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Executive Summary

Lilly’s solanezumab, Roche/Genentech’s Ocrevus and Cempra’s solithromycin are among the key therapies scheduled for major data read-outs or approval decisions in Q4 2016. With the help of Informa Pharma Intelligence’s Biomedtracker, Scrip takes a look at what to expect before we enter the new year 


Scrip | Pharma intelligence


Of the data read-outs due by the end of 2016, perhaps the most eagerly anticipated is the top-line data from Eli Lilly & Co.’s Phase III EXPEDITION study of solanezumab in mild Alzheimer’s disease – failure here would likely be the last the last straw for the product and potentially the amyloid hypothesis on which it is based.

EXPEDITION-3 was predicated on a subgroup analysis of the failed EXPEDITION-1 and -2 studies. Reported in 2012, they showed that solanezumab missed the primary cognitive and functional endpoints in patients with mild-to-moderate Alzheimer’s. But the product lived on as a pre-specified secondary subgroup analysis revealed a significant slowing of cognitive decline in patients with mild disease. Hence EXPEDITION-3, which followed in July 2013 and has enrolled approximately 2,100 patients with mild symptoms and demonstrated brain amyloid burden.

If the results confirm those seen in the subgroup analysis, this would not only provide a boost both for the amyloid hypothesis but also for ongoing efforts to intervene earlier in the disease course. Lilly recently started to push this boundary still further with the recently begun EXPEDITION-PRO, a Phase III trial to study solanezumab in prodromal Alzheimer’s. (Also see "Beta amyloid market prospects still no clearer after AAIC analyses" - Scrip, 22 Jul, 2015.)

Roche/Genentech Inc. should learn the fate of another possible game-changer therapy on Dec. 28 – its anti-CD20 monoclonal antibody Ocrevus (ocrelizumab) for the treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS).

By controlling clinical disease activity as early as possible, Ocrevus has the potential to alter the approach to treating both RMS and PPMS. If approved, Ocrevus would be the first therapy specifically indicated for the treatment of the progressive form of MS, currently estimated to make up 10-15% of all MS patients. This would allow the drug to take a sizeable share of the overall market even if it cannot break into the already crowded relapsing space.

In February 2016, Ocrevus received breakthrough therapy designation from the FDA for the treatment of patients with PPMS. The Ocrevus marketing application is based on results from three pivotal Phase III studies: OPERA I and OPERA II in RRMS and ORATORIO in PPMS. (Also see "Ocrelizumab Shines At ECTRIMS With Standout Data" - Scrip, 13 Oct, 2015.)

(Also see " Roche's Ocrelizumab Strengthens Lead In Primary Progressive MS " - Scrip, 17 Feb, 2016.)


Regeneron Pharmaceuticals Inc./Sanofi’s fully human anti-IL6 receptor monoclonal sarilumab is lining up to join Roche’s Actemra (tocilizumab) on the market for use in inflammatory disease. The second-in-class product is currently under FDA review for moderate-to-severe rheumatoid arthritis with an expected PDUFA date of Oct. 28.

The success of sarilumab’s two Phase III pivotal studies, MOBILITY and TARGET, are the driving factors behind Biomedtracker’s above average likelihood of approval rating for this drug. Tested in two slightly different populations (TNF-intolerant/inadequate in TARGET vs MTX-inadequate in MOBILITY), the ACR responses between the studies have demonstrated a consistent efficacy profile, Biomedtracker analysts say. “With no publicly disclosed roadblocks, sarilumab appears headed towards a straightforward FDA approval.”

However, they add that the success of this drug’s entry into the market is still highly questionable. Although the drug’s ability to demonstrate head-to-head superiority over adalimumab (AbbVie’s Humira) might help the adoption of sarilumab, the biologic will have to face not only a fairly entrenched rheumatoid arthritis treatment paradigm of TNF inhibitors, but also an impending wave of biosimilars, including Amgen’s recently approved adalimumab biosimilar Amjevita. (Also see "Sanofi/Regeneron's Sarilumab Faces Stiff Competition Despite Humira Triumph" - Scrip, 11 Mar, 2016.)


In diabetes a number of major events are due. Firstly, a verdict is expected from the FDA on whether Boehringer Ingelheim GMBH /Eli Lilly’s approved sodium-dependent glucose transporter-2 inhibitor (SGLT-2 inhibitor) Jardiance (empagliflozin) will get a new label indication for CV benefit. In June 2016, an FDA advisory panel was split (12 yes: 11 no) on whether the EMPA-REG cardiovascular outcomes trial (CVOT) – which was initially required by the agency to prove CV safety – also provided substantial evidence of a CV mortality reduction.

While the CV benefit was strong, a major issue for the naysayers was that the primary MACE endpoint was not as robust, and hence they questioned how much confidence one could have in the statistical analysis of CV death by itself, since the latter was essentially a secondary outcome. The fact that the drug's mechanism of action for reducing CV death is unclear also factored into decisions. Additional clinical data submitted to the FDA during the review period was deemed a major amendment, delaying the PDUFA date for the new indication until early December, 2016.

If the sNDA is approved, Jardiance would be the first diabetes drug to have a CV indication. “This should of course help in its marketing, though physicians may infer a class effect and US segment leader Johnson & Johnson’s Invokana (canagliflozin) is expected to have CV data already next year. If the sNDA is rejected this time, Jardiance could still gain supplemental approval after Invokana or AstraZeneca’s Farxiga (dapagliflozin) confirms the benefit, but that of course would negate an advantage of being first-to-market with the indication. Still, confirmation of the benefit should help grow the class. Competition could come, however, from GLP-1 agonist Novo Nordisk AS’s Victoza (liraglutide), which also showed a benefit on MACE in its CVOT, with investigators asserting that its data suggest a more direct impact on atherosclerosis.”

Meanwhile, Novo Nordisk and Sanofi will finally hear whether their two basal insulin / GLP-1 agonist fixed-ratio combination products will get approvals for type 2 diabetes. Both products received three-month extensions from their original PDUFA dates, with new dates expected in the fourth quarter.

Xultophy is Novo Nordisk’s combination of basal insulin degludec and GLP-1 agonist liraglutide, with a PDUFA date in December. Sanofi’s iGlarLixi (Lixilan) combines its popular basal insulin glargine and lixisenatide, with an expected PDUFA date of Nov. 23, 2016.

Despite the very positive FDA advisory committee votes for both drugs, it is not surprising that they received extensions, particularly since there were still a number of questions about the injection devices and units used, said Biomedtracker analysts. There were also questions about which types of patients the drugs should be used in, those naïve to both component classes or those already on one of them.

“All in all, there is a very likely chance that both iGlarLixi and Xultophy will find their way through their regulatory processes, though without more details, it is not certain whether all of the issues will be resolved this time around.” (Also see "Xultophy Expands Label In Europe As First US Approval Decision Looms" - Scrip, 5 Sep, 2016.)

CV products

In the cardiovascular area, further data for two products with new approaches are expected.

Acorda Therapeutics Inc. is set to release Phase III data for twice-daily Ampyra (dalfampridine) Extended Release (ER) tablets in ischemic stroke. The company is exploring its potential to improve walking in people who are suffering from post-stroke walking difficulties (PSWD) after experiencing an ischemic stroke, based on encouraging proof-of-concept results in 2013. The product has been approved since 2010 for improving walking in patients with multiple sclerosis.

The Phase III MILESTONE trial tested two twice-daily doses of the product but enrolment was stopped earlier this year when Acorda decided to pursue a once-daily formulation. Having reached 50% of target enrollment, Acorda is conducting an unblinded analysis of the Phase III trial data. Together with Phase I results from multi-dose pharmacokinetic testing for once daily dalfampridine also expected in the fourth quarter, the data will inform the design of the planned Phase III post-stroke program using the once daily formulation; Acorda plans to run two concurrent pivotal trials in PSWD in mid-2017.

And some better news could come for Alnylam Pharmaceuticals Inc. following last week’s failure of its lead candidate revusiran, with Phase II data due to be presented on Nov. 15 in a late-breaking session at the American Heart Association meeting for its PCSK9 candidate ALN-PCSsc, a systemically delivered RNAi therapeutic, being developed with The Medicines Company. (Also see "Alnylam's 'Day After' Revusiran Failure Bad, Maybe Not Catastrophic" - Scrip, 6 Oct, 2016.)

ALN-PCSsc targets both intracellular and extracellular PCSK9, thereby phenocopying the human genetics observed in loss of function or null human PCSK9 mutations. The ORION-1 Phase II data should show whether the product is likely to be effective in subjects with atherosclerotic cardiovascular disease (ASCVD) or risk equivalent ASCVD and elevated LDL-C when given as biannual or quarterly sc injections. This more convenient dosing schedule would differentiate it from the leading PCSK9 inhibitors Repatha and Praluent, and compensate for its late arrival on the market. (Also see "Alnylam, Medicines Company PCSK9 Drug Has Quarterly Dose Potential" - Scrip, 30 Aug, 2015.)


The fourth quarter is pivotal for Cempra Inc. and its lead antibiotic candidate, solithromycin, for the treatment of community-acquired bacterial pneumonia (CABP). FDA decisions are due for both oral and intravenous formulations on Dec. 27 and 28, respectively, following an Antimicrobial Drugs Advisory Committee meeting on Nov. 4.

Solithromycin is a highly potent next-generation macrolide which has activity against most macrolide-resistant CABP pathogens. This activity is driven by its ability to interact with three sites on the bacterial ribosome, compared with the single binding site of first- and second-generation macrolides. It is the first macrolide since azithromycin to have the potential to be administered both orally and intravenously and is more active than azithromycin or clarithromycin against most macrolide-susceptible bacteria, note analysts at Biomedtracker.

Cempra’s two registrational studies both met the primary endpoint of statistical non-inferiority (10% non-inferiority margin) at the early clinical response. The incidence of infusion site reactions seen with IV solithromycin (34.3% vs. 13.1% with moxifloxacin) raised concerns but this is unlikely to be a major factor given the more severe nature of illness in patients requiring rapid IV administration. “If Cempra can avoid safety concerns from the FDA and have a positive committee meeting outcome, solithromycin could potentially be a blockbuster antibiotic going into 2017.” (Also see "ICAAC 2015: Cempra CEO Sees Solithromycin Potential Beyond Infectious Diseases" - Scrip, 22 Sep, 2015.)

The fourth quarter should also see top-line data for one of RedHill Biopharma Ltd.’s lead drug candidates, RHB-104, for the treatment of moderate-to-severe active Crohn’s disease and multiple sclerosis (MS), from the Phase III MAP US study. RHB-104 is a single capsule, oral combination therapy containing rifabutin, clarithromycin and clofazimine, for the potential treatment of Mycobacterium avium spp paratuberculosis (MAP) infection, which is thought to be a disease-promoting factor in Crohn's disease. RHB-104 has US orphan drug status for the pediatric Crohn’s population.

Hepatitis B

Staying with anti-infectives, two products for use against hepatitis B infection have PDUFA dates slated by the end of the year. Gilead Sciences Inc. should hear back from the FDA on Nov. 11 on its application for tenofovir alafenamide (TAF) for the treatment of adults with chronic HBV infection. TAF also awaits approval in Europe and Japan with a CHMP opinion expected to occur between November, 2016 and February, 2017. (Also see "Gilead's New Hep B Treatment Shows Safety Benefit But Is It Enough?" - Scrip, 6 Jan, 2016.)

TAF is a prodrug of tenofovir, the active agent in Viread (tenofovir disoproxil fumarate, TDF), and designed to yield higher concentrations in lymphoid tissue with lower levels in plasma. The lower dose required for TAF allows for easier formulation with other drugs into a single tablet. TAF is expected to be approved for HBV as it has similar efficacy to that of Viread, but with better long-term safety on bone density and renal measures.

The FDA is also expected to make a decision regarding the biologics licence application (BLA) for Dynavax Technologies Corp.’s prophylactic vaccine Heplisav by Dec. 15. An FDA advisory committee was originally scheduled to review the application for Heplisav on Nov. 16, but the FDA informed Dynavax that the meeting was cancelled and remaining questions would be addressed via the normal process.

Heplisav is based on Dynavax’s proprietary immunostimulatory sequence, which specifically targets Toll-like receptor 9 to stimulate an innate immune response. Dynavax originally submitted a BLA for Heplisav to the FDA in April 2012, but the company received a complete response letter in May 2013, following a negative vote at an advisory committee meeting based on safety concerns.

The company then conducted the Phase III HBV-23 study to compared the safety and immunogenicity of Heplisav with GlaxoSmithKline PLC’s approved vaccine Engerix-B (GSK). “If approved, Heplisav could become a major competitor for Engerix-B, given the higher seroprotection rate and the lower frequency of treatment,” Biomedtracker said. (Also see "Heplisav-B Review Still On Track Even After Cancelled Advisory Cmte., Dynavax Says" - Pink Sheet, 6 Sep, 2016.)

Best Of The Rest

More Phase III data are expected to report for Rigel Pharmaceuticals Inc.’s big hope fostamatinib. The oral syk kinase inhibitor is under development for the treatment of immune thrombocytopenic purpura (ITP) as its lead indication. The results of the second of two identical studies are due in late October or early November to add to those from the first trial reported in August that showed a narrow benefit with the product. (Also see "Rigel Optimistic On Fostamatinib Despite Narrow Phase III Benefit" - Scrip, 30 Aug, 2016.)

“Given the positive yet preliminary nature of these results, much of the regulatory and commercialization milestones will depend on substantiating results in the second Phase III study,” Biomedtracker analysts said. Together, the trials should support and NDA submission planned for 2017.

Synergy Pharmaceuticals Inc. expects to report top-line data from two studies that it hopes will support a wider indication for its guanylate cyclase C (GC-C) receptor agonist plecanatide (SP-304) by year end. Synergy is developing the drug in the first instance for the treatment of chronic idiopathic constipation (an NDA for this was filed in January 2016, with a PDUFA target action date of Jan. 29, 2017), but also wants to market it for irritable bowel syndrome with constipation. The pivotal Phase III program of plecanatide for this patient population consists of two identical studies. With an sNDA filing planned for the first quarter of 2017 in this indication, these pivotal results will play a key role in how the Synergy proceeds. 


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