The Pipeline is Full and Brimming with Promise. Hat Tip to Science.

This past year saw many new scientific advances reach patients. From novel vaccines and therapies to prevent and treat COVID-19 to targeted therapies for what was once considered an “undruggable” cancer, drug approvals in 2021 highlighted breakthrough science. Even more novel therapies are expected to come on the market in 2022. Oncology and rare diseases are areas in which a large number of drugs have been approved, and that pattern is likely to continue in the coming year.

One notable breakthrough in 2021 was Amgen’s Lumakras (sotorasib) to treat patients with non-small cell lung cancer (NSCLC) who have a KRAS G12C mutation. The drug received an accelerated approval in May 2021 based on the results of a study with 124 patients who had received at least one prior therapy. Lumakras is the first treatment for tumors with cells with a KRAS mutation, a target that had been considered resistant to drug therapy.

“That was a big leap forward,” says Maria Whitman, global head of pharmaceutical and biotech practice at ZS, an analytics and strategy consulting firm headquartered in Evanston, Illinois. “KRAS has also been a target we’ve known about for years, and there have been many attempts to develop a target therapy. This is exciting. But this underscores for me that we still have a long way to go in the understanding of these types of targeted therapies.”

Another possible therapy for NSCLC tumors with aKRASG12C mutation is adagrasib, which developer Mirati Therapeutics expects to be approved in 2022. The San Diego-based company began a submission to the FDA for adagrasib in November 2021 under the agency’s Real-Time Oncology Review Pilot Program. The phase 2 KRYSTAL-1 study results evaluating adagrasib in patients with advanced NSCLC showed an objective response rate of 43% and a disease control rate of 80% at 600mg BID.

Lessons from the pandemic

Whitman said vaccine and drug development that harnesses messenger mRNA will stay on the cutting edge this year. The development of mRNA vaccines for COVID-19 has brought attention to this innovative technology. In oncology, mRNA is being researched for use in the development of cancer vaccines, which would activate specific immune T cells to seek out and kill cancer cells.

Before the pandemic, both Moderna and BioNTech, developers of COVID-19 vaccines, were researching mRNA’s application in harnessing the immune system to address cancer.

BioNTech has a portfolio of oncology therapies in the pipeline that are taking several research avenues. The most advanced combines mRNA technology with the company’s lipoplex formulation, which embeds the mRNA in a type of molecule called a lipid. Other BioNTech therapies in development include BNT111, which is in a phase 2 trial as a monotherapy and in combination with Regeneron-Sanofi’s Libtayo (cemiplimab) to treat late-stage melanoma; BNT112, which is in an early-phase trial as a monotherapy and in combination with Libtayo in prostate cancer; and BNT113, which is in a phase 2 trial in combination with Merck’s Keytruda (pembrolizumab) for patients with head and neck squamous cell carcinoma.

BioNTech also has an oncology research program with Genentech to develop an individual neoantigen immunotherapy, which is in a phase 2 trial to treat patients with colorectal cancer.

Moderna is researching mRNA-4157, which is in a phase 2 trial in combination with Keytruda to treat patients with melanoma. Moderna is also conducting early research into using mRNA technology to develop treatments for cystic fibrosis and rare diseases.

“We’re only scratching the surface of what this technology can and should be,” Whitman says. “In the next few years, we’re going to see therapeutic vaccines, we’re going to see prophylactic vaccines, we’re going to see therapeutics in other areas of infection and oncology and respiratory.

“The mRNA COVID-19 vaccines have laid the groundwork for these possibilities,” she says. “It also highlights the challenges that we learned about in terms of supply chain stability and logistics, so we’ll have to continue to advance our global infrastructure to support that.”

Jody Hessen, a clinical account executive at RxBenefits (formerly Confidio), says another important oncology approval in 2021 was Cosela (trilaciclib), which was approved in March 2021 to mitigate chemotherapy-induced bone marrow suppression, specifically in small cell lung cancer. Bone marrow suppression can lead to severe infections and is a dose-limiting factor for many chemotherapy drugs. G1 Therapeutics, a Research Triangle Park, North Carolina, biotech company, developed Cosela but was in partnership agreement Boehringer Ingelheim to promote the drug. Last month, G1 announced that the company and Boehringer Ingelheiim had agreed to end the co-promotion agreement effectivce in March of this year.

In October, G1 released data that consisted of pooled results from three clinical studies. This analysis found that patients who received the drug prior to each chemotherapy treatment had lower use of supportive care therapies than patients who received the placebo. Cosela reduced the occurrence of severe neutropenia, with 11.4% of patients receiving the agent versus 52.9% of patients in the placebo group experiencing neutropenia.

“Although the FDA labeling specifies myelosuppression due to treatment for small cell lung cancer, it is reasonable to assume that it will be used off-label for many different kinds of malignancies, particularly those normally treated with the same myelosuppressive drugs as small cell lung cancer,” Hessen says.

Gene therapy potential

Many experts, including Whitman and Hessen, believe gene and cell therapies will likely play a major role in treatment in the future. The question is how major and how soon into the future. Three gene therapies have been approved since 2017: Luxturna (voretigene neparvovec-rzyl), to treat patients with an inherited form of blindness; Zolgensma (onasemnogene abeparvovec-xioi), to treat children with spinal muscular atrophy; and Kymriah (tisagenlecleucel), to treat patients with acute lymphoblastic leukemia and B-cell lymphoma. “While the gene therapy approvals are not new this year, this is a milestone of a category that has challenged us commercially and logistically. These one-time therapies are life-changing, but we’ve been challenged with the payment models for these therapeutics because of the burden on the system,” Whitman says.

Although these therapies have promise in terms of having good response rates with a single infusion, as a class, they present certain challenges in the areas of manufacturing and administration, Hessen says. First, the process of preparing doses is both time-consuming and expensive. Manufacturers have been working to develop CAR-T cell and other gene therapy products that use cells from healthy donors, which would cut down on production time; however, recent safety issues have led the FDA to halt all testing on those therapies.

“In theory, these products should provide a better balance between effectiveness and toxicity than chemotherapy, due to the fact that they target tumor cells relatively narrowly,” Hessen says.

The FDA and the National Institutes of Health (NIH) recently gave this research in the area a big lift to help address some of these issues. In October 2021, the FDA, NIH and 15 private organizations, including 10 pharmaceutical companies, launched the Bespoke Gene Therapy Consortium, part of the Accelerating Medicines Partnership program, to optimize the development of gene therapy for rare diseases. This is a $76 million effort to improve the development of viral vectors and manufacturing and to support four to six clinical trials.

Additional gene therapies may be approved in the next few years, according to Nicole Kjesbo, Pharm.D., director of pipeline at Prime Therapeutics, a PBM headquartered in the suburban Twin Cities that serves 23 Blues plans. One of the leading candidates is BioMarin’s Roctavian (valoctocogene roxaparvovec). The company plans to resubmit its application to the FDA with two years of follow-up safety and efficacy data from a phase 3 trial in the second quarter of this year. In August 2020, the FDA had sent BioMarin a complete response letter for Roctavian requesting such information. In Europe, BioMarin’s application is under review and a decision is expected in the first half of 2022.

Another gene therapy that might be approved this year is bluebird bio’s betibeglogene autotemcel (beti-cel), a one-time gene therapy for patients with beta-thalassemia who require regular red blood cell transfusions. The therapy adds functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. The company resubmitted its application for beti-cel to the FDA in September 2021, and the FDA has granted it a priority review with an action date of May 20, 2022. The European Commission has granted conditional marketing authorization for beti-cel, marketed as Zynteglo, for patients 12 years and older.

Meanwhile, bluebird is developing other gene therapies, including LentiGlobin, a one-time treatment for sickle cell disease. But LentiGlobin has followed a tortuous path. Early last year, the FDA put a clinical hold on the drug after one patient developed acute myeloid leukemia and another, myelodysplastic syndrome. The hold was lifted in June. bluebird is also investigating elivaldogene autotemcel, a one-time gene therapy for the treatment of early cerebral adrenoleukodystrophy. The European Commission approved the drug in July 2021.

“We are continuing to watch the gene therapy market closely both for the impact on the system to replace other persistent therapies and to solve for rare disease needs that haven’t been met before. We are likely to see more approvals of gene therapies for rare diseases this year,” Whitman says.

One therapy Whitman is excited about is a hemophilia gene therapy from uniQure, based in Amsterdam. In May 2021, the company announced positive results from a phase 3 clinical trial of 54 patients with severe to moderately severe hemophilia B treated with etranacogene dezaparvovec. At one year post-infusion, patients continued to have sustained increases in factor IX activity. The therapy consists of a viral vector carrying a gene cassette with the Padua variant of factor IX.

This therapy had been put on a clinical hold after one patient developed hepatocellular carcinoma, but a review by the FDA determined that it was unlikely that the gene therapy contributed to the cancer. The clinical hold was lifted in
April 2021.

Denise Myshko is senior editor of Formulary Watch®, a website affiliated with Managed Healthcare Executive®.