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BACKGROUND Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRJSPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). METHODS We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β0/β0, β0/β0-like, or non-ββ0/β0-like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. RESULTS A total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (>94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. CONCLUSIONS Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.) [ABSTRACT FROM AUTHOR]

Exagamglogene autotemcel (Casgevy™) is a genetically modified autologous CD34+ cell enriched population. It contains human haematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 (a DNA double strand break-inducing nuclease system) to differentiate into erythroid cells that produce high levels of foetal hemoglobin. Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, exagamglogene autotemcel received its first approval on 16 November 2023 in the UK for the treatment of transfusion-dependent β-thalassemia (TDT) in patients aged ≥ 12 years for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. On the same day, it was also approved in the UK for the treatment of sickle cell disease (SCD) in patients aged ≥ 12 years with recurrent vasoocclusive crises (VOCs) who have the βS/βS, βS/β+ or βS/β0 genotype for whom HSC transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. Subsequently, exagamglogene autotemcel was approved in the USA on 8 December 2023 for the treatment of SCD in patients aged ≥ 12 years with recurrent VOCs and received a positive opinion in the EU on 14 December 2023 for the treatment of TDT and SCD. A regulatory assessment of exagamglogene autotemcel is currently underway for the treatment of TDT in the USA. This article summarizes the milestones in the development of exagamglogene autotemcel leading to these first approvals. [ABSTRACT FROM AUTHOR]

BACKGROUND The Nav1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Nayl.8, on control of acute pain is being studied. METHODS After establishing the selectivity of VX-548 for Na,!.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo. RESULTS A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548. CONCLUSIONS As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.). [ABSTRACT FROM AUTHOR]

Background: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.Methods: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group.Results: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.Conclusions: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.). [ABSTRACT FROM AUTHOR]

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.). [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.Methods: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.Findings: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.Interpretation: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.Funding: Vertex Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.Results: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.Conclusions: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.). [ABSTRACT FROM AUTHOR]

The article presents information on the Top Employers Survey conducted in 2017, which focuses on innovation, positive work culture, and social responsibility at workplaces. The 2017 top company is Regeneron Pharmaceuticals Inc. based in New York City, which has been recognized as the best employer. Denmark-based Novozymes A/S has been recognized for having a work culture that encourages employee loyalty; and Vertex Pharmaceuticals Inc. has been recognized for social responsibility.

The author reflects on present and future roles of flow analysis for reaction control and monitoring in small molecule fine chemical synthesis. Topics discussed include rules are in place to regulate all manufacturing practices ranging from synthesis of active pharmaceutical ingredients (APIs), Vertex Pharmaceuticals received the first new drug application (NDA) approval for using continuous manufacturing technology for the preparation of Orkamb and advancements in the area of flow analysis.

Molecular modelers and informaticians have the unique opportunity to integrate cross-functional data using a myriad of tools, methods and visuals to generate information. Using their drug discovery expertise, information is transformed to knowledge that impacts drug discovery. These insights are often times formulated locally and then applied more broadly, which influence the discovery of new medicines. This is particularly true in an organization where the members are exposed to projects throughout an organization, such as in the case of the global Modeling & Informatics group at Vertex Pharmaceuticals. From its inception, Vertex has been a leader in the development and use of computational methods for drug discovery. In this paper, we describe the Modeling & Informatics group at Vertex and the underlying philosophy, which has driven this team to sustain impact on the discovery of first-in-class transformative medicines. [ABSTRACT FROM AUTHOR]

The article reports on the clinical trials ran by biotech companies CRISPR Therapeutics and Vertex Pharmaceuticals to remove blood stem cells of patient using CRISPR gene-editing tool, and mentions end of need for blood transfusions by the treatment.

The article reports that the U.S. Food and Drug Administration (FDA) has approved the hepatitis C virus protease inhibitors Incivek from Vertex Pharmaceuticals and Victrelis from Merck. The drugs' cure rate is doubled when combined with polyethylene glycol-decorated interferon (INF)-alpha and ribavrin. It reports that following the FDA's approval of the two drugs, a number of companies have moved to developing all-oral combination antivirals without INF-alpha.

The article discusses the results of the journal's 2011 Careers Top Employers Survey and examines the hiring practices and research of biotechnology and pharmaceutical companies which were well rated including Vertex Pharmaceuticals Incorporated, Genzyme Corp., and Novo Nordisk. Science and medical research company executives including Andy Chan of Genentech, Bryan Iams of Bayer, and Susan Bunz of Pioneer Hi-Bred, a DuPont business discuss how they recruit scientists, the corporate culture of their institution, and the effect of the economy on their institutions.

The article discusses a survey of top science employers and factors affecting company ratings including respect for employees and valuing of employee innovation. The company Genentech was ranked first on the list of top employers. Companies that obtained top-ten ratings for the first time included TheTakeda Oncology Company and Vertex Pharmaceuticals Incorporated. Two-way communication strategies that result in mutual respect between managers and employees are discussed. Senior Vice President Lisa Kelly-Croswell of Vertex is cited regarding corporate communications.

Telaprevir (LY 570310; LY-570310; LY570310;MP 424;MP-424; VX 950; VX-950) is an orally administered peptidomimetic inhibitor of the hepatitis C virus (HCV) protease NS3/4A. It is being developed by Vertex Pharmaceuticals and its licensees for the treatment of HCV infections and has recently been submitted to the US FDA for approval. As the first ever HCV protease inhibitor in phase III development, it is being studied in trials in combination therapy with pegylated interferon alfa-2a and ribavirin in Europe, the US, Australia, Canada, and Puerto Rico in treatment-naive and treatment-experienced patients with HCV genotype 1 infection. Phase III trials of telaprevir as combination therapy are also in progress in Japan. This review discusses the key development milestones and therapeutic trials of this drug to date. [ABSTRACT FROM AUTHOR]

The article reports on the approval of Vertex Pharmaceuticals's Orkambi, cystic fibrosis transmembrane conductance regulator (CTFR), by the US Food and Drug Administration (FDA). Topics discussed include views of Brian O'Sullivan, former director of the cystic fibrosis center at the University of Massachusetts, on the same, clinical benefit of Orkambi being modest unlike the improvement in lung function patients received from Kalydeco and efforts Vertex in working towards improved therapies.

The article offers information on the approval of drugs involved in breakthrough therapies of global pharmaceutical companies including F. Hoffmann-La Roche Ltd., Vertex Pharmaceuticals Inc. and Genentech Inc., by the U.S. Food and Drug Administration (FDA) as of December 2013. It mentions the table which lists several drugs approved by the FDA along with their target for cancer treatment. An overview of clinical trial status for the treatment of cystic fibrosis and cancer is presented.

The article offers information on the drugs for treating hepatitis C virus (HCV) such as telaprevir, a protease inhibitors from Vertex Pharmaceuticals Inc. and boceprevir from Merck and Co. Inc. It says that the new drugs targets directly the HCV especially its NS3/4A serine protease. However, it argues that the drugs need to be given together with interferon-α and ribavirin to prevent the emergence of protease-inhibitor resistance.

The article offers an update on the clinical phase trials of telaprevir from Vertex Pharmaceuticals Inc. and boceprevir from Merck and Co. Inc. in the U.S. It notes that both companies are competing to develop the first protease inhibitor for the treatment of hepatitis C virus (HCV) infection to reach the market. Stefan Zeuzem, chief of medicine at the J.W. Goethe University in Germany, stresses that the addition of a protease inhibitor to standard therapy of HCV is a milestone.

The article offers news briefs related to sexually transmitted diseases in the U.S. The National Tuberculosis (TB) Surveillance System reveled that TB cases have reached an all-time low rate in 2008. There were almost 100 genes that support replication of hepatitis C virus (HCV) identified by the researchers at the Massachusetts General Hospital. Meanwhile, the HCV protease inhibitor telaprevir was developed by Vertex Pharmaceuticals Inc., along with two polymerase inhibitors.

The article offers news briefs on HIV/AIDS and sexually transmitted diseases. Vertex Pharmaceuticals will be starting the REALIZE trial, a clinical trial on the protease inhibitor telaprevir for HCV infection treatment. Research indicates that patients with antibiotic-resistant tuberculosis who are inadequately treated can remain infectious. According to research, people with sexually transmitted diseases and women with yeast and bacterial vaginal infection are at risk for HIV infection.

The article offers news briefs on antiviral agents. Vertex Pharmaceuticals Inc. and Tibotec have started screening patients for a Phase 3 clinical trial called the Advance study. The U.S. Food & Drug Adminstration has added information about hepatotoxicity to the warnings section of darunavir prescribing information. An update has been made to Reyataz capsule label to include the recommended dosage for patients aged between 6 to 18 years.

The article focuses on Trikafta, the triple combination therapy from Vertex Pharmaceuticals indicated for the treatment of cystic fibrosis (CF) that target the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein responsible for CF. Topics covered include individual performance of the CF drugs from Vertex that comprised the triple-drug combination therapy against CFTR, impact of Trikafta on CF patients and cost of the triple combination therapy.

The article reports on the successful use of the CRISPR gene editor to help two people with blood diseases by CRISPR Therapeutics of Zug, Switzerland in collaboration with Vertex Pharmaceuticals.

The article reports that Cystic Fibrosis Foundation (CFF) has sold drug royalties it gets from Vertex Pharmaceuticals' drug Kalydeco for 3.3 billion U.S. dollars to Royalty Pharma to reinvest the money on researches to fight the fatal lung disease and to gain financial returns. It mentions the views of Robert Beall, president of CFF on the same and the opinion of other nonprofits such as Juvenile Diabetes Research Foundation (JDRF), and Leukemia and Lymphoma Society on the transaction deal.

This section offers science-related news briefs as of December 2014. Francis Collins, director of the U.S. National Institutes of Health (NIH) has announced the agency's decision to cancel its plans for a multi-decade study of children's health. A draft of oil, defence and nuclear agreements were announced by Russian President Vladimir Putin and Indian Prime Minister Narendra Modi. Geneticist David Altshuler will join Vertex Pharmaceuticals beginning in early 2015.

The article offers world news briefs related to medications. The orexin receptor antagonist Belsomra (suvorexant) from Merck & Co. Inc. has been approved by the U.S. Food and Drug Administration (FDA). Boehringer Ingelheim Pharmaceuticals Inc. and Eli Lilly & Co. has launched the tablet form of Jardiance (empagliflozin). The sale and distribution of the hepatitis C virus protease inhibitor Incivek (telaprevir) from Vertex Pharmaceutical Inc. will be discontiued.

Simon & Schuster, New York, 2014. 448 pp., hardcover, $ 30.00.—ISBN 978‐1451655667 [ABSTRACT FROM AUTHOR]

The authors discuss the perceived obligation of pharmaceutical companies to be more transparent with regard to the pricing of orphan drugs. They criticize the decision by Vertex Pharmaceuticals to set a high price for ivacaftor for treating patients with cystic fibrosis (CF) who carry a genetic mutation called G551D, despite the substantial resources provided by the CF Foundation to the development of the drug. They also advise the industry to consider both financial return and social good.

The article offers news briefs related to clinical and translational research as of April 2013. A team of researchers from cancer research institutions in the U.S. will receive funds to develop new ways to fight cancer. The National Institutes of Health program will provide researchers access to expertise and resources with no charge. Two drugs from the Vertex Pharmaceuticals Inc. has received the first "breakthrough therapy" designation from the U.S. Food and Drug Administration (FDA).

The article focuses on the benefits of and concerns over the U.S. Food and Drug Administration (FDA)'s new rule which speeds up market authorization of new drugs by designating them breakthrough therapy. It mentions that Vertex Pharmaceuticals Inc. has received the FDA approval for its cystic fibrosis drug Kalydeco under the new rule. Greg Dombal, chief operating officer of Boston-based Halloran Consulting Group, expressed concerns over the rule getting watered down over time.