A new class of cancer drug wins approval by changing a protein's shape

The approval

On 13 August the US Food and Drug Administration, the American drug regulator, granted accelerated approval to iberdomide, sold as Zenbexus by Bristol Myers Squibb [1]. It is a 1 mg pill taken once a day on days 1 to 21 of each 28-day cycle, alongside two older myeloma drugs [1]. It is cleared for adults with multiple myeloma, a cancer of the plasma cells in bone marrow [1]. They must already have had at least one prior course of treatment [1].

Two things make it a first. It is the debut of a new class of medicine for this blood cancer [2]. And it is the first drug US regulators have cleared using a more sensitive measure of remission [2].

That measure is minimal residual disease, or MRD - a test that hunts for the cancer cells still hiding after treatment, far below what routine tests pick up. In the EXCALIBER-RRMM trial, 939 patients were assigned by lot to one arm or another [1]. In the primary group of 420, 41 percent on the iberdomide combination reached an MRD-negative complete response at some point, against 21 percent on the comparison regimen [1]. The p-value was below 0.0001, meaning a gap that size would almost never appear by chance alone [1].

The caveats are real. Accelerated approval means the agency cleared the drug on that early signal; staying on the market depends on confirmatory trials showing real benefit to patients [3]. The label carries a boxed warning - the FDA’s most serious - for harm to a fetus and for dangerous blood clots in veins and arteries [1][3]. It also warns of low white-cell counts, infections and second cancers, and the drug is only available through a restricted distribution programme [1].

Why the shape is the whole point

Iberdomide belongs to a class called CELMoDs, which act on a protein called cereblon and help the body clear myeloma cells faster than older drugs do [3]. Cereblon is part of the cell’s disposal service: it selects proteins to be tagged and destroyed. Drugs of this kind - the older ones are lenalidomide and pomalidomide - do not block anything. They wedge into cereblon’s surface and change its shape, creating a new sticky patch that grabs proteins the cell would otherwise ignore, then hands them to the shredder [4]. In myeloma the proteins destroyed are Ikaros and Aiolos, two switches that decide which genes a cell turns on [4].

The entire action of the drug is a change of shape.

The same week, Nature Biotechnology published a map of how far that trick might reach [4]. Combining a laboratory binding test with artificial-intelligence searches of protein surfaces, a team measured what cereblon can be glued to. Around 210 proteins from one family stuck to cereblon in the presence of pomalidomide [4]. The strongest binders were ones already known to be destroyed by drugs of this class [4]. A sweep across the whole set of human proteins turned up 6 known binders and 43 new ones [4]. Those are starting points, the authors argue, for the next round of these medicines [4].

The mirror: a fold that could not be fixed

Shape is also what goes wrong. On 10 August Sionna Therapeutics reported that its cystic fibrosis pill had failed [5][7]. Cystic fibrosis is usually caused by a genetic change that stops a protein called CFTR from folding into its working form. Vertex’s Trikafta and its siblings work by coaxing that protein into shape, and are projected to bring in about $13 billion this year [6]. Sionna’s drug, SION-719, was built to stabilise NBD1 - the part of CFTR that comes out misshapen [5].

In a mid-stage trial of 15 adults already taking Trikafta, the drug produced a mean fall in sweat chloride of 1.0 mmol/L once placebo was subtracted [5]. That was not statistically significant [5]. Sweat chloride is the standard read-out of how well the protein is doing its job. Sionna had set a target of 10; outside experts had said 5 to 7 would do [5]. The shares fell about 90 percent, and the company dropped the programme [5][7].

Folds that go wrong in the brain

Two papers looked at the same failure in nerve cells. In Nature Neuroscience, a team reported that tau - the protein that clumps in Alzheimer’s disease - is made only in the branches of neurons [8]. About a third of every fresh copy is destroyed as it is still being built, by a proteasome, a protein shredder, parked at the cell membrane [8]. Freshly made chains are especially prone to misfolding, the authors note; when that local destruction fails, tau piles up in the wrong compartment and aggregates [8].

A second paper, in Communications Chemistry, mixed tau with amyloid-beta in a dish [9]. Tau droplets acted as reservoirs that held small amyloid clusters and stopped them converting into the long fibres seen in the disease [9]. Both are laboratory work, not patients.

The clearing question is also driving something far less controlled. Nature reported on deep cervical lymphatic-venous anastomosis, a surgery connecting lymph vessels in the neck to nearby veins [10]. The theory is that better drainage flushes waste proteins out of the brain [10]. First performed in China in September 2020, it spread to hundreds of hospitals on the back of viral testimonial videos, with people paying more than 200,000 yuan, about $30,000 [10]. Chinese regulators restricted it to formal research last year, and its pioneer has been in detention since September for undisclosed reasons [10]. Controlled trials are now starting worldwide. Nature spoke to more than two dozen researchers and found a mix of qualified enthusiasm and deep scepticism [10].

Designing shape on purpose

The opposite direction moved too. In Nature Methods, researchers described ProteinDPO, a model tuned on measured stability rather than sequence alone [11]. They applied it to the influenza haemagglutinin trimer, the main component of flu vaccines [11]. About 80 percent of its designs matched or beat the natural protein for stability [11]. Some designs based on recently emerged mammalian strains gained up to 32 degrees Celsius of stability [11].

The rest of the week

Taiho and Cullinan’s zipalertinib hit its main goal in a 285-patient late-stage lung cancer trial [12]. The tumours were driven by a particular EGFR mutation, and the actual numbers have not been released [12]. Nature Medicine reported CD19 CAR T cells - a patient’s own immune cells re-engineered to hunt cancer - still detectable a decade after treatment in people with B-cell lymphoma [13]. PTC agreed to take on Sangamo’s gene therapy for Fabry disease, a treatment nearing possible approval; analysts called it a high-risk, high-reward bet [14].

Money kept flowing to rare disease. Epicrispr raised $90 million for an early-stage therapy in a rare muscle-wasting condition [15]. Vaderis raised $152 million to run a late-stage trial in a rare blood-vessel disorder with no approved treatment [16].

Failures kept pace. aTyr cut 60 percent of its staff to fund a second late-stage attempt in a lung disease [17]. Tenax’s heart-failure drug missed in a pivotal study [18]. The FDA rejected ITM’s radioactive cancer drug over manufacturing problems [19]. In the Democratic Republic of the Congo, a vaccine that only partly matches the circulating Ebola species is being rolled out anyway, with the ethics openly contested [20]. The Lancet published two late-stage trials of upadacitinib in non-segmental vitiligo, an autoimmune disease in which the skin loses its pigment cells [21]. As of early August the agency had approved 30 never-before-marketed drugs this year [22].