'Serial Killer’ CAR-T Could Help Autolus Bounce Back

Data presentations at next week’s ASH meeting will be vital for Autolus to restore confidence in pipeline.

Autolus was spun-out from work done at University College Hospital in London

Autolus Ltd. is looking to get back on track after numerous setbacks in its goal to produce the next generation of CAR-T products.

The UK-based biotech’s problems have been reflected in a share price which has lost nearly two-thirds of its value since January.

This has been caused by setbacks to its pipeline, intense competition in the CAR-T space (leading to abandonment of multiple myeloma candidate AUTO2) and major delays to its cell therapy manufacturing plans.

On top of this, confidence in the company has also been hit by the fall of Neil Woodward, one of its key investors. (Also see "Autolus Faces Life After Woodford With New Czech Backer" - Scrip, 18 Sep, 2019.)

But CEO Christian Itin and lead investor, London-based health venture capital firm Syncona, still believe that Autolus can be a player in the next generation of T-cell based therapies.

The company will be at the American Society of Hematology (ASH) congress in Orlando, Florida (7-10 December) where it hopes several key data presentations will revive investor belief in its pipeline.

This year’s ASH will feature lots of CAR-T contenders, however, and Autolus’s data will have to shine to attract attention.

A CAR-T for Adult ALL

Autolus’s lead product is AUTO1, and is designed to improve upon current treatments for acute lymphoblastic leukemia (ALL) in both children and adults.

Novartis’ Kymriah (tisagenlecleucel) is the pioneer CAR-T in pediatric ALL, and has produced remarkable results in relapsed/ refractory (R/R) patients, with trial data showing two-thirds of treated patients likely to survive for two years after treatment.

Itin presented at the Jefferies investor conference in London on 20 November, and gave an upbeat overview of Autolus’ extensive preclinical and Phase I pipeline of CAR-Ts and other novel T-cell therapies.

Autolus believes it can improve on the durability of response with its next generation CAR-T AUTO1, which is designed to disengage from cancer cells more easily and then move on to the next target, making it a “serial killer” T-cell therapy.

The biggest advantage of this so-called ‘fast off’ mechanism is that it does not produce the high levels of severe cytokine release syndrome (CRS), a major safety issue for nearly half of children taking Kymriah.

But it is the less common adult ALL, for which there are no CAR-T therapies currently approved, that Autolus has made its priority.

There is a small population of just 3,000 adult ALL patients in the US and major European markets. These adult patients are generally less likely to tolerate toxicity compared to pediatric ALL patients, making a CAR-T with fewer CRS adverse events favorable.

The current standard therapy for adult ALL is Amgen’s Blincyto (blinatumomab), and Autolus’s early studies show its therapy achieved a superior complete response rate – 83% to Blincyto’s 42%.

Investigators will present follow-up data from the Phase I trial, including further safety and efficacy at ASH on Saturday 7 December.

 

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For pediatric ALL, AUTO1 achieved a complete response (CR) rate and event-free survival (EFS) slightly better than Kymriah.

Most significantly, it produced no instances of severe CRS, compared with Kymriah’s 47%. Autolus’s dataset for AUTO1 is far smaller than that of Novartis however, with 14 and 75 patients trialed respectively.

The ASH abstract shows that in adult ALL, AUTO1 clearly outperforms Blincyto, achieving 83% compared with its established rival’s 42%. This would make Autolus’s product twice as active as the current standard of care with a similar safety profile.

Autolus is gearing up to begin a pivotal study with around 100 patients in this population, a clinical trial application filed in the UK in November and US IND to be filed in Q1 2020.

The company says this would put it on track to file a biologics license application (BLA) with the US Food and Drug Administration in H2 2021.

Bispecific CAR-Ts

However there are several other companies targeting the adult ALL space, including Gilead’s Kite and Pfizer, which presented encouraging data on a CD19-targeting KTE-X19 at ASCO earlier this year; this product is now in Phase II trials.

The field is now moving on to bispecific CAR-Ts in order to overcome the limitations of CD19 targeting Kymriah and Yescarta (axicabtagene ciloleucel) which can stop working in patients because of the loss of this CD19 antigen in target cancer cells.

Kite and Pfizer will be presenting Phase I data from their dual CD19 and CD22 targeting agent in R/R pediatric and adult ALL patients at ASH. Its abstract data suggest promising efficacy, and CRS cases limited to milder grades 1 and 2.

Autolus has its own CD19+CD22 targeting bispecific CAR-Ts in development, and its NG or next generation version of AUTO1 is set to enter Phase I in the first half of next year. AUTO3 uses the same mechanism, and data from a Phase I trials in ALL and a Phase I/II in DLBCL (the lucrative therapy area currently led by Yescarta) will also be presented in Orlando.

While the company currently has no big pharma partners in any of its programs, it is not clear if it can deliver on its ambitions across multiple targets and novel T-cell platforms. This may well change in the next few months, and Autolus could attract partners if and when it accrues some compelling proof of concept data.

The company has not given up on multiple myeloma, meanwhile, one of the most hotly contested therapy areas. It was forced to abandon its AUTO2 candidate because of fears it could not compete with close-to-market BCMA-targeting contenders such as BMS/Celgene/bluebird’s bb2121, but Autolus has a new myeloma candidate in development with an as-yet undisclosed target, which it says will begin Phase I trials in the second half of 2020.