CEL-SCI ($CVM): Pre-BLA Meeting, The Next Catalyst
"Before anything else, preparation is the key to success." - Alexander Graham Bell
The Revolutionary Meeting, 1883 - Ilya Repin
In the July 1, 2021 Investor Call to Discuss Phase 3 Results, at 35:30, John Cipriano, CEL-SCI’s Senior Vice President of Regulatory Affairs said:
I would like to let you know that I have already contacted FDA, both the Division of Oncology Products, which is the group that will manage any application that comes forward, and the Division of Orphan Drug Products. Our product is an orphan drug, which means it affects under a certain population of patients in the United States. For that purpose sometimes, it is advantageous to the review process, sometimes it will speed it up and helps us along. I have contacted those groups and I told them of our data, our findings briefly, and indicated to them that we will be in contact to line up a pre-BLA meeting at which we will present all the data and seek their approval to submit an application.
In the July 7, 2021 Letter to Shareholders closing remark, Geert Kersten, CEL-SCI’s Chief Executive Officer wrote:
In closing, our very successful data for the Multikine treatment regimen in patients who received surgery plus radiation treatment eliminates the data risk. Since the analyses were pre-specified in the protocol and the SAP and analyses were done after database lock and before unblinding to the study data, we are allowed to use the data showing robust and durable 5-year overall survival benefit in our FDA submission. No safety issues were identified. We have $47M in the bank. We are now preparing to meet with the FDA for a pre-Biologics License Application (BLA) meeting and seek and file for FDA approval.
When will this pre-BLA meeting take place? What is it? Why is it important? Let’s discover all of this in this article.
Timeline of Pre-BLA Meeting
Based on the FDA Meeting Guidelines, a pre-BLA meeting between CEL-SCI and the FDA is a type B meeting which is subject to the following timeline:
Day 0: CEL-SCI requests a pre-BLA meeting
Day 21: FDA responds to CEL-SCI’s request
No later than 30 days before the meeting: CEL-SCI sends the meeting package to the FDA
Within 60 days from the meeting request: the pre-BLA meeting takes place
30 days after the meeting: FDA sends meeting minutes to CEL-SCI (if applicable)
After a pre-BLA meeting, we can expect to see a press release summarizing the outcomes of the meeting.
From what John and Geert said in the Introduction, we believe that CEL-SCI would request a pre-BLA meeting somewhere in July. That means the pre-BLA meeting will likely take place in September at the latest and we should hear about the meeting outcomes by end of September.
Purpose of Pre-BLA Meeting
Based on the FDA’s Standard Operating Policy and Procedure (“SOPP”) 8101.1 named Regulatory Meetings with Sponsors and Applicants for Drugs and Biological Products (“FDA Meeting Guidelines”):
The purpose of the (pre-BLA) meeting is:
To discuss the planned content of the application with the appropriate CBER (Center for Biologics Evaluation and Research) review division. Applicants are strongly encouraged to request this meeting.
To inform CBER of the general information that will be submitted in the marketing application, to discuss preliminary efficacy results derived from studies conducted to support the BLA and appropriate methods for final statistical analysis
To discuss the proposed format for data in the planned marketing application, to identify the studies that the applicant will rely on as adequate and well-controlled.
Although the format and content of a BLA submission are specified in FDA guidance documents, for instance this Guidance to Industry, each FDA division might have different preferences.
In case of CEL-SCI, we expect that the Division of Oncology 2 (“DO2”), which is in charge of Thoracic Head & neck, Neuro-oncology Rare cancers, Pediatric solid tumors in the Office of Oncologic Diseases, will oversee the approval process for Multikine.
Therefore, although not required, it is an excellent idea for CEL-SCI to request a pre-BLA meeting to gain the FDA’s acceptance for the data and the formal BLA submission, and understand the DO2’s preferences for the submission format or any required further support to facilitate the review process.
According to the FDA Meeting Guidelines, to prepare for the pre-BLA meeting, CEL-SCI will need to provide “a summary of the data from the pivotal studies completed; the proposed indication; proposed format of the submission, manufacturing information on the products used in the study(ies) and product intended for distribution if different; outlines of any contractual arrangements for product manufacture, proposed format of the submission and a timeline for submission.” That’s what Geert means by “We are now preparing to meet with the FDA for a pre-Biologics License Application (BLA) meeting and seek and file for FDA approval.” in the July 7, 2021 Letter to Shareholders. There is a lot to do.
Expected Key Discussion Points
We expect CEL-SCI to use this opportunity to clear with the FDA any points which may raise questions from the FDA during the review process. 3 important points come to our mind:
The application for Multikine for patients treated by surgery plus radiation (without chemotherapy) is appropriate, and the Phase 3 data for the radiation treatment arm is sufficient for the application and that no additional data nor trials are required.
The proposed pre-selection methodology to determine which patients appropriately will receive radiation after surgery is appropriate.
Potential Fast Track Designation
Given the radiation treatment arm was pre-specified in the protocol, and the robust results of this arm were based on the “gold-standard” overall survival benefit, we expect point 1 will not require much discussion.
Point 2 should be the primary focus and depends upon how accurately the pre-selection methodology works based on full Phase 3 data. It is important to note that given that Multikine is non-toxic, there is no health-related downside if a “pre-selected radiation” patient were to end up receiving “chemo”. On the contrary, it’s sub-optimal if a “pre-selected chemo” patient ends up receiving only “radiation” and hence would miss the benefit from Multikine. In our view, it’s likely that the FDA will want to make sure the pre-selection methodology is accurate and robust so that Multikine can help the largest number of relevant patients. It will also be important for the pre-selection method to be compliant with Companion Diagnostics guidance in general, and for oncology products in particular.
Point 3 will likely be also very interesting. The FDA has a range of Expedited Programs for serious conditions such as Head & Neck cancer. These programs include Fast Track Designation, Breakthrough Therapy, Accelerated Approval Pathway and Priority Review Designation.
Breakthrough Therapy should be requested “with the IND or after but ideally no later than end-of-phase 2 meeting” so it is not relevant for CEL-SCI at this stage.
Accelerated Approval Pathway is based on “an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict a drug’s clinical benefit.” Given Multikine exceeded the “gold-standard” overall survival objective of the primary end point for the radiation arm, CEL-SCI does not need to go through the Accelerated Approval Pathway and can proceed straight toward a traditional approval.
Priority Review Designation shortens the clock for review of marketing application from 10 months to 6 months and must be requested “with the BLA, NDA, or efficacy supplement submission,” so it’s too early for consideration in the pre-BLA meeting.
Fast Track Designation is however very appropriate for a pre-BLA discussion. Based on the Expedited Programs guidance:
The qualifying criteria for a Fast Track Designation is “a drug that is intended to treat a serious condition; and nonclinical or clinical data demonstrate the potential to address unmet medical need” which is perfectly suited to Multikine as an intent to treat drug for Head & Neck cancer.
Fast Track Designation can be requested “with IND or after but ideally, no later than the pre-BLA or pre-NDA meeting.” and the timeline for FDA response is “within 60 calendar days of receipt of the request” which is the same as the timeline to have a pre-BLA meeting upon the receipt of the meeting request.
Hence, it makes a lot of sense for CEL-SCI to request this Fast Track Designation at the same time as the pre-BLA meeting request, and expect the FDA’s response at the time of the pre-BLA meeting.
The Fast Track Designation allows for a Rolling Review of the BLA which enables individual modules of the BLA to be submitted and reviewed on an ongoing basis, rather than waiting for all sections to be completed before submission. In addition, there are opportunities for frequent interactions between CEL-SCI and the review team, and Fast Track Designation product could be eligible for priority review if supported by clinical data at the time of the BLA.
Overall, receiving a Fast Track Designation is a very strong signal that the FDA is supportive of the product and is ready to give the potential BLA approval sooner compared to a standard review.
Why could the pre-BLA meeting be a catalyst?
We expect CEL-SCI to put out a press release after the pre-BLA meeting, by end of September. This press release could be a major catalyst if a number of points among the following points are confirmed:
The FDA indicates that existing clinical data, nonclinical data, safety database and manufacturing data will support a BLA submission.
The FDA confirms that no additional data / clinical trials are necessary for BLA submission.
The FDA is comfortable with the pre-selection methodology.
The FDA grants a Fast Track Designation, and CEL-SCI indicates a clear timeline to initiate a submission for a rolling review.
So let’s wait for the press release which could remove any remaining doubts regarding the success of Multikine. In the meantime, we’ll prepare a new article to explain why it is a virtual certainty that Multikine will be approved by the FDA. Stay tuned.
If you like what we do, feel free to share it and subscribe to our website.