News

Innovation that Matters

Filter By

2020/07/08

TG Therapeutics’ Early Oncology Research Leading to New MS Therapeutic

At TG Therapeutics in New York City the company didn’t start out looking for new therapies for Multiple Sclerosis (MS). TG began as an oncology focused company but as the data came in from their research the company and President and CEO Michael Weiss believed their assets could be applied in additional disease spaces and are developing a new therapy for MS. More than 2.5 million people suffer from MS worldwide. It is a long-lasting disease that can affect your brain, spinal cord, and the optic nerves in your eyes. It can cause problems with vision balance, muscle control, and other basic body functions. MS is a rare autoimmune disease. Normally, antibodies produced by the immune system help protect the body against viruses, bacteria, and other foreign substances. In people who have MS, the immune system attacks the body. There is no known cure for MS, but Mr. Weiss believes that real progress has been made in developing new treatment options for MS sufferers, and that TG may be offering its own new therapy for MS. WuXi AppTec Communications as part of its special series on MS spoke to Mr. Weiss about the advanced therapeutic approaches TG is developing to treat this debilitating disease. Mr. Weiss founded and has served as the Company’s Executive Chairman, President and CEO since December 2011. Prior to TG, Mr. Weiss founded and was the CEO of ACCESS Oncology (1999) which merged with Keryx Biopharmaceuticals (2004) for which he served as Chairman and CEO until mid-2009. Previously, Mr. Weiss spent several years as a lawyer and then investor in biotech venture capital. Mr. Weiss continues to have a passion for helping early stage biotech companies and serves as Vice Chairman of Fortress Biotech and Chairman of Checkpoint Therapeutics and Mustang Bio.  WuXi AppTec: Many biotech companies are involved in cancer research; how did you chose to target MS as well? Michael Weiss: At TG our number one goal and priority is to create the best possible treatment solutions for patients with B-cell diseases. While we began with a focus on oncology, we’ve known that many autoimmune diseases also result from aberrant B-cell activity, so from very early on we had a vision to also bring our drug candidates into autoimmune disease. When we saw the early data evaluating CD20s in MS we knew this was a great place to start helping patients. WuXi AppTec: What makes MS so difficult to develop effective therapies for? Michael Weiss: One of the biggest challenges in treating MS is that the cause remains unknown. It’s still unclear exactly why this autoimmune CNS disease develops in some people and not in others Most available data points to some combination of genetic and environmental factors sharing the responsibility. In addition, signs and symptoms of MS patients vary widely. That said, while this lack of critical information has so far made targeting the root cause of MS extremely difficult, we believe CD20 treatment is extremely beneficial to patients and is a significant step forward for the treatment landscape. WuXi AppTec: Have you encountered any patient recruitment challenges in your MS program that were different from your experience with other trials you’ve conducted in the past? Michael Weiss: The ULTIMATE trials enrolled incredibly well with a total of approximately 1100 patients across both trials and target enrollment achieved approximately 9 months ahead of schedule. WuXi AppTec: How much progress has been made in MS drug research and development over the last 20 years? Michael Weiss: Progress has been significant to say the least. Think about it: 30 years ago, there were no approved MS drugs in the United States at all. Ten years ago, there were still no oral treatments available. The use of anti-CD20 monoclonal antibodies in treating MS was only first approved in 2017. We’re witnessing several MS treatments in development, and while a true cure remains elusive, I have hope this research will serve to further advance novel therapies and provide new treatment options for the millions of MS patients worldwide. WuXi AppTec: We have been talking about MS research in general. I would like to switch to your specific drug program. What phase is it in? What is its MOA? And what results have you seen so far? And will it treat all stages of the disease? Michael Weiss: Our ULTIMATE I and ULTIMATE II Phase 3 trials in relapsing forms of multiple sclerosis (RMS) are two independent, global, randomized, multi-center, double-blinded, double-dummy, active controlled trials comparing ublituximab to oral teriflunomide. The primary endpoint for each study is annualized relapse rate following 96 weeks of treatment and the trials are designed to support submission for full approval of ublituximab in relapsing forms of MS. As I had touched on earlier, ublituximab is a novel glycoengineered monoclonal antibody that targets a specific and unique epitope on the CD20 antigen found on mature B-lymphocytes. Its mechanism of action is similar to the approved anti-CD20 monoclonal antibodies, but the innovation of ublituximab is that it has been bioengineered to remove certain naturally occurring sugar molecules from the anti-CD20 antibody in a process called glycoengineering. By removing the sugar molecules we enhance the potency of ublituximab, with data showing 50-100x greater activity than non-bioengineered anti-CD20 antibodies. The ULTIMATE I & II trials are fully enrolled and being conducted under Special Protocol Assessment with the FDA. We are targeting top line data from these trials in the second half of this year. WuXi AppTec: Why do you think your approach can be more successful than other companies’ drug programs in this disease? How will it fit in the MS market space? Michael Weiss: Right now, we expect that ublituximab will be the third CD20 to market, following ocrelizumab, which is currently selling, and ofatumumab, which is expected to enter the market in the next six months or so. To my knowledge, there are no other CD20s in development or late-stage development for MS. We believe ublituximab may offer several advantages over the other CD20’s for MS, including the convenience of being a one-hour infusion every six months, versus the current 3-4 hour standard of care with ocrelizumab, at what we expect to be a competitive price designed to optimize patient access. WuXi AppTec: Sounds very promising! Finally, when do you think your drug may be available to patients? Michael Weiss: Assuming all goes well, we plan to possibly prepare a regulatory filing next year. If that is the case, we may be looking at FDA approval in late 2021/2022.    

Read more

2020/05/19

Disease-Modifying RNA Therapies from Recode Therapeutics Target Rare Lung Diseases

The recent merger of TranscripTx and ReCode Therapeutics created a company that combines RNA drug expertise with a non-viral lipid nanoparticle (LNP) delivery platform to develop new genetic therapies for treating the underlying causes of two rare lung diseases: cystic fibrosis and primary ciliary dyskinesia (PCD). The new company retained the ReCode Therapeutics name and made headlines with an oversubscribed $80 million Series A round of financing in March 2020. David Lockhart, Ph.D., former TranscripTx CEO, is the president and CEO of the merged company. He said an essential element in the success of any new genetic therapy depends on a safe, effective and targeted delivery vehicle. The non-viral LNP delivery platform, Lockhart observed, was “a big part of getting the merged company funded. It can be used to package different types of genetic therapy payloads and can be tuned to deliver them in different ways, get them to where you want them to go, and deliver them safely and repeatedly.” Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes the CFTR protein. An absent or defective protein leads to airway hydration problems, inflammation, lack of mucociliary clearance and frequent airway infections – impairing lung function and leading to life-threatening respiratory failure. The rare disease affects more than 70,000 people worldwide. ReCode is developing a transfer RNA (tRNA) therapy to treat a subpopulation of cystic fibrosis patients with so-called nonsense mutations. The tRNA therapy is delivered into lung cells to enable production of the functional CFTR protein and restore lung function. PCD is caused by mutations in a number of different genes that result in dysfunctional cilia on lung cells. When working properly, the hair-like cilia wave back and forth to clear mucus and harmful bacteria from the lungs. When the cilia are defective, mucociliary clearance is impaired, and inflammation and infections damage lungs creating chronic breathing difficulties. Only 3,000 cases of PCD have been confirmed in North America, but according to the PCD Foundation, limited awareness and under diagnosis of the disease means the number of patients could be closer to 25,000. PCD is sometimes considered less severe than cystic fibrosis. But children with PCD suffer from similar complications as those with cystic fibrosis and face shortened life spans due to respiratory failure. In addition, there are no treatments available. ReCode has developed a messenger RNA (mRNA) therapy delivered into cells to produce normal versions of the proteins that make cilia, restoring proper ciliary function on cells throughout the airways and lungs. ReCode’s cystic fibrosis and PCD RNA therapeutics are nebulized and turned into an aerosol that patients will inhale into their lungs. The therapies are in preclinical development and the company expects to file Investigational New Drug applications with the US Food and Drug Administration (FDA) in 2021 to begin clinical trials in both programs. As part of its ongoing series exploring the challenges of rare disease drug development, WuXi AppTec Communications discussed with Lockhart how ReCode’s RNA therapies represent a significant advance in the treatment of cystic fibrosis and PCD. Lockhart has more than 25 years of drug discovery and development experience. Before joining ReCode, he held scientific and executive positions at Amicus Therapeutics, Ambit Biosciences and Affymetrix. Lockhart received his Ph.D. from Stanford University and was a postdoctoral fellow at the Whitehead Institute in the Biology Department at the Massachusetts Institute of Technology. WuXi AppTec: What are the major differences between developing drugs for rare diseases and for more common diseases? David Lockhart: As you know, approximately 7,000 rare diseases have been identified. Obviously, for some rare diseases one of the challenges is that there are so few patients that it’s hard to find enough of them for clinical trials. You have to have clinical sites all over the world and even then, it can be very challenging, especially with “ultra-rare” diseases. Also, rare diseases are often under-diagnosed because many physicians have never seen a patient with a particular disease. So in addition to small patient populations, there is not a lot of information about some of the diseases. WuXi AppTec: What are some of the regulatory challenges you face, such as determining the appropriate endpoints, or outcomes, for clinical trials? David Lockhart: The challenges differ based on the disease. We’re fortunate that for cystic fibrosis and PCD the drug development and regulatory paths are fairly well-established and clear. That’s because of the work done by Vertex Pharmaceuticals to get its drugs approved for cystic fibrosis. The clinical path and primary endpoints, and even secondary and supportive endpoints, are very similar for cystic fibrosis and PCD. But in other rare diseases, if no drugs have been approved, no primary endpoints have been developed for clinical trials and it may not be clear what the clinical endpoints should be. As a drug developer, you may have to create endpoints of your own, then validate them and convince the FDA they make sense. That can be a very difficult process. And then for some rare diseases, the endpoints can be difficult to achieve. For example, if the primary endpoint involves slowing progression of the disease, it can take a long time to see a difference between the treated group and placebo group or an untreated historical control group. For our company, we’re very fortunate to have a primary endpoint that has already been used as the basis for approval of other cystic fibrosis drugs. Just as important, that endpoint has shown rapid improvement in lung function within weeks, not just a slowing of progression over a year or two or longer. That’s a huge advantage for our programs in cystic fibrosis and PCD. WuXi AppTec: What are some of the business challenges, such as raising funds for rare disease drug development? David Lockhart: The primary thing we look for is unmet medical need; that we’re really going after a problem in need of a solution and that patients are in need of a therapy. But then there also are practical matters of selecting diseases with enough patients to run clinical trials and enough patients in the world to make the drug commercially viable. In the context of raising money, the latter is an important part of the conversation. People need to know this is a disease that’s treatable, that a drug can get approved and that with approval the drug can be commercially successful. WuXi AppTec: How important are government incentives, such as the FDA’s orphan drug designation, for rare disease drug research and development? David Lockhart: The short answer is they are really important. With the orphan drug designation there is guaranteed market exclusivity. If your drug gets approved, and has orphan drug status, you’ll know you have a good position commercially. The orphan drug designation also is important because there’s additional help from the FDA. There are more interactions with the agency’s regulators and specific encouragement to meet with them early and often to look at clinical trial design and to make sure things are on track. By the time you get to the more advanced clinical development stages you already know the regulators involved. You’ve established a relationship, and you’re able to work together to develop the drug. WuXi AppTec: How much progress has been made in cystic fibrosis research and drug development? Is a cure in sight? David Lockhart: I can take those two questions one at a time. There’s been significant progress in cystic fibrosis, especially recently. The discovery of the gene and protein that cause cystic fibrosis occurred about 30 years ago. The hope early on was that therapies could be developed relatively rapidly. The disease turned out to be a lot more difficult to treat than people had hoped during the early days. But the good news is there have been multiple drugs approved recently for cystic fibrosis from Vertex Pharmaceuticals. The company has had a series of different small molecule drugs approved that are appropriate for different genetic subsets of the cystic fibrosis population. As a result of all that work, there are therapies that should benefit approximately 90 percent of people with cystic fibrosis. So that’s good progress, and with our targeted genetic therapies we want to reach the 10% of patients who don’t have treatment options yet. But note I said benefit, not cure. The drugs lead to improvement in lung function. They can lead to other improvements in cystic fibrosis symptoms and quality of life as well. But they are not a cure. People still have the disease. They have to keep taking the drugs for life, but it’s certainly better than no therapy at all. There’s also a new type of therapy that has moved into clinical studies from Translate Bio. It’s not a small molecule. It’s a nebulized mRNA therapy that is inhaled into the lungs. The mRNA therapy instructs cells to make the CFTR protein required for normal lung function. Translate Bio has just started clinical studies, so it’s not clear yet whether it’s going to work and how well it will work. But it is encouraging that a new type of drug is going into clinical studies. Do I expect a cure? It depends on what you mean by cure. A cure is a therapy that when administered the patient effectively no longer has the disease. I think that’s still a ways off. But the next best thing is to have treatments that basically make it so the symptoms of the disease are greatly reduced and that people can live long full lives. I think that actually is possible. I don’t know if that counts as a cure, but it certainly counts as a huge improvement in which you basically turn the disease into a manageable condition. Patients still have the underlying cause. They still have the mutation in the CTFR gene. But they can take a medicine and have a long, full, rich life. WuXi AppTec: What is your company’s approach for treating cystic fibrosis and PCD, and how far have you progressed? David Lockhart: For both cystic fibrosis and PCD we have been able to show we can deliver our RNA therapies into human cells using the cell-based model that’s considered to be the gold standard for studying the human airway and testing new approaches. We have been able to show that we can deliver our RNA therapies into those human cells and correct the functional deficiencies. In the case of cystic fibrosis, we show that we get recovery of the CFTR protein function. In PCD, our therapy generates cilia that function normally on the cells. We also have shown we can deliver these therapeutic agents into the lungs of animals and we can do that repeatedly and safely. Now the next step is to do those same types of delivery experiments in larger animals with lungs that are more like those in humans. WuXi AppTec: What kind of RNA therapies are you developing and how do they work? David Lockhart: They are a little bit different for the two programs. For cystic fibrosis we’re delivering tRNA, which helps decode the instructions in mRNA to make proteins. Our tRNA therapy makes it so the CFTR mRNA with nonsense mutations can be translated into a functional version of the CFTR protein, rather than producing a truncated and non-functional protein. The nonsense mutations in the CFTR gene occur in about 5% to 10% of cystic fibrosis patients. These are people with cystic fibrosis who are not helped by the Vertex small molecule drugs. The nonsense mutations in the CFTR gene lead to a premature stop in making the CFTR protein. When the protein is being made from the natural mRNA, the cell machinery comes to a halt so that instead of making the full length protein needed in the airway cells, only part of the protein is made, and it tends to degrade very rapidly. It’s as if the person does not have the needed protein. Our tRNA drug reads the nonsense mutation in the mRNA and makes it possible for the cellular machinery to continue making a functional version of the CFTR protein. Basically, it reinterprets the mutated mRNA so the CFTR protein can be made. It’s very clever, and it makes great sense. It’s a new type of drug. In PCD, people are born with mutations in particular genes responsible for making cilia that don’t move as they should. We deliver into the cells the full-length, normal mRNA that encodes the properly functioning cilia protein. The deficient mRNA is still there, we just add in the correct copy to make the correct version of the protein so that the ciliary machine can work properly. WuXi AppTec: How important are patient advocacy groups and patients in your drug development efforts? Are they helping with clinical trial design? What roles do they play, other than participating in clinical trials, of course? David Lockhart: The patient advocacy groups are extremely important. Sometimes one of the benefits of working on rare diseases is that the patients are very knowledgeable. They’re very engaged. They know about their disease, about the genetics, and about what works and what doesn’t. They know their doctors well. The patient advocacy groups and foundations also set up patient registries. They often are involved in natural history studies. The registries and natural history studies are very helpful in identifying patients, monitoring them and tracking them on how their disease progresses over time. All of these elements are immensely helpful in terms of designing clinical studies, populating the studies, interpreting the studies, and knowing what endpoints to use and what’s likely to happen in those endpoints over time. Fortunately for both cystic fibrosis and PCD there are very well-established foundations and patient groups. It’s an incredible network that involves not only patients, but also caregivers, families, doctors and nurses. WuXi AppTec: In general, what technological breakthroughs will be game-changers for drug developers over the next five years? Will they have an impact on improving the efficiency of drug approvals and lowering the cost? David Lockhart: We’re getting smarter about drug discovery and development all the time. We have made significant progress in developing new kinds of therapies. But the biggest breakthrough in terms of creating better drugs and developing them more rapidly and more efficiently is the delivery. It’s really the delivery side of the equation that can be the most challenging. We need better delivery vehicles that are safe and versatile, meaning they can be used with different types of payloads, such as RNA drugs and proteins, and even the combination of the two. We need to be able to target the drugs so that when they’re delivered they go to the right places, in the right amounts. They go to the right tissues. They go to the right organs and the right cell types. We will speed up drug development and make it more cost-effective when we have a better tool box for delivery of all the new types of genetic therapies.  

Read more

2020/05/19

Powerhouse Collaborator, MassBio’s President & CEO, Bob Coughlin Optimistically Embraces Industry Changes

MassBio is a 35-year standing life sciences trade association consisting of over 1,300 member companies. Today, their programs, services, and industry-critical mass influence, allows them to be truly patient-driven. By utilizing their unparalleled network of innovative companies and industry thought leaders, MassBio is able to advance policy, promote education, and push for innovative cross-industry collaborations. Leading MassBio is President and CEO, Bob Coughlin. Bob focuses on promoting industry growth through the advancement of Massachusetts’ leadership in the life sciences, adding value to the healthcare system, and improving patient lives. Another vital focus for Bob and MassBio is on ensuring collaboration and innovation between the government, industry, and academic sectors. Before joining MassBio, Bob served as the Undersecretary of Economic Development within Governor Deval Patrick’s administration, where he prioritized both healthcare, economic development issues, and advocated for the Massachusetts life sciences industry. Prior to that, he was elected as State Representative to the 11th Norfolk district for three terms. He has also held senior executive positions in the environmental services, capital management and venture capital industries. Currently, Bob serves on the board of directors for The Schwartz Center for Compassionate Healthcare. He is also a member of the Scientific Advisory Board at Boston Children’s Hospital. Recently, Bob sat down with Rich Soll and the WuXi AppTec Content Team to discuss MassBio, their role in the COVID-19 response, industry response takeaways, future preparations, and Bob’s insights into our path forward. WuXi AppTec: What makes Massachusetts unique in the life sciences? Bob Coughlin: We have a critical mass of companies, we have a critical mass of highly educated people, and we have 122 colleges and universities in this state, which is one-sixth the size of California. The high talent pool is a key resource for the life sciences here. We not only educate our own here, we educate the best and brightest from all over the country and around the world. WuXi AppTec: Where does MassBio fit in? Bob Coughlin: Our mission at MassBio is to leverage Massachusetts’ leadership role in the life sciences. We ensure that academia, industry and government are working collaboratively, so together, we can continue to drive innovation. We do that through many different programs and services we offer. Many folks think of us as a lobby entity, but in fact, government affairs amounts to only 15-20% of what we do. Our Innovation Services group works with the amazing tech transfer offices, including five of the top six NIH-funded academic medical centers in the country. They manage our MassCONNECT mentoring program where we funnel those companies, along with other under-the-radar startups, into our Pharma / Partnering days for engagement in business development activities. We help companies grow and raise much-needed capital through traditional fundraising forms or partnerships with large Pharma companies. We help recruit Pharma companies to this area to the extent that today, 18 of the top 20 Pharma companies have a significant physical presence here. We worked closely with the state government on economic development, in a life sciences initiative, which started in 2008 and resulted in a $1 billion investment over 10 years. This really put us in a position to succeed. We offer professional development forums and business services to member companies. For example, MassBio Edge enables our members to procure services and goods at bulk rates, thus offering significant savings, so our membership can work more effectively and collaboratively to address the unmet needs of patients. WuXi AppTec: MassBio has been very involved in taking action during the COVID-19 crisis. Bob Coughlin: Yes, when COVID-19 was coming, we realized early on that this was a particularly tricky virus that could perhaps turn into a pandemic, which it did. Our partners in the health care system were saying, “We are unable to keep our supply chain flowing as it relates to PPE, ventilators, lab supplies, etc. We’re not going to be able to order a lot of the things that come from supply chain partners overseas, because those folks overseas were shut down.” It then became revealing to me — we live in a world of “just in time” inventory. As a consequence, our health care providers were not going to have the proper protection required to care for patients infected with COVID-19. This became our call to action. WuXi AppTec: What action did you take? Bob Coughlin: We have 1300 members in MassBio and there are 500 members in Mass Medic, our counterpart in the medical device space. We thought that if we could inventory in short order what was existing in our member company supply rooms, we may be in a position to help fill some of those voids during the crisis. That led to the creation of the Massachusetts Life Sciences Emergency SupplyHub, known as the SupplyHub, where we could inventory everything our members were able to donate to health care workers. Then, on the needs side, we were able to relay requests from frontline health care providers to the state’s Command Center. First, within 24 hours of initiation, we had close to 200 member companies donate what they had in inventory. Second, more than 500 people volunteered their time to help with supply chain procurement opportunities while also procuring supplies for the hospitals. Third, and most spectacularly, was the giving of commitment by member company volunteers. They would go to the battlefield when frontline health care workers needed relief due to fatigue or sickness. This included doctors, nurses, pharmacists, lab technicians and others. Information was then provided daily to the State and to the Command Center, which then triaged the supply inventory based on needs. Through partnership with the National Guard and Massachusetts Emergency Management Agency (MEMA), the supplies (PPE) were distributed to the sites. The state took over all the operations a few weeks ago, which allowed us to set our energies on getting people back to work. WuXi AppTec: What did you do there especially to be compliant with social distancing? Bob Coughlin: We are working on a program called RESET. Phase 1, which is now completed, was ensuring the buildout of the SupplyHub with sufficient PPE; you can find that information on our website. The next phase focuses on returning more non-essential employees to work. WuXi AppTec: What area do you consider to be of strength of Massachusetts? Bob Coughlin: Our strength is true innovation. Diagnostics, therapeutics, and vaccines go hand in hand, yet who would have thought that in our lifetime the most important thing to the world economy would be a vaccine? In Massachusetts, we have a critical mass in all three areas; there is no better place than here to solve this problem. WuXi AppText: What do you think is the most important lessons learned so far? Bob Coughlin: We have serious supply chain issues in the US that hamper our progress. Despite significant growth in large molecule manufacturing in Massachusetts, certain materials are not readily available so that hinders progress. Yet, this serves as a stark reminder to how essential the life sciences are to the economy in Massachusetts. WuXi AppTec: Yes, health of the life science industry is critically important in Massachusetts. Bob Coughlin: I’ve lived it every day for the last 18 years. My son has cystic fibrosis, but he now has a therapy that works – but it took 18 years to get there. That is why this industry means so much to me—it’s personal. People who once took health for granted think much differently now if they are living through the COVID-19 pandemic, especially if a loved one has suffered from infection. WuXi AppTec: What are two critical areas MassBio has been addressing? First, collaboration is more important than ever because we are in this together; everyone needs to contribute if we are to succeed. The one thing that I’ve noticed, and was inspired by, is the level of collaboration not only between various sectors in the life sciences, but also between the private sector and government. Second, the COVID-19 situation today is unprecedented and we need to better prepare for the future. People are very scared and worried; there is so much misinformation. To help elected officials better communicate with their constituencies, MassBio has established various kinds of briefings, some daily, for elected officials and government officials, especially ones where the complex science needs to be distilled down. WuXi AppTec: Looking to the future– will things be different? Bob Coughlin: Yes, a new norm will result: one that depends on virtual connections and measurable social distancing. I would imagine, until an effective vaccine is in place, we will incentivize infectious disease R&D. We will see more cross-state collaborations and more transparency between elected officials, their constituencies, and supporting industries like ours. I’m going to continue to be an optimist, because I know that this time period is going to change the way we work long-term. I think companies are going to realize that people can work remotely and increase productivity. And really, I think we’re going to be more flexible and nimble as an industry. I think that’s a great thing.   WuXi AppTec: What should be our priority? Bob Coughlin: The most important thing in the world right now is a vaccine; I don’t think you can put a price on it. Our industry has really been showing compassion and willingness to solve problems, and not prioritizing returns. They’re doing the right thing. Closing out, I think we’re going to continue to see more collaborations between companies and private-public partnerships. At this time, many people would say drugs are too expensive. I would say that drugs are too expensive to invent. If this is forcing us all collectively to get better at how we do what we do, it will be less expensive at the end of the day; we’ll be able to bring even more value to the health care system.      

Read more

2020/05/19

Click is Pioneering and Developing Cutting-edge Digital Therapeutics to Transform Medicine

What is digital health? In broad terms, it is the convergence of digital technologies with medicine, health and society to boost treatment efficacy and deliver more personalized and precise patient care. It is an expansive and growing field, covering everything from mobile health apps to sensors to wearable gadgets. But a key component of digital health is the area of digital therapeutics. Digital therapeutics can deliver interventions directly to patients using evidence-based, clinically evaluated software to treat a wide-range of behavioral, mental, and physical diseases and disorders. Unlike other devices, digital therapeutics are held to the same standard as medication or other therapies. It is an expanding sector with global sales projected to hit nearly $8 billion by 2025, according to Allied Market Research. For this inaugural article of a new series on digital therapeutics, WuXi AppTec Communications spoke with Click Therapeutics CEO David Benshoof Klein about the future of the industry and how Click is developing its technology. Click Therapeutics, based in New York City, is one of the early pioneers in digital therapeutics. David Benshoof Klein is the former Managing Director of Opus Point Partners, which created, financed and operated more than ten life science companies. He has been a guest lecturer at Columbia University and NYU Stern School of Business and has served as a senior consultant at Pfizer and strategic advisor at various publicly traded and private life science companies. He holds a BA from Brandeis University. WuXi App Tec: How would you define digital therapeutics? David Benshoof Klein: Digital Therapeutics, simply defined, are software applications that treat a disease. Just like traditional pharmacologic therapies, they are clinically validated through robust clinical trials, and are developed in accordance with relevant FDA, ISO and IEC standards. This sets them apart from other health apps that focus on supporting wellness, patient education, clinical decision support or enabling live teletherapy. In addition, many digital therapeutics, including Click’s, are meant for use as part of a clinical treatment paradigm as prescription products that can only be accessed via a healthcare practitioner. WuXi AppTec: Will biotech and pharma companies develop digital therapeutics, or do you see this as a separate industry? David Benshoof Klein: I really see the industry as separate from pharma–akin to a new class of biotech company. The expertise required for digital therapeutics is quite distinct from pharma and biotech, so we’ll continue to see traditional players actively seek to access the space through partnerships with digital therapeutics companies. Click’s collaboration with Otsuka in depression is the most significant of such collaborations in the industry to date. WuXi AppTec: Why are digital therapeutics necessary in the practice of medicine today? What are the benefits? David Benshoof Klein: One of the great inefficiencies of medicine over the last twenty years, I believe, has been our tendency to impose purely pharmacological solutions on behavioral problems. In reality, modern healthcare is about more than just biology; it relies on social, cognitive and behavioral interventions to provide truly functional treatment. Across disease areas, treatment guidelines continue to recognize that drugs are only one part of a larger toolkit that physicians must have at their disposal, and in many cases recommend non-pharmaceutical options as a first-line approach. Digital therapeutics are vital to ensuring that this treatment paradigm is successfully delivered. They provide safe, effective and convenient treatment modalities that can be easily scaled to dramatically improve access to care. On top of this, they also bolster classic pharmaceutical approaches by generating real world evidence and facilitating greater adherence. The need for digital therapeutics is clear now more than ever. In the past few months, we have all seen how quickly our healthcare system can be overwhelmed and how limited currently available treatment options can be. The COVID-19 pandemic, as terrible as it has been, has only strengthened the case for digital therapeutics. WuXi AppTec: Can you share how you see COVID-19 affecting the digital therapeutics industry and healthcare as a whole? David Benshoof Klein: I think this pandemic has really forced us, as a society, to reevaluate how and when we interact with others. In medicine, for instance, how do we provide patients with the care that they need without putting them in harm’s way or crowding hospital wards? Already we’ve seen a rapid shift from hospital and clinic-based care towards the use of remote treatment whenever possible. With this change has come increased acceptance and adoption of technologies like telemedicine and digital therapeutics. Importantly, the people driving these shifts are the major stakeholders in our industry: patients, physicians, payers, and policymakers. As a digital therapeutics company, we’ve always expected this would happen, but never this quickly. Ultimately, we’ll be feeling the effects of this pandemic for years to come. The steps that we have taken as a community to combat the spread of COVID-19 will give rise to a host of behavioral conditions like depression, anxiety and insomnia being treated almost exclusively remotely, while also highlighting underlying disease areas that may exacerbate the virus, like obesity. All of these conditions are extremely well suited for digital treatments. Given that payers and providers are quickly realizing the benefits of digital therapeutics, I think we will be well prepared to tackle this next wave of post-COVID healthcare challenges. WuXi AppTec: Even with all of the benefits, are there any risks associated with Digital Therapeutics, such as privacy? David Benshoof Klein: Yes, of course privacy should be a central focus of any organization, especially a technology-enabled digital therapeutics company. At Click, our privacy team is dedicated to ensuring that we adhere to all of the relevant laws and industry guidelines and to incorporate privacy by design as we develop our products. At the end of the day, though, digital therapeutics actually lack many of the safety risks associated with traditional pharmaceuticals, positioning them even more strongly in cases where polypharmacy may be an issue. WuXi AppTec: What are the regulatory guidelines for digital therapeutics? Are they still evolving, and if so, what needs to be clarified? David Benshoof Klein: Digital therapeutics that make treatment claims, like Click’s, require marketing authorization from applicable regulatory bodies (e.g. via 510(k) or de novo pathway in the US, or CE marking in the EU). Overall, the regulatory landscape is definitely still evolving, but recent guidance has been extremely encouraging–the FDA recently issued new guidance in response to the COVID-19 pandemic geared specifically towards digital therapeutics and digital health products, further evidencing how regulatory bodies are embracing the immense potential of digital therapeutics. WuXi AppTec: Are business challenges for digital therapeutics different from biopharma drug development? David Benshoof Klein: As a digital therapeutics company, we sit at the intersection of technology and biopharma. This unique position brings with it a unique set of business opportunities and hurdles. One huge benefit is that we can develop our treatments at a much lower cost and shorter time to market than a small or large molecule, and often with a significantly higher probability of technical and regulatory success and potentially even greater upside. The main challenge, and an area in which I think Click really excels, is balancing the diverse expertise (e.g., technology, product, design, science, clinical development and operations, quality management systems, privacy and security, etc.) required to agilely develop a digital therapeutic that drives outcomes and is in accordance with applicable regulatory and quality standards. You also need to build a product that patients actually want to use, which is part and parcel to achieving those clinical outcomes. This is not something that just any digital health or pharma or biotech player can do overnight, or in some cases, ever. WuXi AppTec: How will patients access digital therapeutics and how will they be reimbursed? Will they have more impact on certain groups? David Benshoof Klein: Traditional approaches like pharmacy and medical benefits definitely are one option, but there is also potential for more innovative value-based models, direct-to-payer models and direct-to-consumer prescription models via telemedicine. It’s also possible that reimbursement will vary based on the product area. In any event, the positive impact that digital therapeutics will have is clear: without geographic and distribution barriers, the most at risk and underserved populations will have unprecedented access to the healthcare they need. WuXi AppTec: What kind of digital therapeutics is your company pursuing? What diseases are you targeting? Why? David Benshoof Klein: Click is developing a portfolio of digital therapeutics designed to treat a wide range of disease areas. We are highly evidence-driven in our selection of therapeutic areas to target, focusing on high burden diseases where clinical data support the use of non-pharmacologic approaches and our clinically validated engagement platform can drive meaningful outcomes for patients. Click’s pipeline includes Smoking Cessation, Major Depressive Disorder (MDD), Acute Coronary Syndrome, Chronic Pain, Migraine, Insomnia, Obesity and more. WuXi AppTec: How do your digital therapeutics work? What do they accomplish? Is your approach different from other digital companies? David Benshoof Klein: Click’s digital therapeutics are intended to treat diseases either alone or in combination with pharmacotherapy. To do this, they leverage a growing library of proprietary, clinically validated translational and discovery cognitive and neurobehavioral mechanisms. As a “mobile-first” company, our products are designed from the ground up by our in-house discovery and technology teams to maximize clinical efficacy and engage users natively through their phone. Our algorithms can then learn from user activity to personalize the experience, tailoring the therapeutic to each patient’s specific needs. This has enabled us to build the strongest patient engagement platform in the space with a proven ability to scale (our first marketed product, Clickotine, is available in over 11.5 million lives and counting). With these approaches, Click is really well positioned to tackle new diseases quickly and agilely and drive the growth of the digital therapeutics industry as a whole. WuXi AppTec: Some closing thoughts please. What will be the lasting impact of digital therapeutics on new medicines? David Benshoof Klein: I believe that digital therapeutics will fundamentally change the way medicine is developed, perceived, delivered and monitored. WuXi AppTec: And finally how will digital therapeutics change over the next 5-10 years? David Benshoof Klein: Over the next several years, as patient and provider adoption accelerates, I see digital therapeutics becoming standard of care across a wide variety of disease areas. And for those areas where traditional therapeutics are necessary, I firmly believe that digital treatments and traditional biopharmaceuticals will not be viewed as separate approaches, but rather two sides of the same coin.

Read more

2020/05/19

Vaccinex’s Cancer Research May Lead to Effective Treatment for Deadly Huntington’s Disease

Huntington’s disease (HD), also known as Huntington’s chorea, is an inherited genetic disorder that kills brain cells. The Huntington Disease Society of America describes the disease as “a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain.” The symptoms of HD are described as having ALS, Parkinson’s and Alzheimer’s simultaneously. Symptoms usually appear during prime working years – between the age of 30 and 50 – and worsen over a 10- to 25-year period. Over time, HD affects the individual’s ability to reason, walk and speak. The disease affects men and women equally and children born to a parent with HD have a 50/50 chance of inheriting the faulty gene. There is currently no cure or treatment which can halt, slow or reverse the progression of the disease. Full-time care is required in the later stages of the disease. Treatments can relieve some symptoms and, in some, improve quality of life. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Disease complications and injury from falls reduce life expectancy. Suicide is the cause of death in about 9% of cases. Death typically occurs 15–20 years from when the disease was first detected.  According to the Huntington Disease Society of America,“there are approximately 41,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease.” While only a handful of biopharmaceutical companies are researching new therapies for HD, Maurice Zauderer, President and CEO of Vaccinex, a clinical stage biotech company based in Rochester NY is optimistic the company’s late stage drug pepinemab may be the first effective therapy for HD patients. Ironically, cancer research led Vaccinex to utilize the same technology to target HD. As part of its ongoing series exploring the challenges of rare disease research, Wuxi AppTec Communications spoke with Dr. Zauderer about why he believes pepinemab can make a difference. Dr. Zauderer, Ph.D. has served as President and Chief Executive Officer and a member of the Vaccinex’s board of directors since its inception in April 2001. Prior to founding the company, Dr. Zauderer was an Associate Professor at the University of Rochester and has also held senior faculty positions at Columbia University. During his academic career, Dr. Zauderer held the position of visiting scientist at the Laboratory of Cell Biology, the Ontario Cancer Institute and the National Cancer Institute. Dr. Zauderer received a B.S. in Physics from Yeshiva University and a Ph.D. in Cell Biology from the Massachusetts Institute of Technology. WuXi AppTec: What are the major  differences between developing drugs for rare diseases and for more common diseases? What are some of the unique rare disease regulatory and business challenges? Maurice Zauderer: In general, larger clinical trials and greater financing are required to achieve regulatory comfort for indications that affect large numbers of people. To a large extent, this reflects the inherent diversity of large human populations. In principle, identification of biomarkers that allow functional segmentation could facilitate development. On the science and investment side, there is usually not as much research and knowledge to draw on for rare and orphan diseases, and, importantly, there is often no precedent for therapeutic success. As a result, investors may not be confident that the reward merits the risk. Fortunately, greater pricing tolerance on the part of payers for rare and orphan diseases alleviates some of these concerns. WuXi AppTec:  Many biotech companies are involved in cancer research how did you choose to target Huntington’s? Maurice Zauderer: We are actually developing our lead drug, pepinemab, both as a combination therapy with a checkpoint inhibitor in cancer and as a single agent in neurodegenerative disease. What we learned about the mechanism of action of our drug in cancer actually informed our understanding of its potential in Huntington’s and other neuroinflammatory/neurodegenerative diseases. Our lead antibody, pepinemab, blocks the activity of SEMA4D, a molecule that binds to high affinity plexin receptors to trigger dissociation of the cell cytoskeleton. The cell cytoskeleton gives cells shape, but, more importantly, it makes it possible for cells to change shape. Cells need to change shape in order to extend projections that enable movement in a desired direction. This is, for example, essential for immune cells to infiltrate and attack tumors. Tumors have learned to exploit this pathway as one of several means of evading anti-tumor immune responses. They express high levels of SEMA4D at their margin and this serves to immobilize immune cells that constitutively express the plexin receptors for SEMA4D. Wuxi AppTec: So how did this discovery lead to a potential therapy for Huntington’s? Maurice Zauderer: Based on our understanding of the biochemistry and cell biology of the SEMA4D/plexin pathway, we came to recognize that similar cytoplasmic projections are required for cells to make contacts that enable direct interactions with other cells. Such contacts are central to the normal function of astrocytes in the brain. Astrocyte projections completely cover blood vessels that feed the brain. These projections express glucose transporters, the main source of energy for the brain, and facilitate uptake of glucose from circulation. Similar astrocyte projections cradle synapses and express glutamate receptors that recycle and allow efficient use of the free excitatory transmitter. In response to brain injury, the astrocyte cytoskeleton collapses, they abandon these normal functions and switch over to secretion of inflammatory cytokines. This is an interaction mediated by diffusion of soluble molecules rather than direct cellular contact. We asked what might trigger this important inflammatory transformation, and we wondered whether the SEMA4D/plexin pathway could be involved. Indeed, we discovered that SEMA4D is upregulated on neurons in response to stress or damage during underlying disease progression, and that astrocytes express plexin receptors that, in response to SEMA4D, trigger inflammatory transformation. We determined that SEMA4D blocking antibody ameliorated disease pathology in several animal models of neuroinflammatory/neurodegenerative disease, including Huntington’s, Alzheimer’s and multiple sclerosis. WuXi AppTec: Were there other factors that led to looking at Huntington’s? Maurice Zauderer: In addition to these mechanistic insights, we were motivated to focus on Huntington’s disease because it is an important unmet medical need with unambiguous diagnostic clarity of clinically manifest and asymptomatic gene carriers. The clinical trial experience of our colleagues in the Department of Neurology at the University of Rochester School of Medicine and in the Huntington Study Group were important support for the soon to be completed, potentially pivotal, SIGNAL study of pepinemab as a treatment for Huntington’s disease. WuXi AppTec: How important are government regulatory incentives to encourage rare disease research in general? And as a follow-up, are patient groups also an important driver in Huntington’s?   Maurice Zauderer: It is very important that regulatory agencies recognize the special difficulties of performing clinical trials in rare or orphan diseases and make reasonable accommodation to facilitate such studies. The rare disease community has been historically overlooked and under-researched, and we’re pleased to see that regulatory incentives have played a role in beginning to change this. In addition to the fact that HD is an important unmet need that is devastating to patients and families, a more rapid regulatory pathway motivated us to initially focus on HD, rather than a more prevalent neurodegenerative disease such as Alzheimer’s. The favorable regulatory environment has allowed us to safely and efficiently develop and advance pepinemab, with the hope of being able to rapidly deliver this new therapy to a community that currently has no treatment options, beyond those that address some symptoms of the disorder. Additionally, choosing to address HD first has enabled us to expand our research and help more patients than might not have been possible otherwise. Our promising data in HD has led to welcome support from the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation for a phase 1 Alzheimer’s study that we plan to initiate in the second half of 2020. WuXi AppTec: Why is it so difficult to develop effective therapies for Huntington’s Disease? Maurice Zauderer: All neurodegenerative diseases are challenging because there are numerous important but not well understood interactions between different cell types in the brain. As an orphan disease, HD does not enjoy the concentration of research invested in other slowly progressive neurological diseases such as Alzheimer’s and multiple sclerosis. Fortunately, much can be learned from common pathways and parallel mechanisms in these different brain diseases. A broader perspective can accelerate therapeutic development. WuXi AppTec: How do you overcome patient recruitment challenges in rare disease research when you have much smaller patient populations?  Maurice Zauderer: In our experience, it has been important to work with a CRO that has well-established relationships with investigators and clinical coordinators at a large number of sites. The Huntington Study Group has served us well. WuXi AppTec: How much progress has been made in Huntington’s disease drug research and development over the last 20 years?  Maurice Zauderer: Not enough. The only currently approved drugs for HD are symptomatic treatments like tetrabenazine that suppresses involuntary movements but does not slow disease progression. WuXi AppTec: We have been talking about Huntington’s research in general. I would like to switch to your specific drug program. What phase is it in? What results have you seen so far? And will it treat all stages of the disease? Maurice Zauderer: As discussed above, the SIGNAL study is based on the relatively recent understanding of the key role of astrocytes in neuroinflammation. Much of this work was pioneered by the outstanding late neuroscientist, Ben Barres and his colleagues at Stanford University. Our contribution has been to identify a specific molecular pathway that activates astrocytes. The Vaccinex drug, pepinemab, blocks this pathway and ameliorates the pathology. The soon to be completed SIGNAL study in HD enrolled 265 subjects of whom two thirds had manifest disease and one third were prodromal, that is they were known to have inherited the Huntingtin mutation but did not yet have diagnostic symptoms. Subjects were randomized 1:1 drug to placebo and received 18 monthly treatments of a relatively high concentration of pepinemab antibody administered intravenously. The antibody concentration was calibrated to achieve a targeted biologically effective dose in the brain even though antibodies do not efficiently pass through the blood-brain barrier. This avoided the need for more invasive interventions like intrathecal injections into the spinal cord or intavesicular injection directly into the brain. WuXi AppTec: What were the results you saw first? Maurice Zauderer: In an initial 36 subject phase 2 arm of this study, we determined that pepinemab treatment has a dramatic effect on preserving and even increasing glucose transport as reflected in FDG-PET imaging. This was an exciting observation because we know that glucose transport is a normal function of astrocytes that is abandoned upon inflammatory transformation. Our interpretation, supported by a variety of other evidence, is that our drug blocks reactive transformation of astrocytes. The SIGNAL study will now determine whether pepinemab treatment confers clinical benefit to subjects with early HD including both manifest disease and, potentially, prodromal subjects. WuXi AppTec: When do you think it may be available to patients? Maurice Zauderer: We anticipate completing the SIGNAL study in late June/early July 2020, at which time we will begin the process of locking the database, leading to analysis and topline data in the Fall. This is a potentially pivotal study for FDA registration, and we have already begun to prepare to scale up manufacture and the infrastructure for commercialization should results prove to be positive. Pepinemab has the potential to be the first disease-modifying therapy for HD. WuXi AppTec: Why do you think your approach can be more successful than other companies’ drug programs in this disease?  Maurice Zauderer: I think that what is most important about the Vaccinex treatment strategy for HD is that it targets a pathogenic mechanism rather than just a biomarker of the disease. Biomarkers are useful to identify disease susceptibility and progression, but, as we have seen in many failed trials in Alzheimer’s disease, they are not necessarily effective targets. There is a lot of evidence for the pathogenic role of astrocytes and chronic inflammation in multiple neurodegenerative diseases and these research advances have informed our strategy for HD. WuXi AppTec: Do you see a time when we will have a cure for this disease? What scientific advances are needed to reach this goal? Any predictions when this might happen? Maurice Zauderer: There are multiple new approaches employing novel technologies in development. A lot of good things could happen in the next few years, including potential combination therapies. I am optimistic. WuXi AppTec: Anything we haven’t touched on that you would like to add?  Maurice Zauderer: One of the very rewarding aspects of working in HD is that the Huntington’s disease community, patients and their families, have seen and understand the devastation of this disease. They are wonderfully supportive of each other and of efforts to develop new and effective treatments. It is inspiring to experience and share in the determination and commitment of this community.

Read more