the partnering landscape for cns disorders the rise of the ... · the rise of the cell and gene...

biopharmadealmakers.nature.com | June 2019Dedicated to nurturing collaboration and partnerships in the biopharma industry

The partnering landscape for CNS disorders

The rise of the cell and gene therapy market

Charting a year of biopharma dealmaking trends

The medtech industry: fi nancing and deals review

Originally published as an advertising feature in the June 2019 editions of

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Wallonia: cell therapy powerhouse in the heart of EuropeOver the past two decades, Wallonia has emerged as a global powerhouse of cell therapy and regenerative medicine research and development.

Situated in the heart of Europe, the Belgian region of Wallonia has created a vibrant innovation eco-system by equally investing in, and supporting the growth of, scientific excellence and entrepreneurial leadership. The life science sector in particular has experienced remarkable growth and dynamism, and in the cell therapy and regenerative medicine space, concerted efforts in cell characterization and isolation, technology transfer, and clinical manufacturing and development have resulted in technological and scientific excellence that is gain-ing increased international recognition (Fig. 1).

Key drivers behind this dynamic innovation ecosystem are AWEX, Wallonia Export-Investment Agency, and BioWin, the Health Competitiveness Cluster of the Walloon Region.

AWEX: investing in a unique innovation ecosystemAWEX is a public interest organization in charge of promoting foreign trade and attracting foreign investments to Wallonia with the support of the regional government. As such, AWEX helps drive regional innovation in areas ranging from aero-nautics and space or environmental technologies to transport and logistics or life sciences. AWEX serves as a one-stop destination both for Walloon researchers and entrepreneurs interested in start-ing their own companies and for potential foreign partners and investors interested in partaking in Wallonia’s unique innovation ecosystem.

Wallonia, with its world-class research institu-tions, a highly trained workforce, and one of the densest transportation networks in Europe, pro-vides an excellent gateway into and out of the European market. AWEX embodies the region’s philosophy of dynamic and open innovation through technological partnerships and a robust ecosystem.

BioWin: accelerating life sciences innovationBioWin is the life sciences gateway for Wallonia. The cluster’s mission is to help drive innovation and to develop a competitive knowledge base and job opportunities in the health sector. BioWin takes a collaborative approach that brings together all players involved in this space: academic and clini-cal research laboratories, research centers, large industrial groups, small and medium-sized enter-prises, service providers, engineering colleges and universities, business incubators, investors, policy makers, and associated bodies.

Among BioWin’s strategic areas, its focus on regenerative medicine and cell therapies serves as an example of how a concerted effort to (1) sup-port research and development projects and build a network of infrastructures and platforms, (2) support business growth, (3) develop high-level skilled training programs, and (4) generate international business development opportunities can, over a short period of time, result in a thriving industry that is rapidly becoming a global refer-ence in this space.

AWEX and BioWin are excited to showcase here (pages B19, B20, B22 & B23) some of the companies growing out of their joint efforts to develop the regenerative medicine and cell therapy potential in Wallonia.

Marc DechampsDirector of International AffairsBioWin asblGosselies, BelgiumTel: +32 496 59 03 54Email: [email protected]

Alphi Cartuyvels, Deputy General ManagerEurope & North AmericaWallonia Export-Investment AgencyBrussels, BelgiumTel: +32 81 33 28 64Email: [email protected]

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BioWin asblwww.biowin.org

Fig. 1 | The many strengths of Wallonia. Wallonia, situated in the heart of Europe has emerged as a powerhouse of cell therapy and regenerative medicine. CDMO, contract development and manufacturing organization; GMP, good manufacturing practice; R&D, research and development.

Wallonia Export-Investment Agencywww.investinwallonia.be

B18 | June 2019 | biopharmadealmakers.nature.com

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Paving the way in orthopedics and bone diseasesBone Therapeutics has two innovative products in late-stage development for the treatment of delayed-union fractures, spinal fusion and knee osteoarthritis. The company is expanding its pipeline, including through research and development and commercialization partnerships, to help patients improve mobility.

Bone Therapeutics is a leading biotech company focused on helping patients improve their mobil-ity and rebuild their lives with innovative products for high unmet medical needs in orthopedics and bone disease.

Bone-related disorders encompass pathologies ranging from orthopedic conditions, such as severe fractures, to spinal conditions, such as degenera-tive disc disease. Despite the growing number of biopharmaceutical and medical device companies in the field, there is still a need for further disruptive innovation.

Bone Therapeutics focuses on two major chal-lenges: the production of allogeneic cell therapies that are easily distributed commercially, and the production of enhanced viscosupplements that offer analgesic effects with improved lubrication.

The company’s lead clinical-stage programs are (1) an off-the-shelf, allogeneic cell therapy platform, ALLOB, for patients undergoing spinal fusion proce-dures and patients with delayed-union fractures, and (2) an enhanced viscosupplement, JTA-004, for the treatment of pain in knee osteoarthritis (KOA) (Fig. 1).

Bone Therapeutics is looking to further advance these programs through late-stage clinical devel-opment and to progress its orthopedics and bone disease preclinical pipeline. Key to these efforts is to strengthen and build new and existing research and development (R&D) and commercial partnerships.

“Bone Therapeutics is about excellent science combined with smart business,” said Thomas Lienard, CEO of Bone Therapeutics. “Our ambition is to focus on rebuilding people’s lives by being the leader in orthobiologics.”

Going allo in delayed-union fracturesEach year, approximately 700,000 patients in the US, Europe and Japan fail to achieve bone union within three months after a severe fracture. Currently, a ‘wait and see’ approach is adopted for delayed-union fractures, delaying a patient’s return to normal life. In some cases, fractures will resolve after a long period of time, but in many instances, the patient develops a nonunion, a permanent failure of healing that requires invasive surgery.

Bone Therapeutics has developed an allogeneic cell therapy platform, ALLOB, consisting of human allogeneic bone-forming cells that express master osteoblast genes and mesenchymal and bone matrix adhesion markers and are able to adhere, synthesize and mineralize new bone matrix. ALLOB is administered through a minimally invasive injec-tion, directly to the site of the delayed-union fracture, to initiate bone formation and amplify the natural process of regeneration.

The company’s production process maximizes yield, resulting in up to 100,000 doses of cryopre-served ALLOB per bone marrow donation. Compared with autologous approaches, an allogeneic cell therapy offers numerous advantages, including sub-stantial reductions in overall production costs and simplified supply chain logistics that result in more cost-effective commercialization to large patient populations globally.

“We are very proud of the implementation of our improved and optimized production process for ALLOB, which will deliver consistency, scalability, cost effectiveness and ease of use, all of which are critical factors for the development and commercialization of a successful cell therapy product,” said Lienard.

Combo approach to knee painBone Therapeutics is developing JTA-004, a patented, noncellular enhanced viscosupplement for the treat-ment of pain in KOA, the most common chronic joint condition. KOA is caused by progressive breakdown of the protective cartilage in the knee joint, and symptoms include joint pain, swelling, stiffness and a limited range of motion.

No cure exists for KOA, and existing treatments focus on relieving and controlling pain, prevent-ing disease progression, minimizing disability and improving quality of life. Severe KOA is usually resolved with invasive surgical interventions such as total knee replacement.

Viscosupplements are injectable solutions con-taining hyaluronic acid, a main component of the

synovial fluid of the knee, and aim to provide added lubrication and protection to the cartilage of the arthritic joint. JTA-004 is a next-generation viscosup-plement consisting of hyaluronic acid combined with an analgesic agent and an enriched protein solution. The resulting product protects the knee and provides analgesic activity and prolonged lubrication. JTA-004 has shown superiority over the leading viscosupple-ment in a phase 2 study.

Partnering in orthopedics and bone diseaseThe next steps for Bone Therapeutics’ lead programs, ALLOB and JTA-004, include (1) reporting top-line data from the ALLOB phase 2a study in lumbar spi-nal fusion procedures, (2) submitting a clinical trial application (CTA) in Europe and the US for an ALLOB phase 2b/3 clinical trial in delayed-union fractures, and (3) filing a CTA in Europe and the US for a JTA-004 phase 3 clinical trial in KOA.

According to Lienard, “Bone Therapeutics is com-mitted to further progress its late-stage clinical assets as well as its preclinical pipeline through a growing network of R&D and commercial partnerships.”

Thomas Lienard, CEOBone Therapeutics SAGosselies, BelgiumTel: + 32 71 12 10 00Email: [email protected]

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Bone Therapeutics SAwww.bonetherapeutics.com

Fig. 1| Bone Therapeutics’ expanding pipeline. Advanced assets include ALLOB, an allogeneic cell therapy platform for spinal fusion and delayed-union fractures, and JTA-004, a patented, noncellular enhanced viscosupplement for the treatment of pain in knee osteoarthritis.

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Driving the future of CAR-T cell therapiesUsing a multipronged strategy, Celyad is driving the development of next-generation chimeric antigen receptor- T cell-based therapies to treat cancer. Lead programs include both autologous and allogeneic clinical candidates, and the company is also expanding its pipeline through internal development and external partnerships.

Celyad is a clinical-stage global leader in the devel-opment of chimeric antigen receptor (CAR)-T cell therapies for the treatment of cancer. The company is leading the next wave of CAR-T cell therapy devel-opment using a multitargeted approach that can be leveraged for the treatment of both hematological malignancies and solid cancers. In addition, the company is evaluating both an autologous (using the cells of the patient) and an allogeneic approach, also referred to as an off-the-shelf approach (based on cells from healthy donors), for the development of CAR-T therapies. The company’s clinical pipeline is also complemented by a portfolio of preclinical-stage candidates leveraging several technologies including short hairpin RNA (shRNA).

Celyad’s unique value proposition is its combina-tion of a focus on novel natural killer group 2 member D (NKG2D)-based CAR-Ts, a robust intellectual prop-erty position in particular in the allogeneic field, and the company’s expertise in cell therapy manufactur-ing—with an in-house centralized good manufactur-ing practice (GMP) facility and the logistical capabili-ties to support global CAR-T cell therapy clinical trials and a potential commercial launch.

“Celyad has over a decade of experience in cell therapy development and manufacturing. Our strong focus on NKG2D biology allows us to today have a deep knowledge of the safety and potential of the target. Combined with our newly developed technologies, this will undoubtedly keep Celyad at the forefront of the CAR-T field and allow us to deliver novel therapies to cancer patients,” said Filippo Petti, CEO of Celyad.

Pan-cancer CAR-T cell strategySince CAR-T cells emerged on the cancer therapy scene with great promise for revolutionizing cancer treatment, a key challenge has been to expand their reach beyond a very limited number of tumor types. As conventional CAR-T cells are designed to recog-nize only one tumor antigen, their use is restricted to one type of cancer, potentially hindering the full potential of this novel modality.

Over the past four years, Celyad has been focused on addressing these limitations by developing an alternative approach centered around the natural killer (NK) cell’s activating receptor NKG2D. The receptor, which is naturally expressed on NK cells, plays an important role in the innate immune sys-tem’s ability to protect against infections and cancer. The receptor binds to eight different major histo-compatibility complex class I-related ligands (MHC class I polypeptide-related sequence A (MICA), MICB and UL16-binding proteins 1–6) that are not typi-cally expressed at the surface of most cells but that

are induced in response to stress (for example, upon induction of the DNA damage pathway).

NKG2D ligands are highly expressed across many different types of tumor, including but not limited to acute myeloid leukemia (AML) and colorectal can-cer (CRC). As such, NKG2D-based CAR-T cells could potentially address the vast majority of hematological malignancies and solid tumors. In addition, preclini-cal studies have shown that NKG2D CAR-T cells may have the ability to target not only the tumor cells but also the blood vessels that feed the tumors and the inhibitory cells that help tumors evade the immune system within the tumor microenvironment. This amplifies the direct antitumoral effect of the NKG2D CAR-T cells. In addition, NKG2D CAR-T cells may also trigger the generation of long-term cell memory against targeted tumors following induction of the host adaptive immune response—an effect reminiscent of traditional vaccination. Importantly, because NKG2D-based CAR-Ts can bind to several stress ligands, these CAR-T candidates offer minimal risk of clonal selection and tumor escape, a defense mechanism that tumors have developed to hide from first-generation CAR-T therapies that recognize only a single antigen.

Autologous approach: CYAD-01Celyad’s lead clinical candidate for autologous CAR-T therapy, CYAD-01 (Fig. 1), is currently in phase 1 development for the treatment of relapsed or refrac-tory (r/r) AML, myelodysplastic syndromes (MDS) and metastatic CRC (mCRC), both with or without concur-rent administration of standard-of-care treatments (preconditioning chemotherapy).

In the studies without preconditioning, treatment with monotherapy CYAD-01 showed evidence of antileukemic activity in 60% of the patients and a complete response in 40%, providing confidence that the clinical effect was attributed to the NKG2D-based CAR-T. In solid tumors, CYAD-01 has also dem-onstrated a clinical benefit with disease stabilization observed across multiple dose levels of the treatment and good tolerability. Further data from CYAD-01 for both the treatment of r/r AML or MDS and mCRC are expected throughout 2019.

Allogeneic approach: CYAD-101The barrier to the development of allogenic therapies is overcoming graft-versus-host disease (GvHD), in which the donor T cells recognize the patient’s cells as foreign, resulting in attack of the healthy tissue. This event is attributed to the T cell receptor (TCR) at the surface of the donor cells recognizing human leukocyte antigen (HLA) on the patient’s tissues as foreign and instructing the T cells to attack.

Whereas many in the field have used gene-editing technologies such as transcription activator-like effector nucleases (TALENs), zinc finger nucleases or CRISPR–Cas9 to eliminate the TCR gene from the genome of the donor CAR-T cell, Celyad has focused on a means to modify TCR expression or function without editing the genome.

For instance, Celyad’s first non-gene-edited alloge-neic candidate, CYAD-101, coexpresses the TCR inhib-itory molecule (TIM) peptide plus the NKG2D–CAR utilized in CYAD-01. TIM acts as a competitive inhibi-tor to the CD3ζ component of the TCR and interferes with the ability of the TCR to signal, thus lowering the risk associated with the therapy to drive GvHD.

Celyadwww.celyad.com

“Celyad has over a decade of

experience in cell therapy development and manufacturing. Our strong focus on NKG2D biology allows us to today have a deep knowledge of the safety and potential of the target

Filippo Petti, CEO, Celyad



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Initial results of the first cohorts of patients with advanced CRC treated with CYAD-101 are expected in mid-2019.

“The TIM approach is a very elegant way to turn down the signaling of the TCR in an attempt at pre-venting the onset of GvHD while allowing tumor-spe-cific killing through the CAR. It has been optimized to function with NKG2D-based CAR-T therapies. Upcoming data from the allogeneic therapy CYAD-101 should give more proof of Celyad’s out-of-the-box approach to the field of CAR-T bioengineering,” noted David Gilham, Celyad’s VP of research and development (R&D).

Next-generation shRNA-based allogeneic CAR-TsIn parallel, Celyad has already embarked on the development of the next-generation CAR-T cell therapies that simultaneously target a tumor and specific genes via shRNA-mediated silencing. Celyad’s shRNA platform is the result of an exclu-sive agreement with Horizon Discovery Group for

the use of its subsidiary Dharmacon’s SMARTvector shRNA technology. In the allogeneic setting, Celyad is developing an approach leveraging shRNA to silence the mRNA coding for the CD3ζ component of the TCR. The resulting reduction in TCR expres-sion at the cell surface by shRNA is similar to that observed using gene-editing approaches to target the CD3ζ component, in particular CRISPR–Cas9 (Fig. 2).

In addition, an interesting aspect of the shRNA technology is that it dovetails nicely with Celyad’s ‘all-in-one vector’ concept, which allows for quick and efficient design of the company’s CAR-T candidates in a single-step process, leading to a ‘plug-and-play’ approach, thereby providing efficiencies across all segments of R&D and cell manufacturing.

“From our perspective, we have developed an shRNA platform that rivals gene-editing technolo-gies for the design of allogeneic CAR-T therapies. The potential of this next-generation alternative to gene editing goes beyond our proprietary oncol-ogy programs and represents a great opportunity for us to grow our network of partners advancing CAR-T therapies in different therapeutic areas,” commented Petti.

Closing the production gapA key challenge for the implementation of any CAR-T cell-based therapy is the manufacture and dis-tribution of the cells. Celyad has more than a decade of expertise in cell therapy, including the treatment of over 350 patients through the company’s differ-ent trials with cells manufactured in-house. Celyad has its own manufacturing facility to independently improve and optimize the company’s streamlined processes. This results in the seamless and efficient reproduction of materials to advance the company’s pipeline from the preclinical stage through to clinical evaluation and eventually commercialization.

With a large storage capacity and the capability to globally supply cryopreserved drug products, Celyad is well positioned to execute the company’s clinical trials on a global scale. In addition, Celyad already has the capacity to supply materials to support the treat-ment of more than 1,000 patients annually for the company’s lead candidate CYAD-01.

Anne Moore, VP of Corporate StrategyCelyadMont-Saint-Guibert, BelgiumTel: +32 10 39 41 87Email: [email protected]

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Fig. 1 | CYAD-01. Natural killer group 2 member D (NKG2D) is an activating receptor expressed on natural killer (NK) cells that plays an important role in protecting against infection and cancer. CYAD-01 cells are autologous T cells transduced with a chimeric antigen receptor (CAR) comprising a fusion of the native human full-length NKG2D receptor with the cytoplasmic signaling domain of native human CD3ζ, which allows NKG2D to function as a primary receptor in T cells. The co-stimulatory molecule DNAX-activating protein 10 (DAP10) is not part of the transgene but NKG2D associates with this molecule for membrane stabilization to provide the secondary activation signal. The NKG2D-CAR construct binds eight different stress-induced ligands in a major histocompatibility complex-independent fashion expressed by a broad range of cancers.

Fig. 2 | Knockdown expression of TCR. Celyad’s short hairpin RNA (shRNA) platform shows a similar reduction in T cell receptor (TCR) expression to that of CRISPR–Cas9. CTR, control; MFI, median fluorescent intensity.

“The TIM approach optimized to

function with NKG2D-based CAR-T therapies is a very elegant way to turn down the signaling of the TCR in an attempt at preventing the onset of GvHD while allowing tumor-specific killing through the CAR

David Gilham, VP of research and development, Celyad



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HepaStem: toward an alternative to liver transplantationPromethera Biosciences’ HepaStem platform offers the first allogeneic off-the-shelf, liver-derived stem cell therapy for severe liver diseases that could become an alternative to liver transplantation.

The biopharma company Promethera Biosciences SA/NV is developing the first allogeneic off-the-shelf, liver-derived stem cell therapy for severe liver diseases such as cirrhotic and precirrhotic nonalco-holic steatohepatitis (NASH) and acute-on-chronic liver failure (ACLF). The company provides an end-to-end solution backed by its strong track record in the field of liver diseases, its expertise in manufacturing and building the necessary supply chains to deliver these cell-based therapies to patients in need.

Promethera’s development portfolio includes innovative allogenic product candidates derived from ethically donated cadaveric human liver, and the company has two ongoing HepaStem clinical tri-als: a recently initiated phase 2a study in NASH, and a phase 2a study in ACLF—the first-ever study to use stem cells to treat such indication. The company’s patented cell therapy could become an alternative to liver transplantation, a high unmet need given the increased organ shortage worldwide.

The company is looking to upgrade its selected cell candidates together with international industry partners to ensure success in bringing new life-saving drugs to the market.

“HepaStem has a broad therapeutic potential, being a possible first alternative to organ transplant for an ever-growing patient population in dire need, and we are relentless in our drive to bring it to liver disease patients in the safest and fastest way pos-sible,” said Etienne Sokal, Promethera’s founder and chief scientific and medical officer.

The HepaStem advantageHepaStem is a highly advanced cell therapy plat-form consisting of human liver-derived stem cells that are ethically obtained from healthy donors and expanded in a good manufacturing practice (cGMP)-compliant environment. HepaStem cells are admin-istered intravenously, migrate through the blood-stream and accumulate in the liver via the vascular system. In the liver, HepaStem cells exert a number of different effects: ‘cooling down’ the proinflammatory environment of the diseased liver, inhibiting further hepatic stellate cell activation and slowing down their collagen secretion, thereby reducing fibrosis (Fig. 1). This combination of immunomodulatory and antifibrotic paracrine effects provides the mechanis-tic basis for HepaStem’s therapeutic function.

Promethera’s HepaStem is a first-in-class biotech-nology product for modulating through paracrine effects the immune system and liver fibrosis, which could position it as a viable alternative to liver trans-plantation for the indications cited above.

Making clinical stridesPromethera has advanced HepaStem into phase 2a clinical studies in both ACLF and late stage NASH.

ACLF is a recently recognized syndrome charac-terized by acute decompensation (AD) of cirrhosis associated with organ failure. The prevalence of ACLF patients in Europe, the US and Japan is esti-mated to surpass 70,000 patients annually, for most of whom the prognosis is poor. The only effective cure for patients with ACLF is liver transplanta-tion in association with supportive care before transplantation.

In April 2019, Promethera presented clinical data from an ongoing phase 2a study with HepaStem in patients with ACLF or with AD at a high risk of developing ACLF. This is the first time stem cells have been used to treat ACLF.

No adverse events related to HepaStem occurred at the dosage selected for the trial. In addition to this positive safety profile, the study has already shown positive efficacy trends with improvements in three indicators of liver disease severity evident for up to three months after cell infusion.

NASH is a progressive form of liver disease that carries a risk of progressive fibrosis, cirrhosis and end-stage liver disease. Worldwide, the prevalence of NASH in the general population is 3–5%. In the US, this translates to an estimated >2 million adults with NASH-related, advanced liver disease.

In the second quarter of 2019, Promethera started a phase 2a clinical study of HepaStem in patients with cirrhotic and precirrhotic NASH. The study is expected to be completed in the first half of 2020.

“Moving HepaStem into clinical studies in NASH in addition to the ongoing clinical evaluation in ACLF represents a significant milestone for our therapeutic development activities,” said Sokal. “While this first trial in NASH is conducted in Europe and is designed to deliver first clinical results early next year, the clinical development plan for HepaStem is going to expand into the US and Japan in the mid- to long-term.”

In addition to setting up clinical development and commercialization partnerships for the above programs, Promethera is looking to advance development candidates from its early-stage cell therapy portfolio together with industry partners and to collaborate with external partners to use Promethera’s cell platform to deliver systematically therapeutic candidates of interest.

Alexandra Schiettekatte, Global Associate Director CommunicationsPromethera Biosciences SA/NVMont-Saint-Guibert, BelgiumTel: +32 10 39 43 00Email: alexandra.schiettekatte@

promethera.com

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Promethera Biosciences SA/NVwww.promethera.com/

Fig. 1 | Promethera’s HepaStem advanced cell therapy platform for severe liver disease. The left image shows hepatic tissue or lobule in a diseased state (fibrotic and inflamed); the right shows the expected state after HepaStem treatment.




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PDC*vac: highly potent, versatile, off-the-shelf therapeutic cancer vaccinesPDC*line Pharma is developing cancer vaccines derived from a proprietary allogeneic human plasmacytoid dendritic cell line. Following a feasibility clinical trial in melanoma, the company is actively expanding and diversifying its portfolio of cancer vaccines with a phase 1/2 trial in non-small-cell lung cancer.

Based in Liège (Belgium) and Grenoble (France), clinical-stage biotech PDC*line Pharma is develop-ing a novel class of off-the-shelf cancer immuno-therapies derived from PDC*line, a proprietary plas-macytoid dendritic cell line that can be engineered to display high levels of any cancer-antigen-derived, human leukocyte antigen (HLA)-A2-restricted peptide of choice. The resulting PDC*vac potently primes and boosts fully functional antitumor CD8+ T cells to generate strong cytotoxic activity against tumor cells.

Compared with conventional, mostly autologous dendritic cell (DC)-derived vaccines, PDC*vac is off the shelf, easily scalable, up to ten times more eco-nomical, easily genetically modifiable and exhibits up to 200-fold higher potency. The antitumor activ-ity of PDC*vac can be further increased by using it in combination with anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors to achieve a synergistic effect.

“PDC*vac is derived from the only therapeutic plas-macytoid dendritic cell line available off the shelf and is ready to be used globally,” said Eric Halioua, CEO and president of PDC*line Pharma. “The first preclini-cal and clinical results are very encouraging, and the recent licensing deal we signed with leading Korean pharmaceutical company LG Chem further under-scores the potential of our technology.”

In March 2019, PDC*line Pharma granted an exclu-sive license in South Korea and exclusive options in other Asian countries to LG Chem Life Sciences Company for the development and commercializa-tion of the PDC*lung cancer vaccine. The total value of the deal is $123 million (€108 million) plus tiered royalties on net sales in Asia.

Giving cancer vaccines a PDC boostDC-derived cancer vaccines have been in develop-ment for close to three decades now, but despite some clinical success, there is a need for further improvement and optimization of the approach. Existing DC-based cancer vaccines are mostly autologous, which severely limits the scalability of the approach, and their efficacy is compromised by the challenge of obtaining a sufficient quantity of fully functional DCs and by external factors such as tumor-induced immune suppression.

PDC*line addresses these issues through its increased ability to prime and expand antigen-specific CD8+ T cells compared with conventional (myeloid) DCs. PDC*line achieves this effect through an original mechanism of action involving (1) the

activation of allogeneic CD4+ T cells and (2) the expression of specific cytokines, which together help to fully activate and expand antitumor CD8+ T cells.

In addition, the lack of expression of key costimu-latory molecules prevents the effective proliferation of allogeneic CD4+ T cells, explaining the absence of allogeneic rejection of PDC*line both in vitro and in vivo.

Together, all these features lead to a boosted expansion of antigen-specific CD8+ T cells, resulting in the potent antitumor activity of PDC*vac.

A PDC*vac for every needPDC*line is a professional and universal antigen-presenting cell that is very easy to expand in large quantities. Following in vitro loading with the desired tumor antigen target, the resulting PDC*vac can be irradiated and stored frozen for years. The off-the-shelf product is thawed and directly injected to treat any patient with a cancer type expressing the selected antigens and HLA-A2. Because of the ease of transformation of the PDC*line cells, PDC*vac can be engineered to present different HLAs and/or any type of conventional antigen, neoantigen, shared antigen, peptide, mRNA or even viral vector (Fig. 1).

PDC*vac is currently available in the form of several cancer vaccine drugs. • PDC*mel: PDC*Pharma’s fi rst candidate for melanoma. PDC*mel completed a fi rst-in-human phase 1b feasibility clinical trial in 2017 assessing the safety of the product, the absence of rejection and its biological activity.

• PDC*lung: the company’s leading candidate for non-small-cell lung cancer. PDC*lung targets widely expressed shared antigens. A phase 1b/2 trial evaluating its safety and biological activity, alone and in combination with anti-PD-1 immune checkpoint inhibitors, is being initiated.

• PDC*neo: PDC*Pharma’s next candidate. PDC*neo is in preclinical development as a platform for expressing any kind of neoantigen.

According to Halioua, “with a workforce of 20 people, an experienced management team and a robust financial situation—looking to close a new round of financing of €11 million in 2019 following a previous raise of €17 million—PDC*line Pharma is in a strong position to advance its existing clinical programs and further develop its preclinical pipeline.”

Eric Halioua, President and CEOPDC*line PharmaLiège, BelgiumTel: +32 474 05 78 66Email: [email protected]

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PDC*line Pharmawww.pdc-line-pharma.com

Fig. 1 | Development of next-generation plasmacytoid dendritic cell-based cancer vaccines. These allogeneic vaccines are derived from a potent plasmacytoid dendritic cell (PDC) line and can be engineered to present any cancer antigen-derived, human leukocyte antigen (HLA)-A2-restricted peptide of choice or neoantigen. ATMP, advanced therapy medicinal product.

Growthinbioreactorinsuspensioninsyntheticmedium

Loadedwithtumorantigens

g-Irradiation(proliferationstoppedandfunctionalityconserved)

Off-the-shelf,ready-to-useproduct(storedinliquidnitrogen)

Humanleukemic-cell-derivedHLA-A2+ PDCline

ATMPclassification



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