Pharm Exec's 2016 Pipeline Report

Falling enterprise values have defined the life sciences landscape during these waning days of 2015, accompanied by a storm cloud of negative headlines on industry pricing practices. This, in turn, has fueled the ire of skeptical payers, politicians, and the public at large. Will a drug pipeline harvest full of treatments founded on strong science, supportive regulation, and unmet medical need offer solace to shareholders and the promise of a reputational rebound? Will presidential politics add to the pressures on drug pricing, with a sour coda to the old refrain, “in the US, the market decides?”

Well before their fall leafer excursions to the deciduous tracts north of the Boston-Philadelphia life science corridor, investors were seeing red. But the harsh crimson taint adorning their company’s stock ticker isn’t bringing the same seasonal enjoyment as the red, orange, and yellow hues of the Maple, Beech, and Hickory. 

Much as in nature, where trees that give up their foliage early are often afflicted by invasive pests, many in biopharma are looking to blame a 32-year-old, drug-hiking scrooge named Martin Shkreli and the pricing backlash he wrought. However, as the drug pricing controversy fails to clear and drugmakers and their investors continue to fear a punitive, politically motivated response, one wonders if the forest is simply seeing a correction trailing several years of growth, or if it represents the maturation of an unhealthy ecosystem primed for a more significant burn. In the latter view, that young CEO looks more like a kid playing with matches in a dry thicket.

Nevertheless, biopharma companies continue to reach for those patches of sunlight above the canopy, counting on the potential in their pipelines and the massive markets with unmet medical needs waiting to be tapped. The argument against a bubble continues unchanged: that lofty valuations are justifiable given the stellar line of new products that have leapt into the market along with many others now saltating through company pipelines. 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 hats.

Helping the cause is a more accommodating regulatory process, to the point that some critics warn that the FDA might be too helpful to the industry. Both industry and the FDA assure critics that in comparison to 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 populations. In orphan drugs subject to fast-track procedures, this represents a strong move by the FDA to support R&D in therapy 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 heavily utilizing specialty and accelerated status designations.

So where does that leave us as we reconnoiter this promising pipeline landscape? Yes, there are shadows in the form of 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. 

Alzheimer’s anew

To extend our thematic metaphor, drug development in Alzheimer’s disease (AD) has shed its fair share of leaves, abscising entire branches. But research continues that could produce fruit. A few long studied compounds are hanging on for dear life while new buds are sprouting. The market potential for anything, anything that could impact AD progression substantially would be tremendous, 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 A-beta peptide, Eli Lilly’s solanezumab and Biogen’s aducanumab. The pair have been up and down, and are currently up, sort of, following trial data dumps at July’s Alzheimer’s Association International Conference in Washington, DC.

Solanezumab had all but exited stage left after Phase III failures in 2012. But persistence could pay off for Lilly as it’s 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 III 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 I trial released in March and 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 five-year, Phase III program with 1,350 patients. Key data is expected in 2018  (Biogen reaffirmed its commitment to AD last month, announcing it was pruning its non-AD pipeline-and cutting 830 jobs in the process).

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

Ultimately, for AD, population dynamics are on the drugmakers’ 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 a CNN Money report, citing an investment banker 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. Additionally, impacts in 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 see 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 if the field takes a more aggressive trajectory with a combinatorial drug approach. 

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

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

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

The design of A-beta antibodies and BACE inhibitors is to strike AD at its molecular foundation, and thus has the potential to modify the course of disease. But some researchers argue that symptom alleviation is still important and, at the minimum, should be part of neurologists’ armamentarium, especially when contemplating the potential added therapeutic effect of

cocktail regimens. Some drug developers see the singular bent to focus on disease modification as fallacious, and, hence, they believe the industry is disregarding or downplaying effective therapies that might bring value to AD sufferers and, with it, strong sales. 

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? The question is posed by 30-year-old, former hedge fund wiz, Axovant’s CEO Vivek Ramaswamy, whose company brought in $315 million from venture investors in its June IPO. Axovant’s candidate, RVT-101, bought from GlaxoSmithKline for a cool $5 million, will start into a 1,150-patient, Phase III trial this fall in the US, 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. Axovant is investigating RVT-101 on a stable background of Aricept (donepezil) to support its cocktail thesis and on recognition that symptom alleviation without halting neurodegenerative decline can still be beneficial for patients.

Another small firm making noise in AD and other neurodegenerative diseases is Anavex. 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 II. Early 36-day data is being presented this month, with 52-week, open-label data to follow. The company notes that by targeting sigma-1 and muscarinic receptors, believed through upstream action to reduce protein misfolding, it can alter A-beta, tau, and inflammation. The company has its sights set on Parkinson’s  (PD) disease 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 A-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 Accera CEO Charles Stacey. “It’s an increasingly well-established hypothesis,” he added.

Accera announced that its Phase III, 480-patient study, the first of two, was 75% enrolled in July and should be full by mid-2016. The trial is due to read out in the latter part of 2016 or early 2017. Accera will also launch its second Phase III study in 2016, which will be US and ex-US, said Stacey. With a history as a medical food known as Axona, Accera is coming from a unique place, considering 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 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 will likely be Lewy body dementia, while Anavex lists epilepsy and PD as its next targets.

Acadia Pharmaceuticals chose to take on PD first. It’s drug, Nuplazid (pimavanserin), seeking approval for Parkinson’s disease psychosis (PDP) may also be applied to AD psychosis and schizophrenia. For now, the company has submitted its new drug application (NDA) for PDP, receiving breakthrough designation in doing so, a good sign that the FDA thinks its data is solid; it could issue a ruling in favor by May 2016.

 Analysts believe that Acadia might need a big pharma partner to market Nuplazid if it wants to achieve peak sales that some estimate is in the $1 billion range; so far, the firm is choosing to go it alone. Reservations regarding the company’s lack of regulatory and commercial prowess were supported when the company postponed its NDA submission in March, stating the “decision to move back the planned submission is based on additional time required to complete the preparation of systems to support commercial manufacturing and supply and, in turn, to support FDA review.”

Also late stage for a new PD symptom reliever is Cynapsus’ APL-130277, a sublingual thin film formulation of apomorphine. The company is utilizing the 505(b)(2) pathway for the unique formulation of the drug that is already approved as Apokyn, a subcutaneous injection of the active ingredient marketed by US WorldMeds. Cynapsus initiated a Phase III safety and tolerability trial in September 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 rendering them unable to perform basic tasks like eating and getting dressed, making them increasingly reliant on assistance. 

The company overcame significant formulation challenges to get the drug in the sublingual film, which it believes will pay off. Patients would be able to self-medicate as needed when they feel an “off” episode starting, a severe limitation of apomorphine in its current form. 

Cholesterol to collect

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. 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, pharmacy benefit manager (PBM) giant Express Scripts announced that both Sanofi/Regeneron’s Praluent, and Amgen’s 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 in the mid-$20s and with 52-week range of $18 to $120.96, is Esperion and the saga of its

cholesterol-lowering pill ETC-1002. Esperion touts an impressive management pedigree: it’s founder and chief scientific officer is a co-discover of Lipitor, so the team knows the molecular pathway to lower cholesterol. Additionally, ETC-1002’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 cholesterol. And lastly, amidst all of 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 biologics, which will substantially increase the burden on patients by being expensive and injected. Additionally, the safety profile for ETC-1002 may allow it to be used in conjunction with statins, or even PCSK9s, to achieve maximal cholesterol lowering.

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, Esperion states, the FDA agrees it is. But the elephant in Esperion’s boardroom has been whether approval could come soon or if a long-term cardiovascular outcomes trial is going to be required.

The company said in an August press release that approval in patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) will not require the cardiovascular studies. In September, 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 PCSK9s more time to become entrenched in the clinical setting, damaging the prospects for the eventual launch of ETC-1002 as well.

Regardless of whether an approval can come soon, Esperion will launch a Phase III program for ETC-1002, the specifics which it will finalize by the first half of 2016. 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 also plans to get in on the anti-PCSK9 market with bococizumab which is in Phase III 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 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 as a fifth-in-class entry is instructive. Additionally, Pfizer will try to formulate a bococizumab pill and vaccine, the latter giving the potential for once-yearly dosing. The pill formulation could begin human trials by year-end.

Also banking on the benefits of a long-term cholesterol fix is Alnylam, with its partner The Medicine’s Company, on its Phase II-ready RNAi therapeutic, ALN-PCSsc. The collaborators presented Phase I data in 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 group plans to start Phase II for the RNAi injection this year, with Phase III starting in 2017. Jefferies recently modeled peak sales for ALN-PCSsc at $980 million, though it noted uncertainty given the early stage of the asset.

Cholesterol lowering has seen its share of clinical trial successes, with big sales revenue projected. But this fall also saw a failure leaving one whole class of pipeline candidates in limbo. Lilly’s stock cratered on October 12 with its announcement that it was throwing in the towel on its candidate, evacetrapib, a CETP inhibitor. Other notables targeting CETP are Merck, with anacetrapib, and TA-8995, which Amgen gained by acquiring Dezima Pharma in 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 of a risk they were to begin with. The busted Lilly trial had enrolled 12,000-plus patients, at considerable expense, having pursued studies right up to Phase III. 

Oncology pairings

The industry’s oncology pipeline is both wide and dense, so it can be easy to lose the forest in the trees. Complicating the picture is the fact that combinations of various drugs are likely to start making headlines with solid results. Rational, time-efficient approaches to selecting which agents will complement each other is going to be invaluable as a competitive differentiator. And the pricing debate over the bill for use of two or more novel therapeutics simultaneously 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 Keytruda (pembrolizumab) and Bristol-Myers Squibb’s Opdivo (nivolumab) 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 like head and neck, gastric, breast, and Hodgkin lymphoma. Analysts report that Opdivo could earn BMS $8.8 billion by 2020 while Keytruda could bring in $5.5 billion annually for Merck.

Though projected at sales of a measly $2 billion, Roche’s PD-L1, 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 given its 11 ongoing or planned Phase III studies across lung, kidney, breast, and bladder cancers.

Merck KGaA is partnering with Pfizer for the  PD-L1 inhibitor avelumab, which is in Phase III for non-small cell lung cancer and Phase II 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 Opdivo to Yervoy (ipilimumab) was an obvious combination of immune-oncology candidates, which predictively improved progression-free survival in tandem, versus solo treatment, 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 any oncology specialist 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 pharmas throwing massive resources at the problem to decode tumors and rationally design treatments based on specific tumor types or if small, more nimble, more data-savvy firms will prove better at getting there first-it’s a contest that will be interesting to watch. 

Back to the relatively simple pipeline concept of developing monotherapies in oncology, one potential blockbuster could come from Milllenium: The Takeda Oncology Company, with a potential approval by early 2016. In September, FDA granted priority-review status for the NDA of ixazomib to

treat patients with relapsed and/or refractory multiple myeloma. Given the oral delivery route for its proteasome inhibitor, Takeda hopes the drug will do well amongst competitors to help replenish revenue lost for its blockbuster Velcade.

Looking to hit the market with a label for double-refractory multiple myeloma is the Genmab and J&J partnered drug daratumumab. Janssen Biotech began a rolling submission in June 2015 based on Phase II data and marketing approval could come in 2016. Jefferies analysts project $4 billion peak sales. Empliciti (elotuzumab), a multiple myeloma candidate from a BMS/AbbVie partnership, has also received accelerated review and could gain approval in 2016. 

Also taking aim at an accelerated path is CTI BioPharma, with its Phase III drug for myelofibrosis, pacritinib. The company’s September press release noted that it was requesting the approval based on a single trial, which could drastically reduce the product’s time to market. The drug, like Incyte’s Jakafi, is an oral JAK inhibitor, but has specificity profile impacting JAK2, FLT3, IRAK1, and CSF1R, resulting in less thrombocytopenia and anemia, according to company statements. CTI BioPharma is comparing pacritinib to best available therapy in a Phase III myelofibrosis trial, but the company hopes it can gain approval sooner in patients with intermediate and high-risk myelofibrosis with low platelet counts. Analysts project global sales for pacritinib at around $750 million in myelofibrosis and other blood disorders.

Biosimilars save in cancer, among other indications

While most oncology developments combine great science and patient potential with sticker shock for payers, it’s also necessary to point out an emerging market opportunity in the US 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 the FDA approved the first biosimilar, Zarxio, and as we move into 2016 and beyond, others should follow suit.” 

There are many factors to consider, specifically the fact that biosimilars will not have the same effect as generics. “An important consideration for manufacturers is the resources required to bring a biosimilar to market,” added Grogg. Biologic manufacturing is significantly more intensive and delicate than 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 pre-launch activities as branded biologic manufacturers would and provide post-launch patient services to ensure uptake by physicians, payers, and patients,” Grogg explained.

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 30-40% range. At 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 of oncology into the biggest rheumotology moneymakers, adalimumab and etanercept, all listed as Phase III.

Plenty of other companies are developing biosimilar pipelines as well (see chart below). Apotex could be one of the next 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, 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.

Source: ZS Associates; click to enlarge

Immune deals and break-ups

Though biosimilars will be making an impact in the diseases of inflammation, 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 as in Phase III development for ulcerative colitis (UC) and relapsing multiple sclerosis (MS). The company notes that the ongoing MS trials should have data in 2017, while data in UC could come out in 2018. Approval in MS could come in 2018. Celgene estimated peak sales for ozanimod in the range of $4 billion to $6 billion.

Other immune/inflammatory diseases like rheumatoid arthritis (RA) and psoriasis could see their pipeline of oral alternatives to its mainstay injectables grow. Pfizer’s JAK inhibitor Xeljanz (tofacitinib), already approved in RA, is

striving to add indications, including UC, psoriasis, and psoriatic arthritis, where it’s currently in Phase III or under review. Pfizer did receive a complete response letter (CRL) last month for its supplemental new drug application for Xeljanz in psoriasis. The CRL is yet another snag for the drug, which has had sluggish sales since its approval in 2012; analysts believe Xeljanz could still hit projections in the $1.5 billion to $2 billion range.

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

More in question is the future of Galapagos’ JAK inhibitor filgotinib. The drug is behind baricitinib chronologically, though claims for specificity and safety had some thinking it could be best in class. Galapagos’ partner, AbbVie, was supposed to escort filgotinib into Phase III, or buy it off Galapagos outright. Instead, the company pulled out this fall, prompting many questions about the future of the

 drug. AbbVie says it is now making Phase III plans for its own JAK inhibitor, ABT-494, while Galapagos is back to finding itself a dance partner.

Other inflammatory drama came when Amgen broke up with AZ over its IL-17 inhibitor for psoriasis, brodalumab. The drug was seen as a potential competitor to Novartis’ IL-17 inhibitor Cosentyx, which was approved for moderate-to-severe plaque psoriasis in January and could see peak sales of $4 billion to $5 billion. Suicidal thoughts in a clinical trial are never a good thing, though AZ’s CEO Pascal Soriot, during the company’s Q2 earnings call, said brodalumab was unlikely to be causally related to suicidal ideation. However, in September, the company announced it was calling it quits as well, and auctioned the drug off to Valeant 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; companies are attracted to the space, where there’s generally less competition in a given disease. Additionally, 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 has formed a bit of a crowd. This spring, BioMarin beat Sarepta by mere weeks in submitting its drug, drisapersen, before Sarepta’s  eteplirsen, and a decision

may come out simultaneously before the end of the year. Both drugs utilize exon skipping of exon 51 in the dystrophin pre-mRNA, which could result in a treatment for approximately 13% of DMD sufferers. 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 combinatorial treatment regimens.

Slightly adjacent, PTC Therapeutics’ Translarna (ataluren) targets a different 10% of patients with nonsense mutation by permitting readthrough of a premature stop signal. The company has struggled to show significance in a crucial clinical endpoint, the six-minute walk test. A late Phase III trial showing a 15-meter improvement failed the bar of statistical significance; however, meta analysis of data and observations in a prespecified group of boys should be enough for approval, says company executives. PTC is planning to initiate the rolling NDA submission by the end of the year. Because of its nonsense mutation targeting mechanism of action, PTC is also testing Translarna in nonsense mutation variants of cystic fibrosis (CF), in Phase III and could progress it in mucopolysaccharidosis I. 

Translarna could peak at $900 million in European and US 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.

Collaborating with cutting edge science are Isis Pharmaceuticals and Biogen, whose antisense drug, ISIS-SMNRx, is in Phase III trials for infants and children with spinal muscular atrophy. Data is expected in 2016 or 2017, and sales could approach $2 billion, according to one analyst’s estimate based on a patient population of up to 35,000 in the US and EU, at a $125,000 price tag and 50% penetration.

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

The next gen: Pipelines that don’t look like pipelines

Looking at deep R&D trends, there is potential that pipelines in the future may not all look like what companies display on their websites today. If the trends for organizations to focus on topics like “wellness” and “aging as an indication” continue, it’s tough to see how the Phase I to III 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 in September and some impressive names in its investor syndicate such as OrbiMed, Polaris Partners, Google Ventures, Topspin Partners, and Mission Bay Capital. 

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 that 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 to ever go beyond “self-help” and dieting fads, really big data will have to be applied and therapies will have to be able to address the complex needs of individual patients, including their genomes and microbiomes, and all co-morbidities and behaviors, too. Mastering these emerging fields 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 Pharm Exec's Senior Editor. He can be reached at cmcdonald@advanstar.com.