Amid the constant battle with biology and new complexities in fighting disease, persistence seems to be paying off for drug developers. Major driving forces include the rise of CAR -T and other gene therapy, newly discovered cancer targets, better patient identification methods-and the realization that failures have their place in shaping the pipeline of tomorrow.

	Tantalus had it rough. The character from Greek mythology was forced to spend eternity looking at water he could not drink and fruit he could not eat. Each time he reached out, the water would recede, the branches would rise away.

	Pharmaceutical and biotechnology companies face similar problems. The targets are so enticing, the results often wanting. Consider checkpoint inhibitors. They are quasi-miracle drugs: incredibly powerful for the lucky responders, ineffective for others. 

	There are many variations on this theme. Following the success of cancer drug Gleevec, targeted therapies seemed like a sure thing. They’ve helped, but not as much as many had hoped. Pivoting to the central nervous system, the quest for effective Alzheimer’s disease therapies has been fraught with failure. Ask Merck & Co., Lilly, Axovant, Accera, Lundbeck, etc. 

’s 14th Annual Pipeline Report-offer competitive snapshots, which companies have the upper hand. But in the end, the competition is with biology, which seems to be saying: “Really, you thought it would be that easy?”

	But adversity is good for people and companies. The race is on to match checkpoint inhibitors with other therapies to transform cold tumors into hot ones. Companies’ researchers are reexamining their Alzheimer’s strategies. New targets are being tested in multiple indications. It seems the best way to meet complexity is with more complexity.

	Bad news first. The Alzheimer’s Association projects there may be 16 million people with the disease by 2050, a crushing load for patients, caregivers, and governments. Statistics like this are generating a lot of urgency. Unfortunately, the pipeline keeps coming up short.

	“There have been a lot of high-profile failures for amyloid plaque,” notes Joshua Pagliaro, partner in life science strategy at PwC. “I think a lot of people have had the question: Is this a sound scientific hypothesis?”

	Pagliaro is not alone in his skepticism. “The amyloid theory may need some alterations,” says Les Funtleyder, portfolio manager at E Squared Asset Management and

 Editorial Advisory Board member. “We may need to go back to the drawing board there.”

	That’s not comforting for companies with amyloid therapies in the pipeline. They’ve gone this far, invested this much, they need to believe their science is better-their trial design superior. 

	At present, Biogen’s aducanumab is being tested in two international Phase III trials (EMERGE and ENGAGE). The therapy, which targets beta amyloid, has been fast-tracked by the FDA. 

 in an extension of an early-phase study have been positive, showing the antibody therapy reduced amyloid plaque levels in patients treated up to 36 months. Given favorable results and ultimate approval, EvaluatePharma puts aducanumab sales at $1.5 billion by 2022.

	Biogen has a particularly robust Alzheimer’s pipeline, including beta-secretase cleaving enzyme (BACE) inhibitor elenbecestat, which is being co-developed with Eisai. BACE inhibitors are designed to prevent amyloid plaques from accumulating. The drug has been granted fast-track designation in the US and is also in Phase III. Elenbecestat is projected to earn $296 million in 2022, mostly for Eisai.

	In addition, Biogen is developing anti-amyloid antibody BAN2401, which is currently in Phase II trials. The company has a lot riding on the amyloid plaque hypothesis. 

	Amgen and Novartis have their own BACE inhibitor in the works, CNP520, a small molecule in Phase II, which has also been fast-tracked by the FDA.

	AbbVie’s anti-tau antibody, ABBV-8E12, began Phase II studies early this year for Alzheimer’s and progressive supranuclear palsy. It has both fast-track and orphan-drug status in the latter indication.

	Smaller vTv Therapeutics is in Phase III for its receptor for advanced glycation endproducts (RAGE) inhibitor, azeliragon. RAGE is upregulated in Alzheimer’s and is thought to play a role in inflammation, amyloid buildup, and tau phosphorylation. Azeliragon has a long 

	Farther down the pipeline, companies like Cognition Therapeutics are trying different approaches. The company’s investigational drug CT1812, a small molecule that targets sigma-2 receptor complex on neuronal synapses to mitigate amyloid toxicity, was recently fast-tracked by the FDA.

These organizations may have better success with their Alzheimer’s therapies, or the industry may have to rethink its strategies.

	“Some of the challenges have been around patient recruitment,” says Pagliaro. “We’re recruiting patients who have early signs and symptoms already. Is that really the right time to treat? Should we be treating Alzheimer’s prophylactically, like the way we treat cardiovascular disease?”

	Given the development of accurate biomarkers, this could be a sound strategy. On the other hand, are private payers going to pay top dollar for prophylactic therapies when Medicare reaps the ultimate financial rewards? 

	For now, companies with Alzheimer’s therapeutics in late-stage trials are sweating it out. They’ve seen the carnage, are they next?

	Multiple sclerosis (MS) therapeutics offer a brighter picture. And, yes, this is cheating, since MS can be considered more autoimmune than CNS disorder. 

	Celgene’s ozanimod is one of the brighter spots in the pipeline. The oral, selective S1P 1 and 5 receptor modulator is in Phase III for relapsing MS, ulcerative colitis, and Crohn’s disease. In May, Celgene announced 

 for the RADIANCE trial. The drug’s safety profile may give it a leg up on Novartis’ fingolimod. EvaluatePharma predicts ozanimod could produce $1.4 billion in sales by 2022.

	Novartis is not blind to fingolimod’s shortcomings and is working on its own next-generation S1P modulator, siponimod, which could generate fewer side effects. The drug is currently in a Phase III trial for patients with progressive MS. Evaluate estimates siponimod’s 2022 sales at $915.6 million.

	Actelion, now part of Johnson & Johnson, is testing its S1P drug ponesimod with Tecfidera for patients with relapsing MS. Tecfidera is approved to treat psoriasis.

	Epilepsy is one of the specialty markets that is getting much attention. GW Pharmaceuticals leads the way with its cannabinoid product Epidiolex, which treats Dravet syndrome, Lennox-Gastaut syndrome, and other severe forms of epilepsy. Epidiolex is in Phase III for both indications, as well as tuberous sclerosis, and has received orphan designation from the European Medicines Agency (EMA). Evaluate estimates Epidiolex’s 2022 sales at $1 billion. Despite delays, the drug seems poised for FDA approval.

	GW’s picture brightened when Sage Therapeutics’ GABA modulator, SAGE-547, for super-refractory status epilepticus, failed recently in Phase III. The company continues to look for ways to move the drug forward, perhaps focusing on patient subgroups.

 for its Dravet syndrome treatment, ZX008, which took some of the luster off GW. The drug is low-dose fenfluramine hydrochloride, a serotonin booster. It was both effective and well-tolerated. ZX008 has received orphan-drug designation from both the FDA and EMA. It has also been fast-tracked in the US for Dravet syndrome. Evaluate estimates sales of $219 million in 2022.

	Another interesting specialty market is migraine. Novartis and Amgen are co-developing the monoclonal antibody erenumab (AMG 334 or Aimovig), which is in Phase III studies for episodic and chronic migraines. Erenumab targets the calcitonin gene-related peptide (CGRP) receptor to block pain. A recent 

 from Novartis showed the drug reduced the number of migraine days by as much as 50% for patients who failed previous preventive therapies. Amgen has exclusive commercialization rights in Japan; Novartis has exclusive rights everywhere else.

: EvaluatePharma®, September 2017, Evaluate Ltd, 

	With the first CAR-T approval, checkpoint inhibitors aren’t the big new thing in immunotherapy anymore. Still, they are opening up therapeutic doorways that have been closed for a long time.

	“Checkpoint inhibitors have brought drug development into tumor types that haven’t seen drug development in decades,” says Madelyn Hanson, manager, oncology consulting services, clinical and scientific assessment, at Kantar Health. “The clear example was last year’s approval of Tecentriq in bladder [cancer]. It was the first drug approved for metastatic bladder cancer in 34 years.”

	Checkpoint inhibitors are also driving combo-mania, as pharma companies try to maximize their benefits for

	“The way pharma innovation seems to happen is you get a big change, and then you get iterations, and then you get another big change,” says Funtleyder. “We’ve had the big change in the checkpoint inhibitors. Now we’re trying to figure out how to incorporate them into clinical practice-after trying every drug under the sun with them.”

	Incyte’s epacadostat, an ID01 enzyme inhibitor, has shown 

 when combined with Merck’s approved anti-PD-1 drug Keytruda against metastatic melanoma. Epacadostat is also being tested with two other immunotherapies, Bristol-Myers Squibb’s Yervoy and Opdivo, for other indications. With  the  ability to extend the efficacy of checkpoint inhibitors, epacadostat looks to have a bright future. Evaluate puts 2022 earnings at $1.9 billion.

	Amgen is trying a slightly different strategy, combining their oncolytic viral therapy Imlygic with Yervoy. Phase II 

 were positive. The proportion of patients whose tumors shrank was much higher in the combo cohort compared to patients who received Yervoy alone. Tumor size may not be the best mark of success, but patients who received the combo had a median 8.2 months progression-free survival, compared to 6.4 months with just Yervoy. Imlygic could earn $271 million in 2022, forecasts estimate.

	AstraZeneca has had less-than-stellar results with its durvalumab/tremelimumab combination. The combo recently 

 to improve progression-free survival in non-small cell lung cancer (NSCLC) patients. Durvalumab (Imfinzi), a checkpoint inhibitor, fared equally poorly as a monotherapy against NSCLC. 

	On the bright side, the FDA granted accelerated approval for the monoclonal antibody against metastatic urothelial carcinoma, a common form of bladder cancer. AstraZeneca, which is partnering with Celgene, has high hopes for durvalumab and is testing it as a monotherapy or part of a combo in multiple clinical trials. Evaluate pegs durvalumab’s 2022 overall sales for multiple cancers at around $2.6 billion.

	Roche and AbbVie’s venetoclax (Venclexta) has been approved for chronic lymphocytic leukemia (CLL) with 17p deletion or TP53 mutation, but it’s also showing promise in combination against a broader range of CLLs when combined with Rituxan. A recent 

 showed the combo increased progression-free survival for patients with relapsed/refractory CLL. The drug is also being tested against multiple myeloma, non-Hodgkin’s lymphoma (NHL), and other malignancies and could earn $2.1 billion in 2022.

	Janssen just submitted a new drug application (NDA) for its androgen receptor inhibitor apalutamide for non-metastatic, castration-resistant prostate cancer. The hope is the drug can prevent the disease from metastasizing. 

 study apparently produced good results, though those are not available at this writing. Apalutamide is also being combined with Zytiga in early phase trials against castration-resistant prostate cancer. Evaluate has apalutamide sales at $1.1 billion in 2022.

 to report for duvelisib, a dual-action phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma inhibitor for CLL, increasing progression-free survival from 9.9 months (with ofatumumab) to 13.3 months. The drug also showed efficacy against indolent NHL, and Verastem is planning an NDA sometime in 2018. 

	One of the most interesting possibilities is the 

 strategy, targeting mechanisms that drive cancers in multiple organs. We’ve seen this in checkpoint inhibitors, particularly Keytruda, which receive accelerated FDA approval for adult and pediatric solid tumors that have microsatellite instability or mismatch repair deficiency.

	Loxo Oncology’s larotrectinib (LOXO-101) announced a 

 rate across tumor types at this year’s American Society of Clinical Oncology (ASCO) meeting. Larotrectinib targets tropomyosin receptor kinase (TRK) fusions.

	This is interesting new territory, but it’s unclear how these broad-spectrum therapies will fare in the clinic.

	“The FDA is willing to approve on a tumor-agnostic basis,” says Hanson. “We will see how physicians handle that.”

	CAR-T is a good segue from oncology into gene therapy. This is another area where high hopes have been softened by colossal failures. In March, Juno halted its acute lymphoblastic leukemia (ALL) trial for JCAR015 when three patients developed brain swelling and died. The causes are poorly understood, but Juno believes it may have been chemotherapy patients received to make the CAR-T more effective. Cellectis ran into similar, though not quite so severe, troubles with UCART123.

	Despite setbacks, CAR-T is rolling forward. Novartis’ Kymriah was approved in August to treat ALL. The price tag is steep at $475,000, but pretty much in line with a bone marrow transplant. In October, the FDA approved Kite’s Yescarta for NHL.

	CAR-T is a powerful and risky therapy and drug companies are responding to some of the more worrisome side effects. The FDA recently approved Genetech’s tocilizumab (Actemra) to treat severe cytokine release syndrome (CRS), a potentially deadly side effect to CAR-T therapies. No doubt, drugs like these will be actively incorporated into clinical studies.

	Kite, now part of Gilead, lost the first lap of the CAR-T race to Novartis but may end up a strong finisher. In 

 from two clinical trials for axicabtagene ciloleucel (KTE-C19) in refractory, aggressive B-cell NHL, more than half of patients demonstrated complete responses. Based on trial data, the FDA granted KTE-C19 priority review, and the therapy was approved by the agency last month. Evaluate puts sales at around $1.7 billion in 2022.

	Juno is not giving up, either. The company is partnering with Celgene on early trials for its own CAR-T therapy for relapsed and refractory aggressive B-cell NHL, JCAR017. Early data from a Phase I trial (TRANSCEND) was 

. Half the patients had a complete response after three months and safety was reasonably good. Evaluate puts the therapy’s 2022 earnings at $669 billion.

	One of the issues with CAR-T is breadth-blood cancer but no success in solid tumors. That may be changing, however. In October, Poseida released 

 preclinical results in prostate cancer for P-PSMA-101. Another 

 out of the University of Pennsylvania showed good results against melanoma and pancreatic tumor xenografts. Early days but worth watching. 

	Gene therapy epitomizes the failure/renaissance model of drug development. Following a series of misteps nearly 20 years ago, scientists retreated to the lab to find better paths forward. UniQure’s Glybera was approved in Europe in 2012, but the $1 million price tag has been prohibitive. Now we are poised to see a wide variety of gene therapies in oncology, ophthalmology, hemophilia and other inherited blood disease, sickle cell, 

	In October, an FDA advisory committee gave its blessing to Spark’s gene therapy voretigene neparvovec (Luxturna) for inherited retinal disease. The vote was 16 to 0. The therapy targets RPE-65 mutations and will be the first drug to improve hereditary blindness. In the 

, 93% of patients showed some benefit. It’s an orphan indication, the condition affecting around 6,000 people worldwide. Neparvovec should be approved by January. Spark has a number of early-stage therapies in the works for hemophilia, Batten disease, and Huntington’s disease.

	While it is still early in the trial process, Bluebird Bio received 

 on elivaldogene tavalentivec (Lenti-D), its therapy for cerebral adrenoleukodystrophy (cALD), the disease depicted in the movie 

. In the Phase I/II trial, elivaldogene tavalentivec halted disease progression in 88% of the treated boys even two years after treatment. Most kids with cALD don’t live past 10 years old.

	Bluebird has also received breakthrough therapy designation from the FDA for LentiGlobin to treat beta thalassemia, and inherited blood disorder. The drug is also being tested against sickle cell disease. LentiGlobin has had problems in trials, with some patients responding and others not so much. As a result, the therapy has been reformulated. Evaluate puts the drug’s sales at $589 million in 2022.

 from the FDA to begin the pivotal trial for AVXS-101 for patients with spinal muscular atrophy (SMA) type 1, which causes muscle weakness and paralysis. The trial will measure the therapy’s efficacy after a single dose. AVXS-101 seeks to mitigate the defective SMN1 gene. Evaluate estimates sales at $583 million in 2022.

 for their advanced Parkinson’s disease gene therapy, VY-AADC01, from its Phase Ib trial. Patients showed lasting improvements in motor function after a single dose.

	Development partners Alnylam and Sanofi Genzyme announced promising 

 for their RNAi drug, patisiran, against hereditary ATTR amyloidosis with polyneuropathy, which affects multiple organs. Around 50,000 people suffer from the condition worldwide. 

	Alnylam is also partnering with The Medicines Company on the latter’s Inclisiran, which inhibits PCSK9 synthesis through RNAi to lower cholesterol. Phase II results from the Orion-1 trial showed 

 for both safety and efficacy and Inclisiran is likely headed into Phase III trials. Evaluate estimates Inclisiran sales at $354 million by 2022.

	Are big changes ahead for this field? Gene therapy is not just for biotechs anymore. Pfizer has pledged $100 million to build a gene therapy facility in North Carolina, expanding a plant it acquired after purchasing Bamboo Therapeutics. Pfizer is also collaborating with Sangamo and Spark, so the big pharma appears to have significant plans in the space.

	On the cell-based therapy side, Athersys’ MultiStem has received the FDA’s new regenerative medicine advanced therapy (RMAT) designation. MultiStem is made from human stem cells derived from bone marrow and can be frozen and stored. Once administered, the cells are designed to produce beneficial factors that could help the body repair damage and reduce inflammation. The product has the potential to be an off-the-shelf cell therapy that could treat stroke, traumatic brain injury (TBI), neonatal hypoxic ischemia, and other conditions. 

	Athersys has had challenges moving MultiStem through a Phase III trial in Japan. The company recently partnered with Nikon CeLL to get past some of these manufacturing problems. Evaluate puts MultiStem sales potential at $1.9 billion in 2022.

	Antibiotic resistance is a growing issue and a potential healthcare emergency. Without effective antibiotics, many of the treatments we’ve come to take for granted-chemotherapy, transplants, routine surgeries-would become incredibly risky, perhaps impossible.

	Achaogen’s plazomicin, which received breakthrough designation from the FDA this year, is being developed to treat carbapenem-resistant 

 (CRE) and other serious infections. Last year,

 for plazomicin against CRE and complex urinary tract infection (cUTI). In addition, the company recently presented five posters at IDWeek in San Diego, highlighting the antibiotic’s potential. Plazomicin seems poised for approval. The drug could reach $436 million sales in 2022, according to Evaluate projections.

	Cadazolid, from Actelion Pharmaceuticals, is in development to treat 

-associated diarrhea. The antibiotic is being tested against vancomycin in two Phase III trials (IMPACT 1 and 2). So far, cadazolid has met its 

-non-inferiority to vancomycin-in IMPACT 1 but not IMPACT 2. Evaluate puts potential 2022 revenue at $116 millon.

	MicuRx Pharmaceuticals’ MRX-1 has shown activity against methicillin-resistant 

(MRSA) and vancomycin-resistant enterococci (VRE). The drug is being developed to treat acute bacterial skin and skin structure infection (ABSSSI). MicuRx began enrolling 600 patients in China last year for a Phase III study.

	Iclaprim was initially developed by Roche and has now moved to Motif Bio. An advanced dihydrofolate reductase inhibitor, iclaprim is designed to treat ABSSSI and hospital-acquired pneumonia (HAP). The drug has had its ups and downs but met its 

-non-inferiority to vancomycin-in a recent Phase III study (REVIVE-2). Iclaprim recently received orphan-drug designation from the FDA and is poised for approval. The drug could bring in $522 million between Motif and partners in 2022.

	Circling back to combination treatments, Merck is combining relebactam, imipenem, and cilastatin to treat CRE. The therapy met 

 in a Phase II study against cUTI. Two Phase III trials are ongoing.

	Nabriva Therapeutics’ lefamulin, initially developed by Novartis, has shown potential against resistant gram-positive strains. Lefamulin showed 

 against community-acquire bacterial pneumonia (CABP) in a pivotal Phase III trial (LEAP-1). Evaluate estimates that the drug will generate $293 million in 2022 sales for Nabriva.

	Omadacycline, from Paratek Pharmaceuticals, is a broad-spectrum antibiotic that has shown efficacy against gram-positive and gram-negative bacteria and is being tested against 

. The first Phase III trial (OASIS), compared omadacycline to linezolid for ABSSSI and met all 

. Another Phase III study (OPTIC) found omadacycline effective against CABP. Sales in 2022 could reach $293 million.

	The cardiovascular space is in consolidation mode at the moment. There’s little groundbreaking on the immediate horizon. However, there are always efforts to refine approaches to help more patients.

	The FDA recently accepted La Jolla Pharmaceutical’s NDA for LJPC-501 for patients with distributive or vasodilatory shock who do not respond to vasopressors. A 

 met blood pressure endpoints and showed a trend toward longer survival. Evaluate estimates 2022 sales at $490 million.

	Esperion Therapeutics’ bempedoic acid has shown the ability to 

 when combined with ezetimibe and atorvastatin. Esperion recently completed 

 in its pivotal Phase III trial and expect to file an NDA in the first quarter of 2019. Evaluate puts estimated sales at $466 million.

	EG-1962, from Edge Therapeutics, is being developed to treat aneurysmal subarachnoid hemorrhage (aSAH), hoping to improve on nimodipine, the current standard of care. Edge is evaluating EG-1962 in two clinical studies, including a pivotal Phase III trial. Evaluate estimates $46 million in revenue by 2022.

 results for mavacamten (MYK-461) in the Phase II PIONEER-HCM study in symptomatic, obstructive hypertrophic cardiomyopathy. Patients showed post-exercise peak left ventricular outflow tract. This would be the first new drug for this genetic condition in more than 40 years. Mavacamten received orphan-drug designation from the FDA in 2016. Evaluate estimates 2022 sales at $283 million. 

	Developing an effective drug, earning FDA approval, and getting payer buy-in are all so difficult; it’s a testament to humanity’s inherent stubbornness that these medicines get made at all. Still, persistence pays off. CAR-T and other gene therapies are poised to lift off. New oncology targets are being identified with regularity. Next-generation sequencing is helping identify responsive patient subgroups and streamlining trials. It’s hard, but it’s doable.

	And failures have their place-they help illuminate the biology and lead to better, more effective approaches. This is encouraging for those working on Alzheimer’s disease therapies, though less so for patients and caregivers who need the help now. 

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Analysis shows that persistence is paying off for drug developers, driven by the rise of CAR-T and other gene therapy, newly discovered cancer targets, better patient identification methods-and the realization that failures have their place in shaping the pipeline of tomorrow.

Pharm Exec's 2018 Pipeline Report

	Move over Silicon Valley, there is a new biotech hotspot looking to attract the best and brightest-and it’s not in the US. 

	Taiwan is beginning to attract technology and healthcare talent from inside and outside the region, as the small island nation is quickly becoming home to innovative healthcare care startups, such as Taiwan Liposome Company (TLC). 

	“It’s trying to be a much more knowledge-based type of economy,” says George Yeh, president of TLC, a specialty biopharma based in Taipei, Taiwan.  

 recently sat down with Yeh to talk about his company and Taiwan’s courting of the biotech industry. Using its proprietary drug delivery technologies, TLC’s focus is on lipid-based formulation and 

scale-up  to improve the safety and efficacy of injectable drugs-and thus prolong their product lifecycle.

	TLC has been a long-time supporter of the Taiwan economy. Dr. Keelung Hong founded the company in 1997 after serving as a consultant to a number of biotechs, including Nycomed, Salutar, Onyx, and Sequus. 

	Yeh has been with TLC since 2002, following a stint as vice president of AsiaWired Group, where he was responsible for procuring corporate funding, strategic planning, and integration of high-level management and financial resources for startup companies. 

	Having offices and working in both the Taiwan and  San Francisco areas, as well as his previous experience evaluating funding for startups, Yeh has his pulse on the emerging biotech space. His business connections to some of the top political figures in Taiwan also gives him insight into the economic development the country is leaning toward. 

	As Yeh explains it, Taiwan’s economy is currently geared toward more IT-based businesses, and less on science-based fields-but there is a push to change that. In addition, doctors and medical professionals are well respected  in Taiwan, Yeh says, and as more people with medical degrees run for and are elected to political offices, the higher support there  will be on broadening the economy to bring in more biotech presence. 

	Take Taipei, for example. The city’s mayor, Ko Wen-je, was a doctor at the National Taiwan University Hospital before being elected in 2014. According to his office’s website, he held numerous positions at the university, including assistant professor, associate professor, and professor at the College of Medicine, as well as chairman of the department of traumatology. In Wen-je’s Twitter biography, he refers to himself as a “truly independent political entrepreneur.” Entrepreneurs, specifically those in the biotech industry, are exactly who the country, and city, are trying to attract. 

	The number’s back up Yeh’s comments. 

	According to a report published last year in 

, the country’s biotechnology sector is expected to reach $120.4 billion in production by 2025. 

	Taiwan’s IT-based industries are a draw for many biotechs, Yeh explains. He predicts that in  five to 10 years, we will see a lot of traditional IT companies cross over into the biotech and pharma space. 

	“We will see a lot more [pharma] technology start coming from Asia,” notes Yeh. 

	Yeh, who earned a B.A. from the University of California at Berkeley and a master’s degree from the University of Michigan at Ann Arbor, says that he is observing more and more people returning to Taiwan after their schooling. 

	“Talent has been educated and working in the US, and now they are starting to come back  and build out technology [in Taiwan],” he says. “These are very entrepreneurial people who have a different type of technological ability. The culture there lends itself to becoming the next wave of the biotech talent pool.”

	The combination of technological savvy thinkers, plus entrepreneurs, plus pharmaceutical knowledge is the perfect storm to create the foundation for a lively and active biotech community in Taiwan. 

’s Senior Editor. She can be reached at 

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With its convergence of healthcare talent and tech, the nation is turning into a prime destination for innovative startups.

Taiwan’s Biotech Boom

	A new attempt by European drug firms and patient organizations to chart a course between cooperation and cooption has highlighted the scale of the challenges that healthcare stakeholders face when they reach out to one another. “Any relationship between patient organizations and the pharmaceutical industry can be perceived as commercially motivated,” concluded this exercise, conducted over recent months by the biggest European players on each side: the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the European Patients’ Forum (EPF).

	The paper they have produced, “Working together with patient groups,” is couched in carefully controlled and diplomatically sanitized language, as is to be expected from two such sophisticated organizations, and it aims to present a practical and constructive take. But its proposed solutions are, nonetheless, tantamount to a recognition that the challenges it identifies are far from being met-patient groups still labor under the shadow of accusations of behaving as the drug industry’s hired lap-dogs, and drug firms continue to be suspected of manipulating patient organizations like glove puppets, simply by scattering a few crumbs of their profits among them.

	Continuing financial dependency “may lead some to assume there is undue or inappropriate influence of the industry on patient organizations and their decision-making,” acknowledge EFPIA and EPF. The possible remedies run the familiar gamut of keeping everything clean and above board, ensuring collaborations aim at “clearly identified patient benefit,” observing good governance principles and codes, communicating transparently and “proactively and publicly,” and fuller disclosure of funding links.

	There is much that can usefully come out of cooperation, they say. Patient organizations may collaborate with industry to co-create educational programs and take part in clinical development through working with regulatory authorities, ethics committees, investigators, and industry, or contributing to study design and the development of layperson summaries, or even provide input into recruitment and retention. Patients can provide researchers with insights into the challenges of living with a disease, enabling drug manufacturers to incorporate feedback directly into their R&D processes; and they play an increasing role in regulatory processes, and even in defining the value of medicines.

	But the overall tone is defensive. “Collaboration between pharmaceutical companies and patient organizations fulfill a legitimate need for interactions identified in advance,” the two groups say, subject to some of the reservations and conditions about “how these relationships are managed.” They are at pains to underline the need for independence of patient organizations “in all aspects of their decision-making, development of policies, and external communications” to ensure credibility. But the overall impression from the conclusions is that despite all the efforts to dispel doubters’ concerns, both sides are resigned, at least for the present, to being on the receiving end of persistent skepticism.

	Paradoxically, closer collaboration between health stakeholders is these days being driven by a growing chorus of calls to bring coherence and new efficiencies to Europe’s fragmented health systems. EFPIA and EPF themselves note that in the past, industry, academia, healthcare professionals, regulators, and patient organizations “largely worked in silos.” Decisions about patients’ care, medical research, health information, and service design “were taken without meaningful patient involvement,” leading, they say, “to inefficiencies and low value in process and outcomes.” Nowadays, companies have developed new ways “to incorporate patient insights and to collaborate with patients and patient organizations in a transparent and ethical way,” resulting in “better trials, better engagement, better communication throughout the entire life cycle of medicines-and ultimately better patient outcomes.”

	But the shadows of suspicion are hard to dispel. It isn’t just in the area of drug firms’ direct funding of patient organizations that the attempt to hold hands but to stay at arm’s length runs into trouble. A major project to train betterinformed patient advocates over the last three years, known as the European Patients Academy, and drawing on patient organizations, academics, and regulatory authorities, was repeatedly accused of playing an industry game because part of its support came-in kind-from drug companies.

	At the same time, on everything from drug pricing to drug research, and from cross-border care to assessing the performance of national health systems, the slogan is “work together.” Just before the summer, more than 100 European health organizations wrote an open letter to the European Commission insisting that “EU health collaboration is crucial for Europe’s future,” and demanding that “voices from civil society-patients, consumers, health professionals, epidemiologists, and technical experts-are represented in policy dialogues that build on all available evidence and expertise.” In October, a key recommendation from an EU panel of experts on developing new pricing models for innovative drugs was to “create dialogue platforms involving all relevant stakeholders.”

	The obvious impediment to this vision of utopian harmony among stakeholders is that not every stakeholder shares the view of the others. As George Bernard Shaw sagely advised: “Do not treat everyone as you would treat yourself. Their tastes may not be the same.” So a warning bell immediately starts to ring when, for instance, a new report from the EU on its exploration of best practice in national health systems remarks that health service performance assessment “is a complex combination of activities” that includes at the top of its priorities “the involvement of stakeholders,” and that sees a role for providing citizens “with the information of what they can and should expect from the health system.” It envisions the collection and dissemination of information on the functioning of the health system as “a key element allowing patients to use broader knowledge for more educated choices.” That, of course, depends on what is considered an “educated” choice-and raises the slightly chilling prospect of the Goliath of health systems deciding for each David what his or her educated choice should be, or of neutered patients compliantly abdicating all responsibility for their own decisions.

	A degree of distrust is not only to be expected, it may be valuable in moving toward real rather than apparent solutions. Distrust featured prominently in the input from some civil society contributions to the EU debate on how to promote closer collaboration on health technology assessment (HTA) earlier this year. The European consumers association, BEUC, for instance, while in principle in favor of taking EU-level cooperation further among national HTA authorities to bring greater coherence to EU medicines provision, highlighted the risks of 

industry gaining undue leverage without tight safeguards. “The interests of industry and HTA can differ,” it said in its response to the EU consultation on the future of HTA. Even if early dialogues among industry, drug regulators, and HTA organizations “can be beneficial,” it is essential to take into account “the conflict of interest that might arise.”

	Similar warnings came from Prescrire, the non-profit group of health professionals that publishes independent information on drugs and therapeutic strategies. Prescrire flatly rejected the merits of early dialogue, which it sees as a backdoor allowing industry to stitch up drug pricing deals instead of presenting objective arguments for a drug’s merits. It said that allowing industry access to early dialogues provides them with “a platform that can lead to regulatory capture and enable companies to influence pricing and reimbursement decisions.”

	At a time when the pressure for collaboration and cooperation is increasingly strong-take, for instance, the gathering momentum of personalized medicine, or the influence of the so-called “roundtables” organized by leading drug firms and national health authorities in Europe over the last year, or the countless “joint actions” under the EU’s health program, or the burgeoning public-private partnership of the Innovative Medicines Initiative-it may be time to pause and reflect for a moment on whether all forms of collaboration are as good as they purport to be, and whether everyone swept up in the headlong rush to join is going to benefit equally.

Can health stakeholders be friends without being captives?

The Fine Line of Pharma & Patient Group Collaboration

	FDA regulation of prescription drug and medical product promotion has come under fire in recent years, as federal courts have supported industry challenges to rules limiting communications of unapproved drug uses. But with little to show from two years of meetings and discussions about reconciling long-held promotion restrictions with legal decisions favoring greater protection of commercial speech, the arrival of

 Scott Gottlieb to helm the agency has raised expectations that a more flexible policy will emerge. While marketers maintain they can provide truthful information on drug uses without undermining product safety, no one expects radical change in the current political climate.

	
	The deadly opioid epidemic, moreover, has prompted more intense examination of the role of drug marketing in encouraging excess prescribing of these dangerous medicines. Multiple states and local governments have filed suits against manufacturers for encouraging opioid overuse and abuse, and FDA’s Office of Prescription Drug Promotion (OPDP) has issued enforcement letters citing violative promotion of pain medicines. Most recent is a warning to Cipher Pharmaceuticals for minimizing risk information in professional materials on combination extended release pain therapy ConZip. Another cites Pain Therapeutics and DURECT Corp. for touting its investigational opioid therapy Remoxy ER on its website, prior to approval.

	The HHS inspector general (OIG) is scrutinizing how pharma marketing programs encourage such overprescribing, with an eye out for evidence of doctors receiving kickbacks from manufacturers, noted OIG senior counsel Mary Riordan at the advertising and promotion conference in September sponsored by the Food and Drug Law Institute (FDLI). The Justice Department recently collected more than $7 million from Galena Biopharma to settle allegations that the company paid kickbacks to doctors to boost prescriptions for pain drug Abstral, and the investigators are scrutinizing other cases (see sidebar below).

	Just before the new administration took over in January, FDA issued a memorandum that largely defends agency restrictions on off-label communications. It also published a final rule that changed the definition of “intended use” of regulated products, prompting an outcry from industry that it requires manufacturers to revise labeling for additional uses even when the firm does not support that off-label use.
	
	At the same time, FDA published two new draft guidances that set the stage for more flexible communications with payers and formulary committees on pricing issues and for permitting certain “out-of-label” communications that are “consistent with” FDA-required labeling (CFL). And in March, FDA 

delayed implementation of the controversial “intended use” rule for a year (until March 2018) and began the process of clarifying and finalizing the new guidances.

	OPDP analysts sought to explain the intent and recommendations of the CFL guidance at the FDLI conference, as marketer comments on the proposal indicate a need for clearer examples of what is CFL and recommended disclosure strategies. FDA says it will permit communication of unapproved uses that provides truthful and non-misleading information on approved products and presents no harm to patients. CFL information may address the product’s indication, intended population, dosing and directions for use and should be presented in an “appropriate context,” with clear presentation of study results, claims, and limitations on data. OPDP staffers say they’re ready to advise marketers on whether proposed promotional materials meet the new standard or imply new intended uses. 

	The new draft guidance on manufacturer communications with payers, formulary committees, and similar entities implements a provision in the 21st Century Cures legislation by outlining appropriate presentation of healthcare economic information (HCEI) on approved drugs. More surprising is a second section that describes a process for presenting similar information to payers regarding investigational drugs and devices prior to agency approval. The guidance aims to clarify what information qualifies as HCEI, who can deliver the information, and what type of claims fall outside this policy. 

	If FDA is going to make notable changes in promotion policy, it may start by revising the scope and format of risk information presented in DTC advertising. FDA is examining evidence that limiting warnings in TV commercials to severe, serious, or actionable side effects might be more informative than lengthy laundry lists of potential adverse events. The change reflects research indicating that more targeted presentation of risks actually may help consumers weigh potential side effects (see 

	Such a change is supported by OPDP analysis indicating that consumers may retain more risk information from targeted statements. A separate study by researchers at the London Business School found that consumers regard drugs as less risky when drug ads list all its side effects, and that they better understand warnings and side effects when only the most serious risks are presented. 

	Similarly, another OPDP study raises questions about the value of requiring disclosures about limitations on comparative price information in DTC and professional print ads because most consumers and physicians fail to notice or understand such caveats, even when prominently displayed. The analysts also are examining how larger size and clearer presentation of text running in TV commercials may be better understood and remembered by viewers; if animated TV ads improve understanding of risk information; and changes in

 DTC ad design for older and hearing impaired audiences. 

	OPDP has a long research agenda, which has drawn complaints from industry that many of its projects are redundant and not useful. But Gottlieb pointed to “FDA’s own research on broadcast TV advertisements” in his comments posted in August suggesting that a more targeted method for delivering risk information “may lead to better retention of those risks.” If the commissioner is going to alter TV commercial formats, he wants strong evidence that benefits clearly outweigh risks. As FDA officials move forward on DTC revisions and finalizing the two new draft guidances, they also will be reviewing the continuing debate over how marketers can respond to unsolicited requests and discuss scientific information. But there won’t be any change in the basic requirement that all communications are truthful and not misleading, always.

’s Washington Correspondent. She can be reached at 

Agency leaders go slow in weighing changes to DTC ads and off-label marketing.

FDA Explores Flexible Drug Marketing Policies

	One of my sons recently said, after he watched a paper napkin drift from the table to the floor, “I wonder who was the first person to figure out that if you crumpled paper, it would just fall straight down because of density?” I said, “I don’t know.” His brother said, “Who cares?” Which one do you think is going into the sciences? My other son is gifted in other areas, but it’s the people that question and keep looking for reason

s or answers underlying the surface that probably excel in positions in research and science. I found myself thinking more about these people behind the scenes in pharmaceutical research, and none more so than reviewing this issue’s annual 

	What is true of many people and companies, there is no such thing as an overnight success. In last year’s report, we were highlighting some potential successes in Alzheimer’s, but as contributing writer Josh Baxt notes in this year’s report, high-profiles failures in this disease are leading researchers to question the scientific hypothesis around amyloid plaques. 

	With the first CAR-T therapies being approved in August and October-Kymriah and Yescarta in the blood cancers of leukemia and lymphoma, respectively-I did a cursory Internet search of chimeric antigen receptors. They went back to 2000. Since they probably were being hypothesized longer than the ability to post and quickly search on the Internet, an average of 20 years definitely falls into the overriding truth of the term overnight success. Factor in that studies around CAR were spurred by research into Epstein-Barr virus, discovered in 1964, and built on since then, truly scientific discoveries are a long-time effort in trial and error.

	If you think about what actually is driving the current era of personalized medicine, preceded by the end of the blockbuster era, it is that scientists have found vaccines against deadly viruses; drugs that manage diseases affecting large populations; and effective cures for other diseases. That is what science has done. That science is now on the journey to rare diseases or those with unmet needs, is a testament to the research efforts into polio, rubella, statins, HIV/AIDS, and more. 

	Aside from the science advancing human health, regulatory authorities can positively affect getting the discoveries to patients. Specifically in the US, those pathways include orphan designation, breakthrough designation, priority review, and accelerated approvals. In 1983, the Orphan Drug Act was signed into law. Since then, over 600 drugs have been approved with the designation. A breakthrough therapy designation is for drugs intended to treat a serious condition where preliminary clinical evidence indicates that the drug may demonstrate a substantial improvement over currently available therapies. Since 2013, 87 drugs received approvals under that designation. 

	Many drugs in this year’s pipeline fall under orphan or rare disease categories. For example, Spark’s gene therapy voretigene neparvovec (Luxturna) for inherited retinal disease will, if approved (it won a 16-0 advisory panel backing last month), be the first therapy to improve hereditary blindness, which is an orphan indication that affects around 6,000 people worldwide. Drugs approved this year that advance rare diseases are avelumab, the first FDA-approved treatment for metastatic merkel cell carcinoma; lesipasvir and sofosbuvir is the first HCV direct-acting antiviral approved for use in adolescents; cerliponase alfa is the first FDA-approved treatment for a form of Batten disease; ibrutinib for the treatment of chronic graft-versus-host disease (GVHD); and benznidazole is the first treatment approved in the US for Chagas disease.

	Besides the fact that this month is the popular pipeline report, which would be enough for me to write this editor’s letter around, I heard a radio commercial this morning for Penn Medicine’s cancer services talking about its role in a recent gene therapy approval, and explained to the public how CAR-T worked and how they could consider Penn for cancer services. That, of course, was its role in the approval of Novartis’ Kymriah. 

	Next month, we profile Ruud Dobber, President, AstraZeneca US, and Executive Vice President, North America, who earned a PhD in immunology and eventually became a researcher in the fields of aging and immunology. Dobber explained that as a scientist and a researcher, people learn to be resilient because there are so many failures. He says, “But if you are successful, you have that moment of ‘Eureka’ and that’s phenomenal.”

	These are the times I’m thinking about those really resilient, curious, and dedicated scientists and researchers. I told my son he should go into the sciences. The other one? Maybe he can write about them. 

From the Editor

Our annual look at the drug industry's pipeline-the progress and the setbacks-puts my thoughts on those people driving new science behind the scenes in pharmaceutical research. 

No Overnight Successes

The five ways pharma developers can ensure their early engagement with payers and regulators will pay off when it’s time to demonstrate commercial value

	As regulators lower evidentiary requirements for marketing approval to speed the development and review of new drugs for unmet medical needs, payers are demanding more data for these drugs to justify price premiums. This divide has left drug developers in a difficult position as they try to satisfy both parties in their clinical and commercial evidence plans.

	On one side, for severe diseases with unmet treatment need, regulators increasingly accept clinical trial packages that lack large Phase III comparative randomized controlled trial (RCT) data and use intermediate surrogate endpoints to demonstrate a positive benefit-risk profile.

	On the other side, payers want to see that a new product delivers clinically meaningful benefits (i.e., improvement in quality-of-life and morbidity/mortality endpoints that are directly relevant to patients) in well-conducted Phase III trials versus a locally-relevant comparator, as well as in more diverse, real-world settings. And they want those benefits to be cost-effective, delivering value for money. Payers, therefore, are increasingly using-and demanding-real-world evidence (RWE) to inform their decision-making.

	Recognizing the difficulty sponsors face in meeting their requirements, regulators and payers have developed programs to help pharmaceutical companies get early, formal advice and guidance on how to build an evidence generation plan that will provide the optimal data package for each. 

	However, developers who seek early advice and engagement often find it challenging to reconcile input from stakeholders with differing mandates and goals (see table at bottom). Meetings and discussions alone can’t align these differing needs, and there’s no such thing as a perfect evidence package because there are always trade-offs between time, costs, risks, and utility. 

	Therefore, companies need to be strategic in how they engage with regulators and payers to navigate these complexities, and to avoid duplicating work and creating unnecessary challenges for themselves.

Regulatory approval without market access is a Pyrrhic victory

	The industry’s pipeline is increasingly dominated by transformational therapy classes: CAR-T cell treatments, immuno-oncology, and gene therapies. At the same time, the proliferation of accelerated regulatory pathways across the globe are offering streamlined and more flexible approaches to drug development. For example, if results warrant, it’s now possible for a first-in-human trial of an experimental cancer drug to morph, without pause, into a pivotal efficacy trial. 

	Developers must seek advice on the regulatory requirements for these technologically advanced products, and novel, possibly curative (i.e., single-use) treatments. But regulatory approval does not necessarily confer commercial viability. 

	For example, Glybera, a gene therapy to treat a rare metabolic disease that triggers pancreatitis, was granted a five-year marketing authorization in the European Union (EU) in 2012 under the category “exceptional circumstances.” But the manufacturer (uniQure N.V.) announced it would not renew the EU license when it expired last month. Why? At a cost of $1.1 million per treatment, and addressing a condition that affects only one in one million people (a total market of 150 to 200 people in the EU), Glybera had only been used commercially and paid for once as of mid-2016. Payers decided that the evidence did not justify its price tag. 

	Payers and value watchdog organizations, especially those in Europe, foresee further troubles for these novel drugs. In January 2017, the German health technology assessment (HTA) agency IQWiG (Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen), ruled that the “additional benefit” of Xalkori (crizotinib) for non-small cell lung cancer patients with a ROS1 mutation was “not proven.” If this verdict is ratified, Xalkori would only qualify for reference pricing versus its generic chemotherapy comparators, rather than premium pricing. 

	In a press release announcing the verdict, Beate Wieseler, IQWiG’s head of drug assessment observed, “The current dossier assessment shows what problems can arise for early benefit assessments if drugs are approved early on the basis of relatively few data-we often see this, particularly in rarer diseases. If the European Medicines Agency (EMA) were to implement their ‘adaptive pathways’ plan and in future were to approve even more drugs with even fewer data, then this problem could be further aggravated.”

Early engagement: Smart call, but be savvy

	In the face of these ominous trends, the developer’s goal must be to create a tailored, data-based evidence plan that can reduce risk, guide rational development, support regulatory approval, and demonstrate product value to payers, prescribers, and patients in a timely (and affordable) manner.

	Early engagement with regulators and payers is critical to such a plan, but it’s not always easy to obtain, interpret, or utilize such advice effectively. Here are five ways to get the most out of regulatory and payer guidance:

	There are multiple mechanisms for formal, early interaction with both regulators and HTA bodies. The most advanced of these mechanisms exist in the EU and the US. Data shows that regulatory advice can boost success rates and shorten clinical development time: 

		An EMA study showed that between 2008 and 2012, 85% of marketing authorization applications (MAAs) that received and followed early scientific advice (SA) were approved, as opposed to only 41% that did not seek SA. 

		Of 132 marketing applications submitted to the FDA between 2008 and 2012, the 49 which utilized a pre-investigational new drug (PIND) meeting had a median clinical development time (CDT) of 6.4 years; the 83 applications with no PIND meeting had a median CDT of 8.3 years. 

	For companies seeking advice on what payers want-a major factor in securing market access in many of the EU’s single-payer systems-Europe is the key arena for early engagement. But developers must tread carefully across the fragmented European HTA landscape, which encompasses 77 different agencies in 29 countries. 

	It is important for pharma companies to start engaging in countries with the most established early HTA processes: the UK, France, Germany, Sweden, and Norway. Select target HTA bodies based on factors such as standard of care (SOC)/treatment pathway for the target disease, the track record of prior HTA results in the therapeutic area/indication, and the incidence rates of relevant conditions, which vary by country.

The five ways pharma developers can get the most out of early engagement with payers and regulators when plotting their clinical and
commercial evidence plans.

Pharmaceutical Executive-11-01-2017

Pharm Exec's 2018 Pipeline Report

Taiwan’s Biotech Boom

The Fine Line of Pharma & Patient Group Collaboration

FDA Explores Flexible Drug Marketing Policies

No Overnight Successes

Aligning Early Advice with Long-Term Planning

Navigating the Untapped NASH Market

Interpreting UK’s Post-Brexit Life Sciences Strategy

When HIPAA Doesn’t Apply

Country Report: Austria

Pharmaceutical Executive, November 2017 Issue (PDF)