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Highlights of the upcoming American Society of Hematology meeting include updated data for CAR-T therapies, pivotal results moving major brands into bigger markets, PD-1 inhibitors branching out into new types of hematological malignancies and dueling gene therapies in hemophilia.





Biopharmaceutical companies large and small will jockey for competitive positions in the emerging market of chimeric antigen receptor T-cell (CAR-T) therapies for hematologic malignancies and in moving big-name drugs into large new markets with data presented during the American Society of Hematology (ASH) annual meeting Dec. 9-12 in Atlanta.



The 2017 ASH meeting marks the end of a breakthrough year for autologous CAR-T therapies, during which the US FDA approved Novartis AG's Kymriah (tisagenlecleucel, or CTL019) for relapsed/refractory acute lymphoblastic leukemia (ALL) and Gilead Sciences Inc.'s Yescarta(axicabtagene ciloleucel) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). (Also see "Novartis Beats CAR-T Competitors To The Pricing Punch With Kymriah Approval" - Scrip, 31 Aug, 2017.) and (Also see "Gilead/Kite Pricing For Yescarta Undercuts Novartis's CAR-T Kymriah" - Scrip, 18 Oct, 2017.). The scientific meeting will feature data for both therapies and for CAR-T programs targeting B-cell maturation antigen (BCMA), including bluebird bio Inc./Celgene Corp.'s bb2121 in relapsed/refractory multiple myeloma.



"Among all of the hematological oncology indications, we believe that there will be the most interest in the multiple myeloma presentations and posters," Bernstein Research analyst Aaron (Ronny) Gal said in a Nov. 22 preview note about the ASH meeting.



Programs aimed at the BCMA target will be a major area of focus, with bb2121 garnering the most interest, but investors are "looking closely at competing programs from a range of companies and academic institutions," Gal said.



Investors and competing biopharma firms will be tracking the presentations below, which were flagged by analysts and other experts, at the upcoming meeting. Phase III MURANO data for AbbVie Inc./Roche's BCL-2 inhibitor Venclexta/Venclyxto (venetoclax) with Roche's anti-CD20 antibody Rituxan (rituximab) in chronic lymphocytic leukemia (CLL) also is among key presentations to watch at ASH, as well as first-line multiple myeloma results for Johnson & Johnson's Darzalex (daratumumab).



Abbvie/Roche's Venclexta Blooms

The full report on the Phase III MURANO study in CLL is part of the late-breakers session (Abstract #LBA-2) on the last day of the ASH meeting, Dec. 12. The companies announced in September that the study met its primary progression-free survival (PFS) endpoint. (Also see "MURANO To Drive AbbVie/Roche's Venetoclax In CLL" - Scrip, 19 Sep, 2017.)



Venclexta has long been associated with strong response rates, including complete responses, and the number of patients achieving negative minimal residual disease status will be of interest.



MURANO promises to substantially expand the drug's reach from the niche population of CLL with 17p deletions to relapsed/refractory CLL, as a combination treatment with rituximab. A filing is expected by the end of the year.



Initial results from the Bloodwise TAP CLARITY trial of Venclexta in combination with Johnson & Johnson/AbbVie's Imbruvica will be presented at the meeting on Dec. 10.



Biomedtracker analysts also noted that top-line data from the Phase III CLL14 study testing Venclexta with Roche's next-generation anti-CD20 antibody Gazyva (obinutuzumab) in first-line CLL are expected in 2018.



J&J's Darzalex In First-Line Myeloma

J&J's anti-CD38 antibody Darzalex aced the ALCYONE first-line multiple myeloma study and ASH attendees will get the nitty gritty on the data during the late-breakers session on Dec. 12.



ALCYONE tested Darzelex with Takeda Pharmaceutical Co. Ltd.'s proteasome inhibitor Velcade(bortezomib), melphalan and prednisone (VMP) versus VMP alone in newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplantation. J&J announced in August that the test drug combo demonstrated a reduction in risk for progression of 50% and a tripling of the rate of patients who were negative for minimal residual disease, and submitted a supplementary filing in November. (Also see "ALCYONE Paves Way For J&J/Genmab's Darzalex In Frontline Myeloma" - Scrip, 24 Aug, 2017.) Overall survival data were immature at the time the abstract was reported.



Darzalex, which was licensed from Genmab AS, was first approved in November 2015 for use as a monotherapy after three prior lines of therapy and went on to expand indications for use after one or more prior therapies.



"With a 50% reduction in progressive disease or death, these excellent results should assure this combination’s approval for a subset of frontline multiple myeloma patients," Biomedtracker analysts commented.



While the VMP triplet regimen is appropriate for first-line multiple myeloma patients who are unsuitable for stem cell transplantation, a triplet regimen combining a proteasome inhibitor (Velcade or Amgen Inc.'s Kyprolis (carfilzomib), an immunomodulating agent – Celgene Corp.'s Revlimid (lenalidomide) – and a steroid (dexamethasone) is suited for a wider range of first-line patients.



"There is therefore much anticipation for the results of a Phase II study evaluating the addition of Darzalex to an RVD triplet combination," Biomedtracker analysts noted.



BCMA-CAR Competitors: bluebird, Juno, Novartis

Bluebird's updated Phase I data for its BCMA-targeted CAR-T therapy bb2121 in heavily pretreated multiple myeloma are eagerly awaited (Abstract #740). (Also see "Accelerated Development On The Cards In EU and US For Bluebird, Celgene’s CAR-T Therapy" - Scrip, 16 Nov, 2017.)



The ASH abstract indicated an objective response rate of 89% and 100%, depending on the dose. The candidate was also well-tolerated, with no Grade 3+ neurological toxicities.



The patients had a median of seven prior lines of therapy and the results are "potentially groundbreaking," Bernstein's Gal noted. Data reflecting an additional five months of follow-up will be presented.



"Durability and safety of bb2121 remain questions but concern could be largely assuaged with the latest data," the analyst added.



The company will also be releasing updated data (Abstract #4609) for its gene therapy LentiGlobinin sickle cell disease and beta thalassemia, using an improved manufacturing process (Also see "Bluebird Bio Sings Cheerily Of Its "Biggest ASH Ever"" - Scrip, 2 Nov, 2017.)



Juno Therapeutics Inc. and Novartis will each have Phase I data for their BCMA-targeted CAR-T therapies in relapsed/refractory multiple myeloma – Abstracts #742 and #505 – on Dec. 10 and investors will be on the lookout for differentiation from bluebird's bb2121.



GSK's BCMA Antibody-Drug Conjugate

GlaxoSmithKline PLC's GSK2857916 is an antibody-drug conjugate aimed at the BCMA target. In a Phase I trial (Abstract #741) of relapsed refractory multiple myeloma and other hematologic malignancies expressing BCMA, the drug demonstrated an objective response rate of 60% (21 of 35 patients). If new modalities – such as antibody-drug conjugates and bispecific antibodies – targeting BCMA can achieve a 70% ORR, they could be competitive with CAR-T therapies due to simpler manufacturing and administration, Gal commented.



Pfizer/Cellectis/Servier's UCART19

Pfizer Inc./Cellectis SA/Servier SA will be presenting data from two Phase I studies of their allogeneic, or off-the-shelf, anti-CD19 CAR-T candidate UCART19 in adult and pediatric ALL (Abstracts #887 and #1271). In contrast with autologous, personalized CAR-T therapies, the off-the-shelf approach is much simpler and would be attractive if efficacy and safety are at least as good.



UCART19 was the second Cellectis-originated allogeneic CAR-T therapy to move into the clinic. (Also see "Cellectis Moves First Off-The-Shelf CAR-T Into US Clinical Trials" - Scrip, 3 Jul, 2017.) The company's first – and the first-ever off-the-shelf CAR-T to begin testing in humans – was put on a clinical hold in September due to a patient death, but the hold was lifted in November. (Also see "A Cellectis Trial Death Points To Challenges Ahead For CAR-T" - Scrip, 5 Sep, 2017.)



Juno/Celgene's JCAR017 In Lymphoma

The ASH meeting will provide a closer look at Juno/Celgene's JCAR017, which the companies are positioning as a best-in-class anti-CD19 CAR-T therapy.



The ASH abstract (#581) showed strong data for JCAR017 in the Phase I TRANSCEND study of DLBCL and updated data will be presented at the meeting. Adverse event data are of particular interest as Juno believes the candidate will be safe enough to use in the outpatient setting. (Also see "CAR-T To Go: Juno Sees JCAR017 As Safer, Suited For Outpatients" - Scrip, 2 Nov, 2017.)



Mustang/Fortress Biotech's CD123-Targeted CAR

Fortress Biotech Inc. spinout Mustang Bio Inc.'s promising initial data from the first-in-human Phase I study (Abstract #811) of its CAR-T therapy MB-102 will shed more light on the value of targeting CD123 in acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN).



"CD123 is overexpressed on AML blasts and leukemic stem cell (LSC)-enriched cell subpopulations compared to normal hematopoietic stem cells and myeloid progenitors. High levels of CD123 expression is also one of the diagnostic hallmarks for BPDCN. All these features make CD123 an attractive target for T cell-based adoptive immunotherapy," Biomedtracker analysts noted.



Ablynx's Caplacizumab: Strength Of Hercules

Ablynx NV'santi-von Willebrand factor nanobody medicine caplacizumab is in line to become the first FDA-approved drug for acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood clotting disorder, based on the strength of HERCULES data to be presented during the Dec. 12 late-breaker session at the ASH meeting (Abstract #LBA-1).



Top-line results were reported in October. (Also see "Caterpillar To Butterfly? Ablynx Says Caplacizumab Data Transformational" - Scrip, 2 Oct, 2017.) The drug demonstrated a reduction in the time to platelet count response and faster resolution of aTTP and a clinically meaningful reduction in aTTP-related death. The data helped Ablynx complete one of the largest US initial public offerings this year. (Also see "Ablynx Ups Profile Stateside With $200m Nasdaq Listing" - Scrip, 25 Oct, 2017.)



Second-Gen FLT3 Inhibition

Astellas Pharma Inc.'s Phase III candidate gilteritinib is among the next wave of inhibitors of FLT3 mutations being aimed at AML, along with Daiichi Sankyo Co. Ltd.'s quizartinib, which also is in Phase III, and Arog Pharmaceuticals' crenolanib, which is in Phase II.



Phase I data (Abstract #722) suggest that gilteritinib is well-tolerated and generates high response rates in newly diagnosed AML with FLT3 mutations.



Novartis's Rydapt (midostaurin) became the first drug approved by the US FDA for AML with FLT3 mutations in April. (Also see "Novartis' Rydapt: Two Indications, Two Prices" - Scrip, 1 May, 2017.)



AML is a small indication, with 21,000 new diagnoses in the US in 2017, yet it has been a very active area of development. (Also see "AML Pipeline Update: Pharmas Pursue Big Breakthroughs In Niche Spaces" - Scrip, 6 Jan, 2017.) About one-third of these cases are FLT3-positive.



ASH and FDA are jointly holding a special interest session at the meeting in the late afternoon of Dec. 11 to discuss AML drugs recently approved by the agency, including Rydapt, and "evolving regulatory considerations" for the disease.



Gene Therapies Duel In Hemophilia

Spark Therapeutics Inc. and BioMarin Pharmaceutical Inc. are presenting Phase I/II data for their gene therapies in hemophilia A – Spk-8011 AAV-mediated gene therapy and Bmn 270 AAV5-FVIII gene transfer, respectively – on Dec. 11.



"We think the one investors will be paying more attention to is Spark, simply because we have a better sense for where BioMarin nets out, but have not yet seen much data from Spark," Bernstein's Gal commented.



The Spark presentation (Abstract #604) includes data for three doses and investors are keen to see results for the mid and high doses, Gal commented.



"The questions will be 1) how well do these doses do in getting patients into a good range FVIII activity range and 2) how much more variability do we get as we go up on dose," Gal said.



PD-1s Test The Waters In DLBCL

Safety has been an issue in studies of PD-1 inhibitors in multiple myeloma, causing the FDA to call a halt to multiple trials, but studies are ongoing in other hematological malignancies. (Also see "FDA Eyeing Other PD-1/L1 Drugs With Clinical Hold On Keytruda Myeloma Trials" - Scrip, 31 Aug, 2017.) Merck & Co. Inc. has Phase I data at ASH for Keytruda (pembrolizumab) in combination with the standard R-CHOP chemotherapy regimen in first-line DLBCL (#Abstract 4125).



"Keytruda in the first-line setting, with relatively intact host immunity and coexistence of malignant cells within the tumor microenvironment, may represent a window for effective application of immune checkpoint inhibition in DLBCL. However, the safety of Keytruda with chemotherapy in lymphoma, and anthracyclines in particular, remains undefined," BioMedTracker analysts said.



Otherimmuno-oncology highlights includepromising Phase I/II data for Bristol-Myers Squibb Co.'s PD-1 inhibitor Opdivo (nivolumab) in combination with Imbruvicain relapsed or refractory non-Hodgkin lymphoma and high-risk CLL (Abstract #833).


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