How AstraZeneca's revivified pipeline could boost Pfizer
This article was originally published in Scrip
While the main motive for Pfizer's pursuit of AstraZeneca has been squarely placed at the tax man's door, if the acquisition does go through the US company will find itself in possession of a revivified, but still largely immature, drug pipeline.
Pfizer's CEO Ian Read claims AstraZeneca's pipeline is a major rationale behind his proposed takeover. He has signalled his particular interest in AstraZeneca's oncology portfolio, in addition to its marketed and pipeline cardiovascular drugs and its commercialised diabetes products, and maintains this interest is both for the pipeline's own sake as well as its potential for combination with Pfizer assets such as its PCSK9 inhibitor bococizumab and its early stage diabetes products.
Meanwhile AstraZeneca has some interesting candidates in asthma and psoriasis – not areas of current strength for the US company – and the fact that a large proportion of the portfolio is given over to biologics is also a likely draw for Pfizer.
AstraZeneca's nascent pipeline's potential is now forming a major plank in Pascal Soriot's defense of his company, even as it doubles up as a bargaining chip to wring a better deal out of the US firm. Since taking over from David Brennan in 2012 following a string of pipeline failures, Mr Soriot has focused on three core areas and instigated a reorganization to revive the company's fortunes, and he believes the fruits of these labors are now beginning to be seen. Following last week's second rebuff of Pfizer, Mr Soriot sought to convince analysts – albeit with limited success – that the pipeline as it now stands could produce aggregate risk-adjusted peak-year sales of about $23bn (the non-risk adjusted forecast is a whopping $63bn). A takeover now, he contends, would delay the development of some of these assets, effectively trampling over the seedlings of "one of the most exciting pipelines within the pharmaceutical industry". And to press home this point, the company has since put out a steady stream of press releases flagging the latest R&D successes for key products such as brodalumab and MEDI4736 and its dapagliflozin/saxagliptin combination.
Mr Soriot did concede that AstraZeneca will not reap any substantial sales from its pipeline until at least 2017, but by extension neither would the combined firm; and Pfizer too is set to suffer from declining revenues over the next four years (scripintelligence.com, 29 April 2014). Most observers are expecting an improved offer in the region of £55 per share with an increased cash proportion (up from the current 32%) later this week, although this is not thought likely until after this week's parliamentary select committee meetings (scheduled on 13-14 May).
At the first of these select committee meetings on 13 May Mr Read admitted that if the takeover goes ahead, R&D spending for the combined firm would not reach the sum of each firm's current expenditure (a total of $12bn), which surprised no-one and left the question dangling as to the size of the inevitable shortfall.
focus
Currently, the two companies' pipelines focus on similar areas, although Pfizer's naturally is broader. Both are active in oncology, cardiovascular/metabolic, and immunology/inflammation/autoimmunity. AstraZeneca also has "opportunity-led" interests in infectious diseases and neuroscience that also mirror Pfizer's pipeline, while Pfizer has additional strengths in rare diseases and biosimilars.
(see table below)
According to analysts at Credit Suisse, AstraZeneca would contribute a greater relative proportion of near- and long-term assets to the combined pipeline. And of these, its oncology offering is the chief allure. AstraZeneca has a strong heritage in chemotherapies and anti-hormone treatments for cancer, and oncology is its biggest pipeline area. Pfizer is particularly interested in its candidates for lung and breast cancers and in the hot field of immune-oncology.
oncology
Pfizer has repeatedly said that oncology is a key focus, but its own pipeline beyond the promising CDK 4,6 kinase inhibitor palbociclib in Phase III for breast cancer and two other Phase III NMEs (the pan-HER inhibitor dacomitinib and the CD22 targeted cytotoxic agent for acute lymphoblastic leukemia inotuzumab ozogamicin) is less than impressive. It has only three further NMEs in Phase II compared with AstraZeneca's seven. Moreover, Pfizer appears to have no assets at all in the immuno-oncology space.
Key novel AstraZeneca products in Phase III are its PARP inhibitor olaparib, the MEK inhibitor selumetinib, and the anti-CD22 MAb moxetumomab pasudotox. Olaparib is in Phase III for various ovarian cancer populations, and second-line gastric and metastatic breast cancer, while selumetinib is in Phase III for non-small cell lung cancer, differentiated thyroid cancer and uveal melanoma.
Moreover, these have just been joined by AstraZeneca's lead immuno-oncology candidate, the anti-PD-L1 MAb MEDI4736, which has just begun the first trial in its Phase III program in locally advanced, unresectable NSCLC (Stage III) following completion of treatment with chemoradiotherapy and no evidence of tumor progression. The study, dubbed PACIFIC, is the first pivotal trial of an immunotherapy in this patient population. This product from AZ's Medimmune biologics arm is one of a number exploring PD-1 and its ligands in an immunotherapeutic strategy and will compete with anti-PD1 products from Merck and Bristol-Myers Squibb and Roche in a range of indications.
Overall, AstraZeneca's biologics strategy in oncology takes a dual approach that combines the niche appeal of targeted drugs with the broader use of immune-based products. AstraZeneca says the specific immune targeting (such as with MEDI4736) to generate a potent immunologic response to cancer via T cell modulation as well as other immune cell mechanisms should have applicability in between 60 and 80% of cancers. It also has a range of technologies to produce specific tumor targeting products to produce cell death, including antibody-drug conjugates. The most advanced of these in Phase III is the anti-CD22 recombinant immunotoxin, moxetumomab pasudotox, which is similar to Pfizer's inotuzumab ozogamicin, but in development for hairy cell leukemia.
AstraZeneca sees a peak sales potential for its immune-oncology offerings of $6.5bn and most commercial opportunity in combinations, both of two immune-oncology products and with targeted therapies – a figure that is subject to the usual caveats of drug development. The company is already investigating MEDI4736 in combination with its investigational anti-CTLA4 MAb tremelimumab (ironically originally a Pfizer product) in Phase I for solid tumors but no data are yet available, and it has just announced a Phase I/II clinical study collaboration with the product in combination with Incyte's oral indoleamine dioxygenase-1 (IDO1) inhibitor, INCB24360. A range of other potentially synergistic combinations can be made from its current earlier-stage pipeline, especially in ovarian, lung and breast cancer, for example with AMP-514 (an anti-PD1 MAb) and MEDI6469, an mOX40 agonist MAb, but again these are too early to count on.
AstraZeneca's oncology pipeline – Phase II - Registration
Product | Mechanism | Indication | First Filing | AZ Sales estimate (non-risk adjusted) where given |
Phase III / Registration | ||||
moxetumomab pasudotox* | anti-CD22 recombinant immunotoxin | hairy cell leukemia | 2018 in US and EU | |
olaparib | PARP inhibitor | BRCAm PSR ovarian cancer | filed in US and EU | $2bn |
olaparib SOLO-1 | PARP inhibitor | first-line BRCAm PSR ovarian cancer | not given | - |
olaparib SOLO-2 | PARP inhibitor | BRCAm PSR ovarian cancer | 2016 in US and EU | - |
olaparib GOLD | PARP inhibitor | 2nd-line gastric cancer | 2017 in Japan | - |
olaparib OlympiAD | PARP inhibitor | metastatic breast cancer | 2016 in US and EU | - |
selumetinib* | MEK inhibitor | 2nd-line KRAS+ NSCLC | 2017 in US and EU | - |
selumetinib* ASTRA | MEK inhibitor | differentiated thyroid cancer | 2017 in US and EU | - |
selumetinib* SUMIT | MEK inhibitor | uveal melanoma | 2015 in US and EU | - |
MEDI4736* | anti-PDL1 MAb | NSCLC | 2016 with companion diagnostic | $6.5bn incl combinations |
Phase II | ||||
AZD1775* | WEE-1 inhibitor | ovarian cancer | not given | - |
AZD2014 | mTOR serine / threonine kinase inhibitor | solid tumors | not given | - |
AZD4547 | FGFR tyrosine kinase inhibitor | solid tumors | not given | - |
MEDI-551* | anti-CD19 MAb | haematological malignancies | not given | - |
MEDI-573* | anti-IGF MAb | metastatic breast cancer | not given | - |
selumetinib* | MEK inhibitor | 2nd-line KRAS NSCLC | not given | - |
tremelimumab | anti-CTLA4 MAb | mesothelioma | not given | - |
AZD5363* | AKT kinase inhibitor | breast cancer | not given | - |
Source: AstraZeneca; *partnered product
cardiovascular
Cardiovascular is another key area for both companies and here a combined enterprise could release some market synergies, especially given that both AZ's Brilinta (ticagrelor) and Pfizer's Eliquis (apixaban) have both so far been underwhelming. AstraZeneca's newly FDA- approved fish oil product Epanova (omega-3-carboxylic acids), and Pfizer's promising Phase III PCSK9 inhibitor bococizumab should help shore up this area as Crestor (rosuvastatin) reaches the end of its patent life.
diabetes
In diabetes, a weak area for Pfizer at present, AstraZeneca has the SGLT2 inhibitor Forxiga/Farxiga (dapagliflozin) and the DPP-4 inhibitor Onglyza (saxagliptin), on the market, and has just released Phase III data onsaxagliptin/dapagliflozin combined as a dual add-on therapy in adult patients with type 2 diabetes who were inadequately controlled on metformin. This showed that patients treated with the combination plus metformin achieved significantly greater reductions in HbA1c versus either agent alone plus metformin at 24 weeks, with an adjusted mean change from baseline HbA1c of -1.47% in the saxagliptin/dapagliflozin combination group compared with -0.88% in the saxagliptin group and -1.20% with dapagliflozin. AstraZeneca believes peak sales from this combination could reach around $3bn.
The acquisition of dapagliflozin would allow Pfizer to compete in the highly active SGLT2 inhibitor area ahead of the arrival of its own investigational SGLT2 inhibitor ertugliflozin which is still lagging at Phase III, and complement its own early stage diabetes portfolio which includes an acetyl-CoA carboxylase inhibitor and a partial glucokinase activator.
inflammation
In the inflammation/autoimmunity area, Pfizer would get its hands on AstraZeneca's promising IL-17 product brodalumab (AMG 827; in development with Amgen). AstraZeneca and Amgen have just announced that its Phase III AMAGINE study in moderate-to-severe plaque psoriasis met all primary and secondary endpoints for both evaluated doses, comparing favorably with Novartis's anti-IL17 product secukinumab (which is already awaiting US and EU approval) and positioning it as a potential best in class product (scripintelligence.com, 10 May 2014).
Further head-to-head data for brodalumab against Johnson & Johnson's marketed product ustekinumab (Stelara) are expected later this year, and a filing is slated for 2015. But other competition may come in the form of Eli Lilly's IL17 inhibitor ixekizumab, for which Phase III data are also expected this year.
Another major area where AstraZeneca's pipeline plugs a gap rather than merely complementing Pfizer's is asthma, in particular with the anti-IL-5R product benralizumab for severe disease. Again, however, this is a product that is not first in class and to succeed will need to differentiate itself from its competitors, most notably GlaxoSmithKline's anti-IL5 product mepolizumab which is about two years ahead of it. Once more, AstraZeneca's product retains the potential to be best-in-class here but it still has to prove itself at Phase III (a filing is scheduled for 2016 in the US and EU).
Similarly AstraZeneca's Phase II anti IL-13 tralokinumab will be pitted against Roche's promising IL-13 inhibitor lebrikizumab which is already in Phase III trials for severe asthma, following "unprecedented" Phase II results (scripintelligence.com, 5 March 2014) as excitement builds around the respiratory biologics space. Meanwhile, Pfizer's pipeline interests in asthma are confined to a Phase I vaccine.
AstraZeneca's Phase III NME pipeline (excluding oncology)
| Product | Mechanism | Indication | First Filing | AZ's sales estimate (non-risk adjusted) where given |
| Respiratory / Inflammation / Autoimmunity | | | | |
| benralizumab* | anti-IL-5R MAb | severe asthma | 2016 in US and EU | $2bn |
| brodalumab* AMAGINE-1,2,3 | anti-IL-17R MAb | psoriasis | not given | $0.5-1.5bn (analysts' estimates) |
| brodalumab* AMVISION-1,2 | anti-IL-17R MAb | psoriatic arthritis | not given | see above |
| lesinurad | selective uric acid reabsorption inhibitor | gout (chronic treatment) | 2014 in US and EU | - |
| PT003 GFF | LAMA / LABA | COPD | 2015 in US | $4bn with PT001 |
| PT001 GP | LAMA | COPD | 2015 in US | $4bn with PT003 |
| Infection | | | | |
| CAZ AVI* RECLAIM | cephalosporin / beta lactamase inhibitor | serious infections | 2014 in EU | - |
| CAZ AVI* REPROVE | cephalosporin / beta lactamase inhibitor | hospital-acquired pneumonia / ventilator-associated pneumonia | 2017 in EU | - |
| Neuroscience | | | | |
| naloxegol* | peripheral mu-opioid receptor antagonist | opioid-induced constipation | filed in US and EU | - |