Adaptimmune Therapeutics

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Schorsch11 vom 09.01.20 20:40 Uhr

Summary Adaptimmune is developing TCRs to target solid tumors with key clinical data to be presented in the first half of 2020. Stock is trading down by over 90% of its IPO Price, with cash position running low. The company has also been plagued by patient deaths in clinical trials and key executives departure. If successful, Adaptimmune will bring the first TCR into the market by 2022 and it might be worth it to take a small speculative position. Company Overview Adaptimmune (ADAP) is a clinical-stage biotechnology company developing novel cell therapies in solid tumors. With their proprietary Specific Peptide Enhanced Affinity Receptor ("SPEAR") T cell platform, they identify cancer targets, find and genetically engineer T cell receptors ("TCRs") and product therapeutic candidates for administration to patients. With their affinity engineered TCRs, Adaptimmune aspires to be the first company to have a TCR T cell therapy approved for a solid tumor indication by 2022. Technology Overview T cells and their receptors play an important part in targeting and destroying cancer cells by creating a natural system that is designed to scan the body for diseased cells. In general, cells process proteins internally and then convert these proteins into peptide fragments which are then presented on the cell surface by a protein complex called the Human Leukocyte Antigen ("HLA"). T cells naturally scan all other cells in the body for the presence of abnormal peptide fragments and the recognition of this peptide-HLA complex takes place through the TCR expressed on the T-cells. However, binding of naturally occurring TCRs to cancer targets tends to be very poor because cancer proteins appear very similar to naturally occurring proteins on healthy cells and are not easily recognized by TCRs. Even when TCRs can recognize cancer cells that express novel proteins caused by mutations, T cell response is often suppressed by cancer or elements of the immune system. TCRs can be genetically engineered to circumvent this. However, it is important to first identify and validate a suitable target cancer peptide to ensure that any engineered TCR is specific to targeted cancer and will not bind to the same target on non-cancer cells, or that the TCR does not recognize a similar peptide derived from a protein in normal cells. Adaptimmune's target identification platform will first validate cancer-testis antigens and then identify non-cancer testis antigens that are closely related to a specific disease indication. Lastly, targets are identified in the contexts of different HLA types to ensure a broad patient population can be addressed for any given target across multiple HLA types. Once a suitable target peptide is found, Adaptimmune then identifies TCRs that are capable of binding to the target peptide. The TCRs are then engineered to enhance and optimize their ability to target and bind to the cancer peptides to create a highly targeted immunotherapy. Adaptimmune believes that their SPEAR T cell platform technology enables them to develop a pipeline of targets and TCR therapeutic candidates that are effective in a variety of cancer types that are unresponsive to currently available and experimental therapies. Clinical Pipeline Adaptimmune is developing 2 SPEAR T-cells program in clinical trials with a focus on 2 target antigens, MAGE-A4 and alpha-fetoprotein ("AFP"). Its full clinical pipeline is listed in Figure 1. The ADP-A2M4 SPEAR T cell therapy is directed to a member of the MAGE family of cancer-testis antigen, MAGE-A4, which is among the most expressed cancer-testis antigens. Its lead program is the ADP-A2M4 program which is currently being evaluated in a Phase 2 trial (SPEARHEAD-1) for Synovial Sarcoma and Myxoid/round cell liposarcoma ("MRCLS"). In November 2019, Adaptimmune reported interim data showing that 7 out of 14 patients in the study have had clinical responses (both confirmed and unconfirmed partial responses) representing an objective response rate ("ORR") of 50%. 6 other patients had stable disease, bringing a total of 13 patients showing clinical benefits, representing 93% disease control rate. On the back of the promising data, the FDA granted Orphan Drug Status Designation and Regenerative Medicine Advanced Therapy Designation to ADP-A2M4 for the treatment of Synovial Sarcoma. ADP-A2M4 is also being evaluated in a Phase 1 trial for multiple solid tumors which is expected to run until the first half of 2020 and a phase 1 low-radiation sub-study in collaboration with MD Anderson to evaluate low dose radiation in combination with ADP-A2M4 across multiple tumor types. In July 2019, Adaptimmune also started their first next-generation therapy ADP-A2M4CD8 which differentiates from ADP-A2M4 in that it also expresses the CD8α co-receptor alongside the engineered TCR that targets MAGE-A4. Preclinical data support that the co-expression of CD8α may broaden the immune response against solid tumors and increase antitumor activity. Separately, Adaptimmune is also conducting a phase 1 dose-escalation study of the ADP-A2AFP SPEAR T cell therapy. The trial will evaluate the safety and anti-tumor activity of ADP-A2AFP candidate in patients with advanced hepatocellular carcinoma. The study has so far seen tumor shrinkage in 1 patient and is currently dosing the third and highest dose level. Other Programs and Partnerships Beyond its current clinical programs, Adaptimmune has also developed/is developing other product candidates. The most notable example is the SPEAR T cell therapy targeting NY-ESO which was exclusively licensed to GlaxoSmithKline (GSK). The product candidate, which is now known as GSK3377794, is being evaluated in multiple cancer indications as a monotherapy as well as in combination with checkpoint inhibitor and has been granted PRIME designation by the EMA and Breakthrough Therapy Designation by the FDA. Under the license agreement, Adaptimmune received $61M and will be eligible for future additional payment based on development milestones, tiered sales milestones, and royalties on worldwide sales. In 2017, GSK nominated a second target, preferentially expressed antigen in melanoma ("PRAME"), as part of their collaboration with Adaptimmune. Although the program has since ended, GSK still has the option to nominate 3 additional targets, excluding the programs in which Adaptimmune has already started clinical trials. Adaptimmune is also developing ADP-A2M10 to target MAGE-A10 in 2 separate trials for non-small lung cancer and bladder, melanoma, and head and neck cancers. To date, tumor shrinkage has been seen in lung cancer patients. However, the decision was *** in August 2019 to deprioritize ADP-A2M10 for the corporate focus to be placed on current programs in ADP-A2M4 and ADP-A2AFP. Beyond its own programs, Adaptimmune is also partnering with other companies to develop next-generation therapies. For example, they are working with Alpine Immune Sciences to develop next-generation SPEAR T cell products that incorporate Alpine's secreted and transmembrane immunomodulatory protein to further enhance the design and development of SPEAR T cell therapies with enhanced anti-tumor activities. They are also working with Noile-Immune Biotech to co-develop next-generation SPEAR T cell products, incorporating Noile-Immune's proliferation inducing and migration enhancing technology, based upon co-expression of IL-7 and CCL19, which improves the proliferation of SPEAR T cells. Prospects The company has given guidance that there will be key clinical updates in the first half of 2020, including data updates on the SPEARHEAD-1, SURPASS and ADP-A2AFP trials. With cash and equivalents and total liquidity only at $39.4M and $102.9M respectively, operations can only be funded to the third quarter of 2020 and it is certainly all but assured that dilution will take place to raise more funds before that. It was also revealed recently that 3 patients died from its clinical trials. While the deaths were fortunately not treatment-related, it is not the first time that their trials have been plagued by patient deaths. Given that Adaptimmune is currently trading at more than 90% below its IPO price of $17, investors must be sweating that the upcoming clinical updates would be positive. The company has also experienced a management shakeup in recent times, with its founder James Noble stepping down as CEO to be a non-executive director and their President of R&D, Rafael Amado, leaving to join Allogene Therapeutics (ALLO) as their Chief Medical officer. For investors, it is certainly fair to assume that it is not a good sign that key executives are leaving the company ahead of key data readouts. The silver lining is that the company seems to have finally realized the predicament they are in and that they are making efforts to refocus their resources on key priorities, such as dropping off the ADP-A2A10 program to cut costs. The company has also *** good progress in recent times on its clinical programs in the SPEARHEAD-1, SURPASS, low radiation dose in ADP-A2M4 and ADP-A2ADP trials. It also has its own manufacturing facility which will be an invaluable asset as it prepares for commercialization. Conclusion Adaptimmune's stock has taken a beating since its IPO. Given that their clinical pipelines are relatively early stage and that their cash position is weak, any negative catalysts in their upcoming clinical data updates may send the stock crashing even more. The departure of key executives before the data readouts also raises a red flag. Having said that, Adaptimmune can be considered the most advanced company working on TCR and if successful, their therapies may be applied to solid tumors. Given the limitations of CAR Ts to treat solid tumors, Adaptimmune may well be worth much more than its current market cap of around $120M. If their clinical data goes well, they may even land more deals like the licensing agreement with GSK. Investing in clinical-stage biotechnology companies is risky and investors should always conduct their own due diligence and consider their risk profile and time horizon. Personally, I do not currently hold any position in Adaptimmune but may consider taking up a small speculative position in the coming weeks/months, ahead of the clinical data updates. I have previously covered companies working on developing cell therapies, including Iovance Biotherapeutics (IOVA), who is working on TILs. Adaptimmune: Using TCRs To Fight Solid Tumors https://seekingalpha.com/article/4315797?source=ansh $ADAP, $ALLO, $GSK, $IOVA

Schorsch11 vom 09.01.20 20:34 Uhr

Catalysts 1H 2020 Durability of sarcoma responses ADP-A2AFP data update Safety and response data from SURPASS trial SPEARHEAD-1 interim futility ADP-A2M4 Phase 1 trial continues Beyond 1H 2020 Allogeneic program data update Next targets into clinic Data from SPEARHEAD-1 Data from other programs https://ir.adaptimmune.com/static-files/cf1e7289-a1c8-4d55-b51d-71c10de608d9