Clinical Trials In Review: Big Hits And Misses In 2018

Scrip looks back at the studies released in 2018 and highlights trials that had a large impact, for better or worse.

The biopharmaceutical industry lives and dies on the strength of clinical trials, where a hundredth of a point can be the difference between towering success and crumbling defeat. 

Looking back at the past year in research and development, many trends held true. Certain areas of immuno-oncology continue to deliver, but expanding beyond the known possibilities is still a challenge. Alzheimer's disease remains outside of reach. But some areas have had resounding success, like acute myeloid leukemia and the first new flu drug in 20 years. 

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Submit your 2018 clinical trial success, novel design or development team for Informa's Clinical And Research Excellence Awards. The nomination deadline is Jan. 25.

Cholesterol seems to be one field you can never count out. In 2017, Merck & Co. Inc. surprised everyone with a successful outcomes trial for its CETP inhibitor anacetrapib in REVEAL – a class that had been long written off. (Also see "The Year's Clinical Trials In Review: Big Hits In 2017" - Scrip, 28 Dec, 2017.) Those results may have been too little too late, as Merck has moved on from the program, but Amarin Corp. PLC's successful cardiovascular outcomes trial for its purefied fish oil Vascepa might breathe new life into that business. 

Below, see Scrip's review of the year's most notable wins and losses.

1. Merck's Keytruda Cleans Up In Lung Cancer

In January, Merck & Co. announced positive results in the KEYNOTE-189 study of its PD-1 inhibitor Keytruda (pembrolizumab) with chemotherapy in first-line non-small cell lung cancer (NSCLC), the most valuable indication coveted by sponsors of checkpoint inhibitors. (Also see "Merck Hits IO Bullseye With Keytruda Combo In First-line Lung Cancer" - Scrip, 16 Jan, 2018.)

The news just got better and better as more details were disclosed throughout the year, with momentum building for Keytruda into and out of the American Association for Clinical Research (AACR) meeting in April. (Also see "Roche's IMpower150 Gets AACR Applause But Merck's KEYNOTE-189 Big Winner " - Scrip, 17 Apr, 2018.) With a dramatic improvement in progression-free survival (PFS) and, importantly, overall survival (OS) – as well as consistent results across subgroups – the KEYNOTE-189 study set the standard for the field, a high bar that competitors have not been able to match.

Roche's AACR release of the IMpower150 study of its PD-L1 inhibitor Tecentriq (atezolizumab) in first-line NSCLC was overshadowed by the KEYNOTE data, but since the trial used a different chemotherapy backbone there was still room to hope for Tecentriq. However, at the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC) later in the year, Roche released results for Tecentriq in the IMpower132 first-line NSCLC study that used a similar backbone as KEYNOTE-189 showing atezolizumab improved PFS, but did not significantly improve OS, at least not yet. 

Tecentriq was approved on Dec. 6 by the US FDA for first-line NSCLC. Approval covers use with Roche's VEGF inhibitor Avastin (bevacizumab) and chemotherapy, based on the IMpower150 study. (Also see "Roche's Tecentriq Becomes Second In PD-1/L1 Family To Gain First-Line Lung Cancer Approval" - Scrip, 6 Dec, 2018.)

Keytruda's continuing clinical trial successes have helped it overtake Bristol-Myers Squibb Co.'s once-dominant PD-1 inhibitor Opdivo (nivolumab), surpassing it as the sales leader in the second quarter of 2018. (Also see "First-Line Chemo Combo Data Help Merck's Keytruda Power Past Opdivo" - Scrip, 29 Jul, 2018.)

2. IDO Flames Out In Phase III

Inhibitors of indoleamine 2,3-dioxygenase (IDO1), an enzyme that plays an important part in immune response, had a remarkably high profile for a short period, with big pharmas rushing to embrace the mechanism as complementary to PD-1/L1 checkpoint inhibitors, via very high-priced deals. The drugs were moved quickly into Phase III in multiple indications and hopes were high.

The crash came in April, however, as Merck and partner Incyte Corp. revealed that a study of the PD-1 inhibitor Keytruda and the IDO inhibitor epacadostat failed in the Phase III ECHO-201/KEYNOTE-252 study in metastatic melanoma. (Also see "Incyte/Merck's ECHO-301 Failure Casts More Shadow On IDO Space" - Scrip, 6 Apr, 2018.)

Bristol followed up with news that it was ending Phase III studies of its IDO inhibitor BMS-986205 in melanoma, head and neck, and lung cancer, despite having acquired the drug at high cost from Flexus Biosciences Inc., with an $800m upfront payment. (Also see "A Wake For IDO: Bristol Ends Registrational Trials Of High-Priced Flexus Drug" - Scrip, 30 Apr, 2018.) Pfizer Inc. had returned rights to the IDO inhibitor EOS200271 to iTeos Therapeutics SA early in the year and iTeos announced that it was ceasing its own development in June. (Also see "Pfizer Pulls Plug But iTeos Has High Hopes For IDO1 Inhibitor" - Scrip, 4 Jan, 2018.)

Previously, Roche exited a deal with NewLink Genetics Corp. in 2017 on the Phase I IDO inhibitor navoximod (GDC-0919) following presentation of disappointing results at the American Society of Clinical Oncology (ASCO) annual meeting that year. (Also see "NewLink Absorbs Big Blow As Roche Exits IDO Inhibitor Partnership" - Scrip, 8 Jun, 2017.)

3. MYSTIC Disappoints Investors … Again

While Keytruda has had continued successes in NSCLC, its competitors have stumbled – like Bristol’s infamous Checkmate 026 trial of Opdivo in first-line NSCLC.  (Also see "'Total Disaster' In First-Line Lung Cancer For BMS's Opdivo" - Scrip, 10 Oct, 2016.) AstraZeneca PLC carried on the tradition with its announcement in November that the combination of its PD-L1 inhibitor Imfinzi (durvalumab) and CTLA-4 inhibitor tremelimumab failed to significantly improve PFS or OS in patients with at least 25% PD-L1 expression in the Phase III MYSTIC first-line NSCLC study. (Also see "Mystic Miss Not Make Or Break For Imfinzi" - Scrip, 16 Nov, 2018.) That followed a 2017 announcement of failure on the PFS endpoint in the study. (Also see "MYSTIC Misses: Devastation For AstraZeneca As Imfinzi Fails PFS Endpoint In NSCLC" - Scrip, 27 Jul, 2017.)

The combination of Imfinzi and tremelimumab also failed to improve PFS or OS in the ARCTIC study in late-stage NSCLC, which was unveiled in April. (Also see "ARCTIC Chill Descends On AstraZeneca's Imfinzi/Treme Combo In NSCLC" - Scrip, 24 Apr, 2018.)

But AstraZeneca continues to mine the data for promising signs. In a new analysis of MYSTIC reported in December, AstraZeneca said that Imfinzi monotherapy improved OS in patients with at least 25% PD-L1 expression in a meaningful way; median OS was 16.3 months vs. 12.9 months for chemotherapy. (Also see "AZ Goes Into The MYSTIC And Finds Positives For Imfinzi " - Scrip, 14 Dec, 2018.) The company also reported better results for patients with high expression of the emerging biomarker tumor mutational burden (TMB) on Imfinzi and the combination of Imfinzi/tremelimumab in an exploratory analysis. (Also see "TMB Biomarker Is A Winding Path Rather Than Straight Road" - Scrip, 14 Jun, 2018.)

4. Amarin's Vascepa Achieves Outcomes Target

It has been difficult to prove the value of add-on cholesterol therapies, with a spate of major cardiovascular outcomes trial failures in recent years. That’s why Amarin's results for Vascepa (icosapent ethyl) in the REDUCE-IT study were so impressive. In the study, Vascepa as an add-on to statin therapy was associated with a significant 25% reduction in the occurrence of major adverse cardiovascular events overall and a 20% risk in cardiovascular deaths in patients with hypertriglyceridemia, as reported at the American Heart Association meeting in November. (Also see "Amarin's REDUCE-IT Data For Vascepa May Be Game-Changing, But Not Without Controversy" - Scrip, 12 Nov, 2018.)

However, there were questions about study design, in particular the use of mineral oil as a placebo, which some see as an active comparator. An increase in LDL cholesterol was reported in the placebo arm of the study.

Nevertheless, achieving such a large reduction in events on top of standard-of-care statins is a big deal, as the value of prescription-grade fish oil has been questioned in the past given the wide availability of over-the-counter treatments and mixed data about the benefits for branded and OTC drugs in other trials. (Also see "Amarin, Omthera dip after study knocks fish oil benefit" - Scrip, 10 May, 2013.)

It's also a major achievement generally in the context of the cardiovascular drug development space, which has suffered countless disappointments in big outcomes trials – including the National Institutes of Health’s AIM-High study of AbbVie Inc.’s Niaspan as an add-on to Merck's Zocor (simvastatin) with or without Zetia (ezetimibe) in 2011, dal-OUTCOMES of Roche's CETP inhibitor dalcetrapib in 2012, and HPS2-THRIVE of Merck's Tredaptive (extended-release niacin/laropiprant) as add-on therapy to intense lipid therapy in 2013. (Also see "New Cholesterol Guidelines Follow Long History Of Failed Outcomes Trials" - Pink Sheet, 2 Dec, 2013.)

5. Imbruvica Spares Chemo In First-Line CLL

Highlights of the data presented at the American Society of Hematology (ASH) meeting in December included a Phase III National Cancer Institute (NCI) study of AbbVie/Johnson & Johnson's Bruton's tyrosine kinase (BTK) inhibitor Imbruvica (ibrutinib) with Roche/Biogen Inc.'s anti-CD20 antibody Rituxan (rituximab) versus standard-of-care therapy with fludarabine, cyclophosphamide and Rituxan (FCR) in younger patients newly diagnosed with chronic lymphocytic leukemia (CLL).

In the study, PFS and OS were significantly improved for the patients in the Imbruvica arm, and safety was also much improved by leaving chemo out. (Also see "Imbruvica Replaces Chemo, Darzalex Boosts Standard Of Care In Front-Line CLL, Myeloma" - Scrip, 4 Dec, 2018.)

Imbruvica is approved for use as a monotherapy in first-line CLL and the NCI study is potentially registrational. The results were viewed as practice-changing for first-line CLL and were complemented by data supporting the use of Imbruvica alone and Imbruvica with Rituxan over standard-of-care therapy with bendamustine/Rituxan (BR) in older patients, also presented at the ASH meeting.

Meanwhile, the combination of Imbruvica and Roche's Rituxan follow-on Gazyva (obinutuzumab) is under US FDA review for older patients in the first-line CLL setting and looks poised to change the standard-of-care in that patient population.

Imbruvica has been a success story in CLL from the start. In 2014, its first year on the market, the drug brought in sales of $548m. (Also see "ASH Data Drive Momentum For Revolution In CLL Treatment" - Pink Sheet, 14 Dec, 2015.) In the third quarter of 2018, J&J reported sales of $705m ($334m US and $371m ex-US) for Imbruvica and AbbVie (which obtained rights through its 2015 acquisition of Pharmacyclics for $21bn) reported $812m US and $160m through profit sharing, a total of $972m.

While the drug's oral delivery and solid tolerability profile have been very attractive, there has always been underlying demand for deeper responses and shorter treatment regimens, particularly given high cost of using two branded drugs together for a long time. Sponsors believe that the combination of Imbruvica with AbbVie/Roche's oral BCL-2 inhibitor Venclexta (venetoclax) could help with both of these treatment goals. (Also see "After Imbruvica Passes Chemo-Free Tests, Shorter Duration Regimens Could Be Next Value-Adds" - Scrip, 13 Dec, 2018.)

6. Roche/AbbVie's Venclexta Shines In Banner Year For AML

In addition to CLL, Roche/AbbVie's Venclexta is making a big splash in acute myeloid leukemia (AML). Venclexta has been approved in second-line CLL since 2016 and was cleared by the FDA in November for use in combination with low-dose cytarabine (LDAC) or hypomethylating agents in newly diagnosed AML patients over the age 75 and/or not eligible for standard induction therapy. (Also see "More Good News For AML As Pfizer And AbbVie/Roche Drugs Get FDA Okay" - Scrip, 22 Nov, 2018.)

The approval was one of four for 2018 in AML, along with Agios Pharmaceuticals Inc.'s oral IDH1 inhibitor Tibsovo (ivosidenib), Astellas Pharma Inc.'s oral FLT3 inhibitor Xospata (gilteritinib) and Pfizer's oral hedgehog pathway inhibitor Duarismo (glasdegib). (Also see "AML Paradigm Shift: Doctors Welcome Many New Approvals And Approaches" - Scrip, 6 Dec, 2018.)

That followed the approval of four other drugs in 2017: Novartis AG's oral kinase inhibitor Rydapt (midostaurin), Agios/Celgene Corp.'s oral IDH2 inhibitor Idhifa (enasidenib), Jazz Pharmaceuticals PLC's injectable Vyxeos (daunorubicin/cytarabine), and Pfizer's injectable CD-33 targeted antibody-drug conjugate Mylotarg (gemtuzumab ozogamicin).

Experts at the ASH meeting in 2018 were impressed with the robust nature of the data for Venclexta and potentially broad applicability, though randomized study data are not available yet. (Also see "Roche/Abbvie's Venclexta Outshines Agios IDH Inhibition In AML At ASH" - Scrip, 4 Dec, 2018.)

Venclexta's gain was somewhat of a loss for Agios, which presented new early-stage data for Tibsovo and Idhifa at the ASH meeting. However, specialists advised not to compare the two different approaches and believe that there is a strong future for genetically targeted therapies, considering that AML is not viewed as one disease, but, as one expert said, a "large collection of a bunch of different diseases."

7. SOLO-1 Opens Doors For Lynparza

AstraZeneca's PARP inhibitor Lynparza (olaparib), partnered with Merck, scored a victory with positive results in 2018 in the SOLO-1 study, which tested use as a maintenance therapy after a response to chemotherapy in the first-line BRCA-mutated ovarian cancer.

Full results were presented at the European Society for Medical Oncology (ESMO) meeting in October. Lynparza maintenance therapy was associated with dramatically improved progression-free survival, with a 70% reduction in risk in the trial. (Also see "Stellar Survival Data For AZ's Lynparza Hailed At ESMO" - Scrip, 22 Oct, 2018.)

A supplementary approval for first-line maintenance was approved by the FDA on Dec. 19. (Also see "First-Line Ovarian Cancer Approval Solidifies Lead For AstraZeneca's Lynparza " - Scrip, 19 Dec, 2018.) Lynparza has enjoyed its first-mover advantage in the market and stronger performance compared to Clovis Oncology Inc.'s Rubraca (rucaparib) and Tesaro Inc.'s Zejula (niraparib), the two other drugs in the PARP class approved for ovarian cancer. Lynparza brought in $169m in sales for the third quarter vs. $23m for Rubraca and $63m for Zejula. (Also see "Ovarian Cancer Market Snapshot: AstraZeneca's Lynparza Poised To Lead In Niche Space" - Scrip, 7 Dec, 2018.)

All three have been approved for second-line maintenance treatment and Lynparza will now take the lead in first-line maintenance as the only one of its class cleared for this use.

AstraZeneca and Merck also announced in December positive results from the SOLO-3 study testing the drug as a single agent in third-line BRCA mutated ovarian cancer and will be discussing the results with regulators with a view toward getting another supplementary approval, though this indication is viewed as having modest commercial value. (Also see "SOLO-3 Adds To AZ/MSD’s Lynparza’s Ovarian Cancer Success Tally But Impact Minimal" - Scrip, 20 Dec, 2018.)

In contrast with the good momentum in ovarian cancer overall, the field had a notable setback in December with the Phase III failure of Pfizer/Merck KGAA's PD-L1 inhibitor Bavencio (avelumab) in combination with chemotherapy in first-line ovarian cancer, following failure in later-line therapy. (Also see "Merck KGAA/Pfizer's Bavencio Failure Casts More Shade On Immunotherapy For Ovarian Cancer" - Scrip, 24 Dec, 2018.) This casts doubt more broadly on a big goal for the combination of PARP and PD-1/L1 inhibitors in ovarian cancer. (Also see "Ovarian Cancer Pipeline Review: Sponsors Plan Frontline Punch, Smart Combinations" - Scrip, 7 Dec, 2018.)

8. Roche Moves On In Flu

Roche's single-dose flu product baloxavir marboxil demonstrated superiority over placebo and showed some advantages over the predecessor flu treatment Tamiflu (osteltamivir) in the Phase III CAPSTONE-2 study, which was reported in July and updated in early October. (Also see "Roche Steps Closer To Flu Market Domination With Phase III Baloxavir Results" - Scrip, 17 Jul, 2018.)

FDA’s October approval of the drug – branded as Xofluza – for treatment of acute uncomplicated flu in patients 12 years of age and older was the first novel mechanism of action for antiviral flu treatment to clear the FDA in nearly 20 years. (Also see "Keeping Track: US FDA Clears Novel Flu Treatment Xofluza, Boosts Trintellix Label With Sexual Dysfunction Data" - Pink Sheet, 28 Oct, 2018.)

One key advantage for Xofluza is dosing – the drug is given in a single oral dose whereas Tamiflu involves taking two pills daily for five days.

Although Xofluza was only numerically better than Tamiflu when it came to reducing the time to improvement in symptoms, Roche said in that the newer drug significantly reduced the time to improvement in symptoms compared to Tamilu in patients with lineage B infections (74.6 hours vs. 101.6 hours).

Biomedtracker analysts said at the time, however, that this may not be a differentiator from generics of Tamiflu, because guidelines advise starting treatment for flu right away, as opposed to waiting for laboratory testing, and it's unclear whether information about lineage is available early on. Biomedtracker expects Roche will differentiate the drug based on its convenient single-dose administration and significantly better reduction in viral shedding duration compared to Tamiflu.

Tamiflu is the top antiviral, but sales have been dropping with the entry of generic competition. Roche reported CHF535m in 2017, down 22% from the prior year. (Also see "Scant Pipeline Competition For Roche’s Novel Flu Antiviral" - Scrip, 26 Jun, 2018.)

9. Another Failure For Axovant As Nelotanserin Misses Mark

Roivant Sciences GMBH subsidiary Axovant Sciences Ltd. took a beating on the announcement in December that its 5-H2A receptor agonist nelotanserin failed in a Phase II study evaluating use for treating REM sleep behavior disorder in Lewy body dementias (LBD), having previously failed in visual hallucinations associated with the disease. (Also see "Axovant Closes Chapter On Failed, Second-Rate Small Molecule Strategy " - Scrip, 10 Dec, 2018.)

It's just the latest setback for the company, which discontinued development of the 5-HT6 antagonist intepirdine in early 2018 following that drug's failure in a Phase II study in LBD and a Phase III trial in Alzheimer's disease. (Also see "Axovant's Cupboard Is Bare After Lead Dementia Program Fails" - Scrip, 9 Jan, 2018.) Axovant had acquired the drug from GlaxoSmithKline PLC for only $5m and had an enormously successful IPO in 2015. (Also see "Axovant Builds A Case For GSK’s 5-HT6 Castoff In Alzheimer’s" - Pink Sheet, 3 Aug, 2015.)

Axovant said it is turning away from small molecules and will be focusing on gene therapies for neurological disorders. (Also see "Alzheimer's Prevention: The Next Big Idea For Fixing Drug Trial Failures" - Scrip, 27 Sep, 2017.)

10. Still More Alzheimer's Failures

Alzheimer's disease remains an enormously challenging development space, with many failures in its history, including anti-beta amyloid antibodies like Pfizer/J&J's bapineuzumab and Lilly's solanezumab. (Also see "Lilly’s Solanezumab Fails, But The Surprise Would Have Been Success" - Scrip, 23 Nov, 2016.)

The year 2018 brought the failure of three BACE inhibitors – Janssen Pharmaceutical Cos. terminated the Phase IIb/III EARLY study of the BACE inhibitor atabecestat in late-onset preclinical Alzheimer's due to some cases of serious liver enzyme elevation. (Also see "More Alzheimer's Pain As J&J Pulls Plug On BACE Inhibitor" - Scrip, 18 May, 2018.) Lilly and AstraZeneca stopped Phase III studies of lanabecestat. (Also see "Lilly Stays Committed To Alzheimer's, Including Amyloid Hypothesis, Despite Many Failures" - Scrip, 13 Jun, 2018.) Merck's BACE inhibitor verubecestat had previously failed in mild-to-moderate Alzheimer's disease as well as very early-stage Alzheimer's disease. (Also see "M&A Pressure Mounts For Merck & Co After Alzheimer's Drug Dismissed" - Scrip, 14 Feb, 2018.)

Takeda Pharmaceutical Co. Ltd. announced in early 2018 the failure of the Phase III TOMMORROW study of its PPAR-gamma agonist Actos (pioglitazone) for delaying the onset of mild cognitive impairment due to Alzheimer's disease.

Other failures announced in 2018 included vTv Therapeutics Inc.'s oral RAGE antagonist azeliragon and Boehringer Ingelheim GMBH's PDE inhibitor BI 409036. (Also see "Boehringer Shoots For Schizophrenia With PDE9 Inhibitor, Ends Alzheimer's R&D" - Scrip, 9 Feb, 2018.)

Biogen had mixed Phase II results in an October update for its anti-amyloid antibody BAN2401, leaving investors perplexed about how to gauge the drug's future. (Also see "Biogen's Busy Pipeline: Continued Confusion On BAN2401, But Other Irons In The Fire" - Scrip, 26 Oct, 2018.) The company is continuing with its commitment to Alzheimer's, including the development of the anti-beta amyloid antibody aducanumab, which is being tested in two Phase III studies of early-stage disease, ENGAGE and EMERGE, both of which are set to report in 2020. (Also see "Biogen Spooks With Phase III Aducanumab Changes" - Scrip, 15 Feb, 2018.)

Biogen has stressed that it has a range of assets in development for Alzheimer's with different mechanisms that it believes may work well in combination with the anti-beta amyloid approach – and it remains committed to Alzheimer's research, like many of these sponsors. (Also see "Neuroscience Is The Next Oncology: Why Biogen Is Doubling Down" - Scrip, 23 Nov, 2018.) Hopefully in the next couple years the big R&D upset will be an Alzheimer's victory.