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Not all shots on goal are successful(Source:Alamy)

Bintrafusp In The Bin

A string of disappointing results for Merck KGaA’s bintrafusp alfa culminated in the termination of the German firm’s $4.2bn partnership with GlaxoSmithKline plc for the anticancer product at the end of September.

Bintrafusp alfa had been an important asset for both companies. GSK paid $360m upfront for a stake in the bifunctional fusion protein product that targets PD-1 and TGF-beta in 2019. The idea behind the product was that simultaneously blocking TGF-beta and PD-L1 would improve outcomes for patients with difficult-to-treat cancers. (GSK Exits 42bn Cancer Drug Deal With Merck KGaA After Multiple Failures)

The rot started to set in in January, when bintrafusp failed in its potentially most lucrative indication, non-small cell lung cancer (NSCLC). The Phase III INTR@PID Lung 037 trial was discontinued after an interim analysis suggested the drug would fail to meet its progression-free survival co-primary endpoint and show any improvement over Keytruda in previously untreated patients with PD-L1-positive NSCLC. (Lung Cancer Failure Isnt The End For Merck KGaA And GSKs Bintrafusp

In March, the drug candidate disappointed again as a second-line monotherapy for biliary tract cancer (BTC) – the companies had hoped this niche indication would provide a rapid route to market in a setting not yet addressed by other immunotherapies.

Then August saw a third failure, this time as a first-line treatment in combination with chemotherapy in locally advanced or metastatic BTC, and the die was cast, for GSK at least.

The remaining bintrafusp studies in the INTR@PID program – in NSCLC, triple-negative breast cancer and bladder cancer – were discontinued and Merck said it was going to use advanced analytics to interrogate the data further to see what can be learned about the TGF-beta pathway.

Huntington’s Disappointment For Roche

In March, Roche Holding AG abandoned its Phase III trial studying the investigational drug tominersen in Huntington's disease, dashing hopes that the antisense oligonucleotide could offer a game-changing therapy for the debilitating condition, for which there is no effective treatment.

The pivotal GENERATION HD1 trial was terminated after a pre-planned review of the Phase III study’s data by an unblinded Independent Data Monitoring Committee (iDMC) which threw up concerns over the drug’s benefit/risk profile. As the company said no new or emerging safety signals were identified for tominersen in the review, this suggested poor efficacy was the problem. (Roche Shelves Phase III Huntingtons Candidate Tominersen)

Tominersen is designed to reduce the production of the huntingtin protein, which is the cause of Huntington’s disease, an inherited brain disorder that results in the progressive loss of mental faculties and physical control. The antisense product, partnered with Ionis Pharmaceuticals, Inc. is still listed as under development by Roche, and analysts have suggested it could still have some potential in patient subgroups or use earlier in the disease course.

Tominersen was not the only disappointment for Huntington’s during the year. WAVE Life Sciences Ltd. is now banking on its next-generation gene silencing asset for Huntington disease after the failure of a clinical trial program of two earlier-generation drugs, that same month.

The Phase Ib/IIa PRECISION-HD2 study of WVE-120102 and the PRECISION-HD1 study of WVE-120101 did not show significant efficacy in patients with HD and therefore did not support continued development. WVE-120101 targeted mutant huntingtin protein (mHTT) SNP1, while WVE-120102 targeted mHTT SNP2. (Waves Huntington Drugs Wipe Out As Trials Run Aground)

Wave is hoping that the new drug WVE-003’s improved preclinical pharmacology will raise the odds of success. WVE-003 targets mHTT SNP3. That drug, like its next-generation candidates in other neurologic diseases, uses so-called PN chemistry that the company said in preclinical testing increases potency, exposure and durability across its silencing, splicing and editing modalities.

The Huntington’s R&D pipeline in general is increasingly active, and Roche is still very much in the game. Later in the year, its gene therapy subsidiary Spark partnered with start-up NeuExcell on a adeno-associated virus-delivered gene therapy for Huntington’s disease that researchers say may regenerate functional neurons. (Roche Jumps Back Into Huntingtons With SparkNeuExcell Partnership) (New Player Joins Search For Effective Huntingtons Therapies)

Gilead And Galapagos’ Strained Partnership

A difficult R&D spell for Belgian biotech Galapagos NV that started with the Phase II failure in late 2020 of the osteoarthritis drug GLPG1972, an ADAMTS-5 inhibitor partnered with Servier, continued in February when its Phase III ISABELA program for fibrotic disease candidate ziritaxestat was halted.

While the iDMC’s conclusion that the oral autotaxin inhibitor’s benefit-risk profile no longer supported continuing the studies which were testing it in idiopathic pulmonary fibrosis patients, Galapagos and partner (and major stakeholder) Gilead Sciences, Inc. decided that all clinical trials for the drug would be discontinued, including the long-term extension of the Phase IIa NOVESA trial in systemic sclerosis. (Ziritaxestat Failure Could Spell End For GileadGalapagos Pact)

The failure, coupled with Gilead's decision to walk away from US development of Jyseleca (filgotinib), as it could not see a viable path to approval for the JAK inhibitor after rejection by the Food and Drug Administration for rheumatoid arthritis, saw shares in Galapagos sink this year.

Matters were not helped when, in July, mid-stage results from three trials of the lead product, GLPG3970, from Galapagos's Toledo program, which consists of a series of salt-inducible kinase (SIK) inhibitors and had been touted as a potential pipeline hole filler, were deemed underwhelming by analysts. (Toledo Data Fail To Give Galapagos A Lift

Novartis Hit By Canakinumab NSCLC Miss

Less of a surprise was the failure of Novartis AG’s anti-inflammatory drug canakinumab in the Phase III CANOPY studies in NSCLC.

The Swiss major revealed in March that canakinumab in combination with the chemotherapy agent docetaxel did not meet the primary endpoint of overall survival in patients with advanced or metastatic non-small cell lung cancer in the CANOPY-2 study. The study of the interleukin-1 beta inhibitor was conducted in 237 patients whose disease progressed while on or after previous platinum-based chemotherapy and PD-(L)1 inhibitor immunotherapy. (Novartis Hit By Canakinumab NSCLC Miss)

That disappointment was compounded in October when Novartis unveiled topline results from CANOPY-1 which showed that canakinumab did not meet its primary endpoints of overall survival (OS) and progression-free survival (PFS) in previously untreated patients with locally advanced or metastatic NSCLC. (Novartis Hopes For Canakinumab In Lung Cancer Nosedive)

Canakinumab was first approved in the US back in 2009 as Ilaris and it has since received a host of approvals for several rare diseases, including systemic juvenile idiopathic arthritis and cryopyrin-associated periodic syndromes. Its potential in NSCLC was discovered after Novartis also pursued the drug for heart disease in the high-profile CANTOS trial in 2017. Canakinumab’s therapeutic effect in reducing the risk of major cardiovascular events in patients with prior heart attack and atherosclerosis proved modest, however, and the company has since abandoned its attempts to get a CV indication added to the label.

But the CANTOS data also revealed a reduction in death from cancer, particularly lung cancer, and a reduction in new lung cancer cases in the patients tested, and Novartis began the Phase III NSCLC program on the back of the notion that blocking the IL-1 beta inflammatory signal may potentially reduce lung cancer’s incidence and mortality.

And despite the setbacks to date, the company is not giving up, as it still saw some "potentially clinically meaningful improvements” in both PFS and OS in pre-specified biomarker-defined subgroups of patient, including hs-CRP. Novartis believes that by neutralizing IL-1 beta, canakinumab may inhibit pro-tumor inflammation to enhance anti-tumor immune response, reduce tumor cell proliferation, survival and invasiveness and impair angiogenesis.

It is therefore pressing on with CANOPY-A, a Phase III study investigating canakinumab as an adjuvant therapy, and CANOPY-N, a Phase II trial in the neoadjuvant setting.

Duchenne (And Other) Gene Therapies Stalling

A number of hiccups occurred during the year to mar the progress of the two leading gene therapies for Duchenne muscular dystrophy (DMD). These came against a backdrop of setbacks for other gene therapy products plus increased safety scrutiny for AAV-based gene therapies as a whole, making it a difficult year for the field.

2021 started with a blow to Sarepta Therapeutics, Inc. after a keenly anticipated Phase II Study 102 showed that SRP-9001 (delandistrogene moxeparvovec) failed to significantly improve muscle function. SRP-9001 comprises an adeno-associated virus (AAV) vector that delivers its micro-dystrophin-encoding gene to muscle tissue. It is licensed to Roche outside the US. (Sarepta Sinks On Mixed DMD Gene Therapy Study)

At 12 weeks after treatment, SRP-9001 hit its primary biological endpoint with participants who received the gene therapy showing an increased amount of dystrophin, the protein missing in children born with DMD. However, the study failed to reach significance on the functional primary endpoint, the North Star Ambulatory Assessment score. Sarepta attributed the data to “improbable bad luck in the randomization process”.

The SRP-9001 disappointment came hours after rival Pfizer Inc. announced that the first participant had been dosed in the Phase III CIFFREO study of its investigational gene therapy candidate PF-06939926 (fordadistrogene movaparvovec) in boys with DMD, putting the US major in the lead.

But in May, Pfizer was hit by its own setback, giving Sarepta the chance to play catch up. Pfizer faced a delay to the start of the Phase III trial in the US after enrolment was held up by the US Food and Drug Administration due to outstanding questions the FDA had related to technical aspects of the potency assay metrics. (Pfizer DMD Gene Therapy Phase III Trial Faces A US Delay Can Sarepta Close The Gap)

Pfizer, later in September, reported safety concerns with PF-06939926 in the Phase III trial testing ambulatory function. Three adverse events of muscle weakness, two of which involved myocarditis, were reported, and Pfizer amended the study protocol to exclude patients with certain gene mutations and the study has resumed. (Can Sarepta Beat Pfizer To A Duchenne Gene Therapy Breakthrough) But a further setback came in December when Pfizer reported the death of a patient in a Phase I trial of the product, which the FDA has now put on hold.

Sarepta, meanwhile, has now begun a Phase III trial for its product, but other gene therapy products also struggled. In May, Biogen, Inc.reported that one of the ocular gene therapy candidates it acquired in its 2019 buyout of Nightstar Therapeutics plc missed its primary endpoint in a Phase II/III study, but said it viewed the result as a minor setback. BIIB112 (cotoretigene toliparvovec) failed to demonstrate significance compared to an untreated control group in X-linked retinitis pigmentosa.

All three products use an AAV vector to deliver the target gene, and AAV vector-based gene therapies came under regulatory scrutiny for safety following multiple reports of treatment-emergent serious adverse events (TESAE) in trials, including hepatotoxicities and thrombotic microangiopathies.

A two-day meeting of the US Food and Drug Administration’s Cellular, Tissue, and Gene Therapies Advisory Committee on the subject took place in September to look at potential new measures to identify and limit risk.

On the eve of the panel meeting, Astellas Pharma, Inc. hit the pause button on a Phase I/II study of its gene therapy AT132 for X-linked myotubular myopathy due to a safety issue less than a year after the FDA allowed it to resume following a months-long clinical hold over previous adverse events. (Astellas Pauses XLMTM Gene Therapy Trial After Another Safety Scare)

And just days later, the FDA placed on clinical hold a trial of BioMarin Pharmaceutical Inc.’s AAV gene therapy BMN 307 for the rare disease phenylketonuria after cases of liver cancer in mice receiving high doses of the therapy were reported. (BioMarin Trial Halt Raises Another Safety Flag On AAV Gene Therapy)

The FDA panel found that a lack of reference standards inhibits the ability to make comparisons between products or set caps for total vector genome dose or total capsid dose. The panelists suggested other approaches to prevent and mitigate toxicities, including running longer-term animal studies and investigating the efficacy of immunosuppression prophylaxis and treatment strategies. (Gene Therapy AAV Doses Should Not Be Subject To Fixed Upper Limit US FDA Panel Says)

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