Follow up for MGK

Dear Longs,

u/MGK_2 was completely on fire this last weekend. I am always grateful for his posts and the responses he receives. So much learning resides in his thoughts and other people's input. Just love it when the Longs start roooooollllllllllling on a particular subject. So I am going to follow up on a few things: Manuscripts/Publications and Initiating a trial protocol with clinics/Hospitals and a touch on Partnerships.

After all, MGK put in some serious effort and time with four posts over the weekend and MGK suggested I might want to follow up on a couple of things that I have some experience with. Don't forget that u/pharmaJunkee is a master expert at some of this stuff and I know for a FACT he is CRAZY busy with a submission and has very little time, but he may sneak a comment in here to bring more clarity.

Trial Protocol Initiation at Clinics/Hospitals:

CYDY received approval for 90 HIV patients and these patients will be treated once a week with a dose of LL. I believe that Dr. JL estimated that enrollment would begin summer of 2024. When you have an approved trial protocol from the FDA; that is when you can approach your investigational sites. You have the approved trial protocol in hand and walk the targeted investigational sites thru the protocol and get them to commit to be an official trial site. Then the representative (usually the lead investigator) from that trial site, will submit the trial protocol to an internal committee known as an Internal Review Board (IRB). The IRB is made up of physicians and one person from finance. Their job is to assess the viability of the study/trial, how this study/trial impacts their normal community of patients, and whether it will attract a patient population that they may want to serve for the trial as well as after the trial. They also consider the ethics of the study and whether they can execute the protocol with their normal equipment and the staff they have on hand. There are other considerations as well but there is no need for me to overwhelm with nuanced information. What about the FINANCE person? That person's focus is estimating the costs to the hospital for running the trial and if there is normal reimbursement involved as well. The finance person will calculate the costs add a little buffer and make sure this info is available to the IRB. The IRB meets once a month or once a quarter. They review all submissions at that time and determine if they will move forward with being an investigational site. Let's say, (UCSF) University of California - San Francisco is a target investigational site for CYDY's Chronic Inflammation trial in CISgender HIV patients. After UCSF IRB formally accepts the protocol; UCSF submits a term sheet back to CYDY on what they want money-wise to run the trial. More than likely it will be a per-patient charge. There are tons of charges on other study protocols, but on the surface, this looks pretty straightforward.

Before the trial protocol is approved by the FDA; it is normal practice for a company and leadership to sit down and strategize on who the investigational sites might be. Generally speaking, CYDY knew some of the parameters of the trial and could have "preliminary meetings with potential/target investigators. The meetings are informal and are conducted to gauge interest and get a sense of how quickly they might be able to enroll the targeted patient population.

"5:10: As currently designed, the Inflammation Study will be a randomized, double blind, placebo-controlled trial comparing (2) doses of leronlimab in 90 study subjects. The study will enroll 45 cis-gender men & women and 45 transgender women. The subjects will become eligible to participate in the study after demonstrating evidence of required inflammation at screening as determined by elevated from normal C-Reactive Protein or CRP. Eligible subjects will then be randomized either 350, or 700mg weekly sub-q leronlimab or placebo and treated for 24 weeks."

Final Wrap on the IRB trial protocol. My guesstimate is 2-4 trial sites. 1 site is based in San Francisco, 2 sites are in NY, NY., and for sure UCLA (Dr. Jordon Lake) site in Los Angeles. Based on what I said above, the trial sites should have the actual approved trial protocols already sent to them. It is just a matter of when they conduct their respective IRB meetings. Sometimes these meetings are canceled because they can't achieve a quorum. Then things get rolled back by a month.

Back to UCSF example: If UCSF has the approved trial protocol in the hands of the lead investigator, that person would submit it electronically to the IRB meeting coordinator for April's meeting. The coordinator puts it on the agenda for discussion on Monday, April 29, 2024. On the IRB meeting day, it is discussed and approved. The investigator will tell Dr. JL probably on Friday, April 30th that it is approved and by May 15th we will have a "term" sheet/proposal on costs sent out to you for signature. Once that term sheet/proposal is signed by Dr. JL they might enroll their first patient on June 1st. That is if everything goes right.

Other notes for consideration on these IRB meetings: IRB's want to know who it is that will be involved with their research coordinators. In CYDY's case is it the CRO? Some consultants we hire, or maybe a BP partner we have waiting in the wings? Somebody representing the CYDY protocol has to review the whole trial protocol with the investigational sites people: research RNs, treating physicians or clinicians. Make sure they understand the inclusion/exclusion criteria and where and how data will be blinded to the sponsor and where is the data stored and how it is secured and much more. The investigational sites may approve the whole protocol but need to discuss with the clinic marketing folks about updating the trial page on their website and putting out other communication pieces to inform their patient base that this study will be available and ready for enrollment. This may take some time and the first enrollment might be June 15th or even July. Physicians that have this particular sub-population of patients that fit the profile for inclusion in this study would have their research coordinator call these patients directly or contact them somehow and encourage participation in the trial.

Personally, to use Dr. JL's words: this HIV patient population is in Dr. Jordon Lakes Wheelhouse and she is at UCLA. She might have this particular patient population all geared up and we can get 90 enrolled just at UCLA. I have spent a lot of time in Los Angeles covering cases at UCLA, Cedar Sinai, Good Sam, and other hospitals all over Southern California (SoCal) and I live in the SF/Bay area. Both San Francisco and Los Angeles are perfect for this population group and I do not expect enrollment issues. In some ways, NY, NY might not be needed.

Manuscripts/Publications:

The plan according to Dr. JL is to get four manuscripts published ASAP. Just to give a little background on submitting a polished manuscript to a peer-reviewed Journal for publication. My experience was in Cardiology and Electrophysiology. My Cardiologists that I worked with varied from straightforward work hard on my patients and treating them, to KOLs, to the research is my main gig and I treat patients on the side. The research physicians knew the process of publication really well and they would always say it was a 6-9 month process. No matter what you see

What is the NEJM process?

NEJM maintains a database of more than 30,000 peer reviewers worldwide in all areas of medicine. In almost all cases, two peer reviewers evaluate each submission within one to two weeks and submit written reports to the NEJM editors***. on Google:***

It says two weeks for what most believe is the most prestigious medical journal. But they have a rejection rate of 90% and they have trials that they approved but are waiting in the Que to be published in the journal. So you get approval in 2-4 weeks but are waiting on the sidelines.

I do realize that Dr. JL is not targeting NEJM. And I am out of my depth on which journals he should be going to in regards to the 2-mTNBC manuscript, HIV-MDR manuscript, and Covid manuscript. Nonetheless, I do not think it will take the 6-9 month journey that my Cardiologists experienced. But, everyone reading this should realize that there is a process to submitting a manuscript, editing, reviewing the clinical outcomes and reviewing the statistics and methodology of the trial all re-analyzed for integrity and merit. The journal looks to make sure it meets its criteria or rigor before publishing the trial. Yes, Yes, I know....some of you are going to bitch and moan about some journals allowing publications of crap, no integrity studies..that is true and I can't speak for the editors or reviewers of those journals. But it does happen.

Nonetheless, you should know that EVERY company I have ever worked for in the Medical Device space has a publication strategy. Yes, Marketing, clinical, and clinical education teams work closely together to help their targeted customers publish on the company's products. They at times collaborate with physicians on suggested protocols and head-to-head comparisons. Of course, funding is involved. In CYDY's case; our strategy at this point is to get visibility with the BIG BOYS. Plus, getting published helps build credibility for LL.

Partnerships

I have been a little bit crazy busy lately and I have not read a lot of posts this last weekend, but I did read a few and I want to comment on a theme that I think I picked up on. Theme: when is the partnership announced?

Great question!! One thing is for sure; if you go back and listen to the CC, and read MGK's transcript from the call: it referenced PARTNERSHIPS a lot. It is the normal convention for developmental drug companies to work with partners. This is the normal way to proceed in the developmental cycle. BP pays small little developmental drug companies to move the drug thru the process and BP helps with funding. BOOM ! That is NORMAL. We have an extraordinary CEO in Dr. JL who understands the normal process of co-development agreements with BP and he is going to make it happen. NO DOUBT in my mind that he has had several discussions already and that is why Mitch Cohen was brought on board. Mitch is here to design the agreements so CYDY does not get screwed by BP. Maybe that's why Dr. JL was so happy about Mitch's impact on CYDY so far.

All I can say is we are getting close to a critical juncture and FUNDING in a non-dilutive way is imperative to our current and future existence. We need partners and I believe it has to be close at hand. I wish I knew exactly when but from where I sit it should happen before the IRB's rule on the trial protocols. However, it is possible to run the GBM trial and the HIV chronic inflammation trial before partners come on board.

I do believe it is possible to run the HIV Chronic Inflammation trial on our own with 1-2 clinical trial HIV consultants as our own CRO. If Dr. Jordon Lake is involved and I hope she is, enrollment will be expeditious and clean. The HIV consultant just receives the electronic data when he or she is supposed to for aggregation purposes. If we have a DSMB, then that is a separate charge but not a big one. I don't think this trial will be very expensive. The worst case is we run this trial on our own and then the partners come in WITH MONEY BABY!!