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Kymriah Manufacturing

In 2012, Novartis acquired a specialized facility from the former Dendreon for $43 million. Dendreon went bankrupt trying to establish its once-promising prostate cancer vaccine Provenge.

Dendreon’s Morris Plains, New Jersey, facility is a 173,100 square foot state-of-the-art IMF.

In July 2018, before EU approval, Novartis announced that it had signed an agreement with CellforCure, a French CDMO, to produce CAR-T cell therapies. Manufacturing at Cell for Cure’s site in Les Ulis, a city southwest of Paris, would mimic the processes Novartis has in place at its Morris Plains, New Jersey hub.

In August 2018, when Kymriah get approved in EU, Norvartis said it will spend CHF90 million over three years on an existing building at a production site in Stein, Switzerland. Novartis expects to initially have 260 positions and create up to 450 new jobs by 2021.

New manufacturing capacities are keys to scale up revenue and Novartis acknowledged existing production problems with out-of-spec doses.

In September 2018, Novartis paid $40 million for a 9% stake in Cellular Biomedicine Group (CBMG), a Shanghai-based firm which will manufacture CAR-T cell therapy Kymriah for the China market and license select proprietary technology to Novartis for global use.

In December 2018, Novartis went further to acquire CellforCure from LFB including the cell and gene manufacturing facility located in Les Ulis and the related adjacent land.

The Switzerland facility completed the first clinical production batch in September 2019 and inaugurated at the end of November.

In addition to manufacturing areas for novel CAR-T cell therapies, the new building also hosts the production of innovative, difficult-to-manufacture solid dosage forms such as tablets and capsules.

The manufacturing process of personalized cell therapies is more complex than mass production of traditional drugs.

The location is also extremely important which affects turnaround time.

Yescarta Manufacturing

Kite’s original lease of a 18,000 sqft site in Santa Monica supported its clinical trials while its 43,500 Los Angles facility opened in 2016 was designed for commercialization launch.

The El Segundo site is estimated to have the capacity to produce up to 5,000 patient therapies per year. The plant’s location, adjacent to Los Angeles International Airport, is intended to expedite receipt and shipment of engineered T-cells from and to patients across the United States and Europe. According to Kite, the time from when a patient’s materials are shipped to the facility to when the engineered T cells are returned to the patient is approximately 14 days.

When Yescarta was approved in Oct 2017, Gilead’s statement said in the ZUMA-1 pivotal trial, Kite demonstrated a 99 percent manufacturing success rate with a median manufacturing turnaround time of 17 days, which is important to patients given the potential for rapid disease progression in this population.”

In 2018, three month before Yescarta is approved in Europe, Kite leased a new facility in the Netherlands to engineer cell therapies in Europe – a 117,000 square-foot site in Hoofddorp (SEGRO Park Amsterdam Airport). The plant is expected to be operational in 2020 and saving 3-4 days in delivery (from Europe to LA). The current time including international delivery, from apheresis to delivery of Yescarta, is 26-29 days.

Meanwhile, in addition to the Netherlands facility, Kite said it had recently purchased a new building in Santa Monica from Astellas Pharma Inc. that will be used for cell therapy research, development and the expansion of clinical manufacturing capabilities, and has leased a 26,000 square-foot facility in Gaithersburg, Maryland.

In July 2018, it also added Michael Amoroso as Senior Vice President and Head of Worldwide Commercial, Cell Therapy. Mr. Amoroso was leading Ensai’s American commercialization of oncology business; but more importantly, he worked at Celgene on several oncology roles before serving as Commercial Lead, Global Marketing for Celgene’s CAR T programs. His current title is CMO of Kite.

In April 2019, Kite announced plans for a new 20-acre site in Frederick County, Maryland. Kite bought the 20-acre Urbana site in November 2018 for $7.5 million. The facility will have 62,000 square feet of office space and 217,000 square feet of manufacturing, plant, and shipping space.

On Gilead’s 2019 1st quarter earnings call, its new CEO said they will separate Kite into its own business unit.

In July 2019, Kite announced that Christi L. Shaw will join as CEO of Kite. Ms. Shaw was serving as Senior Vice President of Eli Lilly &. Co., and President of Lilly Bio-Medicines.

Later in July 2019, Kite announced plans for a new 67,000-square-foot facility in Oceanside, California, dedicated to the development and manufacturing of viral vectors, a critical starting material in the production of cell therapies. The facility will go live in the second half of 2021.

Approvals and Acquisition

Back in 2017, when Kymriah by Novartis was first approved by FDA, it marked the beginning of commercializing CAR-T cell therapies in the US.

CAR-T therapies have shown superior effects in treating blood cancers. Kymriah’s initial approved indication is B-cell precursor ALL that is refractory or in second or later relapse for patients up to 25 years of age. There are approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year; 15-20 percent of pediatric B cell precursor ALL patients relapse after their initial remission.

On Aug 28, 11 days after Kymriah’s approval, another CAR-T cell therapy company Kite Pharma was acquired by Gilead for $11.9 billion. The $180.00 per share acquisition price represents a 29% premium to Kite’s closing on Friday, August 25, and a 50% premium to the company’s 30-day volume weighted average stock price.

At the time of acquisition, Kite’s lead candidate was under FDA’s priority review and had submitted the first CAR-T therapy application in Europe for the treatment of relapsed/refractory DLBCL, TFL and PMBCL with the European Medicines Agency (EMA).

On Oct 18, FDA approved Kite’s Yescarta for use in adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. DLBCL is the most common type of NHL in adults, with 24,000 new cases diagnosed each year in the US (1/3 of newly diagnosed NHL).

Concurrently, in Gilead’s press release, it estimated that in the US each year there are approximately 7,500 patients with refractory DLBCL who are eligible for CAR T therapy.

In May 2018, FDA expanded Kymriah’s approval for adults with relapsed or refractory large B-cell lymphoma as well.

In August 2018, Yescarta received European Marketing Authorization for adult patients with relapsed or refractory DLBCL and PMBCL, after two or more lines of systemic therapy; Kymriah was approved in EU for the treatment of pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse; and for the treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

In March 2019, Japan’s Ministry of Health, Labor and Welfare (MHLW) has approved Kymriah (tisagenlecleucel) for the treatment of two distinct indications – CD19-positive relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) and CD19-positive r/r diffuse large B-cell lymphoma (DLBCL).

Clinical Trails and Data

r/r ALL

Kymriah was first approved by FDA based on 82.5% overall remission rate (ORR) reported at 3 months, of which all were MRD– (n=52/63).

• lower limit of the 95% confidence interval for ORR is 70.9%, which is above the pre-set null hypothesis rate of 20%
• 40 subjects (63.5%) had the best response of CR within the first 3 months after infusion
• 12 subjects (19.0%) had the best response of CRi.
• Among the 52 responders, the median duration of response (DOR) was not yet reached (range: 1.2 to 14.1+ months) with the median follow-up of 4.8 months.
• 84% (n=57) experienced Grade 3 or higher events
• Cytokine release syndrome (CRS) occurred in 79% of patients; CRS Grade 3 or higher occurred in 49% of patients

On ASH 2018, Novartis presented an updated ORR rate of 82.3% (n=65/79); relapse-free survival was 62% at 24 months.

r/r DLBCL

Yescarta was approved in 2017 based on an ORR of 72% (n=73/101), with a CR rate of 51%. SAEs Grade 3 or higher occurred in 48 (44%) patients. CRS occurred in 94% of patients; CRS Grade 3 or higher occurred in 13% of patients.

On ASH 2019, Gilead provided updates on ZUMA-1 that median overall survival (OS) was 25.8 months.

When Kymriah was approved for r/r DLBCL in 2018, the overall response rate (ORR) was 50% at 3 months (n=34/68). On ASH 2019, in the 24-month analysis of the JULIET trial, ORR was 52% (N=115).