Pipeline 2016

Editor's Note:This article was first published in the November 2015 issue of Pharmaceutical Executive, another UBM publication. It has been updated to reflect the most current information available at press time.

Biopharma companies continue to count on the potential in their pipelines and the massive markets with unmet medical needs waiting to be tapped. The successes of several recent launches have produced sales figures so impressive that those who had predicted “the end of the blockbuster era” not long ago have quietly shelved their Carnac the Magnificent turbans.

A more accommodating regulatory process is helping the cause, to the point that some critics warn that FDA might be too helpful to the industry. Both industry and FDA assure critics that compared to what was seen during the past years of friction, the evolving quality of basic science now means that drugs are coming forward with better safety and efficacy profiles. In addition, trials are better designed and better recruited.

“FDA standards haven’t changed, but manufacturers are getting better at developing and supporting effective products through approvals,” noted Amy Grogg, senior vice-president of Strategy and Commercialization, AmerisourceBergen Specialty Group.

The fact that many approvals have been for smaller indications geared to orphan disease populations means that drugs are better targeted to tighter patient groups. In orphan drugs subject to fast-track designation, this represents a  strong move by FDA to support R&D in therapeutic areas that offer immeasurable value to small patient populations while unleashing additional scientific and process innovations that can be applied across disease states, added Grogg.

FDA has opened itself to dialogue with companies planning trials and submissions by encouraging regular exchanges that eliminate confusion and uncertainty. Drugmakers have been receptive, leveraging the support and making heavy use of specialty- and accelerated-status designations.

So where does that leave us as we reconnoiter this promising pipeline landscape?  Yes, there are access challenges, ever-higher development costs, and the increasingly vocal - and articulate - denigrators of the profit motive in healthcare. But great scientific advances, some  decades in the making, like the human genome project, have planted seeds of growth that are now yielding visible results in the clinic or in late clinical stages. Scientific and clinical excitement abounds for numerous disease states, especially those that have seen little progress in years. Patient groups are excited - and are more hands-on in the new drug-vetting process than ever.

See also: New drugs raise hopes

Alzheimer’s R&D

Research and drug development in Alzheimer’s disease (AD) continues to bear fruit. A few long-studied compounds are still hanging on, while new entities are sprouting. The market potential would be tremendous for anything, anything that could impact AD progression substantially, so even the slightest sign of progress creates excitement and thus major market interest and volatility.

For years, the industry has put its hope for a disease-modifying treatment in the amyloid hypothesis. The accumulation of plaques in the brain consisting of amyloid- beta peptide has been investigated as the primary driver in the pathogenesis of the disease and the key target for a cure. The most advanced, and still with a reasonable chance of reaching the market, are two humanized monoclonal IgG1 antibodies targeting amyloid-beta peptide, Eli Lilly’s solanezumab and Biogen’s aducanumab, which have been up and down, and are currently up, sort of, following trial data presented at Alzheimer's Association International Conference in Washington, D.C. last July.

Solanezumab had all but exited stage left after Phase 3 failures in 2012. But persistence could pay off for Lilly as its extended-look study, EXPEDITION-EXT, showed an altered slope in the decline for patients who received the drug early, compared to those who first received placebo and then got the drug, a delayed-start cohort. Not everyone is impressed, but for the optimistic, a slightly slower decline into AD ranks as a positive sign in a field that clearly needs one. Lilly’s 2,100-patient Phase 3 EXPEDITION 3 trial should see its last patient visit in October 2016, a release date that puts it ahead of the competition.

Biogen’s aducanumab may benefit, or languish, from sharing the same target as solanezumab, depending on one’s level of optimism and what a second-place finish might mean. It also has recent data for which some are seeing the glass half-full; others are less excited. Optimists will point to the company’s positive results in a 166-patient Phase 1 trial released last March and to the fact that the recent negative analysis could be about getting the right dose. Biogen is willing to wager on the pros and has started the 5-year, Phase 3 program with 1,350 patients. Key data are expected in 2018.

Roche also saw setbacks, but maintains it amyloid-beta antibody program, gantenerumab, with Phase 3 trials active and estimated completion dates listed in 2019 (Roche’s website lists filing as estimated in 2017+). Roche/Genentech also announced plans to progress to the Phase 3 trial with crenezumab, a humanized monoclonal antibody designed to target all forms of Abeta amyloid, discovered by AC Immune.

Ultimately, for AD, population dynamics are on the drugmaker’s side. One widely held prediction estimates the proportion of the world's population over 60 years of age doubling by 2050, from about 11% to 22%. The rising impact of AD on the healthcare system may hit the trillion-dollar mark, and a successful market launch of solanezumab could net Lilly $7.6 billion in yearly sales by 2024, according to CNN Money report, citing a BMO estimate. Of course, a discussion on value and analysis of the degree of benefit seen will go a long way to determine the price tag for any new AD treatment. In addition, indications for only patients with mild symptoms may limit the potential label of most value, while early diagnosis and a necessity to treat promptly at the first sign of AD may eventually yield more patients on therapy.

With this massive market and the potential crisis for caring for so many dependent people in the healthcare system, the number of targets will continue to grow.  But only time will tell whether AD treatments evolve as a step-therapy approach, or whether the field takes a more aggressive trajectory with a combined-drug approach.

See also: What's in the pipeline for 2014?

BACE inhibitors

A subsequent batch of AD therapies could come from the BACE inhibitor group. Leading the class, Merck’s 1,960-patient, Phase 2/3 trials and a 1,500-patient Phase 3 trial for MK-8931 are ongoing, with completion dates set for July 2017 and March 2018 respectively.

Eli Lilly’s first swing at BACE inhibitors saw toxicity problems, but the firm remains in the field. The Phase 2/3 AMARANTH study for its LY3314814 (also known as AZD3293 via the nomenclature of its partner, AstraZeneca) launched in December 2014 and lists a primary completion date as August 2019.

Amgen and Novartis also have agreed to share the risk connected with a BACE program, as announced in September 2015, with CNP520 in Phase 1/2a and other preclinical candidates on deck.

The design of amyloid-beta antibodies and BACE inhibitors is to strike AD at its molecular foundation, and thus has the potential to modify the course of the disease.  But some researchers argue that symptom alleviation is still important and, at the minimum, should be part of neurologists’ armamentarium, especially in light of the possible added therapeutic effect of cocktail regimens. Some drug developers see the singular focus on disease modification as fallacious and therefore believe the industry is disregarding or downplaying effective therapies that might bring value to AD patients and, with it, strong sales.

Other approaches to AD

There is another gap in the research design for AD, best summarized by the question, why dissociate slowing the curve of cognitive decline from the larger effort to improve clinical outcomes? This question is posed by Axovant’s CEO Vivek Ramaswamy, a 30-year-old former hedge-fund whiz, whose company brought in $315 million from venture investors in its IPO last June. The company’s candidate RVT-101, bought from GlaxoSmithKline (GSK) for a cool $5 million, started a 1,150-patient, Phase 3 trial last fall in North America, Europe, and Japan. The MINDSET study promises to be a pivotal trial, as the company will leverage previous data from GSK’s attempts with the drug. To support its cocktail thesis, the MINDSET trial will investigate the safety and efficacy of RVT-101 in patients with mild-to-moderate AD on a stable background of donepezil (Aricept). If successful, Axovant plans to submit a New Drug Application (NDA) to FDA by the end of 2017.

Another small firm making noise in AD and other neurodegenerative diseases is Anavex Life Sciences Corp. The company’s Anavex 2-73 and Anavex Plus, a cocktail that adds donepezil, giving the therapy disease modifying and symptom alleviation properties, is in Phase 2. In January 2016, the company reported a positive dose-response relationship with Anavex 2-73 at 5 weeks of treatment as part of an interim analysis of data from its ongoing Phase 2a trial involving patients with mild-to-moderate AD. Phase 2b is an open-label extension for an additional 52 weeks. The company notes that by targeting sigma-1 and muscarinic receptors, believed through upstream action to reduce protein misfolding, it can alter beta amyloid, tau, and inflammation. The company has its sights set on Parkinson's disease (PD) as well. Anavex has received an influential vote of support from the Michael J. Fox Foundation for this PD research.

Also on board with the cocktail approach is Accera, which hopes to turn a supplement/medical food into a late-stage AD pipeline candidate. AC-1204 is designed “to address the metabolic defect” of the AD brain rather than more traditional amyloid beta and tau pathologies. Accera’s product induces mild ketosis in the body, supplying the brain with ketone bodies, which serve as “back-up fuel.” “We’ve shown that the brain can utilize ketone bodies and continue to metabolize, staving off symptoms,” said CEO Charles Stacey. “It’s an increasingly well-established hypothesis.”

The company announced that its Phase 3, 480-patient study, the first of two, was 75% enrolled last July and should be full by mid-2016. The trial is due to read out in the latter part of 2016 or early 2017. In 2016, Accera also will launch its second Phase 3 study, which will be U.S. and ex-U.S., said Stacey. With a history as a medical food known as Axona, Accera is coming from a unique place, in light of the fact that the product was commercially marketed and has a substantial safety record. Recognizing that the medical food route is less known, in order to reach and benefit the maximum number of patients, the company is now focusing AC-1204 on the clinical pathway.

Elsewhere in the brain

An advantage for pipeline technologies that target symptoms and/or more general aspects of neural decline is that they may also be applied to treat adjacent neurodegenerative disorders. Axovant’s second indication for RVT-101 is likely to be Lewy body dementia, while Anavex lists epilepsy and Parkinson's disease as its next targets.

Acadia Pharmaceuticals chose to take on PD first, with its drug pimavanserin (Nuplazid), a selective serotonin inverse agonist preferentially targeting 5-HT2A receptors, for the treatment of Parkinson’s disease psychosis (PDP). Acadia also is conducting clinical trials of pimavanserin for AD psychosis and schizophrenia. FDA granted the drug breakthrough therapy status in 2014, a good sign that FDA thinks its data are solid for PDP. The company submitted its NDA for PDP in September 2015, and FDA could issue a ruling in favor by May 2016.

Analysts believe that Acadia might need a big pharma partner to market pimavanserin if it wants to achieve peak sales that some estimate are in the $1 billion range; so far, the firm is choosing to go it alone.

Also in late-stage development for a new PD symptom reliever is Cynapsus’ APL-130277, a sublingual thin-film formulation of apomorphine. The company is using the 505(b)(2) NDA pathway for the unique formulation of the drug that is already approved as Apokyn, a subcutaneous injection of the active ingredient marketed by U.S. WorldMeds. Cynapsus initiated a Phase 3 safety and tolerability trial in September 2015 and intends to have data from that study and an ongoing efficacy study ready for NDA submission near the end of 2016. Apomorphine can help PD patients who experience “off” episodes that render them unable to perform basic tasks such as eating and getting dressed, and make them increasingly reliant on assistance. The company overcame significant formulation challenges to get the drug into the sublingual film. Patients would be able to self-medicate as needed, when they feel an “off” episode starting.

Cholesterol: Drug class breakthrough

In contrast to the frustrations and continued wait for better treatments in neurodegeneration, those in the field of cholesterol-lowering are seeing a massive arrival of an extremely effective and highly controversial drug class, PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitors. Big sales are expected, and payers are often portrayed as cowering in fear of the potential budget exposure. So far, however, sales are limited, negotiations are ongoing, and the perceived massive impact of the PCSK9 inhibitors has yet to be felt in full force.

Notably, PBM giant Express Scripts announced that both Sanofi/Regeneron’s alirocumab (Praluent) and Amgen’s evolocumab (Repatha) will be on its national preferred formulary, ensuring that the drugs will reach the specific patient set who will most benefit.

One of the most volatile stocks in biopharma, currently hovering at $14.50 in February 2016 and with a 52-week range of $13.51 to $115.30, is Esperion, with the saga of its cholesterol-lowering pill ETC-1002. Esperion touts an impressive management pedigree: Its founder and CSO is a co-discover of Lipitor, so the team knows the molecular pathway to lower cholesterol.  Additionally, the drug’s data has impressed the field, convincing most that the drug, which works upstream of statins, is an effective way to lower low-density lipoprotein (LDL) cholesterol. And lastly, amid all the strife of pricing the PCSK9 inhibitors, not to mention delivering injections in a population that has been popping statins in pill form for a decade plus, Esperion’s candidate promises a once-daily oral option.

Management conceives of ETC-1002 filling the gap between statins, which are cheap and oral, and the New Age PCSK9 inhibitors, which will substantially increase the burden on patients by being expensive and requiring injection. In addition, the safety profile for ETC-1002 may permit its use in conjunction with statins or even PCSK9 inhibitors to achieve maximal lowering of cholesterol.

So why all the volatility in this hot segment? One concern has been whether LDL-C is seen as a sufficient surrogate clinical endpoint for approval, which, the company states, FDA agrees it is. But the elephant in Esperion’s boardroom has been whether approval could come soon or whether a long-term cardiovascular outcomes trial will be required.

The company said in an August 2015 press release that approval for patients with heterozygous familial hypercholesterolemia (HeFH), or clinical atherosclerotic cardiovascular disease (ASCVD) will not require the cardiovascular studies. In September 2015, the company provided additional clarification surrounding the trials it will be undertaking. But as the company’s language changed from FDA “will not” to “could” require long studies, Wall Street has grown suspicious that the path to real revenues is going to end up being a long one.  A substantial lag to launch would give the PCSK9 inhibitors more time to become entrenched in the clinical setting, damaging the prospects for the eventual launch of ETC-1002 as well.

In January 2016, the company announced the launch of a Phase 3 program to assess the long-term safety and tolerability of ETC-1002; the specifics of the full Phase 3 global development strategy will be finalized by the second quarter of the year. The trials will take a dual approach, evaluating the drug separately for “patients with statin intolerance, in addition to patients who are inadequately treated despite maximally tolerated statin therapy.”

Pfizer, too, plans to get in on the anti-PCSK9 inhibitor market with bococizumab, which is in Phase 3 trials. Key data could be available around mid-2016, with an approval late in 2016 or early 2017. Pfizer will have a lot of catching up to do, though some believe the monoclonal antibody may gain market share if it can live up to the hype as a follow-on - but best-in-class - compound.  In this regard, Lipitor’s own history is instructive.  Additionally, Pfizer will try to formulate a bococizumab pill and vaccine, the latter giving the potential for once-yearly dosing.

Also banking on the benefits of a long-term cholesterol fix is Alnylam, partnered with The Medicines Company on its Phase 2-ready RNAi therapeutic, ALN-PCSsc. The collaborators presented Phase 1 data last September and noted “highly durable effects with LDL-C lowering lasting over 140 days after a single injection.” With the Medicines Company taking the lead, the drug has advanced into a Phase 2 clinical trial this year.

Cholesterol-lowering has seen its share of clinical trial successes, with big sales revenue projected. But last fall also saw a failure, leaving one whole class of pipeline candidates in limbo. Lilly’s stock cratered October 12 with its announcement that it was throwing in the towel on its candidate evacetrapib, a CETP inhibitor.

Other products targeting CETP are anacetrapib, from Merck, and TA-8995, which Amgen gained by acquiring Dezima Pharma last September. That compound could be written off too. The CETP space is littered with failures, and with the recent Lilly revelation, the industry has been reminded just how big a risk they were to begin with. The busted Lilly trial had enrolled 12,000+ patients, a considerable expense, since it pursued studies right up to Phase 3.

Oncology pairings

The industry’s oncology pipeline is both wide and dense, so it can be easy to miss the forest for the trees. Complicating the picture is the fact that combinations of various drugs are likely to start making headlines with solid results. When it comes to differentiators among the competition, rational, time-efficient approaches to selecting which agents will complement each other will be invaluable. And the pricing debate over the bill for simultaneous use of two or more novel therapeutics is destined to follow shortly thereafter.

Immuno-oncology assets clearly continue to draw the biggest crowd, whether you’re an oncologist at a medical conference or an investor watching the newest CAR-T company place its IPO. Merck's pembrolizumab (Keytruda) and Bristol-Myers Squibb's (BMS) nivolumab (Opdivo) are duking it out for PD-1 inhibitor primacy in several cancer types, with patient subpopulations, PD-L1 as a biomarker, and label language making for compelling drama. Melanoma and lung cancer are on the books, but the pipeline includes expansion to more indications, such as head and neck, gastric, breast, and Hodgkin's lymphoma. FiercePharma reports that Opdivo could earn BMS $8.8 billion by 2020, while Keytruda could bring in $5.5 billion for Merck.

Though projected at sales of a measly $2 billion, Roche’s PD-L1 inhibitor, a successor target for Roche's atezolizumab, could ultimately beat analyst expectations with its slightly differentiated mechanism of action. The PD-L1 inhibitor represents a massive investment for Roche, in light of its 11 ongoing or planned Phase 3 studies across lung, kidney, breast, and bladder cancers.

Merck KGaA is partnering with Pfizer for the PD-L1 inhibitor avelumab, which the firms list in Phase 3 for non-small cell lung cancer and Phase 2 for metastatic Merkel cell carcinoma. The two pharma giants have said they will collaborate on “up to 20 high-priority immuno-oncology clinical development programs with avelumab, many of which are expected to commence in 2015.”

For BMS, adding nivolumab to ipilimumab (Yervoy) was an obvious combination of immuno-oncology candidates, which predictably improved progression-free survival in tandem, in comparison with monotherapy, while also upping side-effect risks.

And this is where the potential for oncology pipelines really gets exciting. A simple search for combination efforts quickly becomes a complicated one, with the many candidates already progressing in place. But talk to oncology specialists and they will stress that current possibilities in immuno-oncology are just scratching the surface. The science is in its early stages, having just hit at a few checkpoint targets. But there are a lot more, and with each new target, the potential for new combination opportunities multiplies.

Deciphering which combos will be best for which specific tumors will be a monumental feat. Whether it will be the big pharmaceutical manufacturers expending massive resources to decode tumors and rationally design treatments based on specific tumor types, or whether small, more nimble, more data-savvy firms will prove better at getting there first, is  a contest that will be interesting to watch.

Returning to the relatively simple pipeline concept of developing monotherapies in oncology, we find that one potential blockbuster could come from Milllenium: The Takeda Oncology Company. In November 2015, FDA approved ixazomib (Ninlaro) to treat patients with relapsed and/or refractory multiple myeloma. Given the oral delivery route for the first proteasome inhibitor, Takeda hopes the drug will do well among competitors to help replenish revenue lost for its blockbuster bortezomib (Velcade).

Two more FDA approvals in November 2015 included elotuzumab (Empliciti), a multiple myeloma candidate from a BMS/AbbVie partnership, and daratumumab (Darzalex) for double-refractory multiple myeloma from the Genmab and Johnson & Johnson partnership.

CTI BioPharma announced in February 2016 that FDA had placed a partial clinical hold on its clinical studies for its Phase 3 drug for myelofibrosis, pacritinib. No new patients can be enrolled or start using pacritinib as initial or crossover treatment, and patients who have not benefited after 30 weeks of treatment should stop pacritinib. The company stated that the reason for the partial clinical hold was due to excess mortality and other adverse effects in patients treated with the oral kinase inhibitor. The company will submit modifications of protocols to FDA, including modification of all protocols for randomized trials, to disallow crossover to pacritinib. After its review, FDA will notify CTI BioPharma whether trials can continue under the IND.

Biosimilars save in oncology

While most oncology developments combine great potential for science and patients with sticker shock for payers, it’s also necessary to point out an emerging market opportunity here in the United States for major cost savings. One of the key pipeline events for 2016 will be the entry of biosimilars, according to AmerisourceBergen’s Grogg. “In 2015 FDA approved the first biosimilar, Zarxio, and others should follow suit,” she said.

There are many things to consider, specifically the fact that biosimilars will not have the same effect as generics. “An important consideration for manufacturers entering the biosimilars' space is the resources required to bring a biosimilar to market,” added Grogg. Manufacture of biologics is significantly more intensive and delicate than for small molecule generics, which are easily copied and thus able to offer immediate price reductions.

Also, payer-mandated switching is unlikely to occur immediately when the first biosimilars come to market, because of uncertainty about these new products. “Biosimilar manufacturers will be required to conduct many of the same prelaunch activities as branded biologic manufacturers would, and provide post-launch patient services to ensure uptake by physicians, payers, and patients,” she said.

Zarxio’s initial price tag has been set at a 15% discount to the innovator product Neupogen. As more biosimilars come through the pipeline, analysts expect deeper discounts in the 30% and 40% range. At a 30% discount, gaining the equivalent of 30% market share, one analyst pegs the biosimlar’s revenues at $300 million per year. 

Sandoz has several biosimilars in its pipelines, including copies of pegfilgrastim, Epoetin-alfa, and outside oncology, adalimumab and etanercept, the biggest rheumatology moneymakers, all listed as Phase 3.

Plenty of other companies are developing biosimilar pipelines as well. Apotex could be one of the next companies to launch one, with its biosimilar version of Amgen's Neulasta (pegfilgrastim), which it filed in December 2014. And Hospira, which is now part of Pfizer’s established products business, hopes to market Inflectra (infliximab), a copy of Remicade, as well as Remsima, via its partnership with Celltrion - a match-up that illustrates how confusing the biosimilars market is becoming.

Immune deals and breakups

Though biosimilars will be expected to make an impact in the inflammatory diseases market, clearly there is still much room for innovative products. One of the big buyouts from 2015 was Celgene’s $7.2 billion play for Receptos, gaining it the hot product ozanimod. Celgene’s announcement of the deal lists the oral, once-daily, S1P modulator in Phase 3 development for ulcerative colitis and relapsing multiple sclerosis (MS). The company noted that the ongoing MS trials should have data to report in 2017, while data in ulcerative colitis could be released in 2018. Approval for treatment of MS could occur as early as 2018. Celgene estimated peak sales for ozanimod in the range of $4 billion to $6 billion.

Other autoimmune/inflammatory diseases such as rheumatoid arthritis and psoriasis could see their pipeline of oral alternatives grow. Pfizer’s JAK inhibitor tofacitinib (Xeljanz), already approved for rheumatoid arthritis (RA), is striving to add indications that include ulcerative colitis, psoriasis (oral), and psoriatic arthritis, where it’s currently in Phase 3 or under review. Pfizer did note that in October 2015 it received a complete response letter (CRL) for its supplemental new drug application (sNDA) for psoriasis, yet another snag for tofacitinib, which has had sluggish sales since its approval in 2012. However, analysts believe it could still hit projections in the $1.5 to $2 billion range.

The JAK inhibitor class may see several additions in coming years distinguished by slightly different safety/efficacy profiles. Lilly and Incyte’s baricitinib could give tofacitinib a run for its money. The company announced that the pill beat out the RA standard biologic adalimumab (Humira), though displacing TNF inhibitors in RA would be a tall order. A 2016 launch date is likely. Analysts believe it could also reach sales around $1.5 billion.

More questionable is the future of Galapagos’ JAK inhibitor filgotinib. The drug is behind baricitinib chronologically, though claims for specificity and safety had some analysts thinking it could be best in class. The company’s partner, AbbVie, was supposed to either escort the drug into Phase 3 or buy it from Galapagos outright. Instead, the firm pulled out last fall, a decision that has led to many questions about the future of this compound. AbbVie said it is now making Phase 3 plans for its own JAK inhibitor, ABT-494. In December Galapagos found a new partner, Gilead Sciences.

Other inflammatory drama emerged when Amgen broke up with AstraZeneca over brodalumab, its interleukin-17 (IL-17) inhibitor for psoriasis. Brodalumab was seen as a potential competitor to Novartis’ IL-17 inhibitor secukinumab (Cosentyx), which was approved for moderate-to-severe plaque psoriasis in January 2015 and could see peak sales of $4 to $5 billion. Suicidal thoughts in a clinical trial are never a good thing, though AstraZeneca’s CEO Pascal Soriot said in the company’s Q2 earnings call last year that the drug was unlikely to be causally related to suicidal ideation, However, in a September 2015 press release, the company announced it was calling it quits as well, and auctioned the drug off to Valeant Pharmaceuticals for $100 million, subject to $245 million in milestones and bonuses.

Rare competitors

Developing drugs for orphan diseases is clearly not a fad. With 7,000 rare diseases and 250 new ones identified each year, there is clearly room for growth as companies are attracted to a sector in which there is generally less competition over a given disease. In addition, earning an FDA priority review voucher for successful development in a pediatric condition is a nice added benefit.

However, Duchenne muscular dystrophy (DMD) is one rare disease that is seeing a bit of a crowded field. BioMarin beat Sarepta by mere weeks in submitting its drisapersen (Kyndrisa) before eteplirsen last spring. Both drugs use exon skipping of exon 51 in the dystrophin pre-mRNA, which could result in a treatment for approximately 13% of DMD patients. The two companies have been unusually combative in their interactions and have expressed interest in buying other companies to establish the premier DMD brand that could evolve combination treatment regimens.

PTC Therapeutics’ ataluren (Translarna) targets a different 10% of DMD patients with a nonsense mutation. The company has struggled to show significance in a crucial clinical endpoint, the 6-minute walk test. A late Phase 3 trial showing a 15-meter improvement failed the bar of statistical significance; however, according to company executives, meta-analysis of data and observations in a prespecified group of boys should be enough for approval. PTC Therapeutics completed its rolling NDA submission in January 2016. PTC is also investigating the potential for ataluren in nonsense mutation variants of cystic fibrosis.

Translarna could peak at $900 million in European and U.S. sales, with a projected $300,000 a year price tag. Peak sales estimates for both drisapersen and eteplirsen range from $500 million to $1 billion a year.

Ionis Pharmaceuticals (formerly Isis Pharmaceuticals)  and Biogen are working together to investigate antisense drug Nusinersen (IONIS-SMNRx) for infants and children with spinal muscular atrophy (SMA). Data from these trials are expected in 2017 and peak sales could approach $2 billion, according to one analyst’s estimate, based on a patient population of up to 35,000 in the United States and European Union, at a $125,000 price tag and 50% penetration.

Rather than developing a rare-disease drug candidate from the ground up, Corbus Pharmacuticals has taken a different approach by finding potential gold in a defunct pain asset. Resunab is listed in Phase 2 for the rare inflammatory diseases cystic fibrosis, systemic sclerosis, and dermatomyositis. After receiving support from the Cystic Fibrosis Foundation, the company could rival Vertex in the cystic fibrosis space, with possible sales of $2 billion a year.

Pipelines that don’t look like pipelines

Looking at deep pipeline trends, it is possible that future pipelines might not all look like the pipelines companies display on their websites today. If companies continue to focus on topics such as “wellness” and “aging as an indication,” it’s tough to see how the Phase 1 to 3 chronology can be realistically applied.

Alector is one company taking a novel approach to AD, seeing it as an immune disorder at its core and believing that what immunotherapy is doing for cancer, they will one day do for neurodegeneration. The notion has some early support, with a $32 million Series C funding last September and such impressive names in its investor syndicate as OrbiMed, Polaris Partners, Google Ventures, Topspin Partners, Mission Bay Capital, and others.

Calico is bringing the full force of Google into the aging arena, and investors and patients alike hope to see a promising pipeline develop. But clearly proving a treatment is workable in aging will necessitate trials with unprecedented challenges in terms of design, scale, and of course the productive interpretation of mind-boggling amounts of data.

A new business:  Being well

Regardless of whether aging and wellness represent not just new indications but entirely new branches of medical science, it will be incumbent upon industry R&D departments to take up the technology tools and human expertise necessary to develop products for the space. For example, for wellness ever to go beyond “self help” and dieting fads, really big data will have to be applied, and therapies will have to address the complex needs of individual patients, including their genomes and microbiomes, as well as co-morbidities and behaviors.

Mastering these emerging fields will provide the opportunity for an end to the cyclical ups and downs of conventional acute-care drug discovery by getting much closer to what patients really need to stay healthy across a much longer lifespan.

Casey McDonald is senior editor, Pharmaceutical Executive.