Key person interview

The presentation at the ASH meeting in 2023 has reignited 
incredible enthusiasm about this drug to treat Adenovirus. 
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Medical Director, Bone Marrow Transplant and Immune Deficiency 
Cancer and Blood Diseases Institute Cincinnati Children's Hospital Medical Center　　　　　　　　　　　　　Cincinnati, OH USA   
Michael Grimley, MD Professor of Pediatrics

Question 1. Can you talk about your specialty, the treatment of viral infections after hematopoietic stem cell transplantation?

Patients who have received chemotherapy and immunotherapy to undergo a bone marrow transplant or whom have had a solid organ transplant are severely immunocompromised and those patients are very much at risk for the reactivation or infection with viral pathogens specifically commonly double-stranded DNA viruses such as CMV, EBV, AdV and BKV, and these viruses are often a leading cause of morbidity and mortality after transplant procedure specifically adenovirus has now become a leading cause of significant morbidity and mortality because there are no effective treatments currently approved or available and unfortunately we will see one to two patients a year die in our center from disseminated adenovirus and it's estimated that similar results occur at every transplant center so you can see that adenovirus is a very big and significant problem for both the solid organ and the allogenic bone marrow transplant patient population.　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　The medicine called cidofovir has been used and has shown minimal effectiveness in AdV patients. It is a drug that we use even with its poor efficacy but has a significant likelihood of damaging your kidneys. The lack of treatment options for Adenovirus infections means we do use that drug as a treatment for AdV despite its renal toxicity.　　　　　　　　　　　　　　　　　　　　　　　　　　　We are also reduce the immunosuppression for the patients who are on drugs that reduce their immune system but that can lead to them rejecting their heart or kidney transplant or if you're a bone marrow transplant recipient lowering the immune suppression is associated with a greater chance of developing graft versus host disease which can lead to the patient developing a life-threatening complications with their transplant.

Question 2. How about your treatment with CMV?

CMV has currently four FDA-approved medicines for the treatment of or prevention of CMV and those medicines are generally effective but still patients will develop resistance to the CMV  medicines. Also a problem is these medicines have side effects such as lowering your blood counts or kidney damage so there it is the ongoing problem but compared to AdV, CMV does have more treatment options but CMV is more common to reactivate in transplant or immunocompromised patients so CMV infection is still ongoing concern that additional CMV medicines would be welcomed.　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　Because about 2/3 of our patients after their bone marrow transplant will experience a CMV reactivation or infection and so 2/3 of our patients need CMV treatment even though 80 to 90% of those patients are treated well with the current medicines there is still a significant population of patients that we require multiple medicines or they don't respond to the medicine so yes every several months we have a very problematic patient that has issues with CMV.　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 　 Whereas about 30 to 40% of our patients will have issues with adenovirus after their bone marrow transplant so not as many patients as compared to CMV but because we don't have effective treatments for the AdV that's much more likely for those patients who have adenovirus to develop life-threatening complications from their adenovirus infection compared to CMV so the greatest unmet need in the pediatric transplant world is a safe and effective treatment for the adenovirus.　　
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Question 3. How did you find out about brincidofovir (BCV)?

Question 4. POC granted from ATHENA study

The data that was available before the study started was that the IV form was 10 times more potent than the oral form but the healthy volunteers did not show any gastrointestinal, bone marrow, or renal toxicity so it was a very exciting drug that we would hopefully be able to treat adenovirus infections but not have the gastrointestinal side effects that associated with the oral form of BCV and so that was the basis for ATHENA was to prove that idea that if the drug was safe and then hopefully through the dose escalation to find a safe dose that had high efficacy treating antivirus.
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Question 5. ^​ASH 2023 presentation

Question 6. The presentation at the ASH meeting in 2023 has reignited incredible enthusiasm about this drug to treat adenovirus.

The audience's response was incredibly enthusiastic about the efficacy and the safety of the medicine and I had numerous questions the basic question thrust of the question was what is this medicine going to be available what has struck me since then is I am getting numerous I've been getting numerous emails almost every two or three days about “I have a patient with adenovirus”, I'm in Australia, I'm in Canada, I'm in Great Britain... “How do I get access to the drug?” So, the presentation at the ASH meeting in 2023 has reignited incredible enthusiasm about this drug to treat AdV.

Question 7. Compassionate use program

Compassionate use programs are great while the companies are pursuing a licensing pathway so that the drug can be available to every center everywhere in the world as a physician who needs this drug. I want the company to keep its eye on getting the studies open so that we can prove to the regulatory agencies as quickly as possible that this is a safe and effective drug and bring it to market. Many regulatory agencies will not accept data from compassionate use so. I think the best way to do that is to get these studies open and enroll so that patients everywhere will have access to this drug in the near future.　　　　　　　　　　　　　　　　　　　　　　The results of the ATHENA study have made me again extremely excited that we have developed an effective treatment for adenovirus that is safe and now we just must get enough data. treat enough patients so that will have the data set that we can take to the FDA and the different countries and get this drug approved so that patients worldwide will have access to it.

Question 8: About 2024 Tandem meeting

The tandem meeting is in two and half weeks in San Antonio and we will be presenting ATHENA data reviews the cohorts 1-2 and three and we will be highlighting the safety data showing how safe and well tolerated the drug was then we'll be presenting the efficacy data that's looking at the clearance of the adenovirus in the first four weeks after they started the drug and if they did clear it in four weeks how long did it take it to clear or did they not clear.  So, they are the overall response rates and will be the thrust of my presentation.　　I expected the audience would be even more excited as this is a transplant focus meeting whereas the ASH meeting in December is a very big international meeting but it is not focused on transplantation so the audience at this coming presentation is all transplant doctors and these are the doctors taking care of the patients who are most affected by the adenovirus so I expect a very enthusiastic reception and anticipate lots of questions with are very much focused on how are we going to get this drug approved and how quickly can we get it approved.　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　Many transplant patients have adenovirus infections at some point in their lives and the adenovirus infections in normal individuals cause ear infections, upper respiratory tract infections like the common cold. It can cause stomach flus or gastroenteritis and then once you have that AdV, your body clears it and the adenovirus remains inside of you asleep.　　　　　　　　　　　　　　　　　　　　　　So then when your immune system becomes suppressed the immune system is no longer able to control the adenovirus and so the adenovirus starts to reactivate because one of the places the antivirus is most likes to rest or remain in your body is in your gastrointestinal tract. So when you have no immune system,  the adenovirus reactivates in your intestinal system and as it becomes more prevalent larger numbers your stool burden goes up you start to have diarrhea and investigators in Europe and other places have shown that if your stool burden is increasing with AdV. Then that is likely to lead to it spreading to your bloodstream to your liver to your lungs and so their argument is if we could have a safe medicine to intervene once the stool burden is going up we could be able to stop the adenovirus from ever becoming life-threatening or concerning by treating these patients early.
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Question 9: What do you have to quote on the future development of the AdV or other infections So what kind of expectations do you have?

Having been involved in expected the use of BCV for the last 13 years. I have seen the drug be highly effective against such things as HSV, AdV, EBV, BKV, HHV-6, and CMV which are all double-stranded DNA viruses. There are in my mind many viruses that potentially BCV could be effective against.  The easiest and most dangerous virus to me is adenovirus which has no treatment and is deadly for many patients so that is the easiest if the company if we are our studies can prove that it's effective against adenovirus then it can be approved by the regulatory agencies and be available for everybody.
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Q10. About SymBio Pharmaceuticals

They have been excellent to work since I first met them in Orlando several years ago. They have been very responsive to suggestions and rigorous scientific discussions have advanced quickly into proof of concept studies and have worked very well with the clinicians so I'm very hopeful that that fruitful discussion can continue and collaboration so that we can get BCV approved by the regulatory agencies.　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　I'm very encouraged. I am overjoyed at the results of the study and I look I'm eagerly anticipating the development of the follow-up studies so that we can continue the very positive momentum that BCV and SymBio have established in 2023 I'm hopeful that in the next year or so, we'll be talking about the results of the next study.

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