Rising to the Challenge: An Analysis of the Influenza Vaccine Landscape in Response to the Swine Flu Pandemic

Transcription

1 Rising to the Challenge: An Analysis of the Influenza Vaccine Landscape in Response to the Swine Flu Pandemic Gabrielle Gessner Associate Director, Infectious & Genitourinary Diseases Sean McDonnell Drug Analyst II

2 Influenza viral outbreaks occur annually around the world, with some tropical regions experiencing year round viral circulation (WHO, 2013). Influenza viruses change, or drift, constantly, leading to different virus strains circulating each flu season or sometimes within a single season (CDC, 2013). Worldwide, these annual epidemics result in approximately three to five million cases of severe illness each year, and about 250,000 to 500,000 deaths (WHO, 2013). The swine influenza pandemic in 2009/10 highlighted numerous challenges in providing effective influenza vaccine coverage. These include the long lag time between flu virus selection by government agencies and actual shipment of vaccine, resulting in possible mismatch of vaccine strains; the lack of production capacity; and the reluctance of some individuals to get vaccinated due to intramuscular administration or exclusionary conditions (ex. egg allergy). This paper evaluates the methods manufacturers pursued in response to the swine flu pandemic, with an analysis of alternate manufacturing methods and routes of administration. We analyzed the clinical landscape of influenza vaccines since 2010, including approved vaccines and trial metrics, to identify how manufacturers addressed these issues and how effective they have been. Have the major players in influenza vaccines shifted? Are trial timelines or other characteristics different? With the recent emergence of novel viruses such as the MERS coronavirus, flexible vaccine production and short development timelines become even more vital in addressing future pandemics. 2

3 addressing the challenges in influenza Vaccine Production Manufacturers investigated various strategies since 2009 to address the challenges associated with effective influenza vaccination. Traditionally, influenza vaccines have been produced in chicken eggs which requires a long production time, so the vaccine strains have to be chosen 7-8 months prior to vaccine delivery. Since the circulating influenza strains are not known this far in advance, virus strains that are not a close match to the strains that actually circulate during the upcoming flu season may be selected, resulting in reduced vaccine efficacy against clinical infection. Other issues associated with effective influenza vaccination include limited vaccine supplies or patient preferences. As such, manufacturers explored ways to counteract these obstacles by shortening vaccine production time via alternate manufacturing methods, adding additional virus strains into the vaccine, and developing alternate routes of administration. alternate Manufacturing Methods Using cell culture techniques in the manufacturing process of influenza vaccines is one way to vastly reduce the vaccine production time, primarily by eliminating the long lead time needed to grow the vaccine seed virus in chicken eggs. This gives manufacturers the ability to provide additional vaccine supplies during a season if needed or manufacture a new strain quickly in the event of a pandemic. also offers higher purity and provides a larger initial production volume than traditional egg-based processes. In addition, cell culture eliminates any possibility of residual egg proteins remaining in the vaccine, making the vaccine safe for individuals with an egg allergy. In total, 38 cell culture vaccines were developed targeting influenza since the early 1990s (Figure 1). vaccines make up 37% (14) of these; however, the majority have been developed for specific monovalent vaccines. Figure 1. Cell Cultured Influenza Vaccines By Strain H3N2, (1), (14) H5N1, (12) Pandemic (Unspecified), (3) H1N1, (6) H7N9, (1) H9N2, (1) Source: Pipeline, August

4 Of the 38 cell culture vaccines in development, 27 different companies have been involved (including licensees) (Figure 2, Table 1). The clear leader in this field is Baxter, who invested in 6 separate Vero cell culture vaccines, of which 3 have been successfully launched (PreFluCel, Celvapan H1N1 & Celvapan H5N1). Novartis is also well established in this area with 5 vaccines, including their Phase II MDCK cell-based H5N1 product. Rounding out the Top 3 is GlaxoSmithKline (GSK), developing 4 alternatives to traditional egg-based methods. Figure 2. Companies Developing Cell Culture Manufactured Influnza Vaccines Developing Company Abbott ADImmune Astellas AstraZeneca Baxter International Bharat Biotech BioDiem Cadila Daiichi Sankyo GE Healthcare GlaxoSmithKline Johnson & Johnson Kaketsuken LG Life Sciences Medigen Biotechnology Merck & Co Non-industrial source Novartis Novavax Petrovax Polymun Protein Sciences Sanofi SK Holdings Takeda UMN Pharma Vivaldi Biosciences Number of Influenza Vaccines Source: Pipeline, August 2013 EB66 duck cell Insect (baculovirus) Mammalian MDCK Vero 4

5 table 1. cell-cultured influenza Vaccines Drug name Global status originator licensee Manufacturing influenza type Flucelvax Launched Novartis Mammalian PreFluCel Launched Baxter International Vero Celvapan, H5N1 Launched Baxter International Vero H5N1 Celltura Launched Novartis Pandemic (H1N1) HN-VAC Launched Bharat Biotech Pandemic (H1N1) Celvapan, H1N1 Launched Baxter International Vero Pandemic (H1N1) MonoGrippol Neo Launched Petrovax AbbVie Abbott Pandemic (H1N1) live attenuated influenza vaccine, BioDiem/Nobilon Launched BioDiem Merck & Co Influvac TC Registered Abbott AbbVie MDCK Flublok Registered Protein Sciences Astellas UMN Pharma Vapacel Registered Takeda Baxter International Vero H5N1 influenza, H5N1, cell culture, Kitasato Daiichi Sankyo Preregistration Daiichi Sankyo H5N1 influenza vaccine, PER.C6 Inflexal V, Crucell Phase II Johnson & Johnson trivalent influenza vaccine (H3N2/H1N1/B), Novavax Phase II Novavax Cadila GE Healthcare LG Life Sciences Insect (baculovirus) H5N1 pre-pandemic influenza vaccine, cell culture, Novartis Phase II Novartis MDCK H5N1 VLP vaccine, influenza H5N1, Novavax Phase II Novavax Bharat Biotech LG Life Sciences Insect (baculovirus) H5N1 Panblok Phase II Protein Sciences UMN Pharma Astellas Sanofi Insect (baculovirus) H5N1 Vero-Vac Phase I Polymun Vero 5

6 table 1. cell-cultured influenza Vaccines (continued) AT-301 Drug name Global status originator licensee Manufacturing influenza type Phase I Medigen Biotechnology MDCK H5N1 H3N2c vaccine, Novartis Phase I Novartis H3N2 H5N1 LAIV influenza vaccine, BioDiem Phase I BioDiem Merck & Co H5N1 H5N1 influenza vaccine, Baxter/DynPort Phase I Baxter International Vero H5N1 UMN-0901 Preclinical UMN Pharma Insect (baculovirus) H9N2 H7N9 influenza vaccine, Novartis Preclinical Novartis H7N9 influenza vaccine, GSK, seasonal, cell culture Preclinical GlaxoSmith- Kline Kaketsuken EB66 duck cell influenza vaccine, cell-culture, SK Chemicals Preclinical SK Holdings Pandemic (Unspecified) FluCell quadrivalent Preclinical Johnson & Johnson Cell Culture Source: Pipeline, August 2013 Initially developed targeting avian influenza strains, the cell culture vaccines have exploded onto the influenza landscape in response to the swine flu pandemic. These vaccines have addressed multiple challenges of influenza vaccines, shortening production timelines and opening the market to additional populations, such as those with egg allergies. Quadrivalent Vaccines The other method used to combat the strain drift of influenza added an additional strain to the existing approved seasonal influenza vaccines, producing quadrivalent instead of trivalent vaccines. A number of sponsors pursued this method with successful results. Traditional seasonal influenza vaccines consist of the two main influenza type A strains and one influenza type B strain. However, the 2013/14 season is the first where we will see the availability of several quadrivalent vaccines, which contain an additional B strain. There are currently 4 quadrivalent vaccines approved for use in the upcoming influenza season, with a further 5 vaccines advancing through the pipeline (Table 2). 6

7 table 2. Quadrivalent influenza Vaccines Drug name Global status originator licensee Manufacturing Delivery route FluMist quadrivalent Launched MedImmune (AstraZeneca) Egg-based Inhaled, transnasal Fluarix quadrivalent Launched GlaxoSmithKline Egg-based Injectable, intramuscular Fluzone quadrivalent vaccine, Sanofi Launched Sanofi Egg-based Injectable, intradermal Injectable, intramuscular FluLaval quadrivalent Registered GlaxoSmithKline Egg-based Injectable, intramuscular influenza vaccine, Vaxigrip quadrivalent, Sanofi Preregistration Sanofi Egg-based Injectable, intramuscular quadrivalent VLP seasonal flu vaccine, Novavax Phase II Novavax LG Life Sciences Egg-based Injectable, intramuscular influenza vaccine, quadrivalent (MF59-adj), Novartis Phase II Novartis Egg-based Injectable, intramuscular seasonal influenza vaccine, quadrivalent, Medicago Phase I Medicago Plant based Unspecified FluCell quadrivalent Preclinical Johnson & Johnson Cell Culture Injectable, intramuscular Source: Pipeline, August 2013 AstraZeneca s (MedImmune s) quadrivalent formulation of FluMist was the first quadrivalent influenza vaccine to be approved worldwide (February 2012 in the US), and is also the only quadrivalent vaccine available that is administered intranasally. It is currently awaiting EU approval from the EMA. GSK s quadrivalent Fluarix vaccine was the next to be approved in the US in December It is crucially also approved in the UK (as Fluarix Tetra) and Germany (as Influsplit Tetra), and is currently awaiting further regulatory rulings in Australia, Switzerland, and Taiwan. Being the only quadrivalent influenza vaccine currently available outside of the US should give GSK a huge untapped market for the 2013/14 influenza season, which will no doubt be reflected in their sales revenue for the 4th quarter of Sanofi s quadrivalent Fluzone formulation was approved in the US in June While arriving later to an already crowded field, Sanofi has a major advantage over both AstraZeneca (MedImmune) and GSK in that Fluzone quadrivalent is approved for infants as young as 6 months old, which is a full 18 months earlier than FluMist quadrivalent and 30 months earlier than Fluarix quadrivalent. This gives Sanofi complete exclusivity on all quadrivalent vaccine inoculations of infants and toddlers aged 6 months to 2 years of age in the US, a particularly vulnerable population for influenza infection. The 4th and final quadrivalent vaccine approved in time for the 2013/14 influenza season is GSK s second quadrivalent influenza vaccine, FluLaval quadrivalent, which was approved in the US in August While currently approved, GSK concedes that only a limited amount of FluLaval quadrivalent will be available in However, from 2014 onward, GSK should have the capacity to supply Flulaval quadrivalent to the US from its manufacturing plant in Quebec, Canada and will also continue to manufacture Fluarix quadrivalent from its facilities in Dresden, Germany and Pennsylvania, US. 7

8 current landscape in Quadrivalent Vaccine Development Not surprising given their double threat in approved quadrivalent vaccines, GSK has conducted the highest number of trials using quadrivalent influenza vaccines at 10 trials, followed by Sanofi with 8 trials (Figures 3, 4). Almost all of GSK s (9 out of 10 trials) and Sanofi s (7 out of 8 trials) trials were in Phase III, while AstraZeneca (MedImmune) is the only sponsor conducting Phase IV trials using their FluMist quadrivalent vaccine, as of August Sanofi has the largest number of ongoing (planned, open, or closed) quadrivalent vaccine trials (3 out of 8). Of note, there are no Phase I trials for quadrivalent vaccines, primarily because this first crop were based on trivalent vaccines to speed development. Figure 3. Quadrivalent Vaccine Trials by Phase Trial Phase IV III II/III II Number of Trials AstraZeneca GSK Medicago Novartis Novavax Sanofi Sponsor Source: Trialtrove, August

9 Figure 4. Quadrivalent Vaccine Trials by Status Trial Status Terminated Planned Open Completed Closed 8 Number of Trials AstraZeneca GSK Medicago Novartis Novavax Sanofi Sponsor Source: Trialtrove, August 2013 The other three sponsors testing quadrivalent vaccines in the clinic are Novartis, Novavax, and Medicago (Figures 4, 5). Novavax is developing their quadrivalent vaccine for pediatric, adult, and elderly populations. Notably, CSL decided not to pursue a quadrivalent vaccine, despite being a major player in trivalent seasonal influenza vaccines. 9

10 Figure 5. Current Landscape for Quadrivalent Vaccines Source: Trialtrove, August 2013 With both quadrivalent and trivalent vaccines currently available to the public, it remains to be seen if quadrivalent manufacturers will continue to produce their trivalent vaccines after the 2013/14 influenza season. Provided there are no surprises during this transition season, the trivalent vaccines may eventually be phased out in markets where the quadrivalent vaccine is approved. alternate routes of administration Various sponsors sought alternate routes of administration to address supply issues and tap into increased patient preference and/or additional populations. Traditional influenza vaccines are administered intramuscularly or intranasally. Intradermal (ID) and subcutaneous (SC) administrations have been pursued as dose-sparing methods since they require less volume to administer. These routes of administration may also be preferable to some subjects who aren t eligible for the live intranasal vaccine since they use a smaller needle and don t require placement into the muscle tissue. However, intradermal and subcutaneous administration can be more difficult for health providers to provide consistently without additional training. Additionally, since the intranasal vaccine is a live viral vaccine, it is contraindicated for people with asthma or respiratory issues. As such, another route of administration would provide an alternate to intramuscular vaccines for people with these conditions. 10

11 Sanofi (Sanofi and Sanofi Pasteur MSD) is by far the leader in evaluating vaccines with alternate routes of administration, with 85% more trials than their nearest competitors (Figure 6). This isn t surprising considering they have the only approved intradermal formulation with Fluzone intradermal. Figure 6. Intradermal and Subcutaneous Influenza Vaccine Trials Route of Administration SC ID & SC ID AbbVie Astellas Pharma; UMN Pharma Baxter CLL Pharma CSL Ltd Daiichi Sankyo Denka Seiken Echo Therapeutics Johnson & Johnson GSK Inovio Pharmaceuticals Kaketsuken Medicago Novartis Pfizer Sanofi Sanofi Pasteur MSD SEEK Valneva VaxInnate Source: Trialtrove, August 2013 Sanofi is followed by Inovio Pharmaceuticals and Novartis with 4 trials each. Inovio is also focusing on intradermal administration, while Novartis is pursuing both intradermal and subcutaneous formulations. In subcutaneous formulations, Novartis, VaxInnate and CSL are all active in the clinic with 3 trials each (Figures 7, 8). Figure 7. Intradermal Vaccine Trials by Phase Trial Phase IV III II I/II I CLL Pharma Daiichi Sankyo Echo Therapeutics GSK Inovio Pharmaceuticals Johnson & Johnson Medicago Novartis Source: Trialtrove, August 2013 Pfizer Sanofi Sanofi Pasteur MSD Valneva VaxInnate 11

12 Figure 8. Subcutaneous Vaccine Trials by Phase Trial Phase IV III II/III II I/II I AbbVie Astellas Pharma; UMN Pharma Baxter CSL Ltd Denka Seiken Kaketsuken Novartis Source: Trialtrove, August 2013 Sanofi SEEK VaxInnate changes in the influenza Vaccine landscape To understand any changes that occurred in the influenza vaccine competitive landscape as a result of the 2009/10 swine flu pandemic, we compared a number of areas before and after January 2010, including vaccine approvals, sponsors, and trial metrics. changes in approved influenza Vaccines The 2009/10 influenza virus pandemic placed government agencies worldwide under enormous pressure to act swiftly and decisively due to intensified media coverage. One outcome of this was that manufacturers were encouraged to develop monovalent vaccines against the new H1N1 strain with the promise of expedited regulatory approval. September 2009 saw the initial wave of these H1N1 vaccine approvals (7 in total) as the 2009/10 influenza season began in earnest in the Northern Hemisphere (Figure 9, Table 3). Two vaccines were approved quickly in the EU: GSK s Pandemrix H1N1 and Novartis Focetria H1N1. Both vaccines were initially authorized under exceptional circumstances by the EMA due to the high medical need, despite a lack of clinical information. This limited approval was eventually lifted in August 2010 after both companies were able to supply the necessary clinical data. Similarly, the US also approved 4 H1N1 vaccines in September 2009, manufactured by Sanofi, CSL, Novartis and AstraZeneca (MedImmune). 12

13 Figure 9. Timeline Of H1N1 Vaccine First Approvals By Originator No. of Approved H1N1 Vaccines By Month Sep-09 Oct-09 Nov-09 Dec-09 May-10 Jul-10 Aug-10 Sep-10 Oct-10 ADImmune AstraZeneca Baxter International Bharat Biotech BioDiem CSL GlaxoSmithKline Green Cross Microgen Novartis Petrovax Sanofi Serum Institute of India Sinovac Biotech Zydus Cadila Source: Pipeline, August 2013 October 2009 saw another 5 first-time approvals for monovalent H1N1 vaccines. Baxter s Celvapan H1N1, the only approval that month in the EU, made history by becoming the first cell culture influenza vaccine approved. Green Cross, Microgen and GSK also gained premier approvals for vaccines during October 2009 in South Korea, Russia and Canada, respectively. The number of new approvals trailed off considerably after October, with only 4 new vaccines coming to market in 2009, including Novartis Celtura and Petrovac s MonoGrippol Neo cell culture products. In 2010, a further 5 H1N1 vaccines were approved by regulatory agencies, 4 in India and 1 in Taiwan. 13

14 table 3. H1n1 influenza Vaccines approved Worldwide since 2009/10 Pandemic Vaccine name originator licensee Date of 1st approval region of first approval Panflu.1 Sinovac Biotech Boryung Sep-09 China Pandemrix H1N1 GlaxoSmithKline Sep-09 EU Panenza Sanofi Sep-09 US Panvax H1N1 CSL Sep-09 US Focetria H1N1 Novartis Sep-09 EU Fluvirin H1N1 Novartis Sep-09 US Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal AstraZeneca Sep-09 US Celvapan, H1N1 Baxter International Oct-09 EU Green Flu-S Green Cross Oct-09 South Korea Influvir Microgen Oct-09 Russia Pandeflu Microgen Oct-09 Russia Arepanrix GlaxoSmithKline Oct-09 Canada Celtura Novartis Nov-09 Germany Green Flu-S Plus Green Cross Dec-09 South Korea MonoGrippol Neo Petrovax AbbVie Dec-09 Russia MonoGrippol Plus Petrovax Dec-09 Russia VaxiFlu-S Zydus Cadila May-10 India Serum Institute of India NasoVac BioDiem Merck & Co Changchun BCHT Biotechnology Jul-10 India Enzavac Serum Institute of India Aug-10 India AdimFlu-S ADImmune Sep-10 Taiwan HNVAC Bharat Biotech Oct-10 India Source: Pipeline, August 2013 changes in trial landscape There were some shifts seen in the major players in influenza vaccine development after the 2009/10 pandemic (Figures 10, 11). GSK, Sanofi, and Novartis remained the top three sponsors of influenza vaccine trials both before and after January However, AstraZeneca (Medimmune), Pfizer, and AbbVie dropped off the Top 10 sponsors after January 2010, indicating their shift in focus away from influenza vaccine development. Baxter and CSL remained in the Top 10, with the entrance of Johnson & Johnson, Serum Institutes of India, AdImmune, and Novavax to round out the Top 10 after January

15 Figure 10. Top 10 Industry Sponsors of Influenza Vaccine Trials Prior to January 2010 Sinovac Biotech AbbVie Vaccine Type avian/pandemic seasonal swine/pandemic Baxter CSL Pfizer Medimmune AstraZeneca Sanofi Novartis GSK Number of Trials Source: Trialtrove, August 2013 Figure 11. Top 10 Industry Sponsors of Influenza Vaccine Trials After January 2010 CSL Serum Institute of India Vaccine Type avian/pandemic seasonal swine/pandemic Sanofi Pasteur MSD Novavax Baxter ADImmune Johnson & Johnson Sanofi Novartis GSK Number of Trials Source: Trialtrove, August

16 Looking at the comparison between trial metrics before and after January 2010, there does not seem to be much of a change in the countries per trial or average sites per trial (Figures 12, 13). However, while the average predicted maximum enrollment rate per trial remained the same for most types of vaccines, there was a significant increase in the average enrollment rate for seasonal and avian vaccine combination trials. This could reflect decreased volunteer interest in avian influenza vaccine trials following the swine influenza pandemic. Figure 12. Influenza Vaccine Trial Metrics [Prior to January 2010] Avg Countries per Trial Avg Reported Sites per Trial Avg Predicted Max Enroll Period per Trial (months) Swine Avian, Swine, Avian Source: Trialtrove, Trialpredict, August

17 Figure 13. Influenza Vaccine Trial Metrics [After January 2010] Avg Countries per Trial Avg Reported Sites per Trial Avg Predicted Max Enroll Period per Trial (months) Swine Avian, Swine, Avian Source: Trialtrove, Trialpredict, August 2013 During the 2009/10 swine flu pandemic, manufacturers swiftly responded to the public health crisis with additional influenza vaccine approvals in a very short timeframe. The leaders in influenza vaccines solidified their presence in this area, with the emergence of some new companies in this area as well. 17

18 conclusion The 2009/10 H1N1 influenza pandemic caused a shift in the traditional focus and processes surrounding influenza vaccine production. Manufacturers rose to the challenge posed by the pandemic and explored additional options to increase flexibility in influenza vaccine production. This resulted in even greater innovation and multiple strategies that improved manufacturing processes as well as offering multiple vaccine types, both of which were successful in addressing this serious public health challenge. With the emergence of the H7N9 influenza strain in Asia during the spring of 2013, these methods will be essential in facing new influenza pandemics, and applicable to other viral pandemics that may emerge. Will manufacturers who focused on one strategy, like GSK s two quadrivalent vaccines approved in multiple markets, come out on top? Or will it be the manufacturers that focused on multiple strategies like Sanofi with a quadrivalent vaccine (Fluzone QIV) in additional populations (infants and toddlers), an intradermal vaccine (Fluzone ID), and a high-dose vaccine for the elderly (Fluzone HD)? The upcoming Northern Hemisphere influenza season will be followed with great interest as we see the answers to these questions play out. references CDC, 2013, WHO, 2013, 18

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