Pharm Exec’s 16th Annual Pipeline Report examines six key areas of biopharma R&D-a mix of emerging and maturing-where, for some, promising research efforts are now beginning to pay dividends, as novel advances in science usher in new treatment approaches and curative therapies

	Despite entering-or even strengthening already established footing-in today’s “new era of biopharmaceutical innovation,” developing novel drugs that will bring value and benefit to patients continues to be a difficult challenge. The common and very real prospect of failure will never go away. But, as 

’s 16th Annual Pipeline Report illustrates, the arduous research efforts by life sciences companies are paying dividends, and

 leading to transformative and, in some cases, curative therapies.

	For instance, cell and gene therapy (CGT), including CAR-T and the work with RNA interference (RNAi), is beginning to make an impact. The thousands of research papers and patents in areas ranging from CGT, to CRISPR technology, to CAR-T drugs for cancer are a testament that science will continue to breed new successes in product development, and will generate better outcomes for patients and value for the healthcare ecosystem as a whole.

* All figures and tables in this report are provided by 

(To view the report in an interactive pdf format, click 

	More than 3,300 Phase II through IV CGT trials are underway, according to data provided by Signals Analytics, indicating how active R&D efforts are on this front. Oncology, hemophilia, Huntington’s disease, and sickle cell disease, as well as amyotrophic lateral sclerosis (ALS) are among those conditions targeted in clinical trials.

	Research efforts include work with pluripotent stem cells (iPS), adeno-associated virus (AAV) gene therapies, and immune tolerance technology, among others. 

, the National Institutes of Health, and several universities, among other entities, are involved. (Note that CRISPR technology and 

CAR-T therapies are the focus of their own sections later in this report.)

	In early September, the UK’s National Institute for Health and Care Excellence (NICE) recommended a new gene therapy-based treatment for rare inherited eye disorder for use by the National Health Service. Luxturna (voretigene neparvovec), marketed by Novartis in Europe, is targeted to those who have lost their vision from inherited retinal dystrophy from confirmed RPE65 gene mutations and who have enough viable retinal cells. The RPE65 gene provides instructions for making a protein essential for normal vision. Current treatment involves only supportive care, such as the use of low-vision aids. Clinical trials showed that, in the short term, Luxturna, which is injected directly into the retina, improves vision and prevents worsening of inherited retinal dystrophy.

 is applying its patented MultiStem stem cell therapy for treating neurological, inflammatory, immune, and cardiovascular diseases, among other indications. For ischemic stroke, the company launched its Masters-2 Phase III pivotal study under special protocol assessment by FDA, and in partnership with

, a Phase II/III clinical trial recently commenced in Japan under a new accelerated regulatory framework. MultiStem has priority review designation from Japan’s Pharmaceuticals and Medical Devices Agency. For graft-versus-host disease and hematopoietic stem cell transplantation, a Phase III pivotal study under special protocol assessment has been approved by FDA. The program was awarded orphan-drug status by FDA and the European Medicines Agency (EMA), and is being fast-tracked by FDA. (For more, see and listen to this

 began dosing in a Phase IIb study of different combination regimens, including JNJ-3989 (formerly ARO-HBV), or JNJ-6379, and a nucleos(t)ide analog for treating chronic hepatitis B virus infection.

	JNJ-3989 is a liver-targeted investigational antiviral therapeutic for subcutaneous injection designed to treat chronic HBV infection by RNAi. JNJ-6379 is an orally administered capsid assembly modulator of the class that forms normal capsid structures.

	There also is interest in using cell and gene therapies to treat cystic fibrosis (CF) patients who experience persistent lung infections. There may be curative therapies found in using gene editing or therapy tools in stem cells. If a stem cell receives one of these therapies, every cell that is produced by the stem cell would also have the correct gene. For example, if an airway stem cell had a correct copy of the CF transmembrane conductance regulator (CFTR) gene, the new lung cells produced by that stem cell would also have a correct copy of the CFTR gene.

Scientists have shown that it is possible to make iPS cells using cells from people with CF, apply gene editing to correct CFTR mutations in those cells, and reimplant the correct cells into the lungs of CF patients.

 wants to combine its immune tolerance technology (ImmTOR) platform with several biologic therapies for rare and serious diseases that require new treatment options due to high immunogenicity. SEL-212, its lead product candidate, is being developed to treat chronic refractory gout patients and resolve their debilitating symptoms, including flares and gouty arthritis.

 clinical programs include EB-101, an autologous, gene-corrected cell therapy for recessive dystrophic epidermolysis bullosa, as well as ABO-102 and ABO-101, novel AAV9-based gene therapies for Sanfilippo syndrome types A and B (MPS IIIA and MPS IIIB), respectively.

 announced it will balance its existing contract manufacturing organization (CMO) network with an internal facility to create the infrastructure needed to commercialize its gene therapies.

 autologous gene therapies include five clinical stage programs and the former 

 hematopoietic stem cell (HSC) gene therapy Strimvelis, which was approved by the EMA in 2016 for treating adenosine deaminase deficiency, an autosomal recessive metabolic disorder that causes immunodeficiency. It is still awaiting FDA approval.

 is involved in the translation of RNAi into a new class of medicines. The company’s givosiran is an experimental RNAi therapeutic being developed to treat acute hepatic porphyria. In June, Alnylam completed the rolling submission of its new drug application (NDA) for givosiran, and in August, FDA accepted the NDA and granted priority review. The agency has set an action

 date of Feb. 4, 2020, for givosiran, which is also under regulatory review in Europe.

	Lumasiran is Alnylam’s investigational RNAi drug for treating primary hyperoxaluria type I (PH 1). Enrollment continues in Illuminate-A, a global Phase III pivotal study of lumasiran in children and adult PH 1 patients with preserved renal function. Alnylam expects to report top-line results, and if positive, file for global regulatory approvals in early 2020. 

(See Alnylam’s CGT pipeline snapshot above).

	In notable industry dealmaking centered in the CGT space, Bayer is acquiring BlueRock Therapeutics to build Bayer’s cell therapy pipeline. 

 develops cell therapies for neurology, cardiology, and immunology, using a proprietary induced pluripotent stem cell platform called Cell+Gene. A lead program for treating Parkinson’s disease is expected to enter clinical trials by the end of the year. BlueRock was established in a joint venture by Bayer and 

	Meanwhile, as an indication of the growing impact of CGT and concerns about its costs, health insurance giant 

Cigna is introducing a program intended to protect participating organizations from the high cost of regenerative medicine. It will start with Luxturna for a version of inherited retinal disease, and Novartis’ Zolgensma (onasemnogene abeparvovec-xioi) aimed at treating spinal muscular atrophy in children under two years old.

	Cigna’s Embarc Benefit Protection program aims to remove out-of-pocket payments related to the cost of the therapies. Health plans that adopt Embarc will pay a per-member, per-month fee to participate in a gene therapy network. Physicians will submit prior authorization for the drugs, but once approved, a patient will not be charged a copay.

Next page: New discoveries through CRISPR

	CRISPR (clustered regularly interspaced short palindromic repeats) is evolving into a robust genome editing tool, making the process more efficient and transforming genome editing studies. CRISPR represents DNA sequences in the genomes of bacteria and other organisms. Even though it is in its early stages, interest in CRISPR technology is growing strongly, as evidenced by the increasing number of patents filed and research undertaken, according to Signals Analytics. CRISPR research has received almost $2 billion in funding .

 and Janssen inked an agreement that began moving CRISPR down a novel path. Locus is commercializing research developed by scientists at North Carolina State University involving Cas3 proteins, which eat up DNA, instead of editing the material like the more well-known Cas9-based CRISPR technique. Cas3 removes DNA strains, acting like a shredder, unlike single sequence-targeting Cas9. The system is seen by some as potentially leading to a cure for viral diseases.

	The Janssen-Locus agreement gives Janssen an exclusive license to develop, manufacture, and commercialize CRISPR-Cas3-enhanced products, which attack bad bacteria, to treat respiratory and other organ infections. Locus’ lead program targeting

 is entering clinical development, with a Phase Ib clinical trial in patients colonized with E. coli in their urinary tracts.

 are developing CTX001, an investigational, autologous, CRISPR-Cas9 gene-edited hematopoietic stem cell therapy. It is under evaluation for patients suffering from severe hemoglobinopathies. The first patient has been treated with CTX001 in a Phase I/II clinical study of patients with transfusion-dependent beta thalassemia.

	The partners also are investigating CTX001 for treating severe sickle cell disease. The first patient has been enrolled in a Phase I/II clinical study in the US and will be infused with CTX001. Vertex and CRISPR Therapeutics have also begun a trial to use CRISPR-edited T cells to treat non-responsive or relapsed non-Hodgkin’s lymphoma. Scientists intend to edit the cells using CRISPR to target CD-19, a protein that marks B cells, which turn malignant in certain non-Hodgkin’s lymphoma.

 are pursuing the development of an in-home genetic diagnostic for detecting illnesses at the point of care. In March, the company received an exclusive license from the University of California, Berkeley to a new CRISPR protein, Cas14, which contains up to 700 amino acids and is half the size of other Cas proteins. Cas14 makes it possible to find double-stranded and single-stranded DNA, as well as RNA. Using the Cas14 protein, Mammoth scientists are better able to analyze and detect a virus or bacteria.

	On the academic side, Cas3 research is ongoing at the University of Michigan, Duke University, and Cornell University, among other institutions.

Next page: New fronts in heart disease fight

	A new emphasis on cardiovascular disease

	The statistics speak for themselves. More than 600,000 people die of heart disease in the US annually, according to the Centers for Disease Control and Prevention (CDC), and is the leading cause of death for men and women. High blood pressure, high cholesterol, and smoking are key risk factors, and almost half of Americans have at least one of those.

	While there may be a variety of drugs already on the market for treating hypertension, high cholesterol levels, and other contributors to heart disease, there is no shortage of research on new fronts in cardiovascular disease (CVD). Signals Analytics reports that hypertension, congestive heart failure, and atherosclerosis are the most researched conditions in preclinical phases. Preclinical research in the areas of hypertension and hemophilia is strong. Key players include Bayer and 

	Bayer has a number of clinical programs targeting such areas as pulmonary hypertension, heart failure, peripheral artery disease, thrombosis, and peripheral artery disease, spread across Phase I to III clinical trials.

	Greater levels of plasma vasopressin, which mediates water retention, are associated with the progression of congestive heart failure. Attempting to combat this, Bayer is developing BAY 1753011, a novel, dual-acting vasopressin receptor antagonist. The company is recruiting for a multicenter, randomized, double-blind, active and placebo-controlled study of BAY1753011 in patients who have congestive heart failure.

	Earlier this year, Pfizer received FDA approval for two formulations of tafamidis-based drugs, including a first for treating cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM). Vyndaqel (tafamidis meglumine) is the first US drug approved to treat this rare condition. The agency also cleared Vyndamax, another formulation of tafamidis. The two drugs are approved for ATTR-CM in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. Vyndaqel has been on the market in Europe for treating polyneuropathy since 2011. Vyndamax is a free acid version of the drug.

 filed for FDA approval of oral semaglutide, which would be the first glucagon-like

 peptide-1 (GLP-1) receptor agonist delivered in pill form. Novo also filed for a new cardiovascular indication for its once-a-week injectable form of semaglutide, which was granted approval from FDA in late 2017. The weekly injectable GLP-1 receptor agonist is marketed as Ozempic. Novo submitted two NDAs. One seeks approval to improve blood glucose to treat type 2 diabetes, and the other is pursuing an indication to reduce major adverse events, including heart attacks, strokes, and cardiovascular-related death, in adults with type 2 diabetes and established CVD. (See Novo’s CVD pipeline snapshot).

	Meanwhile, FDA has given fast-track designation for 

 SGLT2 inhibitor dapagliflozin (Farxiga) for patients who have chronic kidney disease, to delay progression of renal failure and prevent cardiovascular  and renal death. In August, the big pharma said that Farxiga met the primary composite 

endpoint in the landmark Phase III DAPA-HF trial, with a statistically significant and clinically meaningful reduction of cardiovascular death or the worsening of heart failure. (See AstraZeneca’s CVD pipeline snapshot).

	Alnylam is evaluating inclisiran, formerly PCSK9si or ALN-PCSsc, an experimental RNAi therapeutic currently in Phase II Orion studies for hypercholesterolemia. The Medicines Company licensed the rights to inclisiran from Alnylam, and a Phase III clinical trial showed that the drug has met its primary endpoint. An NDA is planned.

, formerly Sphingotec Therapeutics GmbH, reported preclinical data on its lead product, Procizumab, a therapeutic antibody targeting circulating dipeptidyl peptidase 3 (DPP3) for treating patients with acute myocardial depression, including acute heart failure and cardiogenic shock. Procizumab, a humanized monoclonal antibody designed to block peptidase activity of DPP3, immediately normalized heart and kidney function in a preclinical model for acute heart failure.

 announced results of a Phase II study involving aprocitentan, an orally active dual endothelin receptor antagonist (ERA). Aprocitentan is under investigation for treating patients whose blood pressure is uncontrolled, despite receiving triple antihypertensive medications (resistant hypertension).

	Developed with Janssen, the drug is intended to lower blood pressure by blocking endothelin receptors in cells lining the blood vessels. Aprocitentan lowered blood pressure in hypertensive patients in the Phase II trial, and is also in an ongoing Phase III study for treating people with uncontrollable hypertension. (See Idorsia's hypertension pipeline snapshot).

	On a down side for cardiology, Sanofi is cutting more than 450 positions in France and Germany, and is terminating new in-house cardiology research programs, as part of a restructuring. Sanofi executives say the organization is focusing on potential therapies licensed from partners and on remaining internal efforts. The company is transitioning more to immuno-oncology and gene therapies.

	It’s been almost three decades since chimeric antigen receptors (CARs) were first reported scientifically. And it’s only in the last few years that researchers have gained ground in transforming the science into therapies for patients in real-world settings.

	These efforts have begun to pay off, as seen in the 2017 FDA approvals of Novartis’ Kymriah for treating acute lymphoblastic leukemia (ALL) in certain pediatric and young patients, and Gilead Sciences/Kite Pharma’s Yescarta, for adults with certain large B-cell lymphomas.

	There are a number of ongoing oncology clinical trials involving CAR-T, according to data provided by Signals Analytics. Researchers have filed and received a number of patents and have authored several scientific papers.

	Among concerns, though, have been access and the affordability of CAR-T therapies, some of which can cost more than $1 million per patient. But concerns were somewhat allayed in midsummer when the Centers for Medicare and Medicaid Services (CMS) announced that it would cover CAR-T for Medicare recipients; the coverage began on Oct. 1. Additionally, CMS pulled back on a proposal to make hospitals collect and report data on patient outcomes over a long period of time. And Medicare coverage will include CAR-T cell therapies for off-label uses, which CMS-approved compendia recommend.

	It is possible that the new policy could speed adoption of CAR-T drugs, something Gilead is hoping for after its $12 billion purchase of Kite in 2017. 

 is focusing on cell therapy, but Yescarta only generated about $260 million in revenue in 2018. More recently, a pivotal Zuma-1 study indicated that the therapy brings better results in older patients, with those 65 and older experiencing a 92% overall response rate at a median 27.1 months, compared with 81% among patients younger than 65. Three-quarters of the older group achieved a complete response, compared with 53% for those younger than 65.

	The findings are important because it is usually older patients with refractory large B-cell lymphoma who have exhausted treatment options and continue to face progressive disease.

	In addition, Gilead has published data on an investigational CAR-T, KTE-X19, for adults with relapsed or refractory acute lymphoblastic leukemia. In Phase I of the two-phase Zuma-3 trial, patients experienced a high rate of response to a single infusion. The Phase II program for KTE-X19 is ongoing. 

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Pharm Exec’s 2020 Pipeline Report

A Voyage Above and Beyond: Chronicling the career “trek” of gene therapy visionary R. Jude Samulski, whose work uncovering the mysteries of adeno-associated virus while navigating the field’s reputational turbulence continues to fuel new hopes for AAV vector technology in transforming therapies for rare disease

	It isn’t every day that a TV show helps change the world. But in the case of Dr. R. Jude Samulski, chief scientific officer and co-founder of Asklepios BioPharmaceutical (AskBio), one certainly provided inspiration. Samulski, a pioneer in gene therapy, grew up watching 

	That’s essentially what Samulski is doing these days-providing hope to people who thought they didn’t have a chance. After years of studying molecular virology in the lab, he co-founded AskBio, a biotech focused on adeno-associated virus (AAV) gene therapy. Today, he holds more than 200 patents related to AAV technology, and his discoveries and dedication continue to propel the field.

	As a graduate student at the University of Florida, Samulski worked in the lab of Dr. Nick Muzyczka. Muzyczka was interested in designing viral vectors to deliver functional genes to patients who lacked them. At that time, genetic researchers everywhere were testing various viruses, such as adenovirus and retroviruses, to turn into vectors.

 and ‘to go where no man’s gone before,’ so I was totally intoxicated on the concept,” he says. “It’s like moon walk–type stuff.”

	Muzyczka, Samulski, and the team were guided toward AAV by Ken Berns, the university’s then- chairman. Berns had spent his career studying the virus, which demonstrated some attractive features.

	“It was considered non-pathogenic and not causing any disease in man, and yet it was a virus that infected man,” says Samulski.

	There was little known about AAV, however, so the team worked from the ground up. In 1984, Samulski cloned the virus DNA into a bacterial plasmid. It was the experiment that propelled many labs to recognize the potential of AAV. It also formed the foundation for the two current FDA-approved AAV gene therapies and for most that are in development today.

	“[It was] the perfect vector because you can grow it in a bioreactor, in a very controlled setting with adenovirus, and then isolate it and put it in another very specific setting, like in the brain of a diseased individual, and it will deliver that payload as if it’s its own payload. And then it’ll go latent, which means it will persist for the life of the cell,” says Samulski. “It was a unique molecular hitchhiker, since it did not cause disease like adenovirus, retroviruses, lentiviruses, herpes, and the others that were being looked at as vectors. We didn’t have to spend any energy trying to uncouple the negative things about the virus from the positive things that we wanted to utilize, which was the latency aspect of the life cycle.”

	One of Samulski’s greatest milestones occurred in 1996, when his team was able to prove AAV worked as predicted. Their experiment showed that after a year and a half, the virus-delivered gene was still being expressed. Until then, every other vector trying the same experiment would fail after two to four weeks, when the immune system started attacking the foreign protein.

	“Dr. Xiao [Xiao, a co-founder of AskBio,] and I were ecstatic,” says Samulski. “That was our eureka moment where we said, ‘This is different. It’s not eliciting an immune response. It’s somehow flying under the radar. It’s keeping the immune system from attacking the new gene.’”

	After that, researchers started leaving adenovirus and retroviruses and began working with AAV. “It was a conversion. It was like a religion. It went viral-no pun intended,” says Samulski. “There was just such compelling data starting to show up. With AAV, if you put it in the brain or the eye or the muscle or the liver, everybody was getting results that were consistent with [our] first

 experiment. The Holy Grail at that point was looking for something that would deliver a gene and avoid the immune system of seeking out and destroying the gene product.”

	Though the science clearly demonstrated the difference between adenovirus and AAV, the nomenclature still produced confusion. This was clear in the aftermath of the death of Jesse Gelsinger, the first patient whose death was linked to gene therapy.

	Gelsinger, 18, suffered from a genetic disease known as ornithine transcarbamylase deficiency syndrome, which

 he controlled with medication. He didn’t have to undergo gene therapy but rather volunteered as a way to help other kids. In 1999, he joined a clinical trial at the University of Pennsylvania. Within four days of receiving the injection, which used adenovirus as a vector, he passed away.

	“That unfortunate event was caused by adenovirus, and a lot of lay people cannot distinguish between adenovirus and adeno-associated virus, so we got thrown into the same paddy wagon,” says Samulski. “I think gene therapy got a black eye, and it’s somewhat out of proportion compared to AAV’s safety profile. Many people have died as part of experimental protocol[s]. Although tragic, it dwarfs in comparison to what happened with the development of other therapeutics that people accept readily now-bone marrow transplant, organ transplant.”

	That blow to gene therapy caused many investigators to re-evaluate their dedication to the field. “There was a purging of the type of science that was being done,” says Samulski. “As a result, what emerged at the other end was high-quality science that’s now translating into success in the clinic.”

	Researchers originally cloned AAV2 because it was prevalent in humans-about 40% of people have an immune response that would fight it because they have already been exposed. AAV2 is just one of many forms of AAV; scientists serologically call the viruses AAV1, AAV2, AAV3, etc., based on how each AAV variant reacts to the immune response.

	Researchers in Samulski’s lab also discovered they could package the same gene into each of the serotypes that existed at the time. This breakthrough was called cross-packaging.

	“What you essentially were doing was developing a Rolodex of capsids that would have different zip codes on them,” says Samulski. “Then you could evaluate them one by one and see if the zip code for AAV4 would go to the lung, and the zip code for AAV8 would go to the liver. We were able to develop the technology that lets you [cross-package] the AAV genome into multiple capsid candidates.”

	This opened the door from AAV2 to virtually everything that’s been developed since, including AAV7, AAV8, and AAV9, discovered by researchers at UPenn.

	Though new vector discoveries are proliferating, only two are approved by FDA: AAV2, for treating retinal blindness with Luxturna, and AAV9, which targets spinal muscular atrophy with Zolgensma. Both drugs are directly related to technology developed by AskBio. Luxturna employs the company’s original AAV2 vector, 

while Zolgensma uses self-complementary AAV, which means that once it is in the cell, it is functional for expressing the therapeutic.

	A challenge remains in how to efficiently deliver the right drug to the right tissue. AskBio is working on delivery systems to muscle, liver, brain, lung, and heart. “What we had was a platform, and we were able to develop many different variations of delivery systems,” says Samulski. “That’s where the excitement is at the moment, because everybody’s convinced we know the therapeutic answer, we just need to deliver it.”

	While many research projects find their footing with help from big pharma and venture capital, Samulski discovered a different source of support.

	“We went to the Muscular Dystrophy Association (MDA) with data and an idea,” he says. “We proposed that if we could get funding, then we could try to put the dystrophin gene…back into [children with Duchenne muscular dystrophy (DMD)]. They said, ‘Jude, we’re tired of funding academic research, because the bottom line is they publish a paper and nothing ever turns into a drug for our kids. If you were a for-profit structure, so that after you developed it, it would continue to go down the pipeline, we would be interested in supporting it.’”

	So Samulski created the first for-profit structure ever to be funded by the MDA. During that process, another source of support emerged.

	Tripp DuPerier, the father of a son with muscular dystrophy offered $3 million, no questions asked, to help families avoid going through what his family had endured. After that, a few more parents approached the team, having learned the researchers might be their child’s only chance.

	“[Our] companies were basically started by parents,” says Samulski. “We took the stewardship of taking their diseases and trying to develop therapies for them. And when we were doing this, with the explicit mission that the parents needed something for their kids, it was driven by the passion or the urgency of, ‘we need to make this happen.’”

	During that time, the team was able to prove the technology worked and was safe, but ultimately, they were not drug makers. They didn’t have the resources or the manpower to take it to the next level.

	“We were developers and innovators and researchers,” says Samulski. “We felt very strong that we had to partner with big pharma, who knew how to develop drugs, so that they could take the baton and cross the finish line with a product that would actually get back to the patients.”

	Past successes were seen with AskBio incubator spin-off companies, including Chatham Therapeutics, for hemophilia, and Bamboo Therapeutics, for diseases including giant axonal neuropathy, Canavan disease, Friedreich’s ataxia, and DMD.

	AskBio currently has a therapeutic in clinical trials for Pompe disease, and treatments for other forms of muscular dystrophy are expected to begin clinical trials in the first half of 2020. The company also is developing therapies for Huntington’s disease, epilepsy, and congestive heart failure, as well as for Parkinson’s disease with its affiliate Brain Neurotherapy Bio.

	In 2016, Bamboo Therapeutics was acquired by Pfizer. In order to make good on his promise to the MDA and the DuPerier family, Samulski took a sabbatical and went to work with Pfizer as VP of gene therapy, to ensure that they could get their work into the clinic. “The data that’s been reported has been positive,” he says. “I think [the drug] is on a trajectory to be approved by the FDA.”

	Samulski’s experience working with FDA has been encouraging. He is appreciative of the support and guidance it has provided to the gene therapy community. In return, he is happy to work with the agency as a consultant.

	“The FDA has and continues to be the best collaborative partner the gene therapy community has out there,” says Samulski. “They went from pre-IND (investigational new drug) to pre-pre-IND, which was basically, ‘don’t wait till you have your package to talk to us, come talk to us before you have your package and we’ll give you guidance.’ That’s unheard of. And they have participated in all the meetings. They show up, they give input.”

	Samulski and Muzyczka received the first US patent of non-AAV genes inserted into AAV. In 2008, Samulski was honored by the American Society of Cell and Gene Therapy with its first lifetime achievement 

award. He met China’s Minister of Health in 2009 to discuss how to bring this new molecular medicine to that nation. He also received an invitation from the Vatican in 2016, for his work in Canavan disease. But Samulski’s greatest achievement is a one-sentence letter written by a boy named Conner Curran, the first DMD patient he worked with.

	“He was going to the third grade, and his teachers said their first assignment was to write the most important thing that happened to them from second grade to third grade,” he says. “All of them were writing things like I got a new bookbag, and his comment was, I’m proud that I can run faster.”

	This hits home for Samulski, having kids of his own. He has framed the handwritten piece of paper and cherishes it.

	“There’s no dividend that yields what you can get from that,” says Samulski. “You can’t explain it to someone. You have to experience it. If you experience it, it’s something that’s solemn and it’s subtle, and yet it shakes the earth. It shakes you to your core. It is the moment that made everything I was doing for the past 40 years come to fruition.”

	Samulski continues to receive frequent updates from Conner’s mother, describing how gene therapy has

 affected her son’s life. In one text she wrote: “My heart is so happy that he has more friends now and doesn’t stand around like he did before you came along, Jude. You are giving him the childhood he was missing out on.”

	When Samulski looks toward the future, he sees gene therapy becoming commonplace. While the field currently tackles many orphan diseases, gene therapy may one day treat more widespread issues, such as cholesterol. Age-related issues, such as muscle tone and memory, could also be targets. “We’ll become accustomed to it, and it won’t be as dramatic; it will lose its pizzazz,” he says. “Envision a day where someone’s going to say, Oh yeah, I was born with CF (cystic fibrosis), but I got gene therapy when I was a baby-and the [procedures are] like vaccinations.”

	While it may be difficult to see that far ahead, Samulski’s unwavering belief in gene therapy is clear and confident. He and his colleagues at AskBio are not only advancing therapeutics into clinical trials, but they’re developing groundbreaking technologies that will lower the cost of goods and increase access for patients in need around the world.

	“This technology is going to work,” he says. “It will be on the backs of the patients that had these rare diseases that the same technology will be used for the more widespread diseases like obesity, heart disease, Alzheimer’s, Parkinson’s, in some form. And it will get refined to where it’s like the medicines that you’re familiar with today-just viewed as another one, nothing novel.”

’s Senior Editor. She can be reached at 

Pharm Exec chronicles the journey of gene therapy visionary R. Jude Samulski, whose work unraveling the mysteries of adeno-associated virus continues to fuel new hopes in transforming drugs for rare disease.

R. Jude Samulski: Gene Therapy’s Guiding Force

	I’ve touched on this point a few times over the years, there is no such thing as an overnight success. What looks like an overnight success is really a good chunk of years of someone’s life, laboring at a point of science-in this world of therapy development-of which they couldn’t let go. And many of these innovations, while they

 have a few successes, CAR-T, gene therapy, immunotherapy, are still in their infancy. Scientists may have been laboring at their research for 20, 25, 30 years, but the current magnitude of innovation is staggering, and, at times, overwhelming. 

	Salim Syed, head of biotechnology research, senior biotechnology analyst and managing director at Mizuho, says, “There is so much innovation going on. Biotech is going faster and faster and no longer can any one person know everything about all that is out there.” And it is clear that this innovation invasion is not lost on pharma executives themselves. Here’s a sampling of what some recent executives have said about innovation and partnering with biotech.

		Joe Jiminez, former CEO of Novartis at the Veeva Systems R&D Summit: “I think what’s happening is big pharma is recognizing that they have to look beyond the four walls of their companies for innovation. Even the ones that traditionally were only focused on internal development. So you’re starting to see some of the big companies say, ‘Wait a second, we’ve got to seed innovation outside and we’ve got to swoop up some of the technologies even before they’re in the clinical stage.’”

		Bernhardt Zeiher, MD, FCCP, FACP, chief medical officer of Astellas, in a recent 

: “Biotechs are increasingly able to take these new molecular entities (NMEs) all the way to approval themselves, which has put pressure on pharma to think about how to bring innovation in-if the biotechs aren’t seeking us as partners earlier in the development of products. There are still opportunities to partner with biotech, but now it’s more of a question of how to structure it in a way that is complementary and attractive to both sides.”

		Sebastian Guth, president of pharmaceuticals, Americas region, Bayer, in an interview to appear on pharmexec.com in December: “[Bayer] had to make a clear choice between pushing the boundaries of science, investing in the big bets in science or staying in the here and now. And we’ve made our choice and are convinced that science and innovation are the way to go. In many ways, the decisions that we have made are already being reflected in our portfolio and pipeline today.”

	All of these points are not lost on Syed, who in his various roles at Mizuho, deals with the financial questions of biotech every day. To Jiminez’s point, pharma is now looking to get into technologies very early, before they are in clinical stage.

	“Five years ago, you would never look at companies that were pre-Phase II; if they wanted to go public, they needed data. Now, they have no data, or are preclinical, or have very small and early 10-20 patient trials,” says 

	“Will that reverse trend in 2020?” he posed. As with most industries, a watchful eye is on the 2020 election year-and where these biotechs want to be is now a concerning business question.

	There are certain things that can stall the pace of innovation. Past examples include an early death in gene therapy that set a chilling effect on that area in the late 1990s; transplantation advances that were shut down during the AIDS crisis; and Vioxx taken off the market in the early 2000s for CV events. Each one of these areas are now new and vital parts of therapeutic innovation, but they had to weather a storm, and in the end, the science grew stronger.

	Financial pressures from uncertain market dynamics, including elections and overall drug pricing and reimbursement concerns, all have effects. But how chilling will they be? With the pace of massive innovation, it seems nothing can stem the tide.

From the Editor

Though uncertain market dynamics remain at play, the current magnitude of innovation in biopharma is staggering, and, at times, overwhelming.  

The Pace of Massive Innovation

	The debate over drug pricing legislation accelerated last month as federal budget analysts calculated huge savings for consumers and the nation’s healthcare system from a lead Democratic proposal. The measure would authorize the government to negotiate prices paid by Medicare on up to 250 high-cost medicines and

 insulin with the aim of lowering US rates to prices in six leading industrial nations. The analysts acknowledged that this requirement would greatly reduce revenue for pharma companies, a development that industry warned would “blow up” the current system. Progressive Democrats, however, complained that the plan was insufficient and called for even broader price negotiations. The long-term impact of the reference pricing plan is unclear, as patients could benefit from increased access to medicines, but society might be harmed by R&D reductions.

	The debate focuses on a key provision in legislation (H.R.3) proposed by House speaker Nancy Pelosi (D-CA) that would require manufacturers to negotiate prices on 25 to 35 medicines a year, eliminating the long-established “noninterference clause” governing Medicare Part D drug plans. The aim is to ensure that US rates are less than 120% of the average international market price (AIM) based on drug costs in Australia, Canada, France, Germany, Japan, and the UK. According to analysis by the non-partisan Congressional Budget Office (CBO), this reference pricing strategy would reduce Medicare spending by $345 billion from 2023 to 2029 and also affect prices in the commercial market.

	On the plus side, lower drug prices would improve the health of Americans by boosting drug utilization and access to medicines. Added savings would come from reduced out-of-pocket spending for drugs and lower health insurance premiums.

	However, CBO acknowledges that the program would cut industry revenues by $500 billion to $1 trillion over the same period, precipitating significant changes in the drug market. Companies would lower spending for R&D, which CBO calculates would lead to eight to 15 fewer new therapies coming to market over the next 10 years. And some analysts predict that the R&D decline would be even more noticeable in the future as pharma companies cancel high-risk research efforts.

	At the same time, the analysts anticipate that pharma marketers will adjust with new pricing and sales strategies. While CBO expects few companies would pull drugs off the US market entirely, firms might boost launch prices in the US and in the reference countries to maintain revenues. Manufacturers also could offset higher prices overseas, CBO explains, by providing “other forms of compensation that effectively reduce the net price of drugs in other countries.”

	Pharma companies that fail to negotiate lower prices or meet other requirements would be subject to a steep excise tax of up to 95% of sales. But the experts don’t expect to collect much revenue from this provision, anticipating that most firms would comply through a range of pricing strategies. At the same time, the tax provision is considered important in driving industry to meet the price reduction provisions, and was key to CBO’s high scoring of potential savings.

	Most Republicans agree with industry that federal price negotiations threaten the development of needed cures. Stephen Ubl, president of the Pharmaceutical Research and Manufacturers of America (PhRMA), set the tone, charging that this radical plan would give the federal government “unprecedented, sweeping authority to set medicine prices” and upend the successful Medicare Part D program.

	A more moderate legislative proposal from the Senate Finance Committee, which gained some GOP support, offers modest savings by limiting Medicare drug price increases to the rate of inflation. Bipartisan 

support is stronger for measures to cap out-of-pocket spending on drugs for Medicare beneficiaries, revise the Part D “donut hole,” and block anticompetitive practices that delay the development of generics and biosimilars.

	An important unknown is whether the predicted decline in new drug development takes a toll on new life-saving breakthroughs or merely deters updated versions of existing medicines. Consumer savings on drugs and health insurance could shift spending to other areas that benefit the economy. CBO emphasizes that its analysis is preliminary and doesn’t cover other aspects of the House proposal, but its report clearly reshaped the debate. Despite enthusiasm for the legislation in the Democratic-controlled House, it’s slated to stall in the Senate where a more modest compromise drug pricing measure may move forward by year-end.

	Meanwhile, Congress did approve a small drug pricing provision in legislation approved in September to continue funding the federal government through Nov. 21. The bill passed quickly to avoid a government shutdown when Congress failed to enact necessary spending measures for fiscal year 2020 by Oct. 1. The largely unnoticed drug provision would save the government about $3 billion by closing a loophole that allowed authorized generic drug prices to be used when calculating a brand’s Medicaid rebates, a process that reduces Medicaid rebates for the product.

	Analysts who want to link drug prices more to value have been pressing for more complex and significant changes to the Medicaid best price rule, which requires manufacturers to pay rebates of 23% to Medicaid plans and even more to meet any lower price offered to another payer. The policy thus discourages value-based pricing arrangements that reduce the payer’s costs if a drug fails to deliver expected benefits for any patient. Under a recent proposal from the Duke-Margolis Center for Health Policy, such value-based pricing arrangements could be bundled with other drug rates to reduce the impact of lower prices on total reimbursement. Although this and other strategies to update Medicaid best price policy appear reasonable and beneficial to analysts, and may be implemented administratively, such technical changes have failed to gain traction among policymakers.

’s Washington Correspondent. She can be reached at 

https://www.cbo.gov/system/files/2019-10/hr3ltr.pdf

Columns

Measure would cut drug costs, slash revenues, curb R&D.

Debate Heats Up Over Reference Pricing Plan

	The agencies that decide how much to pay for a medicine are being twisted every day into new contortions by the challenges of measuring drug benefit. Highly innovative technologies are offering the prospect of dramatically transformative treatment-but they are often expensive, and their offer, in many cases, is  based on slender evidence. Direct-acting antiviral therapies for hepatitis C, for example, or the cell and gene therapies emerging in areas of high unmet need are increasingly reaching the market through accelerated pathways of development and regulatory review, obliging payers to work out new approaches to weighing the full benefit-cost ratio.

	They can find themselves in the same situation as gullible customers at medieval markets, tempted to purchase a promisingly energetic “pig” offered for sale at an attractive price but inside an opaque and sealed bag (a “poke,” or pocket). Only after the transaction is completed can the bag be opened-and the unwary customer may then find they have overpaid for some utterly inedible contents (giving rise to the companion metaphor of “letting the cat out of the bag”).

	Distinguishing a valuable pig from a worthless cat is the challenge every reimbursement authority increasingly faces from accelerating innovation in therapies-giving rise to demands for better demonstrations of potential value even when classic clinical trial data cannot be supplied. In response to the lack of clinical trial data, the fashionable approach is to talk of the potential of real-world evidence (RWE)-but the meaning and significance of the term varies so widely from person to person and country to country that any consistent real-world use seems to be perpetually just over the horizon.

	The Belgian healthcare payer INAMI/RIZIV is putting some energy and effort into clarifying the situation. It has commissioned an exploration of how RWE could help health technology assessment (HTA) agencies and reimbursement authorities make more effective use of it in their decisions. And the list of contributors that Belgium has recruited reads like a “who’s who” of European pharmaceutical strategists-which gives some resonance to the work.

	The discussions embraced HTA bodies, payers, academia, patient groups, healthcare professional organizations, government bodies, and industry. The group has just completed an initial plan, which it is putting out for wide consultation until the end of the year (https://bit.ly/31xV8WE). The group’s first observation is that despite the wealth of attempts so far to bring definition to the concept of RWE, “past initiatives remain fragmented and lack clarity about mechanisms for implementation.”

	Regulators have done better in agreeing on approach, but “now HTA/payers need to develop their own approaches.”

	The ambitious aim is to provide “practical actions for implementation by each stakeholder,” so that “concrete 

issues” can be discussed “and clear actions agreed,” resulting in “better tailor-made decisions on reimbursement.”

	The document reflects on how much valuable RWE can be obtained from real-world data (RWD), and which HTA questions can be answered accordingly, and under which conditions. And it sets out in some detail what each of the stakeholders should be doing.

	The main conclusion is that  collaboration across stakeholders and across geographies is needed to develop the use of RWE and resolve some of the uncertainties that exist in HTA/payer decisions about highly innovative technologies.

	Collaborative strategies are needed to ensure RWD/RWE requirements are aligned, it says. Transparency is also given high priority-including via a proposal for a public portal that summarizes the design and results of major RWE studies, on the model of existing clinical trial registries.

	The specific recommendations-on which views are now being sought by all interested parties-are geared toward creating “a multi-stakeholder collaborative learning network” with wide membership, the group says.

	According to the commission, policymakers and national and European authorities should legislate to ensure a robust governance framework and to enable effective cross-country collaboration for using RWD; the HTA bodies/payers should be identifying the questions that could be answered with RWD/RWE, providing guidance on critical assessment of RWE, and implementing conditional payment models such as outcomes-based agreements using RWD.

	Regulators, at the European and national level, should ensure that RWD collection strategies (such as registries) are multi-stakeholder and fit for regulatory purposes, and, where possible, take account of the needs of HTA and payers. They should also promote use of scientific advice/early dialogue processes with all relevant stakeholders during the development of a highly innovative technology, and support discussions with industry about non-randomized-controlled trial (RCT) methodologies.

	Collaboration with HTA bodies should also seek common ground on registry qualification, post-authorization safety studies, and post-authorization efficacy studies.

	The pharmaceutical industry should engage with other stakeholders on RWD collection, analysis, and reporting over the lifecycle of a highly innovative technology to generate robust RWE that helps resolve HTA/payer decision uncertainties.

	Registry holders should involve all stakeholders in establishing registries and ensuring good governance that addresses data quality, accessibility, and sustainability. They should be prepared to collaborate with regulatory authorities at national and European levels and with  HTA bodies and industry, to identify whether existing registries could be used to resolve uncertainties during the development phase or for post-launch data collection, and to discuss the potential for new registries. Along with industry, they should also be aiming to develop disease-based, rather than product-specific, registries.

	Clinicians and patients should contribute their real-world experience to support collection of RWD that is useful and informs treatment decisions, at the individual and population-level. Healthcare professionals should gain a clearer understanding of the role of RWD in outcomes-based managed-entry agreements so as to ensure both correct usage and adherence, and to collect the data needed.

	Patient groups should engage in co-creation of RWE, communicating the possible uses of RWD and good governance processes to encourage patient involvement. They should also develop EU or international patient group collaborations to engage in RWD initiatives and ensure that outcomes that matter to patients are collected.

	In addition, patient groups, the document says, should provide recommendations on novel and efficient collection methods for RWD (e.g., devices, wearables, mHealth) and help promote the scientific and policy value of data collection and provide access within strict governance frameworks.

	The collaborative platform envisioned would encourage implementation of these recommendations by each stakeholder group, and would check on progress. Where emerging issues require, discussion among all stakeholders should take place. And a body of case studies of challenges should be built up about the use of RWE in HTA/payer decisions, so as to develop and improve approaches.

	Ultimately, what the group proposes is the development of widely-agreed guidance on use of RWE to promote access to highly innovative technologies.  But of course, as the document acknowledges, “this requires appropriate resourcing, knowledge sharing, and governance.”

	There is always a cost to identify just what sort of pig is in the poke.

Reflector is Pharmaceutical Executive’s correspondent in Brussels

A formal effort is underway in Europe to gather concrete clues on the value of real-world evidence in payer decision-making.

The Quest to Measure Drug Effectiveness

	Among the newly accessible technologies that the pharma industry is monitoring or engaging with as it navigates a changing healthcare landscape, the ultra-small biosensor has been gaining traction recently. Technological advances in the area are seeing biosensors move out of the hospital setting and into everyday life. According to some reports, the biosensors market will surpass $30 billion by 2024. The fastest growing segment of this market, notes Labiotech.eu in a November 2018 article, is home monitoring kits, which “could make a big impact in ensuring people comply with the treatments prescribed by their doctor.”

	With European studies showing that around 50% of medicines for chronic diseases are not taken as prescribed, and that almost 200,000 deaths each year result from patients missing or using the incorrect dose,

 the biosensor may become one of the saviors pharma has been looking for.

	The problem of taking the wrong dose does not lie wholly with the patient, of course. “Dosing is a dynamic process,” said Dr. Timothy Rawson in his recent presentation on Imperial College’s research on microneedle-based sensors at the Sensors in Medicine Conference in London. Rawson explained how incorrectly prescribed antibiotic treatments are contributing to the antimicrobial resistance crisis, which is expected to claim 10 million lives per year globally by 2050. Thirty to 60% of antibiotic prescriptions are currently “inappropriate,” said Rawson. By contrast, individualized dosing can reduce the development of antimicrobial resistance, reduce the incidence of toxicity, and, in critically ill patients, reduce 30-day mortality.

	Imperial’s work on microneedle-based sensors offers a hopeful glimpse into how biosensors are “opening up new frontiers” in individualized therapy. Coupling a real-time beta-lactamase sensor to a closed-loop system can offer more individualized use of antibiotics and a better understanding of the relationship between dose and clinical response, explained Rawson’s colleague, Dr. Sally Gowers. What’s more, the microneedle-based sensors are “minimally invasive, painless, and cause no bleeding.”

	Experts predict that the biosensor’s impact on the development of precision and personalized medicine is on the horizon. Observing that no patient experiences exactly the same therapeutic response to a specific dose of the same compound, CatSci’s Ross Burn told 

 monitors to become “much more commonplace,” with the data helping to inform optimized population doses.

	Meanwhile, wearable sensors’ potential for real-time health monitoring will provide “a more complex picture of what’s going on in the body,” Eccrine Systems’ Andrew Jajack told Labiotech. “A lot of the way we diagnose disease is based on single-moment-in-time markers,” noted Jajack. Real-time monitoring via sensors, however, “will lead to more diagnostic techniques across a spectrum of diseases.”

	The pharma industry has been taking note. In September, Astellas Pharma announced a joint research and development agreement with California-based startup iota Biosciences to explore new biosensing and treatment measures using implantable medical devices powered by ultrasound waves from outside the body. iota co-founders and co-CEOs Michel Maharbiz and Jose Carmena said they “envision a future in which our ultra-small implantable devices will be used in combination with, or as an alternative to, conventional diagnostics and therapies.” iota and Astellas plan to use these purpose-built devices in preclinical studies in several diseases.

	It is two years now since FDA approved the first drug in the US with a digital ingestion tracking system-Otsuka Pharmaceutical and Proteus Digital Health’s Abilify MyCite for schizophrenia, bipolar disorder, and as an add-on treatment for depression. It has an embedded, ingestible sensor that records that the medication was taken.

	The Astellas-iota announcement, however, looks like the start of a new era of industry investment in the area of implantable biosensors, which promises to extend their use beyond the realm of patient adherence.

’s Online and European Editor. He can be reached at 

	1. “Biosensors: Monitoring Our Health Anywhere, Anytime,” Labiotech.eu, November 13, 2018.

	2. “Biosensors, wearables and virtual biotech,” chemistryworld.com, March 13, 2018.

Technology grabbing the attention of watchful industry

Biosensors in Pharma: A Dose of Optimism

With pursuits of complex therapies more routine, platform companies are tasked with aligning their science with process and manufacturing proficiency to stand out in an increasingly competitive investment market 

	When it comes to platforms, there is no separating the science from the manufacturing.

	Why have one drug for one indication when you can have potentially multiple drugs, for multiple indications, from one platform, which ultimately offer economies of scale? Thus the underlying attention for drug development platforms. While the pharma industry will continue to focus on what it does best-targeted pipelines, taking drugs from clinical to commercial to realize their full potential, and holding the bottom line-platform biotech companies are fine-tuning their science toward process and manufacturing to entice pharma partners to use their platform know-how for a coveted therapy.

	But while platforms are red hot attention-getters right now, clarifications remain. And most concerning, because platforms inextricably tie together therapeutic delivery and manufacturing, apples-to-apples comparisons are next to impossible due to the lack of transparency in any one company’s process.

	“The reality is with biotech, you discuss manufacturing to a point. In the world of drugs and clinical data, the intricacies of manufacturing, however, aren’t really discussed,” says Salim Syed, head of biotechnology research, senior biotechnology analyst, and managing director at Mizuho. “Now it matters how good you are at manufacturing. And as these therapies get more complex, it matters even more.”

	Platform technologies run the gamut, but there are similarities among platform companies.

		They are largely focused in biologics, which span cell therapy, gene therapy, immunotherapies, Â­vaccines, stem cells, antisense, and many more.

With pursuits of complex therapies more routine, biotech platform companies are tasked with aligning their science with process and manufacturing proficiency to stand out in an increasingly crowded investment field.

Pharmaceutical Executive-11-01-2019

Pharm Exec’s 2020 Pipeline Report

R. Jude Samulski: Gene Therapy’s Guiding Force

The Pace of Massive Innovation

Debate Heats Up Over Reference Pricing Plan

The Quest to Measure Drug Effectiveness

Biosensors in Pharma: A Dose of Optimism

Closing the Science and Manufacturing Divide

Pharmaceutical Executive, November 2019 Issue (PDF)

Country Report: Sweden