On 28 November 2024, Australia’s Pharmaceutical Benefits Scheme (PBS) published its agenda for the March 2025 Pharmaceutical Benefits Advisory Committee (PBAC) meeting.  This follows the PBAC’s publication of its September 2024 intracycle meeting outcomes, which noted that, to date, it had not received an acceptable proposal for an expanded listing to facilitate broad access to PD-(L)1 inhibitors which includes MSD’s pembrolizumab and BMS’ nivolumab.   

For the March 2025 agenda, half of the submissions selected for consideration are for monoclonal antibodies, 17 of which are list for new PBS additions and 6 for amendments. 

Four biosimilars will be considered for new listings: 

• Pfizer’s Ixifi®, biosimilar to Janssen’s Remicade® (infliximab), for severe active rheumatoid arthritis, ankylosing spondylitis, severe psoriatic arthritis, severe chronic plaque psoriasis, severe Crohn disease, complex refractory fistulising Crohn Disease, and moderate to severe ulcerative colitis 

• Sandoz’s Tyruko®, biosimilar to Biogen’s Tysabri® (natalizumab), for relapsing-remitting multiple sclerosis 

• Celltrion’s Omlyclo®, biosimilar to Novartis’ Xolair® (omalizumab), for uncontrolled severe asthma, uncontrolled severe allergic asthma, and severe chronic spontaneous urticaria 

• Samsung Bioepis’ Epyztek®, biosimilar to Janssen’s Stelara® (ustekinumab), for severe chronic plaque psoriasis, severe psoriatic arthritis, severe Crohn disease, and complex refractory fistulising Crohn Disease 

One biosimilar is being considered for changes to an existing listing: Celltrion’s Remsima® SC, biosimilar to Janssen’s Remicade® (infliximab). 

Other applications for PBS listing additions or amendments that the PBAC will consider at its March 2025 meeting include the following: 

On 19 November 2024, MSD (Merck in the US and Canada) announced positive topline results from its Phase 3 trial evaluating subcutaneous (SC) administration of pembrolizumab, together with Alteogen’s berahyaluronidase alfa, administered with chemotherapy.  The SC pembrolizumab (MK-3475A) demonstrated noninferior pharmacokinetics compared to intravenous (IV) Keytruda® (pembrolizumab,) in combination with chemotherapy, in adults with metastatic non-small cell lung cancer (NSCLC).

The Phase 3 trial (MK-3475A-D77) is part of MSD’s SC pembrolizumab clinical development program, which also includes a Phase 3 trial (MK-3475A-F84), evaluating SC pembrolizumab versus IV Keytruda®, each administered alone, for first-line treatment of patients with metastatic NSCLC whose tumours have high PD-L1 expression, and a Phase 2 trial (MK-3475A-F65) evaluating SC pembrolizumab in relapsed or refractory classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma.  MSD is also conducting a Phase 2 patient preference study (MK-3475A-F11) to assess reported preference for SC pembrolizumab versus IV Keytruda®.

In October 2024, MSD reported 17% growth in Keytruda® sales for Q3 2024, to US$7.4 billion, attributed to increased global uptake in earlier stage indications, including triple negative breast cancer, renal cell carcinoma and NSCLC, together with continued global demand for metastatic indications.

At the November 2024 meeting, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorisation under exceptional circumstances for InflaRx’s Gohibic® (vilobelimab) for treatment of adults with SARS-CoV2-induced acute respiratory distress syndrome (ARDS) who are receiving systemic corticosteroids.  A marketing authorisation under exceptional circumstances is recommended when the benefit/risk assessment is positive but where the rarity of the disease means it is unlikely that comprehensive data can be obtained under normal conditions of use.

The CHMP also recommended the following indication extensions:

• MSD’s Keytruda® (pembrolizumab), in combination with pemetrexed and platinum chemotherapy for first-line treatment of adults with unresectable non-epithelioid malignant pleural mesothelioma;
• BMS’ Opdivo® (nivolumab) and Yervoy® (ipilimumab), in combination, for mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer in first-line treatment of unresectable or metastatic colorectal cancer or for treatment of metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy;
• Janssen’s Rybrevant® (amivantamab), in combination with lazertinib, for first-line treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 l858R substitution mutations;
• Sanofi’s Kevzara® (sarilumab), in a new strength (175mg/ml solution for injection in vial), for active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older, who have responded inadequately to previous therapy with conventional synthetic DMARDs, as monotherapy or in combination with MTX; and Sarclisa® (isatuximab), in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant;
• Regeneron/Ultragenyx’s Evkeeza® (evinacumab) as an adjunct to diet and other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of adult and paediatric patients aged 6 months and older with homozygous familial hypercholesterolaemia.

Four biosimilars also received positive opinions at CHMP’s November meeting; two Samsung Bioepis denosumab biosimilars (reported here) and two aflibercept biosimilars for Formycon/Klinge (reported here).

In addition, the CHMP adopted a positive opinion for Eisai’s Leqembi® (lecanemab), as reported here.

On 8 November 2024, Celltrion announced that it has achieved accumulated sales for Q3 2024 of KRW 2.4 trillion, surpassing its 2023 annual sales.  Its quarterly sales are the highest it has ever reported, up 31.2% year on year.

Celltrion attributes its sales growth to the expansion of global prescriptions for its subcutaneous infliximab, Remsima SC® (EU, launched in 2020)/Zymfentra™ (US, launched in March 2024), biosimilar adalimumab.  Yuflyma® (80mg dose US launch January 2024, 40mg dose first approved by the FDA in May 2023, launched 2023, paediatric form US launch March 2024), and biosimilar bevacizumab, Vegzelma® (US launch April 2023).  It has also experienced steady growth in its anticancer products, Truxima® (rituximab, US launch May 2020) and  Herzuma® (trastuzumab, US launch March 2020).

During 2024, Zymfentra™ secured all six public and private insurance contracts operated by the three major prescription drug managers (PBMs) in the US.  Celltrion estimates that it has now secured more than 90% coverage in the US insurance market by completing contracts with 30 mid- to large-sized and regional PBMs and insurance companies.

Celltrion also notes the expansion of its biosimilar portfolio during 2024 with the launch of SteQeyma® (ustekinumab) in major European countries on 1 November.  Celltrion is planning for the 2025 launch of Eydenzelt® (CT-P42, aflibercept).

Celltrion has a number of biosimilars under development, including CT-P41 (denosumab, US aBLA filed December 2023),  CT-P47 (tocilizumab), CT-P55 (secukinumab), CT-P53 (ocrelizumab) and CT-P51 (pembrolizumab).

On 31 October 2024, Merck, known as MSD outside the US and Canada, published its Q3 2024 financial results, including 17% growth (21% excluding foreign exchange impact) in Keytruda® (pembrolizumab) sales, to US $7.4 billion.  This growth is attributed to increased global uptake in earlier-stage indications of Keytruda®, including triple-negative breast cancer, renal cell carcinoma and non-small cell lunch cancer (NSCLC), together with continued global demand for metastatic indications.

The increased global uptake of Keytruda® is reported to have helped drive MSD’s total global sales for Q3 2024 to US$16.7 billion, an increase of 4% year on year.

Recent regulatory milestones for Keytruda® include: the FDA approval in September 2024 of Keytruda® plus pemetrexed and platinum chemotherapy as first-line treatment for unresectable advanced or metastatic malignant pleural mesothelioma; approvals in Europe for Keytruda® plus Padcev® as first-line treatment of unresectable or metastatic urothelial carcinoma (September 2024) and two gynaecological cancers (October 2024, marking the 30^th EU approval); and approvals in Japan for certain patients with NSCLC and for radically unresectable urothelial carcinoma (September 2024).

On 24 October 2024, MSD announced that Keytruda® (pembrolizumab) has received marketing approvals from the European Commission for two new gynaecological cancer indications.  This means Keytruda® is now approved for 30 indications in Europe, including 5 for gynaecological cancer.

The first new indication is for Keytruda®, in combination with carboplatin and paclitaxel, for first line treatment of primary advanced or recurrent endometrial carcinoma in adults who are candidates for systemic therapy.  This indication was approved by the FDA in June 2024.

The second is Keytruda®, in combination with chemoradiotherapy, for treatment of FIGO (International Federation of Gynaecology and Obstetrics) 2014 Stage III-IVA locally advanced cervical cancer in adults who have not received prior definitive therapy.  This indication was approved by the FDA in January 2024 and in Korea in April 2024.

The new indications received positive CHMP approvals in September 2024.

On 18 October 2024, Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) published the outcomes of its September 2024 intracycle meeting.  This included consideration of proposals for broad Pharmaceutical Benefits Scheme (PBS) listings for PD-(L)1 inhibitors, including MSD’s pembrolizumab and BMS’ nivolumab, to allow expanded access to all current and future indications registered by the Therapeutic Goods Administration (TGA) without review of the clinical- and cost-effectiveness of each indication.  Consideration of these proposals had been deferred from the PBAC’s December 2023 meeting.

The PBAC determined that any broad subsidy proposal would need to address a list of parameters, including: “the potential risk of causing harm either directly (forgoing effective current standard treatments, adverse events) or intangibly (false hope, not resolving patient needs, inadequate provision of palliative care)”; the high level of uncertainty in cost-effectiveness when a PD-(L)1 inhibitor is not assessed for a specific listing based on clinical trial data for that use; the potential impact on other medicines (including PD-(L)1 inhibitors) that may already be in the market; and “biosimilar policies that might be in place, noting that multiple biosimilars for pembrolizumab and nivolumab are in the late phase of clinical development, with patents due to expire in some jurisdictions within the next five years”.  PBAC noted that, to date, it had not received an acceptable proposal for an expanded listing to facilitate broad access to PD-(L)1 inhibitors.

However, the PBAC said it is “supportive of implementing simplified listings for PD-(L)1 inhibitors within a specific tumour type if this would facilitate appropriate and timely access for patients”.  It is encouraging sponsors to make submissions for simplified PBS listings within tumour types “via the standard process”.

PD-(L)1 inhibitors currently listed on the PBS include MSD’s Keytruda® (pembrolizumab), BMS’ Opdivo® (nivolumab), AstraZeneca’s Imfinzi® (durvalumab), Merck Healthcare’s Bavencio® (avelumab), Medison Pharma Australia’s Libtayo® (cemiplimab) and GSK’s Jemperli® (dostarlimab).  BeiGene’s Tevimbra® (tislelizumab) and AA-Med’s toripalimab are under evaluation by the TGA.

On 16 October 2024, Formycon announced that results of a comparative analytical evaluation of its FYB206, published in Drugs in R&D, showed FYB206 to be structurally and functionally “highly similar” to MSD’s Keytruda® (pembrolizumab).

FYB206 is currently being evaluated in a phase 1 trial (“Dahlia”) to compare the pharmacokinetics, safety and tolerability of FYB206 with Keytruda® in malignant melanoma (commenced June 2024) and a phase 3 trial (“Lotus”) to compare the efficacy and safety of FYB206 with Keytruda® in combination with chemotherapy in patients with non-small cell lung cancer (NSCLC) (commenced 30 July 2024).

A number of pembrolizumab biosimilars have entered clinical trials this year, including Celltrion’s CT-P51 (Ph 3 trial plan approved by FDA in August 2024), Bio-Thera’s BAT3306 (Ph 1/3 in nsNSCLC commenced 25 July 2024), Amgen’s ABP 234 (Ph 3 in nsNSCLC initiated May 2024), Samsung Bioepis’ SB27 (Ph 3 in metastatic nsNSCLC commenced April 2024) and Sandoz’s GME751 (Ph 1 and 3 commenced in April/May 2024).  In September 2024, Shanghai Henlius Biotech received approval in China for a clinical trial of its pembrolizumab biosimilar, HLX17.

On 8 October 2024,  MSD’s Keytruda® (pembrolizumab) and Astellas/Pfizer’s Padcev® (enfortumab vedotin) were approved by the Medicines and Healthcare products Regulatory Agency (MHRA) as a first-line combination treatment for unresectable or metastatic urothelial carcinoma (UC) in adults who are eligible for platinum-containing chemotherapy.

This follows approval of this combination therapy for the same indication in Europe on 3 September 2024.  Enfortumab vedotin, an antibody drug conjugate, is being co-developed by Astellas and Pfizer under a global development and commercialisation collaboration.

On 3 October 2024, the US Patent Trial and Appeal Board (PTAB) instituted inter partes review (IPR) of Johns Hopkins University’s US patent no. 11,643,462 in IPR2024-00648.  MSD filed a petition on 13 March 2024, challenging the validity of the patent, which is directed to a method for treating, with pembrolizumab, cancer patients having a tumour that is microsatellite instability high (MSI-H) or DNA mismatch repair (MMR) deficient.

This followed the institution of eight IPRs in relation to Johns Hopkins University (JHU) patents relating to pembrolizumab on:

• 27 September 2024 (US patent numbers: 11,649,287 (IPR2024-00647), 11,629,187 (IPR2024-00649), and 11,634,491 (IPR2024-00650)). The petitions for each of these were filed on 13 March 2024;
• 23 September 2024 (US patent numbers 10,934,356 (IPR2024-00622), 11,325,974 (IPR2024-00623), 11,325,975 (IPR2024-00624) and 11,339,219 (IPR2024-00625)). The petitions for these IPRs were filed by MSD on 4 March 2024; and
• 13 June 2024 (US patent number 11,591,393 (IPR2024-240)). The petition for this IPR was filed on 30 November 2011.

In each case, the PTAB determined that MSD had demonstrated there was a “reasonable likelihood that the petition would prevail in showing that at least one challenged claim is unpatentable”.

In November 2022 MSD filed a complaint in the United States District Court (District of Maryland) against JHU seeking declarations of breach of contract, non-infringement and promissory estoppel.  JHU filed a counter-claim on 12 April 2023, including alleging infringement of each of the patents subject to the IPR proceedings referred to above.

The US Court proceeding has been stayed pending the outcome of IPR2024-240.  No trial date has been scheduled.

MSD’s Keytruda® (pembrolizumab) is approved in the US (alone or in combination with other agents) for numerous indications including in relation to endometrial carcinoma, Stage 111-IVA cervical cancer, urothelial carcinoma, gastric/gastroesophageal junction adenocarcinoma, and biliary tract cancer.