By Rich Soll, Senior Advisor, Strategic Initiatives at WuXi AppTec (@richsollwx)

This is the story of a scientist whose quick rise to successful entrepreneur was driven by the sheer dedication and passion to revive a shelved drug of profound effect that saves patients’ lives.

Meet John Hood, CEO of Impact Biomedicines, which was launched in the fall 2016 with a $22 million Series A, and then recently sold to Celgene for $7 billion. Celgene is interested in Impact’s fedratinib, a highly selective oral small molecule JAK2 kinase inhibitor that has shown promise as a potential treatment for a type of blood cancer called myelofibrosis.

That’s just scratching the surface of this compelling story.

Hood co-invented fedratinib while working at a company called TargeGen, which was sold to Sanofi for a $75 million up-front payment in 2010. However, the development of fedratinib was discontinued by Sanofi after the FDA issued a clinical hold subsequent to reports of Wernicke’s encephalopathy (WE), an acute neurological condition indicative of a vitamin B1 deficiency, in patients participating in fedratinib clinical trials.

But, there were numerous patients who benefited greatly from the drug, and after the urging of physicians and patients alike to bring the drug back, Hood quit his job, put up a big chunk of his own money, and set out on a mission to get the FDA to lift the clinical hold on fedratinib, which happened in August 2017.

There are several important pieces to this rapidly advancing and heroic story. I recently caught up with Hood, who walked me through the dramatic ups and downs, as well as the joys that are ultimately reflected in the name of the company – Impact.

Rich Soll: First, let’s talk about the JAK2 inhibitor. Can you provide a brief history of its evolution and its progression into the clinical trials?

John Hood: Fedratinib, as you well know, is a highly selective inhibitor of the kinase JAK2. The JAK family is important for a number of different functions in the body. JAK2 is important for driving stem cells to become red blood cells and platelets and when mutated it drives a host of myelproleritive, neoplasms (MPNs) such as polycythemia vera, essential thrombocythemia and myelofibrosis.  Of those, the worst prognosis is in intermediate to high-risk myelofibrosis where patients typically have two-to-three years to live after diagnosis. At this point, about half of myelofibrosis patients have a single mutation in JAK2 (JAK V617F) and another 40% have mutations that are either MPL or CALR, which lead to activation of JAK2. In either case, JAK2,activation really drives the disease so inhibition of JAK2 should be able to treat the disease. We got into it at TargeGen circa 2006 with publications that identified JAK2, and the mutations in JAK2 as the driver for MPN– if you can inhibit a driver mutation, you have the opportunity to have profound positive clinical impact.

Rich Soll: What is unique about fedratinib and what role did you play in the discovery of this drug?

John Hood: Fedratinib is pretty unique amongst all the inhibitors that have ever been evaluated in clinic for these diseases based on its selectivity. It’s easily the most selective for JAK2 amongst approved agents. This is important because the other JAKs regulate immune function so inhibition could potentially cause immunosuppression and also thrombocytopenia which is a reduction in platelet production leading to bleeding.  A kinome scan further reinforced its selectivity with flt3 being identified as the only other kinase significantly inhibited.

Further, in man, the drug shows a t1/2 of 22h which means that at clinically relevant doses, we are likely to be above the IC90 all day leading to profound coverage of the target and ultimately an opportunity to better benefit the patient.

The compound itself was discovered at TargeGen. Here we have yet another story.  TargeGen was a San Diego biotech founded in 2001 with initial technology that came out of David Cheresh’s lab in gene delivery that I spearheaded; however, at the time, gene delivery turned out to be too onerous within the construct of an early stage biotech.  Our focus in small molecule chemistry became transformative with the hiring of you (Rich Soll), and I had the opportunity to lead most of the biology programs that included being team leader for the JAK2 inhibitor program.

Rich Soll:  What was your strategy in getting people behind fedratinib, which also led to the Sanofi deal?

John Hood: Early on, we engaged the KOLs; we listened to their feedback which helped shape the clinical trials and we collaborated in the preclinical space.  There are publications with leading researchers about fedratinib that came out from Mayo with Ayalew Tefferi, from Gary Gilliland, and also from Dr. Catriona Jamieson. So we had a lot of people who had first-hand exposure to the molecule even before it was in patients. As we were moving forward, I had the opportunity to get a lot of first-hand experience working with these KOLs, was able to develop the clinical protocols, and do outreach with them. At the same time, we were a San Diego VC-backed company, so we were very interested in developing partnerships with other companies that helped us develop the molecule. We eventually got a verbal agreement in 2008 with Sanofi to develop the molecule. They were going to acquire TargeGen in order to get access to the compound. At that point, I departed just as the Phase 1 trials were about to start.

Rich Soll: How did the clinical trials go?

John Hood: The molecule did really well in clinical trials; it wasn’t as immunosuppressive or thrombocytopenic as other molecules that had been tested, so the safety profile was overall quite good. Further, consistent with its profile, it had the highest primary response rate, which was reduction in spleen size, that has been observed with any molecule that has been tested in myelofibrosis patients. More impressive is the Jakarta 2 trial, which demonstrated activity in patients who had developed resistance to the only other approved treatment, ruxolitinib where we saw response rates between 50-60%. As a qualifier, the main response rate for ruxolitinib across three different trials is around 32%. This was almost twice the response rate seen with the approved therapy. So these response rates are profound for patients.

Rich Soll: Although the drug had proven successful in a number of patients, it ran into a snag. Can you walk us through that?

John Hood: In 2013, a French patient developed a disorder known as Wernicke’s encephalopathy after being on the drug for only a few weeks. Anytime you have a patient with a disease associated with a drug it’s pretty scary. The reality is, it’s a vitamin deficiency, vitamin B1, which leads to brain swelling, confusion and some difficulty walking. It’s preventable, treatable and reversible by supplementing the patient with vitamin B1 (thiamine). Wernicke’s appears in about 1.2% of the general population and was seen in far fewer in the fedratinib trials.

At the time of this observation, the drug had been exposed to nearly 1,000 patients. Sanofi retrospectively analyzed the clinical data and identified eight patients who had neurological symptoms that might be Wernicke’s. The FDA put a clinical hold on the program and made recommendations but Sanofi terminated further development of fedratnib.  Sanofi had gathered thiamine data on 160 patients, which were found to be normal.  Needless to say, patients who had durable and successful treatment with fedratinib were taken off the drug, and were put onto standard of care and most of those patients failed.

Rich Soll: What happened next?

John Hood: The patients were trying to get the drug back and were struggling to find a point of contact to enable them to get it because they were dying. They eventually reached out directly to me, both their physicians and in a couple cases, the patients themselves, based on the fact that I played a big role in the Phase 1 (trials), and the physicians  all knew me, extending back to the non-clinical work prior. The initial request by these patients and physicians was to get compassionate use of the limited supplies of existing drug; unfortunately I was not successful in this endeavor.

I was urged to continue my efforts by a number of physicians, including Moshe Talpaz, Claire Harrison, and Catriona Jamieson. For me, the defining moment came from Theresa, a San Diego patient whom I knew through her physician, Catriona Jamieson.  Theresa had been on fedratinib for five-and-a-half years and had seen her bone marrow fibrosis go from grade 3, which is very scarred (it’s a on scale from 0-to-4), all the way to grade 0; her spleen size was completely normal. As long as she was on drug she was living a very normal life with no evidence of the disease.  Soon after coming off the drug she started to fail; she was refractory to ruxolitinib  therapy. We desperately tried to get access to the drug, but unfortunately not in time, and she died. We knew this patient personally. Moshe Taplaz had 11 patients with Phase 1 & 2 that had positive responses to fedratinib, all had passed away since the drug was taken off the market.

Rich Soll: Can you walk us through getting the drug back from Sanofi and moving forward to having the FDA lift the clinical hold?

John Hood: I had physician after physician exhorting me to get this out there because it was such a wonderful drug and helpful for so many people. Patients had been on the drug for up to 5 years before its withdrawal with durable responses.  I saw patients whom I know die from disease where perhaps the outcome would have been different if they had access to the drug. I felt an obligation, indeed a moral duty, to continue the quest to get this beneficial drug to the patients; it was the right thing to do.  My wife endorsed my decision as the right thing to do.

Towards the goal of getting the drug back, I quit my job in March 2016, I put up $250,000 of my own money and had to raise at least $5 million within 120 days due to particular business considerations.  In pursuit of that cause, which was successful, I got Medicxi (out of Belgium) to participate – their only ask was they wanted to put in $15 million instead of $5 million in order to get a reasonable ownership percentage in the company and we moved forward with it.

We trawled over the clinical data related to the clinical hold and concluded that the neurological findings were not drug related. We presented our analysis to the FDA in 2017, resulting in the lifting of the clinical hold, and we further refined the risk mitigation going forward.  The FDA indicated that the Phase 3 trial in 2013 was sufficient for NDA and continues to be sufficient for an NDA – it’s a placebo, double blind phase 3 where response rates were sky high. So we had an agent we could file on without any more clinical studies, a drug with clear efficacy and benefit to the patient with a desired safety profile in that it isn’t immunosuppressive and it doesn’t hurt platelet counts.

Rich Soll: After that, things moved quickly for Impact Biomedicines, including the deal with Celgene. How did that transpire?

John Hood: As you well know, there’s a lot of demand for something that can get to the market quickly so it was not surprising that a number of companies expressed high interest in this product once the clinical hold was lifted.  In our mind, Celgene was the clear partner of choice, particularly in hematology and oncology; they excel in this space with a directed focus on the patient.  With the aid of a banker for our company of six people, we reached an agreement on general terms in late December with Celgene We worked during the entire Christmas break; there were no holidays last year. The day before JPM, we finalized the deal and it was announced on the very first day of JPM.

Rich Soll: Wow, that is a very moving and inspiring story John.  As I recall, the story unfolded rapidly.

John Hood: I was originally contacted by Catriona and the clinicians and the patients starting at the end of March 2016 and we closed financing in October 2016. So that was a total of seven months, but it took a couple of months to get the negotiation with Sanofi and TargeGen, so it was May or so before we started that. Then in June I talked to 20 or so groups and talked to Medicxi around July or August.  Within 30 days, we had a letter of intent and by October I had cash in the bank.

I also need to recognize that I had tremendous advocates, key KOL’s in the field, for this cause:  Claire Harrison, Moshe Talpaz, Ann Brazeau and Catriona Jamieson amongst many others.  In fact, Catriona became a co-founder of this company. I think their advocacy at meetings both to their peers and their patients really drove rapid initial uptake of the drug. After TargeGen initially disbanded, things slowed down. Nonetheless these advocates came in with a great deal of belief in a drug that they saw in their own hands in their own labs worked very well and then they saw it in their patients.

I had assumed that we would get this thing out of hold and get a green light from the FDA.  However, rate limiting was access to CMC (API) and to people in San Diego with late stage / launch experience. We needed to put money into this immediately as we needed to have multiple batches of the commercial material ready to roll out.  One decision I made was to go to the group who already had familiarity and experience with this program, WuXi.  WuXi was absolutely amazing. It was clear we needed a group beyond Sanofi on the CMC.  Whereas starting material access would be 12-to-14 months with some vendors. WuXi did the whole program in less than 4 ½  months.  They performed the whole process under GMP, delivered 69 kg instead of 50 kg, one month ahead of schedule and of spectacular purity.  WuXi was a real hero in this case.

Rich Soll: Thank you for your perspective and your compliments. We have been engaged from the start of this one. In fact, Crelux, which had done the original crystal structures for the TargeGen program, is now a WuXi company.

John Hood: Absolutely. I was talking to some of the discovery folks at Celgene, and one of the things that resonated with them is we have such great selectively for this molecule compared to every other one. I told them a big part of the reason for that is the internal library (it was a small library at TargeGen) had a particular shape due to our focus on inhibitors of the  bcr-abl T315I mutation we had developed, so the general shape of the molecules were very different than what was in everyone else’s library. It’s not like your traditional TKI inhibitors; it’s fitting into a smaller bucket. So the net result was we came up with compounds that had different profiles than everyone else’s. It only took only a few months to get a super potent compound and then we spent another three or four months getting a  super potent compound that had reasonable PK and ADME properties..

Rich Soll: Let’s talk a little bit about you. You were a fast riser from scientist to true entrepreneur with big impact. Can you outline little bit of your history and describe the influences that shaped your career?

John Hood: I grew up in Texas on a ranch and was product of the public school system. I went to Texas A&M for my undergrad and graduate degree; and I came out and worked with Dave Cheresh at Scripps as a post-doc. I was responsible for creating my own project and making it happen. I developed a fair amount of chemistry for the gene delivery project. Scripps was a fairly unique place in that they have both great biologists but also an amazing chemistry department. It was a gene delivery that led to the founding of TargeGen. It is eye opening to take something like that and try to scale it up from an academic project to something you can actually commercialize.

I had the good fortune to work with a very good medicinal chemist at TargeGen (Rich Soll) who gave the big perspective on chemistry that led to the renewed  interest in this field. With the original founding of TargeGen, I got the opportunity to be the pitch man for deals and other considerations as well as to explain the technology to them.

Rich Soll: What do you think is your most notable achievement in your career so far?

John Hood: It was challenging to get the FDA to recognize this small group of largely consultants talking about this drug. They had a very large pharmaceutical company kill this drug and we had to get them to consider our data and look at it carefully. Getting the FDA to be engaged and to listen was the happiest moment in my life. When that clinical hold was lifted, it was like I was five and it was Christmas day.

Rich Soll: Is this another vote of confidence that kinase inhibitors can be used in settings that take you way beyond cancer or oncology?

John Hood: Absolutely, and I do think that’s another area with opportunity. The reality is, oncology and potentially auto immune diseases are several rungs ahead in terms of the level of work, and the level of precision medicine that any other field has.

Rich Soll: So what’s next?

John Hood: I’m going to make sure Celgene gets the NDA filing, so I’m working with them over the next few months. And there are other companies that I’m excited about. I already have some really nice ideas.

Rich Soll: What would you like to say to young people who are thinking about working in the health care industry and drug discovery?

John Hood: There’s an element of gambling to it. You have to place your bets and find ways to shape your own odds. But there’s nothing more rewarding than knowing that the end point of your work is going to save lives. I think if you can do the multi parametric puzzle solving – PK activity, safety, and investors – there’s a huge opportunity to have a great career that you can feel good about.