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(Source:Alamy)

Boehringer Ingelheim And Lilly’s Heart Failure Jardiance Sweep

The detailed results in August of Boehringer Ingelheim GmbH and Eli Lilly and Company's closely watched EMPEROR-Preserved trial of Jardiance were hailed as ground-breaking after its investigators said the SGLT2 inhibitor was the first drug to show "unequivocal benefit" on major harmful outcomes in patients with heart failure and a preserved ejection fraction (HFpEF).

Data from the 5,988-patient study, the highlight of the virtual European Society of Cardiology meeting, showed that Jardiance (empagliflozin) plus standard of care produced a 21% reduction in the composite primary endpoint of cardiovascular death or hospitalization in adults with HFpEF compared with placebo plus SOC. (BILillys Jardiance Crowned As Heart Failure Game Changer After EMPERORPreserved)

The benefit was greater than that seen with the only approved drug for the indication, Novartis AG's Entresto (sacubitril and valsartan) and was independent of ejection fraction, sex or diabetes status. This made Jardiance the only treatment to significantly improve outcomes for the full spectrum of heart failure patients, in the process putting to bed the view of some physicians that SGLT2 inhibitors are primarily diabetes drugs.

The EMPEROR-Preserved results looked particularly impressive when compared with the 13% benefit seen in the PARAGON trial for Entresto, the only drug approved for HFpEF. PARAGON narrowly missed statistical significance and although the US FDA noted that the benefits of treatment with Entresto were "most clearly evident" in patients with left ventricular ejection fraction (LVEF) at the lower end of the HFpEF spectrum, the agency expanded the drug's label to include HFpEF earlier this year.

AstraZeneca PLC’s SGLT2 inhibitor, Farxiga/Forxiga (dapagliflozin), is also being tested for HFpEF in the DELIVER trial, but results are not due until 2022, allowing BI and Lilly the chance to establish the drug as the only approved treatment to significantly improve outcomes for the full spectrum of heart failure patients.

Lilly’s Tirzepatide Bests Novo Nordisk’s Ozempic In Diabetes

Meanwhile, Lilly’s novel diabetes drug, tirzepatide, a potential first-in-class dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist, is expected to receive approval in 2022 based on the SURPASS Phase III trials.

The novel drug is one of Lilly’s five key late-stage candidates with blockbuster potential, which also include donanemab for Alzheimer’s disease. SC144605

In the SURPASS-2 trial study, tirzepatide outpaced Novo Nordisk Pharma AG's blockbuster Ozempic (injectable semaglutide) in type 2 diabetes patients on several endpoints, including reductions in A1C and weight loss, at all three doses, including an important low dose. The data are expected to be critical to carving out a commercial opportunity for tirzepatide in the competitive type 2 diabetes market. (Lillys Tirzepatide Shows Up Novos Ozempic In HeadToHead Diabetes Trial)

Lilly announced results from the SURPASS-2 trial in March, after already releasing positive Phase III data showing tirzepatide on top of Sanofi's Lantus (insulin glargine) was more effective than Lantus alone. 

In late 2020, the SURPASS-1 trial also showed the drug was effective as a monotherapy. However, competing against entrenched once-weekly GLP-1 agonists like Ozempic and Lilly's own Trulicity (dulaglutide) could still be an uphill battle.

Following the presentation of the full SURPASS data at the American Diabetes Association meeting in June, the company said it believed that the blood glucose reductions, weight loss and cardiovascular benefits observed across the clinical trial program justified earlier treatment with tirzepatide to forestall diabetes and cardiovascular disease progression. (Lilly Aims For Earlier Treatment With Novel Diabetes Drugs)

If this strategy proves successful, Lilly could boost its GLP-1 market dominance and maintain its diabetes prominence before its top-seller Trulicity loses patent exclusivity in 2027. The company tripled its diabetes revenue from about $4bn in 2010, when the portfolio’s revenue largely came from insulin products Humalog and Humulin, to about $12bn in 2020, with $5.07bn from Trulicity – a GLP-1 agonist injected once weekly – alone.

Lilly also plans to begin Phase III trials of the drug in obesity-related cardiovascular mortality risk, obstructive sleep apnea and chronic kidney disease. In earlier-stage development, the pharma is working on incretin agonists it believes could offer sustainable weight loss comparable to that achieved with bariatric surgery.

RSV Hotting Up As Two Strategies Show Promise

In April, an earlier than expected and positive read-out of a Phase III trial of AstraZeneca and Sanofi’s nirsevimab put the companies firmly in prime position to shake up the substantial and, as yet, mostly untapped respiratory syncytial virus (RSV) market.

(AstraZeneca And Sanofi March Ahead With Positive Phase III RSV Data)The top-line data were from the MELODY study and showed that the passive immunotherapy met its primary endpoint of a reduction in the incidence of medically attended lower respiratory tract infections (LRTI) caused by RSV through 150 days after a single dose compared with placebo in healthy late preterm and term infants (35 weeks or more) during their first RSV season. Safety data were also positive with little evidence of anti-drug antibodies. (AstraZeneca And Sanofi March Ahead With Positive Phase III RSV Data)

Regulatory submissions are now expected in 2022 (brought forward from 2023) and will be based on MELODY plus the Phase II/III MEDLEY study in high-risk infants (positive data from which were reported in June) as well as positive Phase IIb data for nirsevimab that were published in the NEJM in July 2020.

This makes nirsevimab likely to reach the market substantially ahead of other candidates that focus on immunizing the pregnant mother to confer passive immunity to her child. Of these, the lead candidate is Pfizer Inc.’s RSVpreF vaccine, which in November reported promising Phase IIb data in protecting infants from the disease whose mothers had been immunised, while GSK has another maternal vaccine contender, RSVPreF3, in Phase II. (Pfizers RSV Vaccine Springs Another Surprise This Time In Maternal Use)

While still early, the data for Pfizer’s product were the first to provide evidence of efficacy for the product and drew attention as previous attempts at maternal vaccination to protect infants against RSV had been disappointing.

Vaccination of a pregnant mother requires a very high level of immunogenicity: enough of the mother’s antibodies must pass through the placenta and remain in the child to provide immune protection in the infant for up to 12 months after birth.

SVB Leerink analysts predict the overall RSV market will exceed $7bn by 2030, with consensus estimates forecasting nirsevimab revenues of €514m by 2025.

Enhertu Continues To Conquer In Breast Cancer

AstraZeneca and Daiichi Sankyo Co., Ltd.’s megadeal for the HER-2 directed antibody drug conjugate Enhertu (trastuzumab deruxtecan) continued to bear fruit during 2021.

In September, Enhertu was one of the standout drugs at the European Society for Medical Oncology (ESMO) meeting, with head-to-head data from DESTINY-Breast03 presented showing an overwhelming benefit on progression-free survival (PFS) versus Roche Holding AG's Kadcyla (trastuzumab emtansine) in second-line, HER2-positive breast cancer. (Enhertu Poised To Rewrite The Standard Of Care After ESMO)

The strong results suggest Enhertu is well-positioned to supplant Kadcyla as the second-line choice following initial treatment with trastuzumab and chemotherapy.

The strong data are expected to position Enhertu as the new standard of care in the second-line setting and have raised expectations for the drug's staged move into the first-line breast cancer setting and other solid tumor indications.

The margin of benefit over Kadcyla, an older ADC that combines the monoclonal antibody in Herceptin with a cytotoxic agent, was a pleasant surprise, with Enhertu showing a 72% reduction in risk of disease progression or death compared to Kadcyla at the prespecified interim analysis. The median PFS for patients treated with Enhertu was not reached after 15.5 months of follow-up, while median PFS was 6.8 months for those treated with Kadcyla after 13.9 months of follow up.

Overall survival (OS) data were not then mature, but there was a trend towards improved OS with Enhertu.

The data validated the expensive partnering deal AstraZeneca signed with Daiichi Sankyo in 2019 to gain global rights to the drug. AstraZeneca paid $1.35bn upfront and agreed to pay up to $6.9bn in total for rights to the ADC.

While costly, Enhertu represented a fast-to-market opportunity for AstraZeneca to pivot quickly into a new area in solid tumors. Enhertu received accelerated approval from the US Food and Drug Administration in December 2019 for advanced HER2-positive breast cancer patients who have received two or more anti-HER2 based regimens in the metastatic setting.

AstraZeneca and Daiichi Sankyo are studying Enhertu in colorectal cancer, gastric cancer and non-small cell lung (NSCLC), where they also presented some encouraging early data at ESMO, particularly from the Phase II DESTINY-Lung01 trial.

The Phase III DESTINY-Breast09 study is ongoing, testing Enhertu as a first-line treatment in advanced HER2-positive breast cancer, with the first data expected in 2022 at the earliest.

Welford analysts have forecast $800m in worldwide peak sales for Enhertu coming from the second-line breast cancer setting.

Pfizer’s Oral Abrocitinib Beats Cosentyx But JAK Safety Concerns Slow Progress

In August, Pfizer Inc.'s oral JAK1 inhibitor abrocitinib outperformed Sanofi/Regeneron Pharmaceuticals, Inc.'s blockbuster IL-4/IL-13 inhibitor Dupixent (dupilumab) on efficacy in a head-to-head trial in atopic dermatitis, but the product remains under the JAK safety cloud as it awaits a US approval decision.

The topline data from the JADE DARE study, which was the first to compare the two differently acting products, showed both its co-primary and key secondary efficacy endpoints, comparing the higher 200mg dose of abrocitinib versus dupilumab 300mg in adults on background topical therapy with moderate-to-severe atopic dermatitis. (Pfizers Oral Abroctinib Bests Injectable Dupixent In Atopic Dermatitis Trial)

A larger percentage of patients treated with abrocitinib experienced adverse events, but the proportion of patients who experienced serious adverse events, severe events or adverse events leading to study discontinuation were similar in both treatment arms.

Abrocitinib’s oral administration could be an advantage over Dupixent, which is injected subcutaneously, but Dupixent has a strong foothold in the market and a well characterized safety profile. Dupixent was the first biologic therapy approved for atopic dermatitis by the FDA in 2017.

However, the FDA delayed the action date for abrocitinib in atopic dermatitis as it pushed back the review of other drugs in the class, due to safety concerns, in February.

Pfizer's new drug application for abrocitinib as Cibinqo is based on the Phase III JADE clinical trial program, which compared abrocitinib to placebo – and showed improvements in skin clearance and disease severity.

Pfizer is still waiting to hear from the FDA on Cibinqo though the drug was approved by the European Commission on 10 December, following its first approval in the UK in September.

Meanwhile, Pfizer is taking steps to diversify its inflammation & immunology pipeline with a recently announced acquisition of Arena Pharmaceuticals, Inc. for $6.7bn. At the heart of the deal is etrasimod, an oral, selective sphingosine 1-phosphate (S1P) receptor modulator that Pfizer believes could be best in class. (Pfizer Buys Arena For 67bn In Bid To Diversify In Inflammation Immunology)

While Pfizer said it remained enthusiastic about the prospects for Cibinqo and other JAK inhibitors in development, the company acknowledged that etrasimod could be used ahead of JAKs in the treatment paradigm given the risk-benefit profile.

Etrasimod is in development across a range of immuno-inflammatory conditions, including gastrointestinal and dermatological diseases, and it could be a relatively near-term commercial opportunity for Pfizer.

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