• The comparator in the pivotal trial, ADAPT, is placebo.
• This is a first-in-class human IgG1 antibody FC fragment.
• There is no direct comparator for this novel drug.
• That being said, ravulizumab received an NOC from Health Canda earlier this year (January 2023) for the treatment of adult patients with anti-AChR antibody-positive gMG. It did receive a negative recommendation at CADTH and is awaiting reconsideration. Although it would have been a useful comparison to efgartigimod alfa, the pivotal trial for this submission enrolled patients between August 2018 and April 2020 and would not have aligned to allow comparison to ravulizumab.
• The sponsor did not compare it to eculizumab.

CDEC agreed with the clinical experts.

The requested indication for efgartigimod alfa is for add-on therapy to conventional therapy, which may include AChEIs, CSs, and/or NSISTs in patients with anti-AChR antibody-positive disease. Although the sponsor included rituximab in the list of comparators, it was not included in the studied indication because it is only used in patients whose disease is not anti-AChR antibody-positive. Patients treated with either rituximab or eculizumab within 6 months of screening were also excluded from the study. The sponsor envisions the place in therapy of efgartigimod alfa to be considered as an add-on alternative to immunoglobulins after use of NSISTs and/or CSs as depicted in Figure 1.

The indication is for addition of efgartigimod alfa to 1 or a combination of the 3 conventional therapy classes. The ADAPT trial allowed the inclusion of patients on any combination of conventional gMG treatment, which was limited to AChEIs, steroids, and NSISTs, and did not require the patients to have received or discontinued use of any specific treatment.

It is unclear if a patient’s eligibility for addition of efgartigimod alfa would require trials of medications from all 3 classes or from 1 or 2 classes.

The clinical experts stated that in addition, in the ADAPT trial, not all included patients were refractory (i.e., not all patients needed to have disease that failed to respond to multiple therapies). So, technically from a data and mechanistical perspective, there is no need to have a failed trial of all conventional medications. Realistically, and mostly driven by price, efgartigimod alfa should not be offered in the first line but rather after a patient has tried conventional treatments, which makes the diagram realistic.

CDEC acknowledged the clinical expert’s response and agreed that failure of all 3 conventional therapies would not be required, rather considering trial of at least 1 of AChEIs, CSs, and/or NSISTs in the previous 12 months.

In the ADAPT trial, if a patient was an MG-ADL responder during a previous cycle and then their disease lost response, that patient could qualify for re-treatment. Loss of response was defined as a < 2-point reduction in the MG-ADL total score during the cycle compared to the baseline value for that cycle. Re-treatment in subsequent cycles was permitted if the patient met all of the following criteria:

• completed the prior treatment cycle (3-week treatment period and 5-week follow-up)
• had an MG-ADL total score of at least 5 points with > 50% of the total score attributed to nonocular symptoms
• the subsequent cycle did not start after day 127 and could be completed within the 26-week treatment period

According to the sponsor and the product monograph, following cycle 1, treatment with efgartigimod alfa can be given on an as-needed basis, according to clinical assessment, and thus would vary by patient. This poses a unique challenge for drug plans when instating an approval if there is no certainty on whether a patient will be re-treated and at what frequency.

CDEC agreed with the clinical expert that this approach would be reasonable.

Considering that patients who had received eculizumab within 6 months of screening were excluded from the study, and there were no comparisons to ravulizumab, would patients who failed either 1 or both drugs be considered for treatment with efgartigimod alfa?

CDEC agreed with the clinical expert that this approach would be reasonable.

• The primary end point used the MG-ADL scale, which is an 8-item PRO tool.
• In the ADAPT trial, patients were not re-treated with the IMP while their MG-ADL score remained below 5.
• A clinically meaningful improvement on the MG-ADL scale is defined as a 2-point reduction in the total score (ranging from 0 to 24).
• The primary end point was the percentage of patients in the anti-AChR antibody-positive population who, after cycle 1, had a reduction of at least 2 points on the MG-ADL total score (compared to baseline) for at least 4 consecutive weeks with the first of these decreases occurring within 1 week after the last infusion of IMP.

CDEC noted the clinical expert response and suggested that the MG-ADL scale would be reasonable given its ease of use and that it was used in the ADAPT trial.

Efgartigimod alfa is administered on an as-needed based for clinical response (physician assessment and PROs).

How many times would a patient require re-treatment due to loss of response before being considered for discontinuation?

Likewise, if a patient has a need for increased frequency of dosing, would consideration be given to discontinuation of efgartigimod alfa?

It would be helpful to have a clear definition of loss of response and disease progression that would indicate the need for discontinuation, defined according to MG-ADL scale parameters and/or frequency of dosing.

The other clinical expert indicated that based on the ADAPT trial, patients who disease does not respond after 2 to 3 cycles (no significant improvement or worsening) should discontinue the treatment.

CDEC agreed with the clinical expert, it would be reasonable based on the ADAPT trial, to discontinue the treatment if a patient had no response after 3 cycles (no significant improvement or worsening).

The medication is given as a 1-hour infusion once weekly for 4 weeks (this being cycle 1).

Following the initial dose, subsequent doses and frequency are dependent on clinical response, and thus may vary by patient. There is no further clarity provided in the product monograph regarding frequency of dosing. The sponsor estimates that patients with anti-AChR antibody-positive disease required a mean (SD) number of 4.72 cycles per year, with approximately 24% of patients requiring < 3.5 cycles per year. Bearing in mind that each cycle consists of up to 4 weekly infusions, to a maximum of 3 vials per infusion, this would mean up to 48 vials annually if at maximum dose and with an average of 4 treatments per year.

It is unclear if there is a minimum amount of time that should exist between cycles. Is there a minimum frequency before administering a subsequent dose?

In the ADAPT trial, the median time between the last infusion of cycle 1 and the start of cycle 2 was 7 weeks (mean of 10 weeks).

In a real-world study of use patterns, the sponsor noted an average gap of 50 days to 58 days between the last infusion of cycle 1 and the start of cycle 2.

In the long-term extension study, ADAPT+, subsequent cycles were only started if the patient completed the fourth infusion of the previous cycle at least 4 weeks prior.

If consistent with this information, would re-treatments with efgartigimod alfa require a minimum of 4 weeks following last infusion before initiating next cycle?

The clinical experts stated that they would plan 3 cycles before concluding there was no response, with 4 weeks between each treatment.

The clinical experts stated that based on the RCT (the ADAPT trial), a number of patients whose disease does not respond to cycle 1 see a response with cycle 2, and an even smaller number of patients may yet see a response by cycle 3. Therefore, after cycle 1 if no response is achieved, the experts stated that they would still prescribe 1 to 2 cycles to get these late responders; and if there is a clinical response, they would maintain cycles given efficacy.

The clinical experts highlighted that the minimum length between each cycle treatments is 4 weeks based on the ADAPT+ trial. The experts stated that they would not wait for the patient to deteriorate before the next cycle of treatment, and instead would treat the patient before clinical deterioration or at minimal deterioration.

Administration is by IV infusion only and requires a trained health care professional. The sponsor expects the infusion to be most commonly administered in a patient’s home and less commonly at an infusion clinic. Given this information, a trained health care professional would be required to make home visits to complete the administration.

Administration will require in-home services or infusion clinics. Although the sponsor states a commitment to providing standardized access to all patients, including remote areas, how this accessibility will be provided is a potential concern.

Would there be any potential combination usage of efgartigimod alfa with eculizumab or ravulizumab, specifically considering that Health Canada issued a NOC for ravulizumab plus conventional therapy in the treatment of patients with anti-AChR antibody-positive gMG?

The other expert stated that theoretically, efgartigimod alfa might be combined with either eculizumab or ravulizumab as they have different mechanisms. But indicated that it would be hard to know if the combination would be clinically superior to either alone as there are no data related to these combinations. As such, the expert stated that they would not support concurrent use. Rather, they anticipated that they would be used sequentially if there was no response to 1 of the drugs.

CDEC acknowledged the clinical experts’ response and noted that there was no evidence reviewed for the combination of efgartigimod alfa with eculizumab or ravulizumab.

Administration is by IV infusion only. It requires reconstitution and administration by a trained health care professional, and up to 3 vials may be needed per dose, depending on weight (10 mg/kg).

At the submitted price, efgartigimod alfa is significantly more expensive than conventional therapy and immunoglobulin and/or PE therapies but comparable to the cost of ravulizumab.

At this time, ravulizumab has not received a positive funding recommendation for gMG or gone through pricing negotiations so it is difficult to make a comparison with these unknowns. It is awaiting CDEC reconsideration.

Although not mentioned as a comparator by the sponsor, eculizumab is another treatment for gMG and its pricing negotiations ended without agreement. The reimbursement status of eculizumab for gMG across the jurisdictions is not currently known.