Fampridine Sustained-Release Tablets: High-quality real-world evidence helps patients to "win" step by step-Interviews with Professor Dong Qiang and Professor Feng Huiyu

As the world’s first and only drug approved for improving the walking ability of adult patients with multiple sclerosis (MS) combined with walking dysfunction (EDSS score 4-7) [1-4], Fampridine Sustained-Release Tablets (Compobi Neng™) was approved in China on May 11, 2021, and was included in the 2021 edition of the National Medical Insurance Drug List on December 3 of the same year, bringing good news to MS patients with combined walking dysfunction in China
.

Fampridine sustained-release tablets were included in the national medical insurance only half a year after being approved in China, which fully reflects the country's recognition of the benefits of the drug for MS patients
.

On the one hand, the unique mechanism of action of Fampridine Sustained-Release Tablets provides a solid backing for the efficacy; on the other hand, there is a wealth of evidence-based evidence, including Phase III randomized controlled trials (RCT) and real trials in many countries and regions around the world.
The World Evidence (RWE) has further enhanced people's confidence and expectations of applying the drug to patients in the real world
.

Here, Yimaitong specially invited Professor Dong Qiang from Huashan Hospital Affiliated to Fudan University and Professor Feng Huiyu from the First Affiliated Hospital of Sun Yat-Sen University to share their professional interpretation on the clinical significance of Fampridine Sustained-Release Tablets RWE
.

Expert profile Professor Dong Qiang, PhD supervisor of Huashan Hospital Affiliated to Fudan University Shanghai Leading Talent, Shanghai Top Ten Public Health Worker Director of Neurology Department of Huashan Hospital Affiliated to Fudan University Deputy Director, National Center for Neurological Diseases (Huashan) Deputy Director, Chinese Medical Association Neurology Branch Chairman, Chinese Stroke Society Vice President, Shanghai Medical Association Neurology Specialty Committee Chairman, Shanghai Medical Association Neurologist Branch Chairman, Shanghai Neurological Diseases Clinical Medicine Center Director, Shanghai Neurology Quality Control Center Director, Shanghai Stroke Society Executive Vice President Professor Feng Huiyu Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Deputy Director of Neurology ICU, Chief Physician, Doctoral Supervisor, Deputy Leader of the Eighth Neuroimmunology Group, Guangdong Medical Association Deputy Leader of the Young Physician Professional Group of the Fourth Committee, Deputy Leader of the Neurology Critical Care Group of the Ninth Committee of the Neurology Branch of Guangdong Medical Association The school has been working in the Neurology Department of the First Affiliated Hospital of Sun Yat-sen University
.

Obtained a master's degree in 2005 and a doctorate degree in 2012, with research interests in neuroimmune diseases and neurosurgery
.

He has published more than 50 related works, participated in and presided over a number of provincial and national projects
.

Participated in the compilation of 6 monographs No.
1 "The power of real"-Let the fusion of RWE and RCT become the optimal solution for MS treatment.
Evidence-based medicine emphasizes that any medical decision should be based on the best scientific evidence
.

For a long time, randomized controlled trials (RCT) have been regarded as the standard by the industry for its high reliability, and even become the "spokesperson" of evidence-based medicine [5]
.

However, behind the high reliability of RCT are stringent entry and discharge standards, standardized interventions that are not completely consistent with clinical practice medication, limited sample size, and short follow-up time
.

In reality, RCT’s conclusions are often challenged when extrapolating to complex clinical situations.
RCT for rare diseases is even more difficult and often requires high time costs [5]
.

MS is a rare disease characterized by inflammatory demyelination of the central nervous system.
It is characterized by multiple occurrences in time and space, with high heterogeneity among patients [6]
.

MS is also a highly disabling chronic progressive disease.
Patients must receive effective disease modification therapy (DMT) and symptomatic treatment as soon as possible, so that some experts have issued a cry of "time is myelin"[6,7 ]
.

For the MS field, RCT "walking on one leg" alone is far from enough
.

In the above context, RWE is receiving more and more attention
.

RWE refers to the clinical evidence about the use of drugs and potential benefits-risks obtained through appropriate and adequate analysis of applicable real-world data, including interventions such as retrospective or prospective observational studies or practical clinical trials.
Evidence obtained in research
.

RWE can be applied to support drug regulatory decision-making, covering pre-market clinical research and development and post-market re-evaluation [5]
.

In Professor Dong Qiang's view, both RCT and RWE are important evidence-based evidence
.

The two are complementary rather than substitutes, and drug clinical research is also moving towards a new stage of deep integration of the two: "RCT and RWE are not contradictory
.

By adopting the strict entry criteria of RCT, we can confirm the clinical efficacy of a certain drug Curative effect, but real-world patients cannot be exactly the same as RCT
.

Therefore, we need evidence from real-world clinical applications to confirm the RCT data; in this way, we can use the correct treatment methods in clinical work and bring patients Benefits
.

" Professor Feng Huiyu further pointed out that the in-depth integration of RCT and RWE is the general trend: "RCT is an ideal evidence-based medical evidence, but the actual operation is quite difficult, and the individualized treatment needs of patients may not be reflected.

.

From RCT to RWE is expected to form a continuous chain of evidence, that is, using real-world data to verify the well-designed RCT, and bring valuable information to the clinic
.

The U.
S.
FDA and European EMA have also recognized RWE as a reference basis for consensus on drug inserts and guidelines
.

"On January 3, 2020, the Center for Drug Evaluation (CDE) of the National Food and Drug Administration issued the "Guiding Principles for Drug Development and Evaluation Supported by Real-World Evidence (Trial)" [5].
the great value
.

As a full course of treatment in MS DMT and symptomatic treatment of "indispensable" [6], RWE and the RCT may also need to "complement each other"
.

NO.
2 fampridine sustained release tablets RWE review - RCT evidence On the basis of the “liberation” of real-world patients, many doctors and fampridine sustained-release tablets began their first understanding of two phase III registration studies-the F203/204 study [8-10]; the above two studies were included respectively 300 and 239 MS patients from the United States and Canada had double-blind treatment periods of 14 weeks and 9 weeks, respectively
.
The
study confirmed that Fampridine sustained-release tablets can increase the walking speed of patients by 25% compared with the placebo group, and the proportion of responders is about 40%.
Significantly improve the patient's walking dysfunction
.
The
ENHANCE study [11] is another important RCT of fampridine sustained-release tablets.
A total of 633 patients were enrolled and the double-blind treatment period was 24 weeks
.

The study confirmed that fampridine sustained-release tablets can be used in It took effect within 2 weeks and significantly improved the scores of the patients’ walking dysfunction self-rating scale (MSWS-12)
.

In the LIBERATE real world study [12] that Professor Dong Qiang explained to us, the number of patients enrolled reached 4,646, From 201 regions in 13 countries, the follow-up time was up to 1 year
.

The LIBERATE study is a long-term, multi-center, post-marketing observational study evaluating the treatment of MS patients with Fampridine Sustained-Release Tablets in clinical practice.
It aims to further evaluate the safety of Fampridine Sustained-Release Tablets in the real world
.

The study used a patient self-reported outcome-related scale to assess the patient's subjective efficacy, and used the Clinical Global Impression Scale (CGI) to assess the patient's overall walking ability relative to the treatment baseline [12]
.

"Compared with patients who stopped treatment, Fampridine sustained-release tablets can significantly improve the walking ability objectively assessed by doctors
.

Among them, 61% of patients treated with Fampridine sustained-release tablets improved their walking ability compared to the baseline level.
A proportion of patients who discontinued treatment is only 11% (p<0.
001)
.

The difference between 61% and 11% truly reflects the efficacy of Fampridine Sustained-Release Tablets in clinical applications
.

"Professor Dong Qiang's research on LIBERATE The main results are impressive
.

The clinical benefit of Fampridine Sustained-Release Tablets demonstrated in the LIBERATE study further validated the previous RCT results; as mentioned above, this is also the important value of high-quality RWE
.

It is worth noting that the LIBERATE study paid attention to the mental health of MS patients [12]
.

Mental and psychological problems such as depression and anxiety are quite common in MS patients, and are considered by the "Chinese Expert Consensus on the Diagnosis and Treatment of Multiple Sclerosis (2018 Edition)" as symptoms that require "symptomatic treatment" [6]
.

Similarly, a review published in the authoritative journal "The Lancet" [13] pointed out that at all stages of MS, patient-centered management is advocated; while delaying disease progression, attention and treatment of walking disorders and depression in MS patients Symptoms such as anxiety and chronic pain are key components of the aforementioned management model
.

Professor Feng Huiyu noticed that in addition to the LIBERATE study, Fampridine Sustained Release Tablets also have many RWEs spread across Europe, America and other places
.

Although these studies are different in regions and sample sizes, they all verified the significant benefits of fampridine sustained-release tablets for patients[14-17]: "In four studies conducted in Brazil, Germany, Spain, and the United States, the samples The amount ranged from dozens to more than one hundred cases, and the observation time ranged from six to nine months
.

For example, a German study included 189 patients, and the results showed that the response rate of fampridine sustained-release tablets after 2 weeks of treatment can reach more than 70%
.

the results are very positive, which means we do not need to wait for a long time, you can get a high response rate
.

"Professor Pinghui Yu also pointed out that Haider systematic review and evaluation of the efficacy of Fampridine-release tablets and collaborators carried out In the meta-analysis [18], the pooled analysis of observational studies also yielded positive results-the walking function of patients based on T25FW and MSWS-12 evaluation was significantly improved compared with baseline; based on MSWS-12 evaluation, fampridine sustained-release tablets The effect size of SMD reaches -0.
87 (-1.
09 to -0.
65)
.

The above findings provide the highest level of evidence-based evidence for the real-world efficacy of Fampridine Sustained-Release Tablets
.

NO.
3 The curative effect must be safer-more than 400,000 real-world medication experience, so that domestic doctors and patients can feel at ease for the walking disorder of MS patients.
Fampridine sustained-release tablets can block the K+ channel exposed after demyelination and reduce K+ Outflow, thereby improving the propagation of action potentials in demyelinated axons, and improving the walking ability and speed of MS patients [19,20]
.

However, the excitatory pharmacological activity of Fampridine Sustained-Release Tablets has caused some people to worry about the safety of the drug, especially considering that the Fampridine Sustained-Release Tablets easily cross the blood-brain barrier [4]
.

In response to the above concerns, Professor Dong Qiang and Professor Feng Huiyu formed a highly unanimous opinion after fully reviewing the data that the overall safety of Fampridine Sustained-Release Tablets is good at a therapeutic dose
.

First of all, the confirmed adverse reactions of Fampridine sustained-release tablets are mainly the side effects of the nervous system, which are consistent with the pharmacological activity of Fampridine and reflect a certain degree of predictability [4]
.

More importantly, regardless of the incidence or severity of side effects, RCT and RWE have repeatedly given answers that give us peace of mind
.

"In randomized controlled studies, most of the adverse reactions of fampridine sustained-release tablets, such as dizziness, headache, etc.
, are usually mild to moderate in severity and generally do not lead to treatment termination
.
In an
open, extended study, fampridine sustained-release tablets There are no more serious adverse reactions under long-term treatment
.

" Professor Feng Huiyu pointed out
.

It should be pointed out that in the F203 open-ended extended study, patients have been treated with fampridine sustained-release tablets for up to 5 years; in the F204 open-ended extended study, patients have been treated with fampridine sustained-release tablets for up to 3.
3 years [21 ]
.

In terms of the long-term safety of drugs in the real world, RWE is undoubtedly of high reference value
.

In the LIBERATE study [12], overall adverse events and adverse events of special concern were very low.
The incidence of serious adverse events was only 6.
0%, and the incidence of serious adverse events requiring special attention was 2.
8%
.

Among them, seizures were 0.
4%
.

Other RWEs are constantly confirming the findings of the LIBERATE research
.

For example, a real-world study in Spain [17] showed that adverse events during the treatment of fampridine sustained-release tablets are usually mild and have a low incidence
.

Common adverse reactions included headache (incidence 6.
5%), dizziness (incidence 6.
5%), insomnia (6.
5% incidence) and so on
.

The data of about 107,000 patients (103,700 patient years) in the United States using Fampridine Sustained-Release Tablets [22] show that the incidence of common adverse reactions such as dizziness, insomnia, and falls is relatively low, all of which are less than 6%
.

Professor Dong Qiang also introduced us to a set of important data-as of March 31, 2021, more than 400,000 patients worldwide have been treated with fampridine sustained-release tablets, and the exposure is close to 600,000 patient-years
.

"From the approval in China in May of this year to the entry into the National Medical Insurance Catalogue in December, it means that the number of patients who have the opportunity to receive Fampridine Sustained-Release Tablets treatment will increase significantly
.

" "A drug can land and truly benefit patients.
Benefits not only look at the efficacy, but also safety is very important," Professor Feng Huiyu emphasized, "Considering that the efficacy and safety of Fampridine Sustained-Release Tablets are relatively ideal, the drug is expected to bring good benefits to patients
.

" NO.
4 Summary At the end of the interview, Professor Dong Qiang and Professor Feng Huiyu both talked about the significance of fampridine sustained-release tablets quickly entering medical insurance
.

Two experts pointed out that walking disorders in MS patients are quite common and highly disabling, but domestic patients have long been in the dilemma of "no medicine to cure"
.

Fampridine sustained-release tablets are listed in the domestic market and quickly entered the medical insurance list, reflecting the country’s high attention to rare disease groups and strong support for the development of related drugs.
It is expected to effectively reduce the disability and economic burden of patients, and improve treatment confidence and compliance.
, Return to a quality life as soon as possible; at the same time, it fills the domestic clinical gap, provides a powerful weapon for doctors, and promotes the improvement of clinical practice in the field of MS
.

From the approval of the domestic market to the entry of medical insurance, Fampridine Sustained-Release Tablets have created a remarkable “China speed”
.

It is hoped that the in-depth integration of RCT and RWE will enable more doctors to understand and trust Fampridine Sustained-Release Tablets, forming an insightful "Chinese experience", and ultimately enabling domestic patients to accept this possible change faster, better, and more.
The treatment of his life
.

Fully "recover" and "energy", "the other" can be expected! Biogen-148761-12/2021 Concise prescription Fampridine Sustained-release Tablets Concise prescription information [Drug Name] Generic Name: Fampridine Sustained-release Tablets English Name: Fampridine Sustained-release Tablets Chinese Pinyin: AnbidingHuanshipian [Properties] This product is white to similar White biconvex oval tablet with flat edges
.

"A10" is engraved on one side
.

[Specifications] 10 mg [Indications] This product is used to improve the walking ability of adult patients with multiple sclerosis and walking disorder (EDSS score 4-7)
.

[Usage and Dosage] Dosage plan and method: The recommended dose is 10 mg twice a day, orally, 12 hours apart (one tablet each in the morning and evening)
.

It should not be used higher than the recommended frequency and dosage
.

This product should not be taken with meals
.

This product should be swallowed whole
.

Do not break, crush, dissolve, suck or chew the tablets
.

Initiation and evaluation of treatment with this product: the initial medication should be limited to 2 to 4 weeks, because the patient can usually be determined whether there is clinical benefit within 2 to 4 weeks of taking this product
.

It is recommended to evaluate the improvement of walking ability through such as 25-foot Timed Walking (T25FW) or the Twelve-item Multiple Sclerosis Walking Scale (MSWS-12) within 2 to 4 weeks
.

If no improvement is observed, this product should be discontinued
.

If the patient does not report a benefit, this product should be discontinued
.

Reassess the treatment of this product: If a decrease in walking ability is observed, the doctor should consider interrupting the treatment to reassess the benefit of this product (see above)
.

The reassessment should include discontinuation of the product and assessment of walking ability
.

If the patient no longer improves walking, this product should be discontinued
.

Missed dose: The dosing regimen should always be followed
.

If you miss a dose, do not take a double dose to make up for the missed dose
.

【Contraindications】Patients who are allergic to the active substance of this product or any excipients
.

Patients who are used in combination with other drugs containing Fampridine (4-aminopyridine)
.

 Patients with a history of seizures or current manifestations of seizures
.

Patients with moderate or severe renal impairment (creatinine clearance <50 mL/min)
.

Patients who use this product and an organic cation transporter 2 (OCT2) inhibitor (such as cimetidine) at the same time
.

[Adverse reactions] The identified adverse reactions are mainly neurological reactions, including convulsions, insomnia, anxiety, balance disorders, dizziness, paresthesias, tremors, headaches and fatigue
.

This is consistent with the pharmacological activity of Fampridine
.

In placebo-controlled trials, the most frequently reported adverse reaction in patients with multiple sclerosis after receiving the recommended dose of this product was urinary tract infection (approximately 12% of patients)
.

【Medication for Special Populations】Patients with liver damage do not need to adjust the dose
.

Pregnancy: Limited data on the use of fampridine in pregnant women
.

Elderly medication: Elderly people should undergo renal function tests before starting treatment with this product
.

It is recommended to monitor the renal function of the elderly to find out if there is any renal damage
.

Children's medication: The safety and effectiveness of this product in children and adolescent patients between 0-18 years of age have not been established, and there are no relevant data
.

Detailed information is available on request for Fampridine Sustained-Release Tablets (May 11, 2021)