2022 FDA Approval & Potencial Blockbusters

1. Huateng Pharma https://us.huatengsci.com 2022 FDA Approval & Potencial Blockbusters Last year the FDA's Center for Drug Evaluation and Research (CDER) approved 37 novel drugs, including 22 new molecular entities (NMEs) and 15 biologics license applications (BLAs). This is a drop from the highs of the past 5 years. Note: you can find the approved drugs list on the FDA official website. Figure 1. Novel FDA approvals since 1993. Source: reference [2] Although the number of FDA-approved drugs in 2022 declined compared to the previous five years, there were many highlights this year. ● Approval of several innovative therapies, including the world's first T-cell receptor therapy, and a therapy for amyotrophic lateral sclerosis (ALS)； ● Approval of the first combination formulation targeting LAG-3, the third type of immune checkpoint inhibitor for oncology treatment, after CTLA-4 and PD-1/PDL1;

2. Huateng Pharma https://us.huatengsci.com ● Approval of the first drug capable of intervening in the course of type 1 diabetes and four drugs targeting rare diseases. The Mega-blockbusters of 2022 Approved Drugs Kimmtrak: The First T-cell Receptor (TCR) Therapeutic On January 25, 2022, the FDA approved tebentafusp-tebn (brand name Kimmtrak) for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. This is the first FDA-approved therapy for unresectable or metastatic uveal melanoma, the first approved T-cell receptor (TCR) therapy, and the first bispecific T-cell fusion protein for solid tumors. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform which fuses a gp100–HLA-targeted T cell receptor (TCR) domain to bind cancer cells and an anti-CD3 single-chain variable fragment (scFv) to recruit T cells . The schematics below show how an ImmTAC molecule works. First, ImmTAC molecules recognise and strongly bind to cancer cells displaying a defined target (peptide-HLA) (1). Then, the free end of the ImmTAC molecule (an anti-CD3 antibody fragment) recruits, or redirects’ circulating T cells to the tumour site (2), so that there forms a bridge between the cancer cell and the T cell, enabling the formation of a perfectly optimised immune synapse (3). Finally, Lytic granules are released by the re-directed and activated T cell, leading to destruction of the cancer cell (4).

3. Huateng Pharma https://us.huatengsci.com Figure 2. ImmTAC molecules in action, source: http://www.immuno.myzen.co.uk/ The FDA approved the biologic on the basis of the phase III IMCgp100-202 trial, in previously untreated patients with metastatic uveal melanoma. This randomized pivotal trial evaluated the overall survival of Tebentafusp in patients with previously untreated metastatic melanoma. A total of 378 patients were randomly assigned in a 2:1 ratio to receive tebentafusp or investigator's choice (pembrolizumab, ipilimumab, or dacarbazine). Data from the trial showed that tebentafusp showed a median overall survival benefit as first-line treatment.

4. Huateng Pharma https://us.huatengsci.com Figure 3. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma, Source: https://www.nejm.org/doi/full/10.1056/nejmoa2103485 Opdualag: First Drug Target LAG-3 On March 18, 2022, the FDA approved nivolumab and relatlimab-rmbw (Opdualag, Bristol-Myers Squibb) for adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Opdualag is a fixed-dose combination of the LAG-3 blocking antibody relatlimab and the PD-1 blocking antibody nivolumab. The launch of Opdualag makes LAG-3 the third immune checkpoint in clinical use, after PD-1/PD-L1 and CTLA-4. This approval is based on the results of clinical Phase 2/3 RELATIVITY-047. The study compared the efficacy and safety of Opdualag (n=355) to that of nabumetanib alone (n=359). The RELATIVITY-047 study met its primary endpoint of progression-free survival (PFS). The median PFS was more than doubled in the nabumab and relatlimab combination groups compared to nabumab monotherapy, at 10.1 months (95% confidence interval [CI]: 6.4-15.7) and 4.6 months (95% CI: 3.4-5.6), respectively. Peak sales of the relatlimab plus nivolumab combination could reach $2.3 billion (all forecasts are from BCG's analysis of EvaluatePharma data). Mounjaro: The First New Class Of Diabetes Medicines Introduced In Nearly A Decade

5. Huateng Pharma https://us.huatengsci.com On May 13, 2022, the FDA approved Lilly's new medication Mounjaro (also known as tirzepatide), a GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist for type 2 diabetes management, in addition to diet and exercise. This first-in-class medication has been shown to improve glucose levels and also dramatically improve weight in clinical trials. Three different doses of Mounjaro (5 milligrams, 10 milligrams and 15 milligrams) were evaluated in five clinical trials — SURPASS-1, -2, -3, -4 and -5 — as either a stand-alone therapy or as an add-on to other diabetes medicines. The efficacy of Mounjaro was compared to placebo, a GLP-1 receptor agonist (semaglutide) and two long-acting insulin analogs. Mounjaro outperformed active comparators on blood sugar lowering activity. The newly approved drug also offered weight loss benefits, of around 6.5–14% across dose levels. Figure 4. Tirzepatide for diabetes, source: Moura, F.A., Scirica, B.M. & Ruff, C.T. Tirzepatide for diabetes: on track to SURPASS current therapy. Nat Med 28, 450–451 (2022). https://doi.org/10.1038/s41591-022-01733-2 Peak global sales of this drug could reach $10.8 billion. Sotyktu: The First TYK2 Inhibitor On Septemper 9, 2022, the FDA approved Sotyktu™ (deucravacitinib) a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Deucravacitinib selectively targets TYK2, thereby inhibiting interleukin (IL)-23, IL-12 and type 1 interferon (IFN) signaling, key cytokines involved in the pathogenesis of multiple immune-mediated diseases. Deucravacitinib achieves a high degree of high degree of selectivity by binding to the

6. Huateng Pharma https://us.huatengsci.com regulatory domain of TYK2, resulting in allosteric inhibition of TYK2 and its downstream functions. At physiologically relevant concentrations, deucravacitinib selectively inhibits TYK2. At therapeutic doses, deucravacitinib does not inhibit JAK1, JAK2 or JAK3. Figure 4. Deucravacitinib MOA The approval was based on the results of the pivotal Phase 3 POETYK PSO-1 and POETYK PSO-2 clinical trials, which evaluated the safety and efficacy of Sotyktu (6 mg once daily) versus placebo and Otezla (aprmilast) (30 mg twice daily) in patients with moderate to severe in patients with plaque psoriasis. Across both trials, deucravacitinib showed superior efficacy at 16 and 24 weeks, with responses continuing through 52 weeks vs placebo and apremilast. Peak sales could reach nearly $1.7 billion. Relyvrio: Orphan Drug Designation For The Treatment Of ALS On September 29, 2022, the FDA approved Relyvrio (sodium phenylbutyrate and taurursodiol), developed by Amylyx Pharmaceuticals, for the treatment of adults with amyotrophic lateral sclerosis (ALS). This is the first treatment to significantly slow the loss of physical function and extend survival in people living with ALS in a randomized, placebo-controlled clinical trial. The mechanism by which Relyvrio exerts its therapeutic effect on ALS patients is not clear. One explanation is that they improve the health of intracellular mitochondria and endoplasmic reticulum, thereby delaying the death of nerve cells. Preclinical trials have shown that the synergistic effect of the combination of these two drugs can reduce nerve cell death due to oxidative stress by 90%. Peak sales of Relyvrio could reach $1.3 billion.

7. Huateng Pharma https://us.huatengsci.com Tzield: First Therapy For Prevention Of Type 1 Diabetes On November 17, 2022, the FDA approved Tzield (teplizumab) injection to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes. Teplizumab was first developed as a humanized anti-CD3 monoclonal antibody (mAb) at the University of Chicago, and then further developed at MacroGenics. Eli Lilly licensed the drug from MacroGenics back in 2007. However, a Phase III clinical trial of teplizumab for type 1 diabetes (T1D) failed to meet the primary endpoint. The drug was subsequently acquired by Provention Biologics, which restarted development based on analysis of a subset of the original trials. Figure 5. Teplizumab MOA A randomized, double-blind, event-driven, placebo-controlled trial (TN-10 study) of diabetes prevention with teplizumab showed that teplizumab delays the progression of type I diabetes. Peak sales of teplizumab could reach $1 billion. Selected approvals to watch for in 2023 Several notable new drugs are potentially up for approval in 2023, including two amyloid-targeting antibodies for Alzheimer disease, two RSV vaccines, a haemophilia A gene therapy and a first-in-modality CRISPR-based therapeutic

8. Huateng Pharma https://us.huatengsci.com (Table 1). Hunan Huateng Pharmaceutical Co., Ltd, founded in 2013, is a one-stop contract development and manufacturing organization (CDMO) to manufacture and supply researchers with PEG raw materials & PEG derivatives and products used across the pharmaceutical value chain

9. Huateng Pharma https://us.huatengsci.com including intermediates, excipients, APIs, and reagents. Refernces: [1] Novel Drug Approvals for 2022, https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities- and-new-therapeutic-biological-products/novel-drug-approvals-2022 [2] 2022 FDA approvals: https://www.nature.com/articles/d41573-023-00001-3