AstraZeneca's Pipeline Reaps Rewards Of Return To Science
Executive Summary
AstraZeneca rounded off a busy 2017 full of R&D highs, but some huge lows, with a full Phase III pipeline that it says shows how far the company has come since Pascal Soriot took the reins in 2012 and spearheaded a renewed focus on science. But will the company become a victim of its own success?
A year of "unprecedented" activity and a Phase III pipeline brimming over with products allowed AstraZeneca PLC to claim at an R&D day on Dec. 14 that its focus on science in the five years since CEO Pascal Soriot arrived has changed the culture of its business.
Sean Bohen, chief medical officer and EVP of global medicines development told analysts that the sheer number of positive results announced during 2017 "really outweighed the number of unfavorable outcomes", namely MYSTIC's PFS results for PD-L1 inhibitor Imfinzi (durvalumab), the complete response letter for hyperkalemia treatment ZS-1 and the Phase III failure of asthma product tralokinumab.
High points of the year were the FLAURA trial of Tagrisso (osimertinib), Imfinzi's PACIFIC study and the launch of Fasenra (benralizumab) (see box for more details). Looking forward to 2018, the company is expecting data readouts for Farxiga (dapagliflozin; the DECLARE outcomes study), roxadustat (Phase III), PT010 (Phase III) and anifrolumab (Phase III), while it also continues to advance its oncology lifecycle programs for Lynparza (olaparib), Tagrisso, Imfinzi and Calquence (acalabrutinib). See table below for AstraZeneca's expected late-stage pipeline news flow next year and into 2019.
2017 HIGHS
PACIFIC (Also see "AZ Rides PACIFIC Wave To Be First In Early-Stage NSCLC" - Scrip, 11 Sep, 2017.)
FLAURA (Also see "Big Guns Ready To Roll Into Madrid: ESMO Preview" - Scrip, 5 Sep, 2017.)
Fasenra launch (Also see "AZ Looks To Lead Severe Asthma Market After US Fasenra OK" - Scrip, 15 Nov, 2017.)
2017 LOWS
MYSTIC (Also see "MYSTIC Misses: Devastation For AstraZeneca As Imfinzi Fails PFS Endpoint In NSCLC" - Scrip, 27 Jul, 2017.)
Tralokinumab (Also see "End Of The Line For AstraZeneca’s Tralokinumab In Asthma" - Scrip, 1 Nov, 2017.)
ZS-9 (Also see "AstraZeneca's ZS-9 Timeline Hit By FDA Complete Response Letter" - Pink Sheet, 27 May, 2016.)
"Developing medicines for patients is high risk, high reward, and occasionally you will encounter disappointment. However, this year, we were rewarded with an extensive list of successes across all the main therapy areas following the science that's truly rewarded AstraZeneca this year, and we hope to continue our success in 2018 and beyond," Bohen told analysts. "This is a clear illustration of the improvement in AstraZeneca's R&D productivity and just how the culture of our business has focused on science in the last five years."
In support of his premise, Bohen pointed to the number of US FDA breakthrough therapy designations granted in 2016 and 2017 – five in total. "We rank well compared to the rest of the industry when we look at our three main therapy areas."
All this is resting on increased success rates in early stage development, he added, and this "underpins our confidence that the productive pipeline is sustainable for years to come." AZ has nearly tripled the number of its scientific publications since 2010 and "the number of high-impact publications continues to grow."
"If industry consolidation occurs, between AstraZeneca's full Phase III pipeline, its superior growth, and its comparatively smaller size, it could be a take-out candidate"
Indeed, the brisk pipeline pace set in 2017 is set to continue next year when the company is hoping to return to sales growth, mainly driven by its oncology portfolio. Further out, observers say, earnings are also set to gain momentum. "On a revenue basis, 2017 should be the trough, but EPS may not begin to grow until 2019," said Tim Anderson at Bernstein in a Dec. 14 research note, adding that in the longer term, EPS growth should be among the very best of the nine major EU/US pharmaceutical companies the analysts cover.
But this also means the firm should be wary. "If industry consolidation occurs, between AstraZeneca's full Phase III pipeline, its superior growth and its comparatively smaller size, it could be a take-out candidate," he added.
Natixis analysts also see 2018 as a transition year, owing to the impact of Crestor generics and the fact that new replacements Imfinzi and Tagrisso are "just ramping up". They also said in a Dec. 15 research note that they do not expect to see any real uptick in EPS until 2019, when they expect it to rise by 14%.
Oncology Riches
Overall, oncology will remain the key focus of AstraZeneca's three major therapy areas, which also include cardiovascular/metabolic and respiratory, but Bohen also highlighted interesting candidates for Alzheimer's disease (lanabecestat) and lupus (anifrolumab). "Pipeline opportunities that often get overlooked."
Within oncology, the anti-PD-L1 immuno-oncology product Imfinzi will stay front and center. The company is sanguine, in public a least, about MYSTIC's prospects – slating a second-half filing in first-line lung cancer, following the overall survival results in H1 – although little further was said about it during the R&D day.
Some analysts believe this reticence told its own story. Analysts at Bernstein pointed out that the company's refusal to be drawn on whether a separation could be seen in the PFS curves even without a significant difference bodes ill. Bristol-Myers Squibb Co. was willing to disclose PFS data on its '214, ahead of having OS data, so why not AstraZeneca? A logical inference would be that there was no curve separation," they said.
Natixis analysts were a little more optimistic. "We still think these results could be positive. That said, we may be more cautious on the addressable patient population," they said. "Indeed, based on recent developments in immuno-oncology (IO) we think that while IO+chemo combinations show efficacy in all patients (PD-L1 positive and negative), this is less sure for IO+IO combinations like Imfinzi + tremelimumab tested in MYSTIC."
This means, they added, that there is a possibility that these final results will show efficacy in patients with a PD-L1>25%, which would limit the number of target patients to 40% of the addressable population, i.e. close to 125,000 patients, or peak sales of around $2bn.
For PACIFIC however, AstraZeneca expects a regulatory decision in the US in the first half, followed by the EU and Japan in the second for Imfinzi in locally advanced or Stage 3 unresectable non-small cell lung cancer following standard chemoradiation therapy.
AstraZeneca says there are an estimated 105,000 patients in Stage 3 lung cancer, of which about 76,000 are unresectable. "This is a meaningful opportunity and one that matters a lot for patients and their caregivers," Bohen said. "We continue to see the PACIFIC trial two years to three years ahead of competition in the Stage 3 setting."
Further clinical readouts for Imfinzi in other indications, such as bladder, liver and head and neck cancers, but these markets are much smaller than for lung cancer. The product is also being tested in combination with and IDO1 inhibitor epacadostat, and other lifecycle opportunities are being evaluated.
Following the success of FLAURA of the next-generation EGFR inhibitor Tagrisso in NSCLC the company is looking forward to regulatory decisions on the expansion of its indication to include the first-line EGFR-mutated NSCLC setting. Filings have recently been made in the EU and Japan, with the US expected soon. Overall survival data are still awaited from this study, however, but it is difficult to give guidance as events are slow to accrue and patient crossover is occurring, Bohen told analysts.
Tagrisso is currently on the market for use in second-line T790M-mutated NSCLC patients and performed strongly in the third quarter. (Also see "AZ Confident New Cancer Drugs Can Drive Return To Sales Growth" - Scrip, 9 Nov, 2017.)
AstraZeneca's PARP inhibitor Lynparza features heavily in its pipeline plans. The company presented data from the Phase II basket trial MEDIOLA at the World Congress on Lung Cancer meeting in October.
The data from the small cell lung cancer population showed that the Lynparza plus Imfinzi combination was well-tolerated compared with historical data on topotecan, the current standard of care from a second-line setting. Furthermore, the duration of response and overall survival data exceeded those previously reported with topotecan. "All responses occurred prior to the addition of Imfinzi, suggesting that the initiation of these responses was driven by Lynparza. Interestingly, the median overall survival data suggest that Imfinzi, or the combination, may have long-term efficacy potential, even in patients who lack an objective response," Bohen said.
Further MEDIOLA data reported at the San Antonio Breast Cancer Symposium showed Lynparza and Imfinzi were well tolerated in the germline BRCA-mutated metastatic breast cancer population. "The objective response rate was 52% and a little lower than what we observed in the OlympiAD trial. But this may have been due to later line of therapy and smaller sample size," said Bohen.
AstraZeneca sees significant opportunity to expand Lynparza through its collaboration with Merck & Co. Inc. and the two companies have agreed development plans and more trials are expected to be announced in the first half of next year.
In October, AstraZeneca gained a US approval of its BTK inhibitor Calquence, in a "reasonably small indication", namely previously-treated mantle cell lymphoma (MCL). The company estimated that around 3,000 patients are diagnosed with mantle cell lymphoma each year in the US. It has just presented the MCL data at the American Society of Hematology Meeting, "along with a couple of chronic lymphocytic leukemia trial updates in monotherapy and in combination with GA101, or obinutuzumab, where Calquence demonstrated early efficacy signals along with good tolerability". The major Phase III data for its use in the larger chronic lymphocytic leukemia indication study are not due until 2019.
Cardiovascular
In the cardiovascular/metabolic arena, AstraZeneca says it is "taking a holistic approach". Foremost here are the plans for the SGLT2 inhibitor for diabetes Farxiga and its cardiovascular outcomes study DECLARE due in the second half of next year.
Added to which is the DPAP-HF study in heart failure due in 2019 (although the company wouldn't be drawn on whether an interim analysis would be forthcoming in 2018) and the DAPA-CKD in renal patients in 2020. "We want to stop disease and regenerate organs," Bohen said.
Glossing over the CRL in May for ZS-9 in hyperkalemia, Bohen said: "I want to take this opportunity to remind you of the potential for providing a best-in-class treatment for hyperkalemia, once approved."
It has already had the positive CHMP opinion in the EU and more news in the US will be reported in due course. "We have made significant progress in addressing the deficiencies identified during the FDA inspection of the dedicated facility for ZS-9 in Texas."
For its potential first-in-class treatment for anemia and chronic kidney disease and end-stage renal disease roxadustat, AstraZeneca expects data from the Phase III OLYMPUS trial next year in chronic kidney disease patients who are not receiving dialysis. The primary endpoint is to demonstrate a superior hemoglobin increase with a non-inferior MACE incidence over placebo. This is one of a number of HIF prolyl hydroxylase inhibitors approaching the market. (Also see "Battle Lines Drawn In New Renal Anemia Market" - Scrip, 8 Jun, 2017.)
A Chinese rolling regulatory submission is completed, and a US regulatory submission is due in 2H 18.
Respiratory
The US approval of Fasenra in severe eosinophilic asthma was another high point in 2017. Based on the results of the WINDWARD program, the IL-5α receptor inhibitor is under regulatory review in the EU, Japan and several other countries with decisions anticipated in first half of next year.
Next steps are to develop an autoinjector in the GRECO trial for which a readout is expected in the second half of 2018. Then there is the Phase III VOYAGER program looking at Fasenra in patients with severe COPD. For those patients who have an exacerbation history, "it's pretty well established that there's an inflammatory component underlying those exacerbations. And we're looking at benralizumab as a potent agent to reduce that hyperreactivity and inflammation and reduce that risk of exacerbation," said Bohen.
Its other great hope in respiratory area is tezepelumab, particularly since the failure of tralokinumab. The anti-thymic stromal lymphopoietin biologic is the first epithelium-targeting medicine with potential differentiated efficacy in patients with moderate to severe asthma.
In September, along with partner Amgen Inc., AstraZeneca presented the PATHWAY Phase IIb data for tezepelumab at the European Respiratory Society Congress in Milan, which indicated what AZ believes is potential best-in-disease efficacy. (Also see "AstraZeneca Respiratory Head: Tezepelumab Could Be 'Game Changer'" - Scrip, 8 Sep, 2017.) First Phase III trial NAVIGATOR has initiated with a patient enrolled. "We will need to see the final Phase III profile, but at this stage, tezepelumab has the potential to be one of the broadest and most promising biologic medicines for the treatment of respiratory diseases."
PT010
Progress should also come next year for AstraZeneca's third major respiratory product, the triple combo PT010 (budesonide/glycopyrronium/formoterol), which is being pursued for both COPD and asthma.
There is a significant unmet need in COPD patients that is well established, with around 40% to 50% of patients treated with inhaled corticosteroid and long-acting beta agonist, receiving an add-on medicine in the form of a long-acting muscarinic antagonist.
"The differentiating factor for PT010 will be the pressurized metered-dose inhaler plus the fast onset of action and the inclusion of budesonide," said Bohen. The data readout is expected to start in the first half of next year, followed by regulatory submissions.
Best Of The Rest
Outside its core therapy areas, AstraZeneca sees much promise in its lupus therapy anifrolumab and its Alzheimer's disease therapy lanabecestat, a BACE inhibitor.
Based on promising Phase II data, the anifrolumab development program includes an additional precision medicine strategy to best identify which patients will respond better to anifrolumab based on an interferon gene signature test. The product differs from its competition in that it blocks the interferon receptor rather than targeting interferon itself, thereby providing more complete isoform blockade.
Both its Phase III trials, TULIP 1 and TULIP 2, are fully recruited with primary endpoints at 48 weeks, and readout expected in the second half of next year. Regulatory submissions are due in 2019. Looking forward, AstraZeneca has an ongoing Phase II trial with subcutaneous administration which is also fully recruited, plus an ongoing Phase II trial in lupus nephritis.
But the Natixis analysts said they thought "the group may be tempted to sell this product to a third party, as it does not fit fully with the therapeutic areas it wants to focus on". They estimate anifrolumab to bring in close to $500m in peak sales.
And with Eli Lilly & Co., AstraZeneca is hoping to buck the trend in Alzheimer's with lanabecestat. While acting on BACE, it takes a different approach from other candidates in this field by depleting amyloid beta in cerebral spinal fluid. "We have seen several setbacks with other medicines in this disease," said Bohen. "This is a different mechanism of action than that of the anti-amyloid beta antibodies and is a mechanism underpinned by strong genetic evidence."
The Phase II/III AMARANTH trial for early Alzheimer's disease is now fully recruited, with an interim analysis for AMARANTH that triggered a milestone payment to AstraZeneca earlier this year. A second Phase III trial, DAYBREAK, for mild Alzheimer's disease, is still recruiting.
The product has a fast track designation and the first Phase III data are expected in 2019.
AZ's Late-Stage Pipeline News Flow In 2018 and 2019
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H1 2018 |
H2 2018 |
2019 |
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Regulatory decision |
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Lynparza - ovarian cancer 2L (EU, JP)-breast cancer (US) Tagrisso - lung cancer (US) Imfinzi - lung cancer (PACIFIC) (US) Fasenra - severe, uncontrolled asthma (EU,JP) |
Lynparza - breast cancer (JP) Tagrisso - lung cancer (EU,JP) Imfinzi - lung cancer (PACIFIC) (EU, JP) Bydureon BCise - type-2 diabetes (EU) Bevespi - COPD (EU) |
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Regulatory submission |
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Lynparza - breast cancer (EU) Imfinzi+/-treme - lung cancer 3L (ARCTIC) moxetumomab pasudotox - hairy cell leukaemia 3L Bevespi - COPD (JP) Duaklir - COPD (US) |
Lynparza - ovarian cancer 1L Imfinzi+ treme - lung cancer 1L (NEPTUNE) Imfinzi+/-treme - lung cancer 1L (MYSTIC) - head & neck cancer 1L, 2L (KESTREL, EAGLE) Selumetinib - thyroid cancer Roxadustat - anaemia (US) PT010 - COPD |
Lynparza - pancreatic cancer 1L - ovarian cancer 3L Imfinzi+/-treme lung cancer 1L (POSEIDON)-bladder cancer 1L (DANUBE) Brilinta - CAD2/type-2 diabetes CVOT Farxiga - type-2 diabetes CVOT (DECLARE) Fasenra - COPD Anifrolumab - lupus |
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Key Phase III data readouts |
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Lynparza - ovarian cancer 1L Imfinzi+/-treme - lung cancer 3L (ARCTIC) - lung cancer 1L (MYSTIC) (final OS) - head & neck cancer 1L, 2L (KESTREL, EAGLE) selumetinib-thyroid cancer PT010 - COPD |
Lynparza-pancreatic cancer 1L Imfinzi+treme - lung cancer 1L (NEPTUNE) Farxiga-type-2 diabetes CVOT1(DECLARE) Fasenra - COPD Anifrolumab - lupus |
Lynparza-ovarian cancer 3L Imfinzi-lung cancer (PACIFIC) (final OS) Imfinzi+/-treme - lung cancer 1L (POSEIDON) - bladder cancer 1L (DANUBE) - liver cancer 1L (HIMALAYA) Brilinta-CAD/type-2 diabetes CVOT Farxiga-HF lanabecestat-Alzheimer’s disease |