Reformulation & indication expansion - lifecycle management led by Roche, AZ, BI & Celltrion
In last months’s roundup, we emphasized the continuing deal making momentum from both big pharma and younger ventures to in-license or acquire pipeline assets. In addition to shoring up innovation pipeline, there has also been an active focus on guarding current drug franchises from looming patent cliffs and strategically engaging in lifecycle management. This month, we highlight three individual developments that reflect the momentum around re-formulation, repurposing and indication expansions. With biosimilars competition expanding across global regions, rapid and steep price erosion is no more limited to small molecule drugs. Consequently, the quest to engage in such strategic lifecycle management effort is directed towards biologicals as well: Roche’s Phesgo™- trastuzumab and pertuzumab subcutaneous formulation: Roche’s Phesgo™, a combination of Herceptin™ (trastuzumab) and Perjeta™ (pertuzumab) exemplifies significant reformulation innovation in biologics that deftly balances business potential / lifecycle management with patient benefit. While Roche’s trastuzumab has already lost its exclusivity and there are 5 marketed biosimilars in the US, pertezumab’s patent protection in the USA runs upto June 2024. Just as impact of biosimilar led price erosion becomes evident on trastuzumab revenue, Roche has introduced this fixed-dose combination that can be administered subcutaneously to adult patients with metastatic and early-stage HER-2 positive breast cancer. Approved by US FDA four months ahead of expected decision date, the formulation combines patient convenience and health economic merit as it reduces administration time from the current 60 to 150 minute infusion to 5 to 8 minutes in the novel subcutaneous injection. COVID-19 has resulted in unanticipated challenges in delivery of hospital based cancer care. Paving the way for at-home administration, this formulation expands access to care in the current circumstances and reduces risk of contagion in a highly susceptible population subset. The development has been covered in extensive detail here in our PharmForward update. Celltrion’s Remsima SC – novel subcutaneous formulation: A companion of the Roche in the pursuit of subcutaneous version of IV infusion drugs is an unlikely ally, the Korean biosimilar major, Celltrion. Through the last few years multiple times Celltrion has been heralded as carving a new path for biosimilars encompassing formulation innovation. It is now the first company to launch a subcutaneous (SC) formulation of infliximab, a monoclonal antibody earlier available only as a doctor’s clinic based infusion. In Nov 2019, it received the EMA approval for its SC version for treating rheumatoid arthritis based on pivotal phase 3 data establishing comparable safety, efficacy and pharmacodynamics of the SC and previously approved Intravenous (IV) formulations of Remsima. EMA’s marketing authorization has now been extended beyond rheumatoid arthritis to include 5 additional indications covered by the IV version – ankylosing spondylitis, Crohn disease (CD), ulcerative colitis (UC), psoriatic arthritis, and psoriasis. With infusion at the physician’s office with currently available formulations taking about two hours every eight weeks (on maintenance phase), Remsima SC again implies patient convenience and health economic merit for patients on routine anti-TNF therapy. A phase 3 trial for the SC version is also underway in USA for severe to moderate ulcerative colitis. Celltrion will most likely adopt the 351(a) pathway for FDA regulatory submission since there is no subcutaneous reference product available currently. Read about it in detail here in our PharmForward update. AstraZeneca’s SGLT2 inhibitor stacks up cardiovascular indications: Anti-diabetics have been an evolving battleground with DPP4 inhibitors, GLP1 agonists and SGLT2 inhibitors vying hard for a larger share of the pie. While potential benefit in obese or overweight type 2 diabetes (T2D) patients and recent approval of first oral drug benefits the GLP1 franchise, additional benefit in cardiovascular risk reduction has been a motivator for use of SGLT2 inhibitors for glycemic control in T2D. In December 2016, Boehringer Ingelheim and Eli Lily’s Jardiance (empagliflozin) gained the stamp of FDA approval for reduction of cardiovascular death in Type 2 diabetic patients with established cardiovascular disease. Current developments in May and July 2020 break further ground in expanding clinical use and commercial opportunity with claim expansions. One of the three FDA approved SGLT2 inhibitors, AstraZeneca’s Farxiga (dapagliflozin) has now been approved for cardiovascular indications even in patients without diabetes. Earlier in May this year, Farxiga was approved by FDA to reduce the risk of hospitalizations and cardiovascular death in patients with reduced ejection fraction, with or without diabetes. Now in July 2020, Farxiga has received FDA’s Fast Track Designation to evaluate another indication – reduce hospitalization and death in patients following an acute myocardial infarction or heart attack including patients without diabetes. Similarly, in June 2019, the FDA had also granted breakthrough designation for empagliflozin to be evaluated for reduction of cardiovascular death/ hospitalization for heart failure for patients with chronic heart failure. The expansion of the SGLT2 inhibitors provides much needed life cycle extension in the context of impending genericization. FDA has granted tentative approval to multiple generics for dapagliflozin; and the first drug substance patent as well as exclusivity for use in diabetes 2 diabetes expire in 2020. With the May 2020 approval for cardiovascular conditions, while no additional patents have been filed, exclusivity now extends until 2023. These indication expansions are great benchmarks for rigorous data driven efforts to address meaningful clinical unmet needs in an area of high perceived benefit. Read more about the development here in our PharmFoward update.
COVID-19 Vaccine – Progress across various global candidates
As the COVID-19 challenge continues to be pervasive across countries, there is justifiably high global focus on accelerating development of a vaccine to immunize populations at large. As of the end of July, there are about 165 COVID-19 vaccine candidates under development with 26 COVID-19 vaccine candidates having commenced clinical evaluation. The breadth of this vaccine pipeline and the pace of developments emphatically highlight commitment of the global scientific community, companies across borders and public/philanthropic funders/catalysts. The COVID-19 vaccine endeavour is emerging as a telling tale of potential for collaborative acceleration of critical scientific innovations. At the other end, it has had its share of controversies and a constant undercurrent of nationalist interest given the understandable prioritization of country needs by global leaders. There is also the other more daunting challenge of creating manufacturing capacity for delivering the vaccine at scale in an equitable manner to majority of the world’s population of 7.8 billion individuals. National interests have also led to multiple procurement commitments and deals between countries and COVID-19 vaccine developing companies. We highlight below major developments on clinical advancement and capacity creation during the month of July. Clinical Development momentum: Multiple COVID-19 vaccine candidates enter phase III Including the three inactivated vaccines from SinoVac, Wuhan Institute of Biological Products/Sinopharm and the Beijing Institute of Biological Products/SinoPharm that have entered Phase III clinical trials, and the following three candidates, as on date 6 COVID-19 vaccine candidates have advanced to the stage of demonstrating efficacy in Phase III trials: Oxford University team in early July, published the results from the Phase I/II trial of the ChAdOx1 nCoV-19 vaccine in the Lancet Journal. The single-blinded, randomised, multi-centre study enrolled 1,077 volunteers aged between 18 to 55 years and their results indicated that the vaccine successfully elicited potent immune response, with only mild side effects observed. We have discussed the data in detail in our PharmForward update. Corporate partner AstraZeneca and Oxford have initiated a global phase 3 trial of the vaccine with close to 30,000 participants with anticipated size of 2000 participant in South Africa and 5000 participants in Brazil. To trigger broader global footprint of manufacturing and to accelerate clinical development/market access, AstraZeneca has also forged global partnerships with manufacturing and development partners such as the Serum Institute of India. Moderna also published interim results from its Phase I clinical trial of its COVID-19 vaccine candidate, mRNA 1273, in The New England Journal of Medicine. The interim results from the study conducted in 45 participants’ demonstrated rapid and strong immune response with no serious adverse events. Based on the findings from the trial, Moderna has decided to conduct phase III trials at a dose of 100 µg which is now commenced in collaboration with National Institute of Allergy and Infectious Diseases (NIAID) and Biomedical Advanced Research and Development Authority (BARDA). This phase III trial, COVE (Coronavirus Efficacy) study (NCT04470427), will consist of 30,000 participants across multiple sites in USA. The primary efficacy endpoint of COVID-19 infection prevention will be studied through an event-driven analysis of the number of symptomatic COVID-19 infections. BioNTech and Pfizer also in early July, announced positive data from the Phase 1/ 2 study of their mRNA based vaccine, one of the four advanced vaccine candidates under evaluation as part of its Project Lightspeed. Preliminary results of the BNT162b1 demonstrated that the vaccine is well tolerated and generated a dose-dependent immune response. Preliminary data has been evaluated in 24 subjects who received two injections of 10 µg and 30 µg, 12 subjects who received a single injection of 100 µg, and 9 subjects who received 2 doses of placebo. Neutralization titers peaked 7 days after the second dose of 10 µg or 30 µg, the geometric mean concentration (GMC) of SARS-CoV-2 receptor binding domain (RBD) bindings IgG antibodies were found to be 8-times higher for the 10 µg dose and 46.3 times higher for the 30 µg dose when compared with the GMC from convalescent sera of 38 patients. Two of the four vaccine candidates (BNT162b1 and BNT162b2) of BioNTech were granted FDA Fast Track Designation recently. Additionally, BioNTech has managed to raise USD 250 million from Temasek and other investors for accelerating its vaccine development program and the details are discussed in our PharmForward update. BioNTech has chosen its lead candidate BNT162b2 due to a better safety profile than the BNT162b1 candidate as observed in preliminary data from a phase 1/ 2 study in 120 patients (results not published). BNT162b2 encodes an optimized version of the spike protein RBD and elicits similar neutralizing antibody titers from two 30 µg doses, administered three weeks apart, as elicited by the former BNT162b1 candidate. The Phase 2/3 study has commenced with BNT162b2 and up to 30,000 participants are planned to be enrolled across the globe between the ages of 18 and 85. Trial participants will receive 30 µg dose level in a 2 dose regimen. The companies currently aim to supply approximately 1.3 billion doses by the end of 2021, once regulatory approvals are obtained. Manufacturing & Supply Partnerships: Investments for capacity expansion A looming challenge in the quest for an immunization solution, is creating manufacturing capacity to produce the vaccine at unprecedented scale – a global demand of more than 6 billion doses. With multiple technology platforms being pursued and most pipeline candidates requiring tailored facilities with high biosafety levels, investment risk rides high. More importantly, the urgency of manufacturing capacity creation cannot be undermined as this otherwise likely to be render the vaccine development efforts futile. In our PharmForward update we had earlier discussed the rush from various Governments to secure supplies of the COVID-19 vaccine for national interests, creative funding support models emerging such as equity funding to avert flight of technology to other countries and finally, multiple partnerships with service providers to shore up aggregate manufacturing capacity. In the table below, we have highlighted the recent developments on investments, catalytic funding support, supply commitments and manufacturing partnerships:
In addition to manufacturing agreements, vaccine developers have sought partnerships with research organizations and public health institutions to conduct late-stage trials. In June 2020, Sinovac partnered with Brazil’s Butantan Institute wherein the latter will sponsor SinoVac’s phase III trials in Brazil. Sinovac plans to establish an extensive collaboration with Butantan that will involve technology licensing, market authorization and commercialization of its vaccine CoronaVac. Oxford University has also partnered with the Federal University of Sao Paulo in Brazil for its phase III trials. As scientific efforts globally strengthen the promise of a COVID-19 vaccine in record timelines, we stay hopeful that all stakeholders judiciously straddle the fine balance between co-operation and competition, global solidarity and national interests, country priorities and equitable access.
|Nature of the collaboration
|Biomedical Advanced Research and Development Authority (BARDA)
|Agreement to fund an additional USD 472 in addition to the initial USD 483 million.
|Laboratorios Farmacéuticos Rovi
|Collaboration for large-scale, commercial fill-finish manufacturing of Moderna’s mRNA vaccine candidate in Madrid, Spain to supply in markets outside the US. As part of the agreement, Rovi will provide packaging capacity and vial filling through procurement of a new production line and equipment.
|Large-scale commercial manufacturing of AstraZeneca’s Vaccine candidate AZD1222. The Agreement is valued at USD 174 million and follows a prior contract for development service valued at USD 87 million
|FUJIFILM Diosynth Biotechnologies
|Collaboration to manufacture Novavax’s COVID-19 candidate NVX-CoV2373 for Phase 3 clinical trial and additional 100 million doses by late 2020
|FujiFilm Diosynth Biotechnolgoies
|Biomedical Advanced Research and Development Authority (BARDA)
|USD 265 million funds under the Operation Warp Speed, and to reserve capacity for vaccine manufacturing in Fujifilm’s Texas Plant
|Collaboration to develop and evaluate Medicago’s Coronavirus Virus-Like Particles (CoVLP) vaccine and manufacture of 100 million doses by 2021 end
|Agreement to supply of 30 million doses as part of the agreement with the UK government
|Order of 100 million doses for USD 1.95 billion by the U.S. Government and can expand to upto 500 million doses
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