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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.
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.
Many articles, including this one-Pharm Exec’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 Pharm Exec 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. Recent findings 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 checkered history, but is now moving forward.
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 positive results 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.
Zogenix recently announced positive Phase III results 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 analysis 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.
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 good results 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 results 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 failed 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 Phase III trial 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.
The company’s SPARTAN 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.
Verastem had good news 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 pan-cancer 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 76% objective response 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 results 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 encouraging. 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 positive preclinical results in prostate cancer for P-PSMA-101. Another study 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,
cardiovascular disease, etc.
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 pivotal trial, 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 good news on elivaldogene tavalentivec (Lenti-D), its therapy for cerebral adrenoleukodystrophy (cALD), the disease depicted in the movie Lorenzo’s Oil. 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.
AveXis has received the go-ahead 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.
Voyager Therapeutics also received good news 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 Phase III results 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 positive results 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 enterobacteriaceae (CRE) and other serious infections. Last year,
Achaogen announced positive Phase III results 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 Clostridium difficile-associated diarrhea. The antibiotic is being tested against vancomycin in two Phase III trials (IMPACT 1 and 2). So far, cadazolid has met its primary goal-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 Staphylococcus aureus (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 primary endpoint-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 endpoints 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 strong results 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 ABSSSI and CABP. The first Phase III trial (OASIS), compared omadacycline to linezolid for ABSSSI and met all endpoints. 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 Phase III study 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 reduce LDL when combined with ezetimibe and atorvastatin. Esperion recently completed enrollment 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.
MyoKardia recently reported positive 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.
But if anything, the current pipeline shows persistence pays off. Given enough work, even the most intractable indications can crack.
Josh Baxt is a freelance science and healthcare writer
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