yet approved for use outside of clinical trials.Biogen sponsored this study and reviewed the results when this study ended. Biogen thinks it is important to share the results with the participants and the public.
We hope this helps the participants understand and feel proud of their important role in medical research. If you have questions, please speak with the doctor or staff at the study site.
What was the purpose of this study?
ALS is a disease that affects the motor nerve cells in the brain and spinal cord that help control movement. ALS causes weakness in muscles that leads to difficulty in walking, speaking, eating, and breathing. It is a progressive disease, which means that it slowly gets worse with time. In the case of ALS, this eventually leads to death most often due to individuals not being able to breathe.
In 1-2% of people with ALS, this disease is caused by a mutation in the superoxide dismutase 1 gene, also known as SOD1. The mutation of the SOD1 gene causes an abnormal SOD1 protein to be made. Researchers think this abnormal protein can cause the nerve cells in people with ALS to break down and die. Depending on the type of mutation within the SOD1 gene, one person may have faster disease progression than another person who has a different mutation.
In this study, the researchers studied an investigational drug called tofersen. Researchers believe that tofersen can reduce the creation of SOD1 protein, including its abnormal forms. A decrease in levels of abnormal SOD1 protein might slow the worsening of ALS. This study was done to learn more about how tofersen works and its safety in people with SOD1-ALS.
This study had 3 parts: Part A, Part B, and Part C. Parts A and B of the study were completed before Part C began, and the results of Parts A and B are provided in a separate summary. In Parts A and B, researchers learned about the safety of tofersen, how it moved through the body, and how it affected participants’ medical test results. They used this information to decide the best dose of tofersen to use in Part C. In Part C, researchers wanted to test this dose in a larger group of participants.
The main question researchers wanted to answer in Part C of the study was:
• Did tofersen slow down the progression of ALS as measured by a specific test, the ALS Functional Rating Scale–Revised (ALSFRS-R)?The other questions researchers wanted to answer in Part C of the study were:
• Did tofersen lower the amount of SOD1 protein in the fluid around the spinal cord?
• Did tofersen lower the amount of neurofilaments in the blood?
• Did tofersen help participants with how well they were able to breathe?
• Did tofersen help participants keep their muscle strength in their arms and legs?
• Did tofersen help participants live longer or prevent them from needing permanent ventilation?
• Did tofersen help participants live longer?
• What adverse events did participants have during the study?Who took part in the study?
Part C of the study included 108 participants at 32 research centers in 9 countries.
The study took place in the following countries: Belgium, Canada, Denmark, France, Germany, Italy, Japan, United Kingdom, and the United States.
Participants took part in this study if they:
• Were 18 years of age or older
• Had ALS associated with a SOD1 mutation
This study enrolled a variety of people with SOD1-ALS. Researchers split participants into two subgroups based on:
1. The type of SOD1 mutation they had
2. How quickly their scores on the ALSFRS-R were going down over time before joining the studyFor this study only, the participants who were more likely to experience their ALS worsening more quickly during the study were in the “faster-progressing” subgroup. The rest of the participants were in the “slower-progressing” subgroup.
In addition to the requirements above:
• Participants in the faster-progressing subgroup had to have at least 65% predicted slow vital capacity (SVC)
• Participants in the slower-progressing subgroup had to have at least 50% predicted SVC
Researchers used a slow vital capacity (SVC) test to measure how well participants were able to breathe. An SVC test measures how much air is exhaled slowly. The result is shown as a percentage of predicted values. It compares respiratory function with what is expected for people with similar age, gender, and height.
For more information on who could take part in the study, please refer to the websites listed at the end of the summary.What happened during the study?
The study started in March 2019 and ended in July 2021. At the beginning of the study, participants answered questions about their medical history and received a medical exam.
This was a double-blind study. This means none of the participants, doctors, or other study staff knew if each participant took tofersen or placebo. This was done to make sure the study results were not influenced in any way.
A placebo looks like the study drug but does not contain any active drug. Using a placebo helps researchers learn if the results of the study are due to the study drug or other factors.
Study participants could receive either tofersen or placebo. Tofersen or placebo were injected into the fluid around the spinal cord. This fluid is called the cerebrospinal fluid, also known as CSF. This medical procedure is known as a lumbar puncture. The dose of tofersen was measured in milligrams, which is shortened to mg.
Each participant that was enrolled in Part C stayed in the study for about 32 or 36 weeks.
This included up to 4 weeks of screening, 24 weeks of treatment, and 4 or 8 weeks of follow-up.During Part C, 108 participants were randomly placed into 1 of 2 treatment groups. There was 1 tofersen group and 1 placebo group. Participants had a 66% chance of receiving tofersen and a 33% chance of receiving placebo.
36 participants received up to 8 doses of placebo.
72 participants received up to 8 doses of tofersen 100 mg.Researchers asked participants to return to the clinic for a follow up and testing 4 weeks after their last dose.
Participants who completed the study were given the opportunity to join another study to receive tofersen. The second study focuses on the long-term effects of tofersen. If a participant did not enroll in the long-term effects study, they had another follow up visit 8 weeks after their last dose.
What were the study results?
When Part C of the study ended, Biogen reviewed the data and created a report of the results. This is a summary of that report. Below is an overall summary of the results and the key questions researchers asked during the study.
A total of 108 participants took part in the study and received tofersen or placebo. However, analysis of the clinical effects of tofersen was focused on the 60 participants who were more likely to experience faster progression of ALS. These participants were part of the faster-progressing subgroup. Researchers believed that the differences between the tofersen and placebo groups may be clearer in participants whose symptoms were worsening more quickly. This is because 24 weeks of treatment may not be long enough to show a difference in the slower-progressing participants.
The results for all participants were collected and analyzed. More detailed results can be found in the websites at the end of this document.
Did tofersen slow down the progression of ALS as measured by a specific test, the ALS Functional Rating Scale–Revised (ALSFRS-R)?
Researchers used a scale called the ALSFRS-R to see if tofersen slowed down the progression of ALS. They compared scores from just before participants began receiving tofersen or placebo to Week 28 of the study.
What is the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)?
It is a scale that measures a variety of physical functions such as speaking, eating, writing, walking, and breathing. Scores range between 0 and 48. Higher scores mean that participants maintained more function.The results for the faster-progressing subgroup are given below. The numbers show how much function participants in each treatment group lost. Lower numbers are better because it means participants maintained more function.
Reduction in ALSFRS-R scores at Week 28:
Placebo (21 participants): 8.1
Tofersen 100 mg (39 participants): 7.0Compared to the placebo group, there was a smaller decline in the tofersen group. This difference was not statistically significant.
Since there was no statistically significant difference found in the results for the main question of the study, the results for the other questions were considered exploratory. This means that they were not officially analyzed for statistical significance.
Did tofersen lower the amount of SOD1 protein in the fluid around the spinal cord?
To answer this question, researchers measured the levels of SOD1 protein in the participants’ CSF. Researchers believe that a decrease in levels of SOD1 protein, including its abnormal forms, might slow the worsening of ALS.
Researchers compared participants’ SOD1 protein levels in the CSF from just before participants began receiving tofersen or placebo, called the baseline, to Week 28 of the study. They calculated a ratio between the baseline levels and Week 28 levels for each treatment group and expressed them as a % decrease or % increase from baseline.The results for the faster-progressing subgroup are given below. The numbers show the change in SOD1 protein levels in the CSF at Week 28 in the study:
Placebo (21 participants): 16% increase
Tofersen 100 mg (39 participants): 29% decreaseThe tofersen group had a decrease in SOD1 protein levels in the CSF compared to an increase in the placebo group.
Did tofersen lower the amount of neurofilaments in the blood?
Researchers were interested in the amount of a protein called neurofilament light chain, also known as NfL. When neurons are injured, an increase in NfL levels can be measured in the blood and CSF. In Als, researchers have found that higher levels of NfL are related to faster disease progression and shorter survival. They believe that a decrease in NfL levels may reflect a response to treatment.
To answer this question, the researchers measured the levels of NfL in the participants’ blood. Researchers compared participants’ NfL levels in the blood from just before participants began receiving tofersen or placebo to Week 28 of the study. As before, they expressed the results as a % decrease or % increase from baseline.The results for the faster-progressing subgroup are given below. The numbers show the change in NfL levels in the blood at Week 28 in the study:
Placebo (21 participants): 20% increase
Tofersen 100 mg (39 participants): 60% decreaseThe tofersen group had a decrease in NfL levels in the blood compared to an increase in the placebo group.
Did tofersen help participants with how well they were able to breathe?
Researchers used the slow vital capacity (SVC) test to measure how well participants were able to breathe. An SVC test measures how much air is exhaled slowly. The result is shown as a percentage of predicted values. It compares respiratory function with what is expected for people with similar age, gender, and height.
Higher percent predicted means better respiratory function. Researchers compared SVC percent predicted from just before participants began receiving tofersen or placebo to Week 28 of the study.The results for the faster-progressing subgroup are given below. The numbers show the amount by which participants’ breathing got worse over time. Lower numbers are better because it means participants lost less of their breathing ability.
Reduction in SVC percent predicted at Week 28:
Placebo (21 participants): 22
Tofersen 100 mg (39 participants): 14Did tofersen help participants keep their muscle strength in their arms and legs?
Researchers used a Handheld Dynamometry (HHD) test to measure participants’ muscle strength in their upper and lower limbs. They combined the scores from 16 different muscles to produce a single HHD megascore. Higher scores mean greater muscle strength. Researchers compared participants’ HHD megascores from just before participants began receiving tofersen or placebo to Week 28 of the study.
The results for the faster-progressing subgroup are given below. Lower numbers are better because it means participants lost less muscle strength in their arms and legs.
Reduction in HHD megascores at Week 28:
Placebo (21 participants): 0.37
Tofersen 100 mg (39 participants): 0.34Did tofersen help participants live longer or prevent them from needing permanent ventilation?
As ALS progresses, it can cause death by weakening the muscles we use to breathe. People with ALS who need help to breathe may make use of a breathing machine, also known as a ventilator. For this study, researchers considered participants to be on permanent ventilation if they required ventilation for 22 hours per day or more for at least 21 consecutive days. Researchers wanted to measure how long participants could live without the need for permanent ventilation.
Of the 60 participants in the faster-progressing subgroup, 3 out of 39 participants in the tofersen group and 2 out of 21 participants in the placebo group needed permanent ventilation. One participant died during the study.
Because very few participants needed permanent ventilation or died, no conclusions could be made on whether tofersen helped participants avoid permanent ventilation or live longer.
Did tofersen help participants live longer?
Researchers planned to measure how long participants lived. As only 1 participant died during the study, no conclusions could be made about whether tofersen helped participants live longer.
The participant who died was in the tofersen group and the cause of death was heart failure. Researchers did not believe this was related to treatment with tofersen.
What adverse events happened during the study?
This section is a summary of the adverse events the participants had during the study. An adverse event is a new or worsening medical problem that may or may not be caused by a study drug. A lot of research is needed to know whether a study drug causes an adverse event. An adverse event is considered serious when it results in death, is life-threatening, causes lasting problems, or requires hospital care. These are called serious adverse events. When new drugs are being studied, researchers keep track of all adverse events that participants have during the study. Not everyone experiences the same adverse events.
One goal of this study was to learn more about the potential adverse events of tofersen. The results in this section include all 108 participants who received tofersen or placebo.
Only those adverse events that the study doctors believed to be related to treatment with tofersen or placebo are included in this section.
Did any related adverse events happen during this study?
The researchers recorded all adverse events that the study doctor considered to be related to study treatment experienced by the participants in the study.
A summary of the related adverse events that happened in Part C is listed below.
Placebo – 36 participants
2 participants (6%) had related adverse events.
No participants had related serious adverse events.
No participants stopped treatment because of a related adverse event.Tofersen 100 mg – 72 participants
28 participants (39%) had related adverse events.
4 participants (6%) had related serious adverse events.
2 participants (3%) stopped treatment because of a related adverse event.No participants died because of a related adverse event in Part C of the study.
What related serious adverse events happened during the study?
In Part C, 4 out of 108 participants (4%) had serious adverse events that were considered to be related to treatment by the study doctor. All of these participants were in the tofersen 100 mg group.
Tofersen 100 mg – 72 participants
1 participant (1%) had a condition where a pinched or inflamed nerve in the lower back causes pain.
1 participant (1%) had inflammation on both sides of the spinal cord.
1 participant (1%) had inflammation in a large area of the spinal cord.
1 participant (1%) had inflammation of the membranes that surround the brain and spinal cordWhat common related adverse events happened during the study?
The most common adverse events considered related to treatment by the study doctor that happened in at least 5% of participants in each group during Part C are listed below.
Placebo – 36 participants
No participants had any related adverse events that happened in at least 5% of participants.Tofersen 100 mg – 72 participants
6 participants (8%) had headache.
5 participants (7%) had muscle pain.
5 participants (7%) had limb pain.
4 participants (6%) had procedural pain.How has this study helped patients and researchers?
The results show that there was no statistically significant difference between the tofersen and placebo groups in the reduction in ALSFRS-R scores that reflect ALS disease progression.
For the other questions, researchers compared test results from just before participants began receiving tofersen or placebo to Week 28 of the study and found that:
• The tofersen group had a decrease in SOD1 protein levels in the CSF compared to an increase in the placebo group.
• The tofersen group had a decrease in NfL levels in the blood compared to an increase in the placebo group.
• The tofersen group lost less of their breathing ability (SVC test) and less of their muscle strength (HHD test) compared to the placebo group.
• No conclusions could be made about the effect of tofersen on survival or survival without permanent ventilation due to the limited number of events.Further research on tofersen in SOD1-ALS is ongoing as of 2022.
Where can I learn more about the study?
You can find more information about the study online at https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C51dc66aeafaa430f547208dab018d0f6%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638015917872009984%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=NW2K9SaGHAZqdJpa%2FnNbxpwgZqbShgsxkWuqIemzTCc%3D&reserved=0. Once on the site, type NCT02623699 into the search box and click Search.
You can also find more information online at Clinical Trials Register. Once on the site, click Home & Search, then type 2015-004098-33 in the search box and click “Search”.
If you have questions about tofersen or the results of this study, please speak with the doctor or staff at the study research center.
Official Study Title: A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics and
Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Biogen, the sponsor of this study, has its headquarters in Cambridge, Massachusetts (USA).
The results presented here are for a single study. You should not make changes to your therapy based on the results without first consulting your doctor.
Thank You.
Biogen
225 Binney Street
Cambridge, MA 02142
USA
ClinicalTrials@Biogen.comREC name
Yorkshire & The Humber - Leeds East Research Ethics Committee
REC reference
16/YH/0024
Date of REC Opinion
18 Apr 2016
REC opinion
Further Information Favourable Opinion